Hiromichi Suzukia, Takao Sarutah aDepartment of Nephrology, Saitama Medical School, Moroyama-machi, Saitama and bDepartment of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
The kidney is involved in the maintenance of peripheral vascular resistance through the action of angiotensin II (Ang II), which is the final product of the renin-angiotensin system (RAS) and participates in the volume control of cardiac output by regulating urinary salt and water excretion. Since it is well known that arterial pressure is equal to cardiac output multiplied by total peripheral resistance, the kidney is indispensable for regulation of blood pressure. When the blood pressure rises above normal, the kidneys excrete increased quantities of fluid, and progressive loss of this fluid causes blood pressure to return toward normal. Conversely, when the blood pressure falls below normal, the kidneys retain fluid, and the pressure normalized. Neurohormonal and possibly other factors limit urine sodium excretion, thereby expanding extracellular fluid volume or requiring higher renal perfusion pressure to permit sodium excretion adequate to prevent extracellular volume expansion. When the kidney is injured by any cause, it leads to a physiological changes that are responsible for progressive hypertensive renal diseases . For example, patients with a strong family history of hypertension who undergo heminephrectomy for any reason become hypertensive .
The key factor is the regulation of renin. Excess of sodium intake decreases renin synthesis and secretion in the juxtaglomerular cells, and conversely, reduction of sodium intake increases renin synthesis and secretion. Blood volume and cardiac output are affected by the vasoconstrictor substance, Ang II, which is derived from angiotensin I (Ang I) by the action of angiotensin-converting enzyme (ACE); this occurs mainly in the lungs where circulating
Ang I is converted to the active, 8-amino-acid Ang II. Ang II is one the most potent renal vasoconstrictors, as well as a potent regulator of circulatory volume.
To delineate the role of kidney in the control mechanism of blood pressure, we describe three major mechanisms that are involved, namely, renal blood flow (RBF), sympathetic nerve system, and pressure-natriuresis control (illustrated in figure 1). Blood pressure regulation in the kidney involves the interplay of these factors.
RBF receives 25% of cardiac output and the normal kidney adjusts its vascular resistance so that the RBF is kept nearly constant over a wide range of perfusion pressures. This ability is maintained in hypertensive animals, although the RBF autoregulation is adjusted to higher perfusion pressure levels. In hypertension, as well as in congestive heart failure, the RBF is kept constant by an autoregulatory mechanism in spite of a reduction in cardiac output, thus maintaining adequate levels of glomerular filtration rate (GFR). There are two components to the autoregulation of RBF, the myogenic response of the afferent arteriole and the tubuloglomerular feedback by the juxtaglomerular apparatus (JGA).
Given the powerful influence of changes in renal hemodynamics (i.e., blood pressure, GFR and RBF) on urinary sodium excretion, it is evident that the influence of changes in renal sympathetic nerve activity (RSNA) on urinary excretion of sodium remains constant. By using electrical stimulation of the efferent renal sympathetic nerves at threshold frequencies that result in a decreases in RBF, a reversible decrease in urinary sodium excretion occurred in the absence of changes in GFR, RBF and blood pressure, indicating that low-frequency renal sympathetic nerve stimulation increased overall renal tubular sodium reabsorption via a direct action on the renal tubule, independent of changes in renal hemodynamics. In a series of studies, it was found that the effects of RSNA on renin secretion from the JGA were graded with respect to the intensity of the RSNA that interacted with other mechanisms of renin secretion, i.e., the renal arterial baroreceptors through the effects of RBF and the renal tubular macular densa receptors through the amounts of urinary sodium excretion .
Pressure natriuresis refers to the effect of increased arterial pressure that leads to an increase renal sodium excretion, an effect that becomes especially powerful with long-term changes in blood pressure. The mechanisms of pressure natriuresis continue to operate until blood pressure returns to the initial set point, which is determined by multiple factors that influence renal excretory ability. When the RAS is fully functional, the long-term relation between arterial pressure and sodium excretion is extremely steep, so that minimal changes in blood pressure are needed to maintain sodium balance over a wide range of sodium intakes. Conversely, changes in activity of the RAS have a major influence on renal-pressure natriuresis, and the inability to adjust the activity of this system appropriately makes pressure natriuresis less effective .
As noted above, all mechanisms closely relate with the RAS. With these under consideration, we would like to view the JGA as the center of regulation of blood pressure in the kidney and/or the human body (illustrated in figure 2). Renin is secreted from the JGA via the macula densa. As physical stimulants, both pressure and flow mediate renin synthesis and secretion . As chemical factors, inorganic and organic compounds stimulate renin synthesis and secretion. For example, Cl ion (inorganic stimulants) is shown to be a mediator of renin secretion. Moreover, as a biophysical stimulant, the role of renal sympathetic nervous stimulation might be important for regulation of renin secretion.
Kurokawa  noted in his review that Cl ions are essential for regulation of JGA and/or TGF. He introduced the studies by Holstein-Rathlou  who, using a Cl ion-sensitive microelectrode, revealed the presence of fairly regular oscillations at about 20 cycles/s in the distal tubular fluid Cl ion just beyond the macula densa, and of the proximal intratubular pressure, a reflection of single nephron GFR.
Chloride ions play an important role in the regulation of JGA as does the relationship between RSNA and JGA. The quantitative relationships are (1) substantial stimulation of JGA and antinatriuresis can occur with levels of RSNA that do not affect GFR and renal vascular resistance and (2) levels of RSNA that decrease RBF and GFR will stimulate JGA and produce antinatriuresis.
These regulator mechanisms of JGA prompted the examination of pathophysiological conditions in which it had been long suspected that increased RSNA and RBF played an important role in antinatriuresis and/or influenced the function of the JGA. These regulatory mechanisms are normally autoregulated under the control of neuro- and hormonal factors, such as Ang II, norepinephrine, vasopressin, etc. Among these factors, the RAS is the most important system for renal regulatory mechanisms of blood pressure. A growing body of evidence suggests that Ang II is involved in regulation of RBF, RSNA, pressure natriuresis and intraglomerular pressure feedback system, etc. These effects involve conversion of angiotensinogen (substrate) to Ang I by renin (enzyme) and subsequent conversion of Ang I to Ang II by ACE. Hypertension and congestive heart failure are important examples where this system plays a role. In focusing on these processes, our group has been investigating the complex pathophysiological processes. In this article, we have reviewed mainly the work from our group; however, we acknowledge and recognize that many investigators in this field have made important contributions to understanding the mechanism of blood pressure regulation by the kidney.
Although there are many factors involved in the etiology of hypertension [8-15], the important role of the kidney in regulation of volume and vascular resistance makes it a prime suspect as a mediator of hypertension. Neurohumoral and possible other factors limit urinary sodium excretion, thereby expanding extracellular fluid volume or requiring higher renal perfusion pressure to permit adequate sodium excretion to prevent extracellular fluid volume expansion. Early studies of Bianchi et al.  and more definite well-controlled experimental studies of Rettig et al.  showed that 'blood pressure goes with the kidney'. Transplantation of the kidney from a genetically hypertension-prone donor rat, even when it had been kept normotensive from weaning by antihypertensive medications, caused progressive increase of blood pressure in a recipient animal, which was immunologically manipulated to prevent a rejection reaction. Also, human renal transplant studies showed that there is a genetic component associated with the renal factors that mediate hypertension. Thus, previously nor-motensive renal transplant recipients without a family history of hypertension, who receive a kidney from a donor with a family history of hypertension, develop hypertension more frequently and require more medication for blood pressure control compared to those patients who receive a kidney from a donor without a family history of hypertension . To investigate more precise mechanisms of hypertension and the effects of antihypertensive medications on the regulatory factors such as RSNA, RBF, and pressure natriuresis, animal models of hypertension have been used.
Spontaneously Hypertensive Rats (SHR)
Various pathophysiological aspects of hypertension have been investigated using the SHR model.
The pressure-natriuresis mechanism is known to be impaired in SHR, and some studies have suggested an inadequate adaptation of the RAS to salt loading; however, no decisive evidence has been presented until recently. Takenaka et al.  compared the pressure-natriuresis response curves of SHR and Wistar-Kyoto (WKY) rats. The pressure-natriuresis relationship curve in SHR was shifted toward higher pressure in comparison to WKY rats. The inhibition of intrarenal RAS by MK-422 (ACE inhibitor) in SHR resulted in the excretion of more sodium at a given pressure, whereas no significant changes were observed in WKY rats which showed significant changes in blood pressure, indicating that intrarenal RAS might be important for pressure-natriuresis mechanisms in SHR. Moreover, in SHR, administration of a kinin antagonist did not affect the recovered pressure-natriuresis relationship during intrarenal RAS inhibition with an ACE inhibitor. Similarly, administration of an angiotensin antagonist produced an increased sodium excretion accompanied by an increase in renal plasma flow. Conversely, administration of Ang I to WKY rats produced anti-natriuretic effects without any significant changes in renal hemodynamics. Following this work, Ikenaga et al.  clarified the role of nitric oxide (NO) in pressure natriureis in SHR. NO is well known as an important modulator of blood pressure and renal function [21-23]. They demonstrated that inhibition of NO synthesis using L-NG-monomethyl-L-arginine (L-NMMA) markedly lowered the slope of the pressure-natriuresis curve of WKY, while L-arginine administration improved that of SHR. These effects on the pressure-natriuresis response are considered to be mediated by NO, because they were effectively reversed by the concomitant infusion of L-NMMA and L-arginine. In all cases, there were no changes in the GFR, indicating that there was no filtered sodium load on the glomeruli. It has been suggested that suppression of tubular sodium reabsorption due to interstitial hydrostatic pressure elevation is essential to the mechanism of pressure-natriuresis response, and that papillary hemodynamics play a critical role in the regulation of the