Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension.
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Journal: 2003/October - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
Abstract:
Pulmonary artery (PA) hypertension was studied in a chronic hypoxic-pulmonary hypertension model (7-21 days) in the rat. Increase in PA pressure (measured by catheterism), cardiac right ventricle hypertrophy (determined by echocardiography), and PA remodeling (evaluated by histology) were almost entirely prevented after oral dehydroepiandrosterone (DHEA) administration (30 mg/kg every alternate day). Furthermore, in hypertensive rats, oral administration, or intravascular injection (into the jugular vein) of DHEA rapidly decreased PA hypertension. In PA smooth muscle cells, DHEA reduced the level of intracellular calcium (measured by microspectrofluorimetry). The effect of DHEA appears to involve a large conductance Ca2+-activated potassium channel (BKCa)-dependent stimulatory mechanism, at both function and expression levels (isometric contraction and Western blot), via a redox-dependent pathway. Voltage-gated potassium (Kv) channels also may be involved because the antagonist 4-amino-pyridine blocked part of the DHEA effect. The possible pathophysiological and therapeutic significance of the results is discussed.
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Proc Natl Acad Sci U S A 100(16): 9488-9493
PMID: 12878719

Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension

Institut National de la Santé et de la Recherche Médicale, EMI 0356, Physiologie Cellulaire Respiratoire, Université de Bordeaux II, 146, Rue Léo Saignat, 33076 Bordeaux Cedex, France; Institut National de la Santé et de la Recherche Médicale, U441, Athérosclérose, Avenue du Haut-Lévèque, 33604 Pessac, France; and Institut National de la Santé et de la Recherche Médicale, U488, Stéroïdes et Système Nerveux, Hôpital de Bicêtre, 94276 Le Kremlin-Bicêtre Cedex, France
To whom correspondence should be addressed. E-mail: rf.mresni.bk@ueiluab.
S.B. and E.D.-d.-L.-R. contributed equally to this work.
Contributed by Etienne-Emile Baulieu, June 17, 2003
Contributed by Etienne-Emile Baulieu, June 17, 2003
Copyright © 2003, The National Academy of Sciences

Abstract

Pulmonary artery (PA) hypertension was studied in a chronic hypoxic-pulmonary hypertension model (7–21 days) in the rat. Increase in PA pressure (measured by catheterism), cardiac right ventricle hypertrophy (determined by echocardiography), and PA remodeling (evaluated by histology) were almost entirely prevented after oral dehydroepiandrosterone (DHEA) administration (30 mg/kg every alternate day). Furthermore, in hypertensive rats, oral administration, or intravascular injection (into the jugular vein) of DHEA rapidly decreased PA hypertension. In PA smooth muscle cells, DHEA reduced the level of intracellular calcium (measured by microspectrofluorimetry). The effect of DHEA appears to involve a large conductance Ca-activated potassium channel (BKCa)-dependent stimulatory mechanism, at both function and expression levels (isometric contraction and Western blot), via a redox-dependent pathway. Voltage-gated potassium (Kv) channels also may be involved because the antagonist 4-amino-pyridine blocked part of the DHEA effect. The possible pathophysiological and therapeutic significance of the results is discussed.

Keywords: hypoxia, potassium channels
Abstract

Exposure of animals to chronic hypoxia leads to the development of chronic hypoxic-pulmonary hypertension (CH-PHT). In human beings CH-PHT is frequently associated with severe pulmonary diseases. CH-PHT involve pulmonary arterial vasoconstriction and remodeling (1). Although the endothelium is involved in the pathogenesis of CH-PHT, the role of vascular smooth muscle cells (SMCs) is increasingly recognized (2).

Both the contractile status and the proliferative status of SMCs are regulated by the levels of intracellular Ca ([Ca]i). The [Ca]i levels are determined in part by the influx of Ca through the voltage-gated, L-type Ca channels. In pulmonary artery (PA) SMCs, the membrane potential is regulated by large conductance Ca-activated channels (BKCa) (3) and voltage-gated K channels (Kv), including shaker family Kv (4, 5). K channel (BKCa and Kv) function and expression are down-regulated with development and maintenance of CH-PHT (6, 7). CH reduces K current density in PASMCs, resulting in a state of depolarization (8, 9), followed by elevation of [Ca]i, which induces contraction and proliferation (10).

The mechanism for K channel down-regulation is unclear, but recent work suggests that it is related to the altered redox state induced by CH (8). Lungs of rats with CH-PHT are in a more reduced redox state than those of normoxic controls, as indicated by increased levels of reduced glutathione (8). A reduced redox state has potential for both short-term effects through modulation of K channels function (11) and long-term effects by activating several oxygen-responsive genes including hypoxia-inducible factor (HIF) (12).

We sought to enhance expression and function of BKCa by using DHEA, a BKCa opener in hypoxic human pulmonary cells (13), which can shift the redox balance toward an oxidized state leading to both BKCa and Kv activation and thus repolarization of the PASMCs membrane potential and its effects on the [Ca]i.In vivo PA pressure (PAP) as well as right ventricular (RV) wall thickness were measured in closed-chest rats undergoing CH. Remodeling was determined in small and medium pulmonary arteