Polyamine Transport as a Target for Intervention in Hypoxic Pulmonary Hypertension

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...

Endotheliumderived Mediators and HPV

Pgf2a Pathway

Although there is strong evidence that the pulmonary vascular endothelium is important, possibly crucial, for development of sustained HPV, and that its action appears to be via an increase in vascular smooth muscle Ca2 sensitivity mediated via RhoA Rho kinase, the mediator responsible has not been identified Fig. 2D . Moreover, the pulmonary endothelium also has a powerful modulatory influence on pulmonary vasomotor tone and vascular resistance via the action of numerous other mediators, and...

References

Balasubramaniam V, Le Cras TD, Ivy DD, Grover T R, Kinsella JP, and Abman SH. Role of platelet derived growth factor in vascular remodeling during pulmonary hypertension in the ovine fetus. Am. J. Physiol. Lung Cell. Mol. Physiol. 2003 184 L826-L833. 2. Blumberg FC, Lorenz C, Wolf K, Sandner P, Riegger GA, and Pfeifer M. Increased pulmonary prostacyclin synthesis in rats with chronic hypoxic pulmonary hypertension. 3. Christou H, Yoshida A, Arthur V, Morita T, and Kourembanas S. Increased...

Microdomains and Organized Signaling in Regulating Kv Channel Function in PASMC

An emerging idea in signal transduction posits the existence of spatially organized complexes of signaling molecules in microdomains 62, 65 of the plasma membrane. Recent studies have focused on the distribution of signaling molecules in caveolae, which are cholesterol and sphingolipid-enriched regions that can form distinct structural invaginations of the plasma membrane and are enriched of the protein caveolin 97 . This notion of signaling microdomains is attractive in that it would account...

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...

The Role of Microcirculation in Hypoxic Pulmonary Hypertension

The role of the capillary blood vessels of the lung in HPH is to reduce the resistance to flow in pulmonary microcirculation. The reason that these vessels can do it is because of their geometry. When the pulmonary capillary blood vessels of cat were photographed on face, they appeared as shown in Figure 1 A. When these capillary vessels were photographed in cross section, they appear as shown in Figure IB. From these photographs one sees that the capillaries form sheets of blood space that are...

Role of Deficient NO and PGI2 in Hypoxic Pulmonary Hypertension

Endogenous NO, derived largely from eNOS, is a potent inhibitor of pulmonary vasoconstriction and HPH 15 . Although eNOS is moderately upregulated in hypoxic hypertensive lungs, and NO suppresses an increased endogenous ET-1-mediated pulmonary vasoconstriction 41, 46, 48 , hypoxic ventilation limits lung NO production 53 . Therefore, deficient production of NO likely plays a role in the development of HPH. Chronic inhaled NO inhibits HPH, and transgenic eNOS-overexpressing mice have increased...

Acute Hypoxia Induces Membrane Depolarization by Inhibiting Kv Channels

Pulmonary Artery Pressure Rats

In rat PASMC, acute hypoxia reduces K currents by inhibiting Kv channels Fig. 4Ca 5, 63, 82, 83, 117 . The inhibitory effect of hypoxia on Kv channels appears to be selective to PASMC hypoxia has little effect on Kv currents K V in mesenteric artery smooth muscle cells MASMC isolated from the same rat Fig. 4Cb . The inability of acute hypoxia to reduce K V in MASMC also explains why acute hypoxia has little effect on mesenteric vascular tone 120 . The acute hypoxia-mediated inhibition of Kv...

Complex I Nadh Ubiquinone Oxidoreductase

During oxidative phosphorylation, electrons pass through a series of membrane-bound multiprotein complexes that translocate protons across the membrane, resulting in a proton-motive force used by ATP synthase to make ATP 1 . It couples the transfer of two electrons from NADH to ubiquinone to the translocation of four protons across the inner mitochondrial membrane. Complex I is the first of these electron transfer complexes and accounts for up to 40 of the pumped protons 50 . In human...

Treatment of PPHN

Pre And Post Ductal Sats Pphn

In general, management of the newborn with PPHN includes the treatment and avoidance of hypothermia, hypoglycemia, hypocalcemia, anemia and hypovolemia correction of metabolic acidosis diagnostic studies for sepsis serial monitoring of arterial blood pressure, pulse oximetery pre- and post-ductal and transcutaneous PCo2, especially with the initiation of high frequency oscillatory ventilation HFOV . Therapy includes aggressive management of systemic hemodynamics with volume and cardiotonic...

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...

The Endothelium Ca2 and Ca2 Sensitization

Hpv Biphasic Response

Our studies in rat small pulmonary arteries have shown that the relationship between Ca2 and tension development during sustained HPV 2060 min is not straightforward. Whereas Ca2 j measured using Fura-2 simultaneously with tension shows an initial transient rise followed by a raised but stable plateau, after an initial transient constriction, tension continues to rise progressively without any further change in Ca2 Fig. 1 20, 26, 28 . Moreover, removal ofthe endothelium does not alter the...

Pathogenesis of PPHN

Pphn Pathophysiology

Several experimental models have been studied to explore the pathogenesis and pathophysiology of PPHN 21, 54 . Such models have included exposure to acute or chronic hypoxia after birth, chronic hypoxia in utero, placement of meconium into the airways ofneonatal animals, sepsis and others. Although each model demonstrates interesting physiologic changes that may be especially relevant to particular clinical settings, most studies examine only brief changes in the pulmonary circulation, and...

Clinical Presentation and Evaluation

Clinically, PPHN is most often recognized in term or near term neonates, but clearly can occur in premature neonates as well Table 1 . PPHN is often associated with perinatal distress e.g., asphyxia, low APGAR scores, meconium staining however, idiopathic PPHN can lack signs of acute perinatal distress. PPHN often presents as respiratory distress and cyanosis within 6-12 hrs of birth. Laboratory findings include low glucose, hypocalcemia, hypothermia, polycythemia or thrombocytopenia....

Hypertension And Ihd 2011

Adnot S, Raffestin B, Eddahibi S, Braquet P, and Chabrier P. Loss ofendothelium-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia. J. Clin. Invest. 1991 87 155-162 2. 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,...

Mitochondria Regulate Hypoxic Stabilization of Hypoxiainducible Factor1

Hydroxy Hif

Cells respond to hypoxia by activating a multitude of responses designed to prevent cells from reaching 0 oxygen. The best-characterized cellular response is the activation of the transcription factor HIF-1. HIF-1 is a dimeric transcription factor composed of HIF-1 a and HIF-1p subunits. HIF-1 is a transcriptional activator that is required for the upregulation expression of genes encoding for vascular endothelial growth factor, erythropoietin, glycolytic enzymes, and endothelin-1 in response...

Additional Heterogeneities

The flow diverting effectiveness ofHPV may depend not only on some of the factors indicated above, but also on the cause of the poor ventilation. For example, in pneumonia, both the host and pathogen mediated inflammatory response would be expected to affect local HPV and or its modulation 6, 41, 91 . In addition, the extent to which the arteries serving the region are mechanically influenced by the alteration in local lung mechanics responsible for the local hypoventilation may have an effect...