interstitial hydrostatic pressure. These findings prompt us to propose the hypothesis that NO participates in the pressure-natriuresis response through regulation of intrarenal blood flow distribution. Moreover, the deficiency in NO system might be one of the responsible factors for the impaired pressure natriuresis in SHR. Based on their studies, it was proposed that deficiency in NO and activation of the RAS system produced impaired pressure natriuresis in living animals as well as humans. From these studies, it is clear that NO plays an important role in regulation of blood pressure in the kidney. Kumagai et al.  examined the role of NO in relation to RBF and the sympathetic nervous system using conscious rabbits. In renal innervated rabbits, L-arginine increased RBF and decreased RSNA. In contrast, no changes occurred in any variable during D-arginine infusion. L-NMMA attenuated the RBF and RSNA responses to L-arginine. In renal denervated rabbits, L-NMMA also attenuated the RBF response to L-arginine and abolished these responses but not in those of renal innervated rabbits. These findings indicate that exogenous L-arginine elicits a reduction in RSNA and that the reduction in RSNA could contribute to the increase in RBF as well as other mechanisms such as a direct vasodilator action of NO on vascular smooth muscle tone. In parallel with these studies, Jimbo et al.  examined a possible role of NO in modulating sympathetic nerve activity through its action on baroreceptor reflex arc. L-Arginine infusion decreased blood pressure, aortic, cervical, and renal nerve activity without significant changes in heart rate. I-NMMA infusion increased blood pressure and aortic nerve activity and decreased heart rate, while it tended to increase cervical and renal nerve activity which was not statistically significant. From these results, it may be inferred that NO modulates efferent sympathetic nerve activity, not by altering the afferent or efferent limbs of the baroreceptor reflex arc, but by interacting with the sympathetic pathways in the central nervous system. Moreover, considering Ikenaga's study, it is suggested that the renal circulation is especially sensitive to NO formation.
We also examined the effects of antihypertensive drugs on baroreceptor reflexes in SHR. Evidence from other studies suggests that an arterial barore-ceptor reflex mechanism modifies regional blood flow and that the effectiveness of the baroreceptor reflex mechanisms would be very limited if the resetting process is not reversible. Restoration of baroreceptor reflex function (i.e. normalization of reflex sensitivity and reversibility of baroreceptor resetting) is important in preserving internal organ function since it may alleviate the risk of decreasing regional blood flow. Kumagai et al. [26, 27] reported two remarkable findings. First, that a possible critical phase sensitive to intervention with antihypertensive treatment exists during the development of hypertension. Secondly, as expected, the effects of four different class of antihypertensive agents, namely, a diuretic, an ACE inhibitor, a ^-blocker, and a calcium antagonist on baroreceptor reflex, calculated by using the relation between RSNA and mean blood pressure, were similar when these drugs were used early in the treatment of hypertension. In this experiment, attenuation of the development of hypertension is responsible for the restoration of impaired baroreceptor reflex control of RSNA and heart rate. In contrast to these findings, the late start of treatment with calcium antagonist or ACE inhibitor, but not a diuretic agent or (3-blocker, moderately improved the RSNA gain, whereas only the calcium antagonist slightly improved the heart rate gain. In addition, none of the four agents with a late start of treatment improved the range of reflex sympathetic excitation. These studies clearly demonstrated that in SHR modulation of barore-ceptor reflex depends on blood pressure control, if cardiovascular remodeling and vessel distensibility were not fully developed.
In parallel with the findings of Kumagai et al. [26, 27], Ichikawa et al. [28,29] found that the responses of the afferent part of the baroreceptor to antihypertensive treatment were also impaired in SHR. In untreated SHR, the correlation curve of arterial pressure and aortic nerve activity was shifted to the right, that is, to a higher pressure level, and the maximum gain was depressed compared with untreated WKY rats. An equivalent decrease in arterial pressure with the four different antihypertensive drugs produced a leftward shift of the arterial pressure-aortic nerve activity correlation curve to a similar extent in SHR. From these findings it can be inferred that antihypertensive treatment with the four different classes of agents equally enhances the arterial barore-ceptor function through blood pressure reduction but not through specific depressor mechanisms at the early stage of hypertension. Ichikawa et al.  also examined the effects of long-term treatment with the four different classes of antihypertensive drugs on aortic baroreceptor activity in SHR with chronic hypertension. They found that (1) the four drugs induced baroreceptor resetting to a lower pressure level and that (2) baroreceptor sensitivity is augmented more by the calcium antagonist or the ACE inhibitor than by the diuretic agent or the (3-blocker. These findings might be explained as follows: chronic hypertension induces changes in the aortic medial layers (such as smooth muscle hypertrophy and increased collagen content) that affect baroreceptor sensitivity through changes in vessel distensibility and/or mechanical coupling of the baroreceptors to the vessel. Calcium blockers and ACE inhibitors have been shown to prevent these medial changes to a greater extent than diuretics and (3-blockers, probably by acting directly on vascular smooth muscle. These beneficial effects on the aortic media may contribute to the preserved baroreceptor sensitivity.
