High Blood Pressure Cure Diet

Hypertension Exercise Program

Blue Heron Health News has a blood pressure program that promises to help you lower your blood pressure with just 3 easy exercises. The methods described in this book makes users refresh your whole body in which your kidneys, brain, heart and all cells are altogether struggling against your hypertension. And then the heart rate will slow down to decrease the pressure on the arteries to balance the excretion of water and sodium from the kidneys. Your body will produce itself healing mechanism, controlling your high blood pressure quickly and easily. Along with the main program, you also get a bonus called The Natural Blood Pressure Lifestyle Report. This report complements the blood pressure program by helping you understand how high blood pressure occurs, how you can tweak your diet and lower it, different herbal medications that can help, and how your lifestyle can influence your blood pressure in a big way, plus much more. Read more here...

Hypertension Exercise Program Summary


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Pathogenesis Of Hypertension In Diabetes

Several factors are involved in the pathogenesis of hypertension in patients with diabetes mellitus. These include genetic factors, sodium retention, and hyperin-sulinemia. Genetic predisposition plays an important role in the development of hypertension in both type 1 and type 2 diabetes. The higher prevalence of hypertension in certain ethnic groups, such as African Americans, suggests the role of genetic factors (5). Diabetic patients with hypertension are reported to have high frequencies of family history of hypertension (23). Elevated levels of sodium-lithium countertransport activity (24,25) and sodium-hydrogen countertransport activity (26) have also been found to play a role in the genetic predisposition to hypertension.

Clinical Trials Relevant To Treatment Of Hypertension And Prevention Of Cardiovascular Complications In Diabetes

Treatment of hypertension is crucial for the reduction of cardiovascular complications. There have been a considerable number of prospective randomized trials showing the benefits of treating hypertension in diabetes. The SHEP (Systolic Hypertension in the Elderly Program) trial showed that treatment of isolated sys- -o tolic hypertension in elderly type 2 diabetic patients with a diuretic, chlorthali- Hypertension in Europe (Sys-Eur) Trial, treatment of isolated systolic hypertension in elderly patients with type 2 diabetes with an intermediate-acting calcium channel blocker, nitrendipine, showed a significant decline in cardiovascular J In the United Kingdom Prospective Diabetes Study (UKPDS), 1148 hypertensive patients with type 2 diabetes were randomized either to tight blood pressure control (defined as

The Cerebral Vasculature Adapts to Chronic High Blood Pressure

In conditions of chronic hypertension, cerebral vascular resistance increases, thereby allowing cerebral blood flow and, presumably, capillary pressures to be normal. The adaptation of cerebral vessels to sustained hypertension lets them maintain vasoconstriction at arterial pressures that would overcome the contractile ability of a normal vascula-ture (Fig. 17.2).

Role of CGRP in SNSalt Induced Hypertension

To determine if the compensatory depressor effect of CGRP could be observed in a second model of hypertension we, therefore, examined the effect of endogenous CGRP on blood pressure in SN-salt-induced hypertension, another type of low-renin, salt-dependent hypertension (22). SN-salt and normotensive controls were instrumented and given saline or CGRP837 as described earlier (Fig. 2). The effects of two doses of CGRP8_37 in the control group were similar to those observed with saline, which did not significantly alter the MAP. In contrast, administration of the antagonist to the SN-salt rats produced a dose-dependent increase of the elevated MAP similar to what was observed in the DOC-salt rats. These results suggest that, in this setting, CGRP is also playing a compensatory depressor role. Surprisingly, when the CGRP mRNA and peptide levels were quantified in the DRG from hypertensive and control rats, there were no detectable differences. These results suggested a second mechanism by...

Genome Wide Screens for Hypertension

Genome-wide scans for linkage to Mendelian traits have been successful for the monogenic syndromes with a hypertensive component as described above. A similar strategy may be applied to complex traits, such as essential hypertension, but the approach is modified to utilize smaller pedigree sizes and non-parametric statistical methods (46-48). A genome-wide screen for linkage to a complex trait typically yields several regions of a large size, anything up to 20 or even 40 million base pairs, for which there is some statistical support. An example is the recent Medical Research Council funded British Genetics of Hypertension (BRIGHT) study of Caulfield et al. (44). This is the largest study to date in a single ethnic group (1599 sib pairs), and four loci with genome-wide significance were found (p 0.05). Given an estimated 35,000 genes in the genome, each of these regions could contain up to 500 genes. The challenge is to identify which of these loci represent a true positive result...

Renal sodium handling and dopaminemediated high blood pressure

Reduced renal sodium excretion is a central mechanism in the development and maintenance of essential hypertension. Subjects with elevated blood pressure have an inappropriate delay in responding to and excreting a salt load. Dj-like receptors are important in the regulation of basal blood pressure because blood pressure is increased when dopamine receptors are chronically blocked (saline-loaded Wistar rats and normotensive humans) (172,173). Some forms of hypertension can be the result of a decreased synthesis of dopamine, or a failure of proper Dj-like receptor signaling in the kidney. Interestingly, both human and rodent hypertension have similar defects in dopamine-regulated sodium excretion (12,13,26,42,45,47,86,115,116). In both rats and humans with genetic forms of hypertension, there is a well-documented failure of the normal inhibition by Dj-like receptors of the activities of NHE3, Na+ HCO3-, Cl- HCO3-, and Na+ K+-ATPase (but not Na Pi or NHE1) in the renal proximal tubule...

Genetic evidence for the renal d1like receptor defect in hypertension

There is an evidence that the uncoupling of the Dj-like receptor in hypertension is genetic because it precedes the onset of hypertension in a variety of rodent models for genetically acquired hypertension (37,46,63,102,105,116). Furthermore, the hypertensive phenotype cosegregates with hypertension (genetically segregated this term has a different meaning) in the SHR (62,140,141). There are polymorphisms in human D5 receptor (142) and Dj receptor (143). A polymorphism in the noncoding region of the D1 receptor has been associated with hypertension in one study (143). There are no polymorphisms of the D1 and D5 receptors in SHRs but a renal D5 receptor defect may still be present in genetic hypertension because D5 receptor expression is decreased in the renal cortex of SHRs (81).

Animal Models of Hypertension

As linkage data provide limited positional information, each BP-related region in the rodent model is large, as in human studies. To improve resolution, congenic mapping approaches may be used (32). Interestingly, a single linkage peak may break down using a congenic approach but will reveal several tightly linked disease genes (69-71), and this appears to be the case for a hypertension locus in the distal region of rat chromosome 2 (72,73). This observation should be borne in mind when results of initial linkage screens in disparate species are compared. To date none of the genes underlying rodent linkage peaks or congenic effects has been cloned.

Insulin resistance and hypertension

Hypertension is frequently associated with decreased insulin sensitivity (3) reduced insulin sensitivity has been observed in normotensive offspring of first-degree relatives of hypertensive patients, independent of obesity (4). Insulin resistance also predates hypertension in normotensive persons. In a prospective investigation of CVD risk factors involving 840 normotensive persons, insulin sensitivity was inversely related to development of hypertension over a 5-yr period (5). This observation has been confirmed in other large studies (6). There is accumulating data that insulin resistance is associated with abnormalities of the renin-angiotensin system (3,7). For example, the level of insulin resistance in hypertensive persons is influenced by a relatively common polymorphism of the angiotensin-converting enzyme (ACE) gene, their being a significantly greater insulin resistance with the DD geno type (8). Recent evidence suggests that tissue overexpression of the RAS leads to...

The role of hypertension in the metabolic syndrome

Within the metabolic syndrome cluster, hypertension is defined as systolic blood pressure (SBP) 130 mmHg and diastolic blood pressure (DBP) 85 mmHg. It is present in 84.2 of men and 76.7 of women with metabolic syndrome (Fig. 1) (15), and contributes directly to many adverse clinical outcomes. In its early stages, hypertension-related vascular and end-organ damage is often subclinical, manifesting itself only when a catastrophic cardiovascular event occurs (such as myocardial infarction or stroke). The development of microalbuminuria may serve as an early indicator of widespread vascular damage, being not only a pressure-dependent functional phenomenon in the glomerular vessels, but reflecting permanent atherosclerotic abnormalities throughout the entire vascular system. Hypertension is also tightly associated with obesity. Obesity contributes to hypertension by activating the renin-angiotensin-aldosterone and sympathetic nervous systems. Chronic obesity also causes marked structural...

Use of antihypertensive drugs

Once a decision has been made to adopt a pharmacological approach to hypertension management, the challenge is to select the most appropriate drug. According to JNC7, thiazide diuretics, -blockers, ACE inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers are suitable for reducing blood pressure and preventing hypertensive complications in patients with metabolic syndrome (16). Antihypertensive drug selection should be tailored to the individual, taking into account the metabolic syndrome determinants present and any comorbid conditions, such as renal disease, that are compelling indications for specific agents.

High Blood Pressure Hypertension

Read this chapter to learn that hypertension WHAT IS HIGH BLOOD PRESSURE, OR HYPERTENSION High blood pressure is a pressure greater than 140 85. It is measured in millimeters of mercury (mm Hg). It is the most common WHY IS HIGH BLOOD PRESSURE DANGEROUS If our blood pressure is too high, the pressure inside the arteries puts a strain on the arteries, which become stiffer. The high pressure inside the arteries pushes globules of fat (cholesterol) into the walls of the arteries. The higher the pressure in the arteries, the harder the heart has to work to force blood around the arteries. If the heart has to work too hard for too long, the walls of the heart can initially get thicker, but after some time (usually a few years), the heart becomes weak and it fails. High blood pressure is the most common cause of heart failure. Once the heart fails, it cannot repair itself, although it can be controlled to some extent with medication. Yes. High blood pressure affects mainly Treatment for...

Hypertension guidelines 19722005

Since the first VA trials, treatment of hypertension has been linked to better outcomes for stroke and CV disease. Goals, as well as the tools to reach those goals, have evolved simultaneously with greater appreciation of the advantages of lower BP. Before the introduction of thiazide diuretics in 1957, only hypertensives with life threatening levels of BP were the candidates for treatment. Sympathectomy or poorly tolerated and toxic drugs (ganglionic blockers, peripheral adrenergic blockers, and vasodilators) were too risky to use in any other patients. The VA trials employed a fixed dose combination of a thiazide diuretic, a peripheral sympathetic blocker, and a vasodilator. These studies demonstrated the efficacy and tolerability of these newer antihypertensive therapies and enlarged the number of patients who could be treated safely (7,8). With the development of more effective and better-tolerated medications (Table 1), safe drugs could now be offered to hypertensive patients...

TABLE 422 Examples of Selected Antihypertensive Combinations

ANTIHYPERTENSIVE may find it necessary to prescribe a different antihyper-tensive drug when the patient experiences no response to therapy. Some antihypertensive drugs are used only in severe cases of hypertension and when other less potent drugs have failed to lower the blood pressure. At times, two antihypertensive drugs may be given together to achieve a better response (see Fig. 42-1). Diazoxide (Hyperstat IV) and nitroprusside (Nitropress) are examples of intravenous (IV) drugs that may be used to treat hypertensive emergencies. A hypertensive emergency is a case of extremely high blood pressure that does not respond to conventional antihypertensive drug therapy.

Introduction Definition of Pulmonary Hypertension

Pulmonary hypertension (PH) is an important clinical complication in approximately 30 of interstitial and other non-neoplastic lung diseases in humans. The mean pulmonary artery pressures are between 25 and 45 mmHg and this elevation can compromise right heart function. The underlying mechanisms of PH in these conditions probably relates to pathologic vessel remodeling associated with progressive alveolar hypoxia and or peripheral vessel destruction from inflammation and or scarring. In contrast, a small fraction of patients with severe pulmonary hypertension in whom the pulmonary artery pressures are in excess of 40 mmHg are at risk life threatening right ventricular failure. While little is known of the natural history of primary pulmonary hypertension (PPH), the use of rodent models has provided great insight into the etiology of hypoxic PH. Additional experimental models using techniques such as monocrotaline injection, air embolization, or ligation of the ductus arteriosus...

Cardiovascular disorders Hypertension

Pre- and postoperative monitoring is required, since increased blood pressure can result in a greater risk of postoperative bleeding. It should be noted that the patient taking antihypertensive drugs may be susceptible to hypertension when undergoing general anaesthesia.

Medial Thickening of Distal Pulmonary Arteries in Pulmonary Hypertension Alternative Sources of Cells

These findings raise the possibility that BM-derived progenitor cells contribute to the remodeling process in pulmonary hypertension. Indeed, this concept has been recently tested in our laboratory in the chronically hypoxic neonatal calf model of pulmonary hypertension. In this model system the increase in vessel wall mass is associated with a significant increase in adventitial vasa vasorum, indicating a neovascularization process in response to chronic hypoxia. It is postulated that this vasa vasorum forms, at least in part, as a result of a postnatal vasculogenic process in addition to angiogenesis. This is based on our preliminary observations that demonstrate that there is a rapid appearance of cells expressing the c-kit receptor, the ligand for stem cell factor, in the adventitial compartment (7). The adventitia in these hypoxic animals is characterized by a marked increase in the expression of fibronectin, VEGF, and thrombin thus providing an environment not only conducive to...

Arterial Hypertension

The significance of regular blood pressure monitoring in successful antihypertensive therapy is well known and understood. Furthermore, it was evidenced that 20 of patients' self-reported blood pressure measurements may differ by more than 10 mm Hg 39 . These circumstances make patients with arterial hypertension a well-suited target group for telemonitoring applications. Telemonitoring systems designed for patients with arterial hypertension include systems using data transmission through standard telephone lines to those based on Internet technology and also offering educational and supportive information. The results of the trials focussed on the use of telemonitoring systems for patients with arterial hypertension demonstrated high potential for better control of blood pressure and higher compliance with physicians' recommendations 2 5 21 . Nowadays, telemonitoring applications used by patients with arterial hypertension encompass such functions like automatic transmission of...

Long Term Effects ofET1 on Blood Vessels in Experimental Hypertension

ET-1 participates in the remodeling of large and small arteries found in hypertension (18). In some models of experimental hypertension, particularly those that are salt-induced, such as DOCA-salt hypertension or in Dahl salt-sensitive rats, as well as in severe hypertension, there is typically hypertrophic remodeling of resistance arteries with increased cross-sectional area rather than the eutrophic remodeling without true vascular hypertrophy more often found in essential hypertension and in spontaneously hypertensive rats (SHR) (18). This hypertrophic remodeling appears to be the signature of an effect of ET-1 (19,20), in contrast to the effects of endogenous Ang II, which is associated with eutrophic remodeling (21). Collagen deposition participates in the remodeling occurring in hypertension. EGF receptor transactivation appears to play an important role in the vascular fibrotic component of remodeling (22). In transgenic mice harboring the luciferase gene under the control of...

The et system in essential hypertension

Immunoreactive ET plasma levels, which reflect poorly ET-1 tissue production, are not elevated in essential hypertension (61), except in African Americans, in whom the circulating ET is elevated in hypertensive subjects (62). Hirai et al. (63) recently studied immunoreactive ET in plasma in 1492 subjects and showed by multiple stepwise regression analysis that age, creatinine, and smoking were significantly correlated to plasma ET. No relation was demonstrated between plasma ET and BP, suggesting that high ET is not related to hypertension, but to subclinical renal dysfunction and smoking. However, vascular levels of immunoreactive ET are increased in patients with moderate-to-severe hypertension (Stage 2 of the JNC 7 classification), compared with normotensive subjects or patients with mildly elevated blood pressure (Stage 1) (64). Studies in hypertensive humans have shown that ETA receptor antagonists cause a greater degree of vasodilatation in forearm vessels of essential...

Hypertension and Cardiovascular Injury by AAVMediated Kallikrein Gene Delivery

Adeno-associated virus (AAV) vector is attractive for long-term gene expression. However, the rate-limiting step in employing AAV gene delivery is the production of high titer-virus for in vivo studies. We have recently shown that a single intravenous injection of the recombinant AAV vector encoding the human tissue kallikrein gene into SHR resulted in a significant reduction of the systolic blood pressure from 2 weeks post gene delivery, and the blood-pressure lowering effect lasted for 20 weeks throughout the course of the experiments (71). Persistent expression of recombinant human kallikrein in rats was confirmed by ELISA and RT-PCR. Histological analysis showed remarkable amelioration of cardiovascular hypertrophy, renal injury, and collagen depositions in SHR receiving kallikrein gene transfer. In addition, reduced urinary albumin levels were detected following AAV-mediated kallikrein gene delivery. These studies showed that AAV-mediated delivery of the kallikrein gene rendered...

Hypertension Induced Stroke

Hypertension is a critical factor in the development of stroke in humans and animal models. In stroke-prone spontaneously hypertensive rats (SHR-SP), high-salt intake accelerates the development of malignant hypertension (88). In the brains of SHR-SP, fibrinoid necrosis and associated thrombosis primarily affect cerebral arterioles, leading to their obstruction and infarction, whereas cerebral hemorrhage is caused by micro-aneurysms (89). A high dose of cerivastatin, a HMG-CoA reductase inhibitor, protected against hypertension-induced stroke and ameliorated stroke-associated symptoms, which were accompanied by reduced superoxide production and inflammatory cell infiltration to the stroke lesion in SHR-SP (90). Lovastatin and simvastatin have also been shown to reduce brain injury during cerebral ischemia via upregulation of eNOS (91). Moreover, a lethal form of hypertension develops in Dahl-SS rats fed a high-salt diet at an early age (92). Pathological changes in the brain of...

Gene Targeted Mouse Models in Research on Hypoxic Pulmonary Hypertension

Studies in gene-targeted mouse models during the past few years have also provided insights into the pathogenesis and the potential treatments of hypoxic pulmonary hypertension Consistent with the findings in eNOS transgenic mice (19), studies of eNOS knockout mice have also suggested the importance of eNOS in the pathogenesis of hypoxic pulmonary hypertension (4, 5). The hypoxic pulmonary hypertension observed in eNOS knockout mice raised under mildly hypoxic condition was markedly more severe than that in controls or eNOS knockout mice raised under conditions simulating sea level (4, 5). Further studies suggested that the exacerbation of hypoxia-induced pulmonary hypertension in eNOS knockout mice was caused by reduced pulmonary vascular proliferation and remodeling in response to chronic hypoxia (20). Furthermore, studies of knockout mice lacking other isoforms of NOS showed that inducible NOS, but not neuronal NOS, also plays an important role in hypoxic pulmonary hypertension (4,...

Hypertension And Ihd 2011

Christou H, Yoshida A, Arthur V, Morita T, and Kourembanas S. Increased vascular endothelial growth factor production in the lungs of rats with hypoxia-induced pulmonary hypertension. Am. J. Respir. Cell. Mol. Biol. 1998 18 768-776. 3. Eddahibi S, Adnot S, Frisdal E, Levame M, Hamon M, and Raffestin B. Dexfenfluramine-associated changes in 5-hydroxytryptamine transporter expression and development of hypoxic pulmonary hypertension in rats. J. Pharmacol. Exp. Ther. 2001 297 148-154. 5. Eddahibi S, Hanoun N, Lanfumey L, Lesch KP, Raffestin B, Hamon M, and Adnot S. Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J. Clin. Invest. 2000 105 1555-1562. 6. Eddahibi S, Humbert M, Fadel E, Raffestin B, Darmon M, Capron F, Simonneau G, Dartevelle P, Hamon M, and Adnot S. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension . J. Clin. Invest. 2001 108 1141-1150. 7....

Role for ROS and RNS in Hypoxic Pulmonary Vasoconstriction and Pulmonary Hypertension

Pulmonary Hypertension Mechanism

For over one hundred years, it has been known that during hypoxia or low P02 the systemic arteries dilate to supply more oxygen to the deprived organ, however, on the contrary the pulmonary arteries constrict to balance the ratio of perfusion to ventilation. This phenomenon is generally termed as acute hypoxic pulmonary vasoconstriction. If HPV is prolonged it leads to pulmonary hypertension (PH). PH is characterized by pulmonary arterial vasoconstriction and remodeling. Under physiological conditions, the pulmonary arterial circulation is a high-compliance, low-pressure, low-resistance system, which carries blood into pulmonary microcirculation for gas exchange. Pulmonary artery pressure varies with age, from early childhood to the sixth decade of life, where the upper limit of normal pulmonary arterial pressure is regarded as 20 mmHg. Based on this observation, PH generally is defined as a mean pulmonary artery pressure greater than 25 mmHg at rest or 30 mmHg during exercise....

