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Hypoxic Pulmonary VasoconstrictionDecember 2003CitationBonnet S, Dumas-de-La-Roque E, Begueret H, Marthan R, Fayon M, Dos Santos P, Savineau JP, Baulieu EE. Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension. PNAS. 2003 Aug; 100(16):9488-93.Linkwww.pnas.org/cgi/doi/10.1073/pnas.1633724100BackgroundHypoxic pulmonary vasoconstriction (HPV) is an adaptive mechanism unique to the pulmonary circulation that allows redirection of blood flow to alveoli with higher oxygen tension, thereby reducing ventilation/perfusion mismatch. Under prolonged hypoxia, this mechanism plays an important role in the development of chronic hypoxic pulmonary hypertension (CH-PHT). The increased vascular tone in HPV is a due to a shift in balance between vasoconstrictor molecules (e.g., endothelin-1, thromboxane) and vasodilators (e.g., NO, prostacyclin) and is primarily determined by the contractile state of the pulmonary artery smooth muscle cells (PASMC). The contractile status of PASMC is dependent on the concentration of intracellular calcium, which in turn, is partly regulated through L-type, voltage dependent Ca2+ channels. During chronic hypoxia, several potassium channels including large conductance Ca2+-activated channels (BKCa) and voltage-gated K+ channels (KV) are down-regulated thereby reducing the potassium current inflow and depolarizing the PASMC. This depolarized state opens the L-type, voltage dependent Ca2+channels, raising intracellular calcium and promoting PASMC contraction. The mechanism by which potassium channels are down-regulated during CH-PHT is not entirely known but may be closely related to the reduced redox state caused by hypoxia.HypothesisThe authors test the hypothesis that administering DHEA, a known BKCa channel opener, will shift the redox balance to an oxidized state leading to potassium channel (BKCa and KV) activation and repolarization of PASMC membrane potential. Repolarization prompts a decrease in intracellular calcium concentration with subsequent relaxation of smooth muscle cells and resolution of CH-PHT.MethodsAdult male rats were randomized into five groups: 1. Normoxia (1 atm), no DHEA given. 2. Normoxia, DHEA (30 mg/kg po every other day). 3. Hypoxia (0.5 atm pressure) for 3 weeks, no DHEA. 4. Hypoxia and DHEA for 3 weeks. 5. Hypoxia for 3 weeks, DHEA administered during last week only. Hemodynamic measurements included pulmonary artery pressure using PA catheterization, systemic blood pressure monitoring, and right ventricular thickness and cardiac output calculation using echocardiography. Pulmonary vascular remodeling was assessed histologically by measuring the thickness of small and medium-sized pulmonary arteries. Intrapulmonary arteries were dissected to remove the intimal and adventitial layers; the medial layer was used to obtain rings for isometric contraction measurements and to isolate PASMC. Intracellular concentration of calcium in PASMC was measured fluorometrically using a calcium-sensitive fluorophore. Western blot analysis of pulmonary artery extracts was employed to compare the expression of BKCa under the various experimental conditions.ResultsThe most important results of this article can be summarized as follows:
DiscussionThis paper is one of two recent publications investigating the role of DHEA1, a naturally produced androgenic steroid, in hypoxic pulmonary hypertension. The authors show that oral administration of DHEA can prevent the development of pulmonary hypertension and right ventricular hypertrophy in chronically hypoxic rats; furthermore, DHEA treatment after establishment of pulmonary hypertension partially but significantly reversed this process. Additionally, intravenous administration of DHEA to chronically hypoxic rats significantly reduced pulmonary artery pressure in a dose-dependent manner. One measurement not reported in this study was the effect of DHEA on hematocrit. It is well known that HPV is closely dependent on RBC concentration2, and although the exact mechanism is still unclear, this potential confounder should be ruled out.The proposed mechanism of action of DHEA is through opening of large conductance potassium channels (BKCa) that allow PASMC to repolarize from their hypoxia-induced depolarized state. Repolarization promotes a decrease in intracellular calcium resulting in smooth muscle cell relaxation and resolution of pulmonary arterial hypertension. The authors confirm this mechanism by initially showing that DHEA reduces intracellular calcium in PASMC of chronically hypoxic rats, and subsequently determining that selective inhibition of BKCa significantly blocked this effect. However, complete abolition of the DHEA effect required additional inhibition of KV channels, suggesting that DHEA may affect both classes of potassium channels. Using a similar setup, the authors investigated several signaling pathways potentially involved in this process. Only DTT, a reducing agent, prevented DHEA from decreasing intracellular calcium in chronically hypoxic PASMC, implying a redox-dependent mechanism of action for DHEA. These in vitro studies provide evidence of DHEA’s interaction with potassium channels, but do not elucidate the mechanism of this interaction. Furthermore, DHEA probably has anti-proliferative properties in smooth muscle cells independent of its effects on ion channels3; this may partly explain its effect in reducing pulmonary vascular remodeling. Although DTT abolished DHEA’s ability to decrease intracellular calcium in hypoxic PASMC, no other objective method such as measuring glutathione levels, was employed to assess the redox state of the DTT-treated smooth muscle cells. Overall, the results of this article are very interesting for several reasons. DHEA’s role in hypoxic pulmonary vasoconstriction is elegantly studied in an animal model for the first time. Although many molecules have been implicated in HPV and hypoxic pulmonary hypertension, very few have proven useful from a therapeutic standpoint. DHEA is a promising candidate because it is produced endogenously by the adrenals and gonads, and can be safely tolerated at relatively high doses by humans. More importantly, DHEA has been studied extensively in randomized prospective clinical trials for endocrine, cognitive and other disorders, without significant side effects. The fact that administering DHEA after the development of pulmonary hypertension in rats significantly reversed this process may have significant implications for its usefulness in clinical practice. Another attractive feature of DHEA may be its low cost and generic availability (although this may also diminish the likelihood of pharmaceutical sponsorship of large clinical trials). However, before proceeding to human studies, the authors point to a need for important preliminary work. Above all, the effect of DHEA in preventing and reversing PASMC contraction and proliferation has not been confirmed in human PASMC yet. This has important implications because the circulating level of DHEA in rats is 3 to 4 orders of magnitude less than in humans (10-9 M vs. 10-5 to 10-6 M). Human pulmonary arteries may already be exposed to relatively high concentrations of DHEA and potentially be more resistant to its effect in reversing HPV and CH-PHT. References
Sina A. Gharib, M.D. | |||||||||||||||||||||||||||||
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