In Dahl salt-sensitive (DS) rats, elevation of blood pressure has been shown to result from salt loading and renal transplantation from DS rats to Dahl salt-resistant (DR) rats is able to elevate the recipient's blood pressure. In DS rats, the pressure-natriuresis relationship is blunted compared to that of DR rats. These findings implicated an intrinsic defect in the kidney of DS rats.
Takenaka et al.  examined the role of prostaglandins on pressure natri-uresis in DS rats. When DS rats are untreated, the pressure-natriuresis curve is blunted and secretion of prostaglandin E2 is decreased in comparison to the DR rats. Treatment with indomethacin blunted the pressure-natriuresis curve in the DR rats, while no significant changes were observed in the DS rats. This study suggested that a decrease in renal prostaglandins plays some role in blunting of pressure natriuresis in DS rats.
Increased sodium reabsorption by the kidney has been suggested to be a factor in this. Tominaga et al.  reported that decreases in sex hormones and increases in sodium sensitivity are important factors in the genesis of post-menopausal hypertension. Otsuka and Sasaki [33-35] investigated the effect of ovariectomy on pressure natriuresis in DS rats. The impaired pressure-natriuresis response of DS rats was further blunted by ovariectomy and that of DR rats was not. The ovariectomized DS rats developed hypertension by salt loading earlier than sham-operated DS rats. This study indicated that ovariectomy enhances genetic salt sensitivity by blunting the pressure-natriuresis response, which precedes the development of overt hypertension in female DS rats.
Since an animal model of renal hypertension was first produced by Goldblatt, renal hypertensive animal models have been used for investigation mainly focused on pathophysiological role of the RAS . Nakamoto et al.  examined the effects of long-term oral administration of either L-arginine or the NO synthesis inhibitor, N-nitro-L-arginine on systemic and renal hemodynam-ics in dogs with chronic two-kidney, one-clip renovascular hypertension. Their study demonstrated that chronic inhibition of NO synthesis exacerbated reno-vascular hypertension in dogs. Furthermore, suppression of NO was associated with blunted activation of the circulating RAS during the evolution of renovascular hypertension. The ischemic kidney showed a greater depression of RBF and GFR in the presence of NO inhibition. This was associated with a significant reduction in RBF but not in GFR of the contralateral untouched kidney. In contrast, oral administration of L-arginine did not modify the magnitude of the hypertension produced by renal artery constriction, but it did have a beneficial effect on the residual function of the ischemic kidney. These findings led to the conclusion that NO provides a basic vasodilator tone that limits vasoconstrictor activity of the RAS during the evolution of renovascular hypertension. Again, the findings indicate that the balance between NO production and the activation of the RAS is critical for regulation and evolution of hypertension.
In clinical practice, there is still controversial whether calcium antagonists or ACE inhibitors are superior to protect end-organ damage due to hypertension. A number of studies examining the effects of these drugs on systemic and renal hemodynamics have been presented. However, very few studies comparing the effects of these two classes of hypertensive drugs on RSNA in hypertensive animals have been conducted. Kumagai et al. [38, 39] examined the different effects of an ACE inhibitor and a calcium antagonist on RBF and RSNA using two-kidney, one-clip renal hypertension in rabbits. First, the baroreflex control of RSNA and heart rate (HR) before and after reduction of blood pressure (BP) was similar in magnitude with an ACE inhibitor and a calcium antagonist. The maximum slopes of the curves relating BP to RSNA and HR in renovascular hypertension were significantly smaller than those in normotensive animals. In renovascular hypertensive animals, the maximum slope of BP-RSNA response curve was increased with ACE inhibitor compared with vehicle. In contrast, the maximum slope of BP-HR response curve was increased with the calcium antagonist compared with vehicle. These data indicate that in renovascular hypertension, the baroreflex control of RSNA and HR are differently regulated with different classes of antihypertensive drugs. Further study revealed that these two drugs induced different RBF and RSNA responses. RBF increased consistently in response to BP reduction with an ACE inhibitor. The increment was associated with a decrease in plasma concentration of Ang II. In contrast, RBF decreased significantly after BP reduction with a calcium antagonist. The calcium antagonist increased the plasma concentration of Ang II and induced a smaller increase in RSNA than that induced with the ACE inhibitor. This study suggested that the more complex regulatory mechanisms of RBF and RSNA under the conditions of elevated BP due to endogenous Ang II.