Case 32 Primary Pulmonary Hypertension

Oligemic Lung Fields

This patient fits the typical clinical and radiological profile of a patient with primary pulmonary hypertension. The pulmonary arteries are markedly enlarged with the right atrial chamber also enlarged. The normal right pulmonary descending artery diameter is less than 16 mm in males and 15 mm in females. The lung fields are clear and the lung volumes normal making lung disease causing pulmonary hypertension unlikely. Other causes to be ruled out are congenital heart disease and chronic pulmonary thromboembolism.

Hypertension Is a Sustained Elevation in Blood Pressure

Epidemiological data show that chronically elevated blood pressure is associated with excess cardiovascular morbidity and mortality. In adults, hypertension is defined as sustained systolic blood pressure of 140 mm Hg or higher, sustained diastolic blood pressure of 90 mm Hg or higher, or taking antihypertensive medication. Hypertension causes damage to the arterial system, the myocardium, the kidneys, and the nervous system, including the retinas. Medical treatment that lowers blood pressure to normal values significantly reduces the risk of damage of these target tissues.

Involvement of Renal Sympathetic Nerve in Pathogenesis of Hypertension

Neuron Renal

Conversely, if BP is reduced by standing or antihypertensive drugs, the activities of vagal afferents, the NTS, and CVLM neurons are reduced. Then, the activity of RVLM neurons is increased, and efferent sympathetic nerve activities should be activated. Thus, BP is increased to the original level. Fig. 1. The SNS and arterial baroreceptor reflex. RVLM (shaded area) rostral ventrolateral medulla CVLM caudal ventrolateral medulla GABA 7-amino butyric acid NTS nucleus tractus solitarius. Activated RVLM neuron increases peripheral sympathetic nerves to the heart, kidney, and arterioles, thus inducing hypertension. Fig. 1. The SNS and arterial baroreceptor reflex. RVLM (shaded area) rostral ventrolateral medulla CVLM caudal ventrolateral medulla GABA 7-amino butyric acid NTS nucleus tractus solitarius. Activated RVLM neuron increases peripheral sympathetic nerves to the heart, kidney, and arterioles, thus inducing hypertension. Hypertension Fig. 2. Functional roles of renal sympathetic...

Role of Deficient NO and PGI2 in Hypoxic Pulmonary Hypertension

PGI2 elicits pulmonary vasodilation and inhibits pulmonary VSMC growth due at least partly to activation of adenylate cyclase and production of cAMP (65). Lung-specific overexpression of PGI2 synthase in mice attenuates HPH (17). In contrast, decreased lung PGI2 production is implicated in severe pulmonary hypertension, and PGI2 receptor knockout mice develop exaggerated HPH (23). Decreased expression of PGI2 synthase and production of PGI2 may contribute to exaggerated HPH in ETB receptor deficient rats (25). The effects of chronic hypoxia on rat lung and pulmonary artery COX-2, PGI2 synthase, and PGI2 receptor expression are unclear (2,7). As mentioned earlier Rho Rho-kinase signaling inhibits COX-2 expression and subsequent PGI2 production in VSMC (10). Thus, it is possible that Rho Rho-kinase signaling modulates COX-2, PGI2 synthase, and or PGI2 receptor expression in HPH. Conversely, a decrease in production of cAMP may enhance Rho Rho-kinase signaling.

Transgenic Mouse Models in Research on Hypoxic Pulmonary Hypertension

During the past few years, many transgenic mouse lines have been established for research on hypoxic pulmonary hypertension (6, 17, 19, 29). Studies with these mice have provided significant insights into the pathogenesis and potential treatment of hypoxia-induced pulmonary hypertension. Patients with severe pulmonary hypertension have low levels ofprostacyclin synthase (PGIS) (3), but the pathogenic significance ofthis deficiency is unclear. Recently, transgenic mice overexpressing PGIS specifically in distal respiratory epithelium of the lung were generated with a construct containing the 3.7-kb human surfactant protein-C promoter and rat PGIS cDNA (6). The transgenic mice produced twofold higher pulmonary 6-keto prostaglandin Fta (PGF vessels in the transgenic mice. The nontransgenic mice had vessel wall hypertrophy after exposure to chronic hypobaric hypoxia. These results suggest that PGIS transgenic mice are protected from the development of hypoxia-induced pulmonary...

ET Antagonists in Essential Hypertension

Because ETB receptors are both vasoconstrictor and vasodilator, and additionally at least in the mouse have a natriuretic effect, there has been ongoing controversy on whether selective ETA or combined ETA ETB receptor blockers would be more efficacious therapeutically in cardiovascular diseases including hypertension. However, there are no clinical trials available comparing an ETA antagonist to a combined ETA ETB blocker. The combined ETa ETb antagonist bosentan (500 mg to 2000 mg d for 4 wk) given to patients with mild-to-moderate essential hypertension lowered blood pressure by 5.7 mmHg, comparable to the reduction observed with the ACE inhibitor enalapril (20 mg d) (76). More recently, the selective ETa antagonist darusentan was shown to reduce systolic blood pressure by 6.0 (at 10 mg d for 6 wk) to 11.3 mmHg (at 100 mg d) (77). Elevation of liver enzymes, a side effect sometimes found with bosentan, was not encountered with darusentan. Although these results have been promising,...

Role in pathophysiology of hypertension and cardiovascular disorders

In response to an increase in atrial distension, ANP is released into the circulation and mediates natriuretic, diuretic, and vasorelaxant effects. High levels of endogenous ANP are thought to compensate the condition of patients with heart failure by reducing preload and afterload. Evidence suggests that a high plasma ANP-BNP level is a prognostic predictor in humans with heart failure (257-259). Studies with ANP-deficient genetic strains of mice demonstrated that a defect in the ANP synthesis can cause hypertension (210). The blood pressures of homozygous null mutant animals were elevated by 8-12 mmHg when they were fed with standard or intermediate salt diets. Heterozygous animals showed normal blood pressures and normal amount of circulatory ANP, however, they became hypertensive and blood pressure was elevated by 20-27 mmHg if these animals were fed with high salt diets (207,210,260). Those previous findings clearly demonstrated that genetically reduced production of ANP can lead...

Conclusion For Pulmonary Hypertension

The role of growth factors in HPH is an open book, with no ending in sight. As novel vascular growth factors are discovered, and as we learn more about their biological and pathobiological role, we add a new level of understanding in HPH. Undoubtedly, abnormal vascular cell growth is at the center of pulmonary vascular remodeling in pulmonary hypertension (Fig. 3). In the next few years, the elucidation of master control levels of pulmonary vascular remodeling using genomics and proteonomics of human lung tissue compromised by pulmonary hypertension and transgenic models of pulmonary hypertension may shed important information in the relative contribution of growth factor in the pathogenesis of HPH.

Essential Hypertension

The vast majority of people with hypertension have essential hypertension. An increased total peripheral resistance is a universal characteristic of this condition. Cardiac rate and the cardiac output are elevated in many, but not all, of these cases. The secretion of renin, which is correlated with an-giotensin II production and aldosterone secretion, is likewise variable. Although some people with essential hypertension have low renin secretion, most have either normal or elevated levels of renin secretion. Renin secretion in the normal range is inappropriate for people with hypertension, since high blood pressure should inhibit renin secretion and, through a lowering of aldosterone, result in greater excretion of salt and water. Inappropriately high levels of renin secretion could thus contribute to hypertension by promoting (via stimulation of aldosterone secretion) salt and water retention and high blood volume. Sustained high stress (acting via the sympathetic nervous system)...

Severe paroxysmal hypertension

There are some patients with severe paroxysymal hypertension in whom the baroreflex failure, pheochromocytoma, and medullary vascular compression all appear to be absent. Sometimes paroxysmal hypertension is seen in patients with renal artery stenosis, but this can usually be ruled out with standard diagnostic techniques. In other patients, the etiology is less clear, but certainly it is observed in rare conditions such as tumors in the fourth ventricle or in the ancillary structures (26), Leigh's syndrome (4), and pseudopheo-chromocytoma, a poorly characterized nonepileptic disorder proposed to be related to abnormalities in dopamine function (27).

Role of CGRP in Chronic Hypoxic Pulmonary Hypertension

As described previously, CGRP participates in the regulation of regional organ blood flows both under normal physiological conditions and in the pathophysiology of various disease states. For example, in the lung, CGRP plays a critical role in modulating local pulmonary vascular tone. An excellent review describing the role of CGRP and other endogenous lung neuropeptides in the regulation of the pulmonary circulation has been published (28). Indeed, to the best of our knowledge, the first report demonstrating a role for CGRP in hypertension of any type was a study showing that CGRP and somatostatin modulate PH. Two earlier clinical studies suggested that CGRP might be involved in the pathophysiology of this disease (29,30). However, for this review we focus on studies using rodent models of PH and the antihypertensive effects of CGRP. Chronic

Dangers of Hypertension

If other factors remain constant, blood flow increases as arterial blood pressure increases. The organs of people with hypertension are thus adequately perfused with blood until the excessively high pressure causes vascular damage. Because most patients are asymptomatic (without symptoms) until substantial vascular damage has occurred, hypertension is often referred to as a silent killer. Hypertension is dangerous for a number of reasons. First, high arterial pressure increases the afterload, making it more difficult for the ventricles to eject blood. The heart, then, must work harder, which can result in pathological changes in heart structure and function, leading to congestive heart failure. Additionally, high pressure may damage cerebral blood vessels, leading to cerebrovascular accident, or stroke. (Stroke is the third-leading cause of death in the United States.) Finally, hypertension contributes to the development of atherosclerosis, which can itself lead to heart disease and...