Deoxycorticosterone Acetate (DOCA) Salt Hypertension
This model is known as a low-renin hypertension model [40-42]. In spite of many investigations , no precise role for ACE inhibitors and Ang II blockers has been implicated in this model. Using conscious DOCA salt dogs Naitoh et al.  demonstrated that the ACE inhibitors (captopril and imidapri-lat) produced significant reductions in blood pressure and significant increases in RBF, GFR, and urinary excretion of sodium, while an ATI receptor antagonist (losartan) caused significant increases only in urinary excretion of sodium without significant changes in blood pressure, RBF, and GFR. These investigators performed simultaneous infusion of a bradykinin receptor antagonist and found that it inhibited the ACE inhibitor induced reduction in blood pressure and increases in RBF. The results of their studies showed that in low-renin hypertension, inhibition of Ang II production in the kidney participates in the natriuretic action of ACE inhibitors. However, hypotensive and other renal effects are mainly due to the action of bradykinin. These results suggest that in the kidneys, the effects of ACE inhibitors and Ang II antagonists might be different.
Besides the hypertensive animal models such as SHR, Dahl rats, renovas-cular hypertension, etc., that have been studied extensively, another model namely neurogenic hypertension has been less investigated. Matsukawa et al.  attempted to elucidate the interaction between the SNS and the RAS in neurogenic hypertension produced by sinoaortic-denervated and norepinephrine-infused conscious, unrestrained rabbits. They found that in sympathetic-activated animals postsynaptic interaction between norepinephrine and Ang II is important in regulation of blood pressure.
Ryuzaki et al. [46, 47], using sinoaortic-denervated rabbits, provided convincing evidence for association between neurogenic hypertension and the kidney. They demonstrated that renal nerve stimulation contributed to neurogenic hypertension through a combination of elevation of plasma vasopressin as a result of sinoaortic denervation and renal afferent nerve stimulation.
Both clinical  and experimental [49-54] studies clearly demonstrated that glucocorticoid excess produces elevation of blood pressure; however, precise renal as well as cardiac hemodynamics had not been clarified until Nakamoto's study [55, 56]. He found that administration of a low dose of glu-cocorticoid did not produce hypertension, while large doses induced elevation of blood pressure with reduction of cardiac output and markedly increased the total peripheral resistance. Moreover, he demonstrated that depressor system such as prostaglandins and bradykinins played an important role in regulation of blood pressure in this model . From these studies it is suggested that renal mechanisms are at least in part involved in pathogenesis and regulation of blood pressure elevation in glucocorticoid excess hypertension.
Recent clinical and experimental studies have demonstrated that the blockade of the RAS produced an improvement of symptoms and survival rate of patients with congestive heart failure. We examined the role of vasopressin in congestive heart failure induced by rapid right ventricular pacing in dogs. In the dogs with impaired cardiac function, effective RBF and GFR were decreased mainly due to reduction of cardiac output. In these dogs, plasma renin activity, norepinephrine and vasopressin were all elevated. Murakami et al.  provided interesting data by studying the dogs with impaired cardiac function. They compared the acute effects of an ACE inhibitor and an angiotensin type 1 receptor antagonist on cardiac output and RBF. Interestingly, these two types of drugs showed distinct effects; captopril increased both cardiac output and RBF, however, losartan increased RBF but failed to alter cardiac output. Furthermore, Matsumoto et al.  found a synergistic action with an ACE inhibitor and a neuroendopeptidase inhibitor which together produced an improvement of cardiac output and RBF in dogs with congestive heart failure. The findings of these studies indicated that in congestive heart failure regulation of cardiac output and RBF is mutually dependent. Naitoh et al.  clearly showed that when the heart is failing, vasopressin plays an important role with respect to hemody-namics as well as renal circulation. Combined administration of vasopressin-1 and -2 antagonists produced a marked improvement in cardiac output (+30%) and renal plasma flow (+50%). Moreover, in dogs with impaired renal function and reduced GFR (—15% compared to the normal), vasopressin antagonist improved the GFR by 35%. In addition, Okada et al. [61-64] have provided evidence for the crucial role of vasopressin in hypertensive animals.
The relationship between obesity and hypertension is now widely recognized. Experimental studies have shown that weight gain raises blood pressure and clinical studies showed that weight loss is effective in lowering blood pressure in most hypertensive patients. In obesity, a close relationship has been proposed to exist between impaired natriuresis and increased RSNA and hypertension; however, there have been few studies directly addressing this relationship. Suzuki et al. [65, 66], using a genetically obese rat, Wistar fatty rat, found that in spite of no apparent impairment of baroreceptor reflex, RSNA was increased. In addition, without salt loading, blood pressure was not elevated even though pressure natriuresis was dysregulated. Taken together, obesity-induced hypertension might be intimately related to salt loading which stimulates RSNA and produces volume in impaired pressure natriuresis.
The syndrome of hypertension is intimately related to kidney function, and there is good evidence that each can manifest effects in the other. Our current studies are likely to provide clues for understanding the pathophysiology of hypertension and heart failure relating to regulatory mechanisms of the kidneys.
1 Suzuki H: Treatment of hypertension in chronic renal insufficiency. Intern Med 2000;39:773-777.
2 Ohishi A, Suzuki H, Nakamoto H, et al: Status of patients who underwent uninephrectomy in adulthood more than 20 years ago. Am J Kidney Dis 1995;26:889-897.