Role of CGRP in LNAMEInduced Hypertension During Pregnancy

Pregnancy Induced Hypertension

The purpose of this series of experiments was to determine the involvement of CGRP in the vascular adaptations that occur in normal pregnancy and its role in hypertensive L-NAME-treated female rats. Yallampalli et al. (27) has demonstrated that the inhibition of NO synthesis with L-NAME in pregnant rats causes hypertension, proteinuria, fetal growth retardation, and increased fetal mortality. The co-administration of CGRP with the L-NAME prevented the gestational, but not the postpartum hypertension and the proteinuria and also significantly decreased pup mortality. Further studies revealed that this differential effect of CGRP on BP during gestation and postpartum is mediated by progesterone (23). Similar to the findings in postpartum rats, CGRP reversed the hypertension in L-NAME-treated ovx rats receiving progesterone injections. Therefore, these studies suggest that CGRP is antihypertensive in L-NAME-treated pregnant and non-pregnant rats and that the vasodilator effects of CGRP...

Polyamine Transport as a Target for Intervention in Hypoxic Pulmonary Hypertension

Polyamine Transport

The hypoxia-induced increase in polyamine uptake by pulmonary vascular cells raises the question of whether lung cell polyamine regulatory pathways could serve as targets of pharmacologic intervention in hypoxic pulmonary hypertension. Based on the finding that hypoxia decreases ODC activity, ODC blockade would not seem to be a promising approach. Pharmacologic manipulation of polyamine import has not, until recently, been possible owing to the lack of suitable agents. Recently, however, Weeks et al. reported the development of a lysine-polyamine conjugate, ORI1202, which specifically inhibited polyamine import in a variety of transformed cells (37).

Hypertension Induced by Chronic Inhibition of NO Synthesis

Long-term administration of NOS inhibitors by oral or intravenous administration has been demonstrated to result in sustained hypertension in different species such as mice, rats, rabbits, and dogs (2,5,6,15). Common characteristics of this hypertension model are systemic hypertension, renal vasoconstriction, a reduction in glomerular Kf, and sodium retention (32,33,38,61). In addition to the renal effects, which lead to retention of sodium and water, the increase in arterial blood pressure is also associated with systemic vasoconstriction owing to the blockade of the tonic vasodilating effect of NO. In addition, there is evidence that increases in renin release and activation of the renin-angiotensin II system also contribute to the development of hypertension during chronic systemic inhibition of the NOS activity (62). Although chronic oral or intravenous administration of NOS inhibitors produce hypertension, it is unclear whether the observed hypertension was primarily a result of...

Augmentation Of Intrarenal Agt And Ang Ii In Hypertension

Although increased internalization of Ang II contributes to the increased intrarenal Ang II in the Ang II-infused model of hypertension, the overall Ang II levels are also due to additional Ang II formation as a consequence of enhanced AGT production. In vivo and in vitro studies have shown that Ang II stimulates intrarenal AGT mRNA localized in proximal tubule cells (75,77,146). Several recent studies have focused on long-term changes in the intrarenal AGT formation in Ang II-dependent hypertension. Kobori et al. (74,75,83,129,147) evaluated the effects of Ang II infusions on intrarenal AGT and Ang II levels and the relationship between urinary excretion of AGT and kidney Ang II levels in hypertensive models. They reported that Ang II-infused rats had increases in renal AGT mRNA (75) and protein (74), and an enhancement of urinary excretion rate of AGT (147). Chronic Ang II infusions to normal rats significantly increased the urinary excretion rate of AGT in a time- and...

Tissue kallikrein in hypertension

Tissue kallikrein was first discovered as a hypotensive substance in 1909 by Abelous and Bardier as they showed that intravenous injection of human urine into the anesthetized dog causes a transient reduction of blood pressure (14). This hypotensive substance was later isolated and identified as an enzyme, which was called kallikrein, a Greek synonym for pancreas (15,16). Although pancreas has been shown to be the major site of human tissue kallikrein synthesis (17), urinary kallikrein mainly originates from the kidney (18). Tissue kallikrein is widely expressed in tissues relevant to cardiovascular and renal function including heart, kidney, brain, and blood vessels. Reduced renal (urinary) kallikrein levels in the patients of essential hypertension were documented in 1934 (19). Four decades later, this important finding was verified by a series of studies showing abnormally low kallikrein excretion in patients with essential hypertension and renovascular hypertension and in...

How Common Is High Blood Pressure Hypertension In Women

High blood pressure is unusual in young women and usually occurs together with other cardiovascular risk factors, for example, obesity, diabetes, and a high cholesterol level. High blood pressure increases the risk of heart attacks and strokes (Chapter 9). High blood pressure is more common in women after the menopause possibly because they are older. Women with high blood pressure are at least three times more likely to develop coronary heart disease than women with normal blood pressure. High blood pressure is more dangerous in women than in men.

Role of cgrp in hypertension

Although CGRP administration can markedly decrease high BP in humans (2,7), it is not clear what role CGRP plays in human hypertension. Data concerning circulating levels of iCGRP in hypertensive humans have been conflicting. These results have been attributed to several factors including the assay itself, heterogenity of the disease, severity and duration of the hypertension, the degree of end organ damage, and the variety of treatment regimens used in these patients. In contrast, a direct role for CGRP in experimental hypertension has now been established. Earlier reports demonstrate that CGRP can attenuate chronic hypoxic pulmonary hypertension (PH) (19) and we have, for the first time, demonstrated that CGRP acts as a compensatory depressor mechanism to partially attenuate the BP increase in three models of experimental hypertension (1) deoxycorticosterone (DOC-salt 20,21), (2) subtotal nephrectomy (SN-salt 22), and (3) NG-nitro-L-arginine methyl ester (L-NAME)-induced...

ET1 and Renal and Cardiac Target Organ Damage in Experimental Hypertension

ET-1 plays a role in renal and cardiac target organ damage in hypertension. ET-1 production is enhanced under conditions of salt loading, and via renal ETB receptor activation, inhibits sodium re-absorption (46). Ang II infusion combined with high salt increases renal ET-1 (47). In Ang Il-infused mice, the dual ETa ETb receptor blocker bosentan partially prevented the activation of the procollagen gene (48). However, Rothermund et al. studied transgenic rats overexpressing the ren2 gene (TGR(mRen2)27) that have renin-dependent hypertension (Ren2) and were treated between 10 and 30 wk of age with the selective ETa receptor antagonist darusentan or the ETa ETb receptor antagonist LU420627 (49). The elevated blood pressure and mortality of Ren2 was not affected by either ET receptor antagonist. Proteinuria and glomerulosclerosis, tubulo-interstitial damage, and renal osteopontin mRNA expression were reduced by an angiotensin receptor blocker but were unchanged in ET receptor...

Multiple roles of kallikreinkinin in hypertension cardiovascular and renal disease and stroke

Using strategies of transgenic and somatic gene transfer, as well as protein infusion approaches to achieve a continuous supply of kallikrein-kinin in vivo, we have shown that the KKS plays an important protective role in the development of hypertension in several animal models (Table 1). In addition to blood pressure reduction, kallikrein gene delivery or kallikrein protein infusion improves cardiac, renal and neurological functions,

Hypertension Induced by NOS Deficit in the Dahl SS

A series of studies were performed to determine whether Dahl SS rats respond similarly to normal rats in which NOS activity in the renal medulla was blunted by selective delivery of L-NAME to the medullary interstitium. Chronic intravenous infusion of Angll (3.0 ng kg min) did not induce an increase of arterial blood pressure in normotensive BN rats maintained on a low NaCl (0.4 ) diet (79). In marked contrast, intravenous infusion of the identical dose of Angll led to a sustained hypertension in Dahl SS rats, which were also maintained on the low salt diet. Interestingly, a low dose of AngII significantly reduced MBF in SS rats, but not in BN rats (79). These studies demonstrate that the ability of the BN rats to buffer Angll induced reductions of medullary blood flow is dependent on the release of medullary interstitial NO because of Dahl SS rats that failed to increase medullary NO in response to Angll exhibited a significant reduction of blood flow (79). Similar results to those...

Treatment of Hypertension

The first form of treatment that is usually attempted is modification of lifestyle. This modification includes cessation of smoking, moderation of alcohol intake, and weight reduction, if applicable. It can also include programmed exercise and a reduction in sodium intake. People with essential hypertension may have a potassium deficiency, and there is evidence that eating food that is rich in potassium may help to lower blood pressure. There is also evidence that supplementing the diet with Ca2+ may be of benefit, but this is more controversial. If lifestyle modifications alone are insufficient, various drugs may be prescribed. Most commonly, these are diuretics that increase urine volume, thus decreasing blood volume and pressure. Drugs that block Pi-adrenergic receptors (such as atenolol) lower blood pressure by decreasing the cardiac rate and are also frequently prescribed. ACE inhibitors, calcium antagonists, and various vasodilators (table 14.10) may also be used in particular...

CGRP is Protective Against Hypertension Induced End Organ Damage

The results described above in Sections 4 and 4.2 demonstrate that the a-CGRP CT deficient mice display a significant increase in basal blood pressure and a significant decrease in basal coronary flow rates. Hypertension-induced end organ damage is one of the most severe and common consequences of chronic increased blood pressure. Because CGRP has such potent biological effects on the heart and kidneys, and in light of several lines of indirect evidence suggesting that CGRP is an endogenous organ-protective agent These data demonstrate that deletion of the a-CGRP gene enhances hypertension-induced end organ damage in the heart and kidney. The mechanism of this increased tissue damage may be through the loss of CGRP-mediated vasodilator activity and or to an increase in the local tissue production of reactive oxygen species. Indirect mechanisms such as activation of the sympathetic nervous system and or the RAS system may also be involved. To our knowledge this is the first report of a...

Abdominal Obesity Fatty Acids and Neurogenic Hypertension

As noted previously, NEFAs have been linked epidemiologically to hypertension and its genesis. NEFAs have several actions that could contribute to hypertension and help explain the link between the obesity epidemic and increasing prevalence of hypertension (37). Hypertensive patients are more likely to be overweight and obese than normoten-sive individuals. Moreover, when matched for body mass index, hypertensives are more likely to have a centralized fat pattern and a greater amount of visceral to subcutaneous abdominal fat than normotensives (38). Even within the normotensive range, abdominally obese subjects have higher blood pressures than individuals with gluteofemoral obesity, and these blood pressure differences are related to insulin resistance (39). improved the action of insulin to suppress plasma NEFAs during a euglycemic clamp (43). The blood pressure reduction during enalapril treatment in obese hypertensive patients correlated with the improvement in insulin's capacity...

Proteomic Analysis of Renal Kallikrein Pathway in Hypoxia Induced Hypertension

Obstructive sleep apnea syndrome (OSAS), a disorder characterized by episodic hypoxia (EH), is a major public health problem. OSAS affects 4-5 of the general adult population and 1-2 of children in the United States. One of the major consequences of untreated OSAS is systemic hypertension. In addition to hypertension, OSAS has also been associated with both proteinuria and end-stage renal disease. A rat model of EH was used to obtain proteins from the kidney after EH induction, which were resolved by two-dimensional PAGE and then identified by MALDI-MS (72). Proteomic analysis showed that EH induces changes in renal protein expression consistent with the impairment of vasodilation mediated by kallikrein-kallistatin pathway. However, transgenic rats expressing human tissue kallikrein were protected from EH-induced hypertension. The results obtained from kallikrein transgenic rats reinforce the proteomic data. Therefore, EH-induced hypertension may result, in part, from altered...

Role of CGRP in Two Kidney One Clip Hypertension

Recently, the role of capsaicin-sensitive sensory nerves in two-kidney, one-clip (2K1C) renovascular hypertension has been investigated (24). Systolic blood pressure (measured by the tail-cuff method) was significantly elevated approx 25 in the 2K1C group compared to control rats 10 d following the initiation of the protocol. Treatment with capsaicin, which selectively depletes neuropeptides in sensory nerves, enhanced the hypertensive response to the procedure by another 20 at the same time period. A second injection of capsaicin produced an additional 25 increase in systolic blood pressure compared to the rats that had received a single injection at the second time point (30 d postoperative). The expression of a-CGRP mRNA in DRG, the level of CGRP in the plasma, and the density of CGRP immunoreactive fibers in mesenteric artery were all significantly increased in the 2K1C rats compared to the sham-operated controls. Treatment with capsaicin prevented the increase in CGRP expression...

Rhokinase Blocker Inhibits Development of Hypoxic Pulmonary Hypertension

To evaluate whether Rho Rho-kinase signaling is involved in the development of HPH, we treated rats exposed to 2 weeks of hypobaric hypoxia (equivalent to -10 02) with either vehicle or Y-27632 (40 mg kg day) via subcutaneous osmotic minipump. Measurements of mean pulmonary artery pressure and right ventricular (RV) weight left ventricular (LV) plus septal (S) weight (RV LV+S) showed that treatment with the Rho-kinase inhibitor reduced the severity of pulmonary hypertension (Fig. 5A), without reducing systemic arterial pressure or altering cardiac output (not shown). Y-27632 treatment did not affect the hypoxia-induced polycythemia (hematocrit 47 1 in normoxic controls and 67 2 and 70 2 , respectively, in vehicle and Y-27632 hypoxic groups). We have similarly found that treatment with Y-27632 also reduces HPH in mice (16), and preliminary results support the possibility that the attenuation of pulmonary hypertension is associated with increased expression of eNOS (Fig. 5B), and...

Nodose Ganglionectomy Hypertension

E., Price, W. A., et al. (1990) Nonpeptide angiotensin II receptor antagonists. VII. Cellular and biochemical pharmacology of DuP 753, an orally active antihypertensive agent. J. Pharmacol. Exp. Ther. 252, 711-718. 10. Carey, R. M., Wang, Z. Q., and Siragy, H. M. (2000) Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function. Hypertension 35, 155-163. 15. Carey, R. M. (2005) Cardiovascular and renal regulation by the angiotensin type 2 receptor the AT2 receptor comes of age. Hypertension 45, 840-844. 21. Horiuchi, M., Akishita, M., and Dzau, V. J. (1999) Recent progress in angiotensin II type 2 receptor research in the cardiovascular system. Hypertension 33, 613-621. 22. Carey, R. M. (2001) Theodore Cooper Lecture Renal dopamine system paracrine regulator of sodium homeostasis and blood pressure. Hypertension 38, 297-302. 25. Ozono, R., Wang, Z. Q., Moore, A. F., Inagami, T., Siragy, H. M., and Carey, R. M. (1997)...

Role of CGRP in DOCSalt Induced Hypertension

The first evidence that CGRP plays a role in systemic hypertension was provided by studies using the DOC-salt rat (20,21). For these studies, we used DOC-salt rats during the onset stage (4 wk after the initiation of the protocol) and four groups of normotensive rats to control for pellet implantation, uninephrectomy, and or salt administration. In our initial studies, we demonstrated that CGRP mRNA accumulation was significantly increased in DRG, and correspondingly, iCGRP levels were elevated in laminae I II of the spinal cord compared to the control groups. Furthermore, this increase in neuronal CGRP expression in the DOC-salt rats was specific for the DRG, because we did not observe any alterations in the brain or in the brainstem. In order to determine if these changes in CGRP were playing an important hemodynamic role, groups of rats had intravenous (for drug administration) and arterial (for continuous mean arterial pressure, MAP) catheters surgically placed and were studied in...

Supine hypertension in msa

One of the most unexpected findings in recent years has been the constitutive role of sympathetic activity in the supine hypertension of autonomic failure. Supine hypertension is seen in approximately half of the patients with autonomic failure. The mechanism of supine hypertension in these patients is heterogeneous. In patients with MSA, also termed as Shy-Drager syndrome, blood pressure was uniformly and considerably reduced by ganglionic blockade. This implied that the residual sympathetic activity accounted for most of the hypertension in these subjects. In contrast, ganglionic blockade had little to no effect in patients with pure autonomic failure (PAF). This finding indicates that mechanisms other than sympathetic tone were responsible for hypertension in PAF patients (41).


Hypertension is a well-described risk factor in insulin-resistant clinical states, but correlation between blood pressure and plasma insulin levels appears to be -o Insulin has also been found not to potentiate the blood pressure or kidney effects of other vasoactive substances, such as norepinephrine or angiotensin-II (102,103). Further, in obese subjects who are resistant to the metabolic and vasodilator effects of insulin, elevated insulin did not appear to increase arterial pressure (104). Therefore, the results of several clinical research studies strongly suggest that hyperinsulinemia does not explain the increased renal tubular NaCl reabsorption, shifts of pressure natriuesis, or the hypertension associated with obesity in both animals and humans (101). In contrast to the above, results from rodent studies suggest that long-term elevated insulin levels may result in significant elevations in arterial pressure. This effect may be mediated through interactions with the RAS and...

Intrarenal Angiotensin Ii Receptors

However, glomerular ATj receptor density was not increased in the 1K1C model although vascular ATi receptor density was increased (110). In the Ang II-infused rat model of hypertension, total kidney ATi mRNA levels and receptor protein were not significantly altered by 2 wk Ang II infusion sufficient to cause marked hypertension (111). However, Wang et al. (112) reported that ATia receptor protein was reduced in both ischemic and contralateral kidneys of 2K1C Goldblatt and 2-kidney-1-wrap hypertensive models, and in kidneys of Ang II-infused rats. AT2 receptors were downregulated only in ischemic kidneys. In the transgenic rat TGR(mRen2) harboring the mouse renin gene, Zhuo et al. (113) found increased AT1 receptor binding in vascular smooth muscle of afferent and efferent arterioles, JGA, glomerular mesangial cells, proximal tubular cells, and renomedullary interstitial cells. It was suggested that upregulation of AT1 receptors in multiple renal cells may contribute to...

Heterogeneity in Lung Structure and the Physiological Role of Hypoxic Pulmonary Vasoconstriction

Disadvantages of increasing pulmonary artery pressure in response to global alveolar hypoxia (e.g., ascent to high altitude, hypoventilation) or to the decrease in mixed venous Po2 during exercise. The acute response to hypoxia has a rapid onset and is quickly reversed by an increase in Po2 (43), whereas chronic hypoxia produces vascular remodeling and pulmonary hypertension that is sustained even after the alveolar Po2 is returned to normal (75). A causal relationship between the acute and chronic response is generally assumed. What that relationship is has not been established, but the potential for contributing to chronic pulmonary vascular remodeling has been considered to be one of the potential risks of HPV as means of controlling the V Q distribution.

The Physical Laws Obeyed by the Blood and Blood Vessels

With the advancement of biomechanics, the truth of the axioms of classical continuum mechanics began to be doubted. When the problems of atherosclerosis and hypoxic pulmonary hypertension came into focus, a revolution in the system of axioms of mechanics became inevitable. Some ofthe reasons will be explained in detail in Section 8 infra. In fact, it appears that a new system of axioms has to be introduced to replace the old system in biomechanics. Our new system is listed in the right-hand column of Table 1 (10).

The Role of Pulmonary Veins

The resistance to blood flow offered by pulmonary veins to the pulmonary circulation is far more important than the resistances to flow offered by peripheral veins to peripheral circulation. If the pressure drop from the largest artery to the smallest arterioles is compared with the drop in the capillaries and veins, we obtain the results shown in Table 2. It is seen that in the normal lung, we may expect that the pressure drop in the pulmonary veins be larger than that in the pulmonary arteries. If we assume that the vascular smooth muscles in pulmonary arteries and veins are similar, that their contractile mechanism, their chemistry, Ca2+roles, and ion channels are similar, then the pulmonary veins are equally effective as the arteries in producing pulmonary arterial hypertension in hypoxia. The veins exert a powerful remote control on the arteries. The veins, by their contraction, can reduce the resistance of the pulmonary capillaries to blood flow, and increase the pressure in the...