3 DiBona GF: Neural control of the kidney: Past, present and future. Hypertension 2003;41:621-624.
4 Cowley AW Jr: Long-term control of arterial blood pressure. Physiol Rev 1992;72:231-300.
5 Ichihara A, Suzuki H, Miyashita Y, Naitoh M, Hayashi M, Saruta T: Transmural pressure inhibits prorenin processing in juxtaglomerular cell. Am J Physiol 1999;277:R220-R228.
6 Kurokawa K: Kidney, salt and hypertension: How and why. Kidney Int 1996;(suppl 55):46-51.
7 Holstein-Rathlou NH: Oscillation and chaos in renal blood flow control. Am J Physiol 1990;256: F1007-F1014.
8 Ohno Y, Matsuo K, Suzuki H, et al: Genetic linkage of the sarco(endo)plasmic reticulum Ca2+-dependent ATPase II gene to intracellular Ca2+ concentration in the spontaneously hypertensive rat. Biochem Biophys Res Commun 1996;227:789-973.
9 Ohno Y, Matsuo K, Suzuki H, Tanase H, Takano T, Saruta T: Increased intracellular Ca2+ is not coinherited with an inferred major gene locus for hypertension in the spontaneously hypertensive rat. Am J Hypertens 1997;10:282-288.
10 Ohno Y, Suzuki H, Matsuo K, Tanase H, Takano T, Saruta T: Augmented Ca2+ mobilization is a hypertensive trait discriminated from a 'major gene' in backcross analysis between SHR and Donryu rats. Clin Exp Pharmacol Physiol Suppl 1995;22:S220-S222.
11 Ohno Y, Suzuki H, Yamakawa H, Nakamura M, Kato Y, Saruta T: Correlation of sodium-related factors with insulin sensitivity in young, lean, male offspring of hypertensive and normotensive subjects. J Hum Hypertens 2001;15:393-399.
12 Ohno Y, Suzuki H, Yamakawa H, Nakamura M, Otsuka K, Saruta T: Impaired insulin sensitivity in young, lean normotensive offspring of essential hypertensives: Possible role of disturbed calcium metabolism. J Hypertens 1993;11:421-426.
13 Ohno Y, Suzuki H, Yamakawa H, Nakamura M, Saruta T: Insulin sensitivity and calcium homeo-stasis in young, lean, normotensive male subjects. Hypertens Res 2000;23:433-440.
14 Yamakawa H, Suzuki H, Nakamura M, Ohno Y, Saruta T: Role of platelet cytosolic calcium in the response to salt intake in normotensive subjects. Clin Exp Pharmacol Physiol 1991;18:627-629.
15 Yamakawa H, Suzuki H, Nakamura M, Ohno Y, Saruta T: Disturbed calcium metabolism in offspring of hypertensive parents. Hypertension 1992;19:528-534.
16 Bianchi G, Fox U, Di Francesco GF, Giovannetti AM, Pagetti D: Blood pressure changes produced by kidney cross-transplantation between spontaneously hypertensive and normotensive rats. Clin Sci Mol Med 1974;47:435-448.
17 Rettig R, Folberth C, Strauss H, Kopf D, Waldherr R, Unger T: Hypertension transmitted by kidneys from stroke-prone spontaneously hypertensive rats. Am J Physiol 1989;257:F197-F203.
18 Manunta P, Cerutti R, Bernardi L, Stella P, Bianchi G: Renal genetic mechanisms of essential hypertension. J Nephrol 1997;10:172-178.
19 Takenaka T, Suzuki H, Furukawa T, Ogata Y, Saruta T: Role of intrarenal renin-angiotensin system on pressure natriuresis in spontaneously hypertensive rats. Clin Exp Hypertens A 1990;12:1377-1394.
20 Ikenaga H, Suzuki H, Ishii N, Itoh H, Saruta T: Role of NO on pressure natriuresis in Wistar-Kyoto and spontaneously hypertensive rats. Kidney Int 1993;43:205-211.
21 Hishikawa K, Nakaki T, Suzuki H, Saruta T, Kato R: L-Arginine-induced hypotension. Lancet 1991;337:683-684.
22 Murakami M, Suzuki H, Ichihara A, Naitoh M, Nakamoto H, Saruta T: Effects of L-arginine on systemic and renal haemodynamics in conscious dogs. Clin Sci (Lond) 1991;81:727-732.
23 Hishikawa K, Nakaki T, Tsuda M, et al: Effect of systemic L-arginine administration on hemodynamics and nitric oxide release in man. Jpn Heart J 1992;33:41-48.
24 Kumagai K, Suzuki H, Ichikawa M, et al: Nitric oxide increases renal blood flow by interacting with the sympathetic nervous system. Hypertension 1994;24:220-226.