The Physiological Changes in HPH Changes in Anatomical Dimensions Zero Stress State Chemical Histological and

If we want to know how blood vessels change when the blood pressure is raised, it is worthwhile to learn the full story by measuring the changes from time zero when an increase of blood pressure occurs. Let's use the rat for illustration. With a step decrease of the oxygen concentration from the normal sea level 20.9 to a level of 10 in the gas that a rat breathes, the pulmonary arterial blood pressure increases, the materials in the wall of the artery will change as shown in Figure 3 (11). Here the histological cross sections of the largest left pulmonary artery (of order 12) are shown in the first row, beginning with the normal state, then in a state after 2 hours of hypertension, then 12 hours, etc. In each panel, from top down, are the blood space, the endothelium, the basement membrane, the layers of vascular smooth muscle cells and elastin, and the adventitia. Looking at the media layer in the first row of Figure 3, we see a great thickening at 12 hours of hypoxia. Then the...

Correlation of Gene Actions with Physiological Changes

To study the relationship between the action of the genes and the physiological changes in tissue remodeling, we used the same hypoxic hypertension rat model described earlier, took the arterial specimens at scheduled times, extracted the total RNA in each specimen. Then the mRNA was isolated, polymerized cDNA, colored with biotin, and prepared for hybridization, all with known procedures and commercial kits described in detail in Refs. 4, 21, and 25. The genes in each of these processed specimen solutions are called probes. The solution of each specimen containing all the probes was used to measure gene expression in a microarray test equipment designed and constructed by Peck and his associates (4). In Peck's array, 9,600 selected genes were deposited as targets on a nylon membrane in a rectangular matrix pattern. They were PCR products ofhuman cDNA clones rearrayed from the IMAGE Consortium cDNA libraries based on the Unigene clustering (4). When the specimen solution was spread...

Receptor Tyrosine Kinases

Increasing evidence suggests that there is a cross-talk between GPCR and RTK. GPCR utilize signaling pathways downstream of RTK to exert cellular effects. AT1 activation-mediated mitogenic responses may be regulated by activation of RTK. Ang II can activate RTK, even though it does not directly bind to RTK (101). This process of transactivation has been demonstrated for EGFR, PDGFR, and IGFR (101). Ca2+, Pyk2, Src, and redox-sensitive processes are involved in Ang II-induced transactivation of RTKs. ATj-induced EGFR transactivation is important for some of the trophic effects of Ang II. Studies have demonstrated that the EGFR activation is involved in Ang II-induced vascular contraction, cell growth, cardiac hypertrophy, and hypertension (102).

Summary And Conclusions

The RAS is a hormonal cascade that regulates cardiovascular, renal, and adrenal function, as it relates to fluid and electrolyte homeostasis and arterial pressure. The RAS has been further delineated as a local, self-contained, paracrine, autocrine, and intracrine system. The tissue RASs are likely important in normal physiological responses, as well as in the pathophysiology of disease states such as hypertension, cardiac hypertrophy, congestive heart failure, and post myocardial infarction remodeling. Although major progress has been made in our understanding of the physiology and pathophysiology of the circulating RAS, it will be important to more completely elucidate the role of tissue RASs in normal physiology and in the pathophysiology of cardiovascular diseases.

Vascular smooth muscle cells

Since the time of its first demonstration, a multitude of studies have confirmed that the AT2 receptor mediates its vasodilator action via the BK-NO-cGMP pathway (7,10-12,73). Subsequent studies have revealed that both endogenous Ang II (increased by dietary Na+ restriction) and exogenously infused Ang II stimulate an increase in cGMP, an effect abolished by pharmacological AT2 receptor blockade and AT2 receptor antisense oligodeoxynucleotide administration, as well as by BK B2 receptor blockade and NOS inhibition (70-72,74,75). In normal rats as well as a renal-wrap model of experimental hypertension, Ang II infusion induced an AT2 receptor-mediated increase

Effects of ang ii on vascular repair

As part of the inflammatory response, tissues undergo repair. This process involves cell growth and fibrosis, both of which are modulated by Ang II (Fig. 1). Ang II influences cell growth by stimulating hyperplasia, hypertrophy, and apoptosis (77). In cultured VSMC through the ATjR, Ang II induces hyperplasia (increase in cell number associated with DNA synthesis) or hypertrophy (increased protein synthesis and or increased intra-cellular cell water volume). These effects are partially mediated through transactivation of EGFR, PDGFR, and IGFR and involve activation of growth-signaling pathways including c-Src and MAP kinases (78-80). Vascular cell hyperplasia and hypertrophy contribute to remodeling associated with vascular injury and inflammation (81,82). Ang II also has antigrowth and pro-apoptotic actions, mediated primarily through AT2R (83-85). These effects are particularly important in pathological conditions associated with vascular inflammation in which AT2R may be...

Channel as an Effector

Exposure to hypoxia for 1-2 weeks elicits chronic hypoxic pulmonary hypertension (CH-PHT). Rodent CH-PHT is a relevant model for PHT that occurs in humans living at high altitude and in patients with chronic lung diseases. Paradoxically, acute hypoxic pulmonary vasoconstriction is blunted in CH-PHT, whilst the response to other vasoconstrictors is preserved or enhanced (71, 90). This is associated with inhibition ofPASMC K+ current (113) and a selective downregulation ofmRNA expression of some, but not all, PASMC K+ channels (e.g., Kv1.5, Kv2.1, Kv4.3 andKv9.3) (97, 135). CH also selectively

Markers of inflammation in cardiovascular disease

Prospective studies reported that CRP is an independent predictor of risks of future myocardial infarction, stroke, and peripheral vascular disease (144,149-151). In a recent study, a cohort from the Framingham Heart Study, in which the participants were free of cardiovascular disease, the relationship between CRP and coronary calcification was evaluated (152). The authors found that CRP levels were associated with epicardial coronary calcification, even after adjustment for age and the traditional risk factors. The clinical utility of CRP has also been assessed to predict future risk of sudden cardiac death in apparently healthy men who have no clinical evidence of coronary heart disease (144,149,151). In addition to its predictive value for cardiovascular events, CRP has been associated with the development of type II diabetes, metabolic syndrome, and hypertension (153-155). Taken together, these clinical data further support a role for inflammation in cardiovascular disease and...

Mineralocorticoid receptor

From Contemporary Endocrinology Hypertension and Hormone Mechanisms Edited by R. M. Carey Humana Press Inc., Totowa, NJ The MR has similar in vitro affinity for aldosterone and cortisol. In many tissues, including the kidneys and vasculature, 11 -hydroxysteroid dehydrogenase-2 (11 -HSD2) is found in association with the MR. This enzyme converts cortisol to cortisone, thereby preventing the activation of the MR by glucocorticoids (11). In humans, inactivating mutations of 11 -HSD2 or consumption of licorice containing the 11 -HSD2 inhibitor glycyrrhetinic acid leads to hypertension, volume expansion, and hypokalemia because of the cortisol activation of the renal MR (12).

Primary aldosteronism a reappraisal

Patients with primary aldosteronism have excess aldosterone production, which causes sodium retention, volume expansion, and suppression of renin and Ang II. This patient population provides a unique opportunity for studying the cardiovascular effects of aldosterone in the relative absence of its primary secretagogue, Ang II. Patients with primary aldosteronism have high rates of left ventricular hypertrophy (LVH), proteinuria, retinopathy, and stroke (19-22). There is an excess of LVH and proteinuria in these patients when compared to patients with a similar degree and duration of essential hypertension. Furthermore, patients with primary aldosteronism who are treated with surgical resection of an aldosterone-producing tumor appear to have more LVH regression than patients treated with medical therapy despite similar reductions in blood pressure (22). Myocardial damage (estimated by thallium myocardial scintigraphy) is more severe in primary aldosteronism than in essential...

Chronic Hypoxic Regulation of Kv Channel Expression

As mentioned earlier, the major physiological function of acute HPV is to maximize oxygenation of the venous blood in the pulmonary artery by optimizing the ventilation-perfusion ratio (see Chapter 1). However, persistent hypoxia (e.g., patients with airway obstructive diseases and congenital heart diseases) and chronic exposure to hypoxia (e.g., residents in high altitude) cause sustained pulmonary vasoconstriction and vascular remodeling characterized by significant medial (smooth muscle) hypertrophy, which lead to pulmonary hypertension. A common hypothesis is that pulmonary vasoconstriction and PASMC proliferation use overlapping signaling processes that result in parallel intracellular events (e.g., a rise in cytoplasmic Ca2+) causing pulmonary hypertension. As discussed earlier, an increase in in PASMC is a major

Promoter Expression and Regulation by Regulatory DNA Elements and Transcription Factors

While AP-1 binding may be involved more in cellular proliferation and the pulmonary remodeling induced by prolonged hypoxia, HIF-1 activation is intimately involved in hypoxia-induced pulmonary hypertension (111). The biological activity of HIF-1 is regulated by the expression and activity of the HIF-la subunit. Under normoxic conditions, HIF-1 is ubiquitinated and rapidly degraded, thereby never allowed to form functional heterodimeric HIF-1 proteins. Under hypoxic conditions, HIF-i a ubiquitination is inhibited and HIF-la dimerizes with HIF-1 P subunits to form functional HIF-1 which is responsible for activation of a number of target genes including vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1). The role of these growth factors and mitogens in HPV is discussed in the following section.

Kidneys Renal Vascular Inflammation

Animals given L-NAME, Ang II, and a moderately high-sodium diet develop severe renal arteriopathy with fibrinoid necrosis of the vascular wall, medial thickening, proliferation of the perivascular connective tissue, perivascular inflammation, focal thrombosis in glomeruli, and proteinuria (Fig. 5) (33). This injury is significantly reduced by MR antagonists or adrenalectomy but recurs when aldosterone is infused into adrenalectomized animals. Similarly, aldosterone-infused uninephrectomized rats fed a high-salt diet develop severe hypertension, renal inflammation and injury, albuminuria, and elevated expression of several proinflammatory molecules (39). These effects are attenuated with MR antagonists. In both these models, the protective effects of MR antagonism do not appear to be mediated by changes in blood pressure.

Summary and the Road Ahead

HPV is a critical physiological mechanism to ensure maximal oxygenation of blood. Persistent HPV or pulmonary vascular remodeling during chronic hypoxia causes pulmonary hypertension that may lead to right heart failure. A rise in Ca2+ cyt in PASMC triggers pulmonary vasoconstriction and stimulates PASMC proliferation. Therefore, an increase in Ca2+ cyt in PASMC may serve as a critical step in acute HPV and in chronic hypoxia-mediated pulmonary vascular medial hypertrophy (Fig. 10). An important mechanism in elevating Ca2+ cyl is membrane depolarization-mediated Ca2+ influx through voltage-dependent Ca2+ channels. Given the fact that Em is primarily determined by K+ permeability and the resting Em is regulated predominantly by whole-cell K+ currents through Kv channels in PASMC, regulation ofKv channel function and expression has been demonstrated to be a mechanism by which hypoxia induces pulmonary vasoconstriction and stimulates PASMC proliferation.

Aldosterone Dietary Sodium and Vascular Injury

Development of aldosterone-mediated vascular injury appears to require the combination of a moderately high salt intake and an underlying co-morbidity, such as hypertension, CHF, or renal disease. Control animals fed a high-salt diet do not develop cardiovascular injury (52). Animals given L-NAME Ang II in the presence of sodium restriction also do not develop cardiovascular damage, despite a 10-fold increase in plasma aldosterone levels compared to animals on a high-salt diet (Fig. 6) (53). Rather, injury occurs in L-NAME Ang II animals on a high-salt diet with low-to-normal plasma aldosterone levels and can be prevented by an MR antagonist. The influence of dietary sodium on the adverse effects of aldosterone in vivo raises concerns regarding the applicability of in vitro studies of aldosterone's actions.

Transient Receptor Potential Channels and Capacitative Ca2 Entry in Hypoxic Pulmonary Vasoconstriction

Voltage-gated Ca2+entry is amajor Ca2+ influx pathway in the smooth muscle cells of most blood vessels. The ion channel that mediates it is selectively permeable to Ca2+ and activated by membrane depolarization above a threshold of around -30 mV. The channel is selectively blocked by calcium antagonist drugs like nifedipine and diltiazem their well established antihypertensive effects illustrate the important role of voltage-gated Ca2+ channels in regulating Ca2+ j and tone in vascular smooth muscle.

Role of g proteincoupled receptor kinase type

In humans with essential hypertension, the uncoupling of the D like receptor from its G protein effector complex has been shown to be a consequence of an activating variant in a member of the G protein-coupled receptor kinase (GRK) family of kinases that are responsible for G protein receptor inactivation following agonist stimulation. (79,120,132,144-153). The complex of phosphorylated D1 receptor, arrestin, and adaptor proteins undergo internalization, via clathrin-coated pits into an endosome in which the GPCR can be degraded by lysosomes or proteasomes, or dephosphorylated by phosphatases (e.g., GRK2A) (28,33) to be recycled back to the plasma membrane. Dephosphorylation can also occur directly at the plasma membrane (154), and desensi-tization may be clathrin-independent (133). Uncoupling of the D1 like receptor in essential hypertension involves the D1 receptor and not the D5 receptor in hypertension (155,156) and unpublished studies . The D1 receptor is...

Definition and diagnosis what is the metabolic syndrome

Occurrence of three or more of the following prespecified risk factors is sufficient for a positive diagnosis abdominal obesity (most common feature Fig. 1D , hypertension, hypertriglyceridemia, low plasma high-density lipoprotein cholesterol, and elevated fasting plasma glucose) (see Table 1 for defining levels) (1). Patients rarely present with all of the five factors.

Reducing blood pressure through lifestyle changes

Therapeutic lifestyle changes focusing on weight reduction, exercise, and healthy eating (restricted sodium intake, the dietary approaches to stop hypertension DASH eating plan, and moderate alcohol consumption) is the foundation of hypertension management in persons with metabolic syndrome (Table 3) (16). Individuals should also be counseled to stop smoking to reduce their overall CVD risk. A realistic weight loss target is 10 of initial weight over 6 mo. Losing 22 lbs (10 kg) reduces SSP by 5-20 mmHg in a large proportion of overweight individuals (16). Motivating patients to maintain lifestyle changes as a means of long-term blood pressure control presents another challenge to the physician. For example, many patients find it difficult to adhere to weight-reduction programs, or regain the lost weight after discharge from clinical care. Continued observation and encouragement with combined lifestyle interventions and antihypertensive therapy can help patients attain their blood...

ROS May Contribute to Insulin Resistance

The DASH combination diet, which is high in fruits, vegetables, and low-fat dairy products, lowered systolic blood pressure by 11.4 mmHg in hypertensives but only 3.5 mmHg in normotensives (114). The high fruits and vegetables diet lowered systolic pressure by 7.2 mmHg in hypertensives but only 0.8 mmHg in normotensives. Thus, much of the benefit of DASH in hypertensives reflected greater intake of fruits and vegetables, which are high in antioxidants, K+, Mg2+, and fiber. The trial of hypertension prevention found that diets supplemented with K+, Ca2+, and Mg2+ had minimal effects on blood pressure (115). Thus, most of the blood pressure reduction with fruits and vegetables may reflect effects of antioxidants in fruits and vegetables.

Clinical Settings in Which Hypoxia Causes Pulmonary Vascular Disease

In persons living at high altitude, there is chronic elevation of pulmonary artery pressure, only a small portion of which is reversible with administration of oxygen. The peripheral arteries are more muscular than normal and have a decreased lumen diameter. The severity of pulmonary hypertension is variable and almost always improves on return to sea level, at least at rest. In response to exercise, it may increase markedly, suggesting limited functional reserve, owing to persistent structural abnormalities (17).

Upper Airway Obstruction

Severe upper airway obstruction from a variety of causes may be complicated by the development of pulmonary hypertension. These include, obstructive sleep apnea which may be associated with the Pickwickian syndrome. Obesity, through the increased work of breathing andC02 production,

Adventitial Remodeling Elastin and Collagen

Stenmark et al. (43) took newborn calves to a simulated high altitude of 4,300 m and observed severe pulmonary hypertension with right-to-left shunting owing to the rapid development of suprasystemic levels of pulmonary artery pressure. There was striking medial hypertrophy and remarkable proliferation of a dense adventitial sheath that, in large vessels, was sometimes seen to exhibit neovascularization (Fig. 1). Hypoxiainduced adventitial fibroblast proliferation has been related to protein kinase (11). The contribution ofthe extensive vaso vasorum of the adventitia has been recently investigated (12). Stem cells have been identified in these vessels which have the capacity to differentiate into both endothelial as well as smooth muscle cells and may play a critical role in the

Proteolytic Activity and Hypoxic Pulmonary Vascular Disease

While some studies have shown that increased activity of metalloproteinases is prevalent during the regression ofvascular disease (48) but inhibition of metalloproteinases appears to aggravate experimental pulmonary hypertension in rats (50). Our group has focused on the specific contribution of serine elastase activity to the progression and regression of pulmonary vascular disease. We showed that there is heightened activity of a serine elastase 2 days after exposing rats to chronic hypobaric hypoxia and that inhibition of elastase by infusion of elastase inhibitors will greatly ameliorate the severity of pulmonary hypertension as well as the associated structural abnormalities which include extension of muscle into normally non-muscular peripheral arteries, medial hypertrophy of muscular arteries and reduction in the number of small peripheral arteries (28). Similar repression of disease is observed in a transgenic mouse in which there overexpression of the naturally occurring...

Rho Rhokinase in Systemic Vascular Diseases

Rho Rho-kinase signaling is implicated in the pathogenesis of various systemic vascular diseases (58). The Rho-kinase inhibitors Y-27632 and fasudil cause greater acute systemic vasodilation in hypertensive rats and patients than in their normotensive counterparts, implying an increased contribution of Rho-kinase-mediated Ca2+ sensitization to the regulation of systemic vascular tone in hypertension. Treatment with Rho-kinase inhibitors also prevents coronary artery medial hypertrophy and perivascular fibrosis in hypertensive rats (29, 39). 5-HT-induced vasospasm of coronary arteries is associated with In contrast to the considerable evidence for its involvement in systemic vascular diseases, there is little information on the importance of Rho Rho-kinase signaling in the pathogenesis of pulmonary hypertension. Recent studies in our laboratory (16, 37, 42, 47) and others (1, 18, 22, 44) indicate that Rho Rho-kinase signaling plays a role in both HPH and monocrotaline-induced pulmonary...

Goaloriented management

Although the Hypertension Service at Rush University manages patients via individual physician encounters and has doctors with different practice styles, we believed that a University hospital-based Hypertension Specialty Clinic could equal BP control rates seen in clinical trials. Alternatively, if excellent BP control rates could not be acquired in a clinic staffed by knowledgeable specialists such as the Rush Clinic, then the outlook would indeed be poor for good BP control in other settings. In our study of 437 consecutive patients seen at Rush, we judged our performance against (1) the Health Employer Data Information Set (HEDIS) 2000 measures, (2) JNC VI, and (3) the more stringent goals of the ADA and National Kidney Foundation (NKF) for diabetic patients. Most patients were referred by physicians because of difficult-to-manage or resistant hypertension. Using goal-oriented management, our four physicians aimed at satisfying current guideline criteria for BP control. Similar to...

Rhokinase Activity Mediates Increased Basal Vascular Tone in Hypertensive Rat Lungs

To investigate if Rho Rho-kinase signaling plays a role in increased vascular tone in HPH, we measured acute effects of intravenous Y-27632 (10 mg kg) on pulmonary and systemic arterial blood pressures and cardiac output in normoxic control and chronically hypoxic rats breathing 21 02 (47). Normoxic control rats were kept at Denver's barometric pressure of -630 mmHg (inspired Po2 The chronically hypoxic rats were exposed to hypobaric hypoxia (barometric pressure 410 mmHg, inspired Po2 76 mmHg) for 3 to 4 weeks before being returned to normoxia for 2 days for catheterization and hemodynamic measurements. Although these rats were no longer undergoing hypoxic vasoconstriction, they maintained high pulmonary artery pressures, i.e., residual pulmonary hypertension . While the Rho-kinase inhibitor had little effect on pulmonary artery pressure and pulmonary vascular resistance in control rats, it almost normalized the residual pulmonary hypertension in chronically hypoxic rats (Fig. 3)....