25 Jimbo M, Suzuki H, Ichikawa M, Kumagai K, Nishizawa M, Saruta T: Role of nitric oxide in regulation of baroreceptor reflex. J Auton Nerv Syst 1994;50:209-219.
26 Kumagai K, Suzuki H, Ryuzaki M, et al: Effects of antihypertensive agents on arterial baroreceptor reflexes in conscious rats. Hypertension 1992;20:701-709.
27 Kumagai K, Suzuki H, Ichikawa M, et al: Comparison of early and late start of antihypertensive agents and baroreceptor reflexes. Hypertension 1996;27:209-218.
28 Ichikawa M, Suzuki H, Kumagai K, et al: Effects of antihypertensive agents on baroreceptor function in early hypertensive rats. Hypertension 1994;24:808-815.
29 Ichikawa M, Suzuki H, Kumagai K, et al: Baroreceptor function is restored by antihypertensive therapy through lowering of blood pressure in adult SHR. Clin Exp Pharmacol Physiol Suppl 1995;22:S67-S69.
30 Ichikawa M, Suzuki H, Kumagai K, et al: Differential modulation of baroreceptor sensitivity by long-term antihypertensive treatment. Hypertension 1995;26:425-431.
31 Takenaka T, Suzuki H, Sakamaki Y, Itaya Y, Saruta T: Contribution of prostaglandins to pressure natriuresis in Dahl salt-sensitive rats. Am J Hypertens 1991;4:489-493.
32 Tominaga T, Suzuki H, Ogata Y, Matsukawa S, Saruta T: The role of sex hormones and sodium intake in postmenopausal hypertension. J Hum Hypertens 1991;5:495-500.
33 Otsuka K, Suzuki H, Sasaki T, Ishii N, Itoh H, Saruta T: Blunted pressure natriuresis in ovariec-tomized Dahl-Iwai salt-sensitive rats. Hypertension 1996;27:119-124.
34 Otsuka K, Ohno Y, Sasaki T, et al: Ovariectomy aggravated sodium induced hypertension associated with altered platelet intracellular Ca2+ in Dahl rats. Am J Hypertens 1997;10:1396-1403.
35 Sasaki T, Ohno Y, Otsuka K, Suzawa T, Suzuki H, Saruta T: Oestrogen attenuates the increases in blood pressure and platelet aggregation in ovariectomized and salt-loaded Dahl salt-sensitive rats. J Hypertens 2000;18:911-917.
36 Suzuki H, Ferrario CM, Speth RC, Brosnihan KB, Smeby RR, de Silva P: Alterations in plasma and cerebrospinal fluid norepinephrine and angiotensin II during the development of renal hypertension in conscious dogs. Hypertension 1983;5(suppl I):139-148.
37 Nakamoto H, Ferrario CM, Buckalew VM, Suzuki H: Role of nitric oxide in the evolution of renal ischemia in two-kidney, one-clip renovascular hypertension. Hypertens Res 1998;21:267-277.
38 Kumagai H, Suzuki H, Matsumura Y, Ryuzaki M, Saruta T: Differential effects of captopril and nicardipine on baroreflex control of sympathetic nerve activity and heart rate in renal hypertension. J Hypertens 1992;10:1485-1491.
39 Kumagai H, Suzuki H, Ichikawa M, et al: Different responses of renal blood flow and sympathetic nerve activity to captopril and nicardipine in conscious renal hypertensive rabbits. J Cardiovasc Pharmacol 1995;25:57-64.
40 Saruta T, Suzuki H, Takita T, Saito I, Murai M, Tazaki H: Pre-operative evaluation of the prognosis of hypertension in primary aldosteronism owing to adenoma. Acta Endocrinol (Copenh) 1987;116: 229-234.
41 Shibata H, Suzuki H, Murakami M, Sato A, Saruta T: Angiotensin II type 1 receptor messenger RNA levels in human blood cells of patients with primary and secondary hypertension: Reference to renin profile. J Hypertens 1994;12:1275-1284.
42 Suzuki H: Pathophysiology and diagnosis of primary aldosteronism. Biomed Pharmacother 2000; 54(suppl 1):118-123.
43 Itaya Y, Suzuki H, Matsukawa S, Kondo K, Saruta T: Central renin-angiotensin system and the pathogenesis of DOCA-salt hypertension in rats. Am J Physiol 1986;251:H261-H268.
44 Naitoh M, Suzuki H, Arakawa K, et al: Role of kinin and renal ANG II blockade in acute effects of ACE inhibitors in low-renin hypertension. Am J Physiol 1997;272:H679-H687.
45 Matsukawa S, Suzuki H, Kumagai H, Itaya Y, Saruta T: Interaction between the sympathetic nervous system and the renin-angiotensin system in neurogenic hypertension in conscious rabbits. J Hypertens 1996;4(suppl 6):290-296.
46 Ryuzaki M, Suzuki H, Kumagai K, et al: Role of vasopressin in salt-induced hypertension in baroreceptor-denervated uninephrectomized rabbits. Hypertension 1991;17:1085-1091.