Factors Involved in Oxygen Sensing

While the mechanism of oxygen sensing is being progressively unraveled, at least three transcription factors regulate the cellular response to hypoxia in the lungs. The best characterized is hypoxia-inducible factor-1 (HIF-1), a heterodimer that recognizes a cognate sequence within the promoter of several genes involved in the cellular response to hypoxia (Table 1) (25). The a subunit is regulated by the 02 concentration whereas the P subunit is constitutively expressed. HIF-1 knockout mice die from failed vascularization at mid-gestation, but heterozygous mice develop normally under normoxic conditions. Surprisingly, when stressed under hypoxic conditions, the pulmonary hypertension and vascular remodeling present in the wild type animals is attenuated in the heterozygotes. Table 1 Growth Vasoactive Factors Implicated in Hypoxia-induced Pulmonary Hypertension

Growth Factors Involved in Medial Smooth Muscle Cell Remodeling

Hypoxia has been demonstrated to induce the secretion of serotonin from intact pulmonary neuroepithelial bodies and the expression of a 5-hydroxytryptamine transporter (5-HTT) (10). In addition, patients with primary pulmonary hypertension have elevated levels of serotonin, and an increased frequency of a polymorphism within the 5-HTT which renders cultured pulmonary artery smooth muscle cells more susceptible to the growth promoting effects of serotonin (7). Numerous animal studies have demonstrated a role for serotonin in the development of HPH. Continuous infusion of serotonin into rats exposed to chronic hypoxia augmented the vascular remodeling (8). 5-HTIB-receptor knockout mice exposed to chronic hypoxia developed less pulmonary hypertension and a non-significant decrease in vascular remodeling, but had no contractile response to a serotonin agonist (13). Although controversial, the mitogenic effects of serotonin appear to be mediated, at least in part, by the 5-HTT. Mice...

Inflammatory Cytokines Interleukin6 and Interleukin8

The role of inflammation in pulmonary hypertension has been observed in numerous animal models. Increased inflammation and cytokine production was directly observed in mice exposed to hypoxia. RNA prepared from hypoxic mouse lungs showed elevated levels ofIL-1, IL-6, MIP-2 (functional homologue of human IL-8), and monocyte chemoattractant protein, MCP-1 (19). Interestingly, these levels were reduced in transgenic mice overexpressing lung heme-oxygenase-1, animals which were also protected from developing HPH (19). Furthermore, rats treated with a PAF inhibitor (20) or the 5-lipoxygenase inhibitor MK866, or mice lacking 5-lipoxygenase (32) had decreased pulmonary The critical role of VEGF in maintenance of lung vascular reactivity was highlighted by the findings that chronic hypoxia in combination with a VEGF receptor blocker cause severe pulmonary hypertension associated with endothelial cell proliferation in rats (27). This model has several features in common with human severe...

Importance of Medullary NO Production in the Long Term Control of Medullary Blood Flow and Arterial Pressure

The first evidence that basal NO production in the renal medulla plays an important role in determining the long-term level of arterial blood pressure arose from observations made in our laboratory that indicated the chronic intravenous administration of the NOS inhibitor L-NAME led to a selective decrease in blood flow in the renal medulla, the retention of sodium, and the development of hypertension in conscious rats (63). It was unclear, however, whether the medullary NO production perse played an important role in the long-term regulation of renal medullary blood flow, sodium excretion, and arterial pressure. Further studies were then performed in which L-NAME was infused chronically into the renal medullary interstitium of Sprague-Dawley rats for 5 d (64). As shown in Fig. 3, the renal medullary interstitial infusion of L-NAME resulted in a sustained reduction of renal medullary blood flow ( 30 ) with no measurable changes of cortical flow. The selective reduction of medullary...

NO Regulation and LArginine Uptake in Renal Medulla

The studies outlined above indicate that a deficit in NO synthetic ability in the renal medulla may be important in the development of hypertension. The deficit in NO production could be related to NOS enzyme as described above (79), or this effect could be mediated by other alterations in the NO synthetic pathway. Related to this possibility, it has been demonstrated that supplementation of l-arginine (L-Arg), the substrate for NOS, is capable of preventing salt-induced hypertension in Dahl SS rats when administered by oral or intravenous routes (81-84). Experiments in anesthetized rats demonstrated that the pressure-natriuretic response and the transmission of perfusion pressure into the renal interstitium were normalized by L-Arg treatment (83,84). These observations led us to hypothesize that the major antihypertensive actions of L-Arg in Dahl SS rats could be mediated through actions of this NO precursor in the renal medulla. A dose of L-Arg (300 g kg min) was then infused into...

Vascular effects of et1

ET-1 generation is modulated by shear stress that downregulates its release by endothelial cells (10). NO production, stimulated by shear stress, is an important inhibitor of ET-1 release (11), and may thus be a mediator of this effect. Hypoxia, epinephrine, thrombin, Ang II, vasopressin, cytokines, insulin, and growth factors such as TGF- 1 stimulate endothelial release of ET-1. Leptin has also been shown to upregulate ET-1 production by endothelial cells (12), which could explain in part increases of ET-1 in obesity. This may represent a mechanism that relates obesity to frequently associated cardiovascular conditions including hypertension and atherosclerosis, or that contributes to the evolution of the metabolic syndrome toward type 2 diabetes. Peroxisome proliferator-activated receptors (PPARs) are nuclear factors involved in adipocyte differentiation and insulin sensitivity that have been recently shown to exhibit potent anti-inflammatory and antigrowth properties (13-15). Both...

Changes in Pulmonary Vascular Reactivity During Exposure to Chronic Hypoxia

Upregulation of eNOS has consistently been found to correlate temporally with the progression of hypoxia-induced pulmonary vascular remodeling (32). Increased inducible NOS (iNOS) expression has also been observed in lung tissue from chronically hypoxic mice. Although eNOS protein expression is increased, vasodilation in response to endothelium-dependent agents such as acetylcholine, ionophore, or serotonin is abolished, whereas the response to NO is preserved in isolated lungs from chronically hypoxic rats. This suggests that eNOS activity is reduced in chronically hypoxic pulmonary hypertension (1).

Genetics of the ET System

A polymorphism (EDN1 K198N) located in the coding region of the prepro-ET-1 gene (89) has been associated with increased vascular reactivity, and as already mentioned, could contribute to increased vascular tone in hypertensive patients (74). This polymorphism has also been associated with blood pressure levels in overweight individuals (88). A polymorphism of ECE-1b (ECE1 C-388A) in the 5'-regulatory region of the ECE-1b gene (338 bp upstream from the translation start site), resulting in a binding site for the transcription factor E2F-2 was recently described in two cohorts of hypertensive patients. This C-to-A substitution is associated with increased promoter activity, as demonstrated in promoter-reporter gene experiments (90). In a group of untreated hypertensive German women, the A allele of this polymorphism had a codominant effect on daytime and night time systolic and diastolic BP (90). In another cohort from the tude du Vieillissement Art riel (EVA) study, an epidemiological...

Hypotension in Transgenic Mice Expressing Human Tissue Kallikrein or Kinin B2 Receptor

Although epidemiological and genetic linkage analyses implicate a protective role of tissue kallikrein in the development of hypertension, molecular evidence documenting a direct link between kallikrein gene expression, and alteration of blood pressure is lacking. This is because of the difficulty in eliciting and maintaining high levels of either kinin or kallikrein in experimental animals. Gene transfer technology provides a novel approach to study the role of the KKS in blood pressure regulation. In order to evaluate the physiological role of the KKS, we have established transgenic mouse lines expressing KKS components. Transgenic mice expressing human tissue kallikrein were permanently hypotensive throughout their lifetime compared to their control littermates (47-49). Similarly, transgenic rats expressing human tissue kallikrein are also hypotensive (50). Administration of aprotinin or icatibant to the transgenic mice raised their blood pressures to normal levels (47,48). These...

Summary and Future Directions

The integrated response of the pulmonary circulation to hypoxia is complex, involving many different cell types, mediators, and transduction pathways. The polyamines, by virtue of their role in multiple signaling events, would seem to be an important point of integration of the many stimuli acting on hypoxic lung cells. Our findings that polyamine transport, rather than de novo polyamine synthesis, seems to be the dominant pathway regulating lung vascular cell polyamines during hypoxia suggest that polyamine transporter(s) may be an isolated target for intervention. The inhibitory effect of the polyamine transport inhibitor, ORI1202, on hypoxia-induced p38 MAP kinase phosphorylation in PASMCs is provocative. If the effector cells in hypoxic pulmonary hypertension rely on augmented polyamine import as a source of signaling molecules, while cells not intimately linked to the hypoxic response continue to synthesize polyamines via the actions of ODC, then transport blockade could be a...

Kallikrein Kinin Administration on Blood Pressure

Intravenous infusion of tissue kallikrein or kinin results in a transient reduction of blood pressure that lasts only 1-2 minutes (10). The short duration of tissue kallikrein-kinin in the circulation is due to the presence of tissue kallikrein inhibitors as well as kinin degrading enzymes in the blood vessels. Oral administration of purified pig pancreatic kallikrein has been shown to temporarily lower both the supine and upright blood pressure of hypertensive patients (59-60). However, continuous oral kallikrein intake three times daily is required to maintain low blood pressure. The benefit of kallikrein in inducing blood pressure-lowering effect disappeared quickly on the termination of oral kallikrein intake. Therefore, somatic gene delivery that leads to continuous expression of a gene of interest for an extended period of time may be used as an alternative approach to circumvent this problem.

Systemic Gene Delivery ofHuman Tissue Kallikrein Reduces Blood Pressure in Genetically Hypertensive Rats

We employed gene transfer approaches to study the role of the KKS in hypertension, cardiovascular, and renal disease in animal models. To investigate the impact of supplying tissue kallikrein by gene delivery, we generated a series of human tissue kallikrein gene constructs under the control of the metallothionein metal response element, the albumin promoter, the Rous sarcoma virus 3' long terminal repeat, or the cytomegalovirus

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