47 Ryuzaki M, Suzuki H, Kumagai K, et al: Renal nerves contribute to salt-induced hypertension in sinoaortic-denervated uninephrectomized rabbits. Am J Physiol 1992;262:R733-R737.
48 Saruta T, Suzuki H, Handa M, Igarashi Y, Kondo K, Senba S: Multiple factors contribute to the pathogenesis of hypertension in Cushing's syndrome. J Clin Endocrinol Metab 1986;62:275-279.
49 Okuno T, Suzuki H, Saruta T: Dexamethasone hypertension in rats. Clin Exp Hypertens 1981;3: 1075-1086.
50 Suzuki H, Handa M, Kondo K, Saruta T: Role of renin-angiotensin system in glucocorticoid hypertension in rats. Am J Physiol 1982;243:E48-E51.
51 Handa M, Kondo K, Suzuki H, Saruta T: Urinary prostaglandin E2 and kallikrein excretion in glucocorticoid hypertension in rats. Clin Sci (Lond) 1983;65:37-42.
52 Handa M, Kondo K, Suzuki H, Saruta T: Dexamethasone hypertension in rats: Role of prostaglandins and pressor sensitivity to norepinephrine. Hypertension 1984;6:236-241.
53 Kageyama Y, Suzuki H, Saruta T: Role of glucocorticoid in the development of glycyrrhizin-induced hypertension. Clin Exp Hypertens 1994;16:761-778.
54 Sato A, Suzuki H, Murakami M, Nakazato Y, Iwaita Y, Saruta T: Glucocorticoid increases angiotensin II type 1 receptor and its gene expression. Hypertension 1994;23:25-30.
55 Nakamoto H, Suzuki H, Kageyama Y, et al: Characterization of alterations of hemodynamics and neuroendocrine hormones in dexamethasone-induced hypertension in dogs. Clin Exp Hypertens A 1991;13:587-606.
56 Nakamoto H, Suzuki H, Kageyama Y, Murakami M, Naitoh M, Saruta T: Central nervous system mediates an antihypertensive property in glucocorticoid hypertension in dogs. J Hypertens 1995; 13:1169-1179.
57 Nakamoto H, Suzuki H, Kageyama Y, et al: Depressor systems contribute to hypertension induced by glucocorticoid excess in dogs. J Hypertens 1992;10:561-569.
58 Murakami M, Suzuki H, Naitoh M, et al: Blockade of the renin-angiotensin system in heart failure in conscious dogs. J Hypertens 1995;13:1405-1412.
59 Matsumoto A, Suzuki H, Naitoh M, Murakami M, Nakamoto H, Saruta T: Effects of neutral endopeptidase combined with ACE inhibitor on cardio-renal hemodynamics in heart failure with chronic renal failure in dogs (abstract). Annual Meeting of American Society of Nephrology, 1994.
60 Naitoh M, Suzuki H, Murakami M, et al: Effects of oral AVP receptor antagonists OPC-21268 and OPC-31260 on congestive heart failure in conscious dogs. Am J Physiol 1994;267:H2245-H2254.
61 Okada H, Suzuki H, Kanno Y, Saruta T: Effects of novel, nonpeptide vasopressin antagonists on progressive nephrosclerosis in rats. J Cardiovasc Pharmacol 1995;25:847-852.
62 Okada H, Suzuki H, Kanno Y, Saruta T: Evidence for the involvement of vasopressin in the pathophysiology of adriamycin-induced nephropathy in rats. Nephron 1996;72:667-672.
63 Okada H, Suzuki H, Kanno Y, Yamamura Y, Saruta T: Chronic and selective vasopressin blockade in spontaneously hypertensive rats. Am J Physiol 1994;267:R1467-R1471.
64 Okada H, Suzuki H, Kanno Y, Yamamura Y, Saruta T: Effects of vasopressin V1 and V2 receptor antagonists on progressive renal failure in rats. Clin Sci (Lond) 1994;86:399-404.
65 Suzuki H, Ikenaga H, Hayashida T, et al: Sodium balance and hypertension in obese and fatty rats. Kidney Int Suppl 1996;55:S150-S153.
66 Suzuki H, Nishizawa M, Ichikawa M, et al: Basal sympathetic nerve activity is enhanced with augmentation of baroreceptor reflex in Wistar fatty rats: A model of obesity-induced NIDDM. J Hypertens 1999;17:959-964.
Hiromichi Suzuki, MD
Department of Nephrology and Kidney Disease Center, Saitama Medical School Moroyama-machi, Iruma-gun, Saitama 350-0495 (Japan)
Tel. +81 492 761611, Fax +81 492 957338, E-Mail [email protected]
Suzuki H, Saruta T (eds): Kidney and Blood Pressure Regulation. Contrib Nephrol. Basel, Karger, 2004, vol 143, pp 16-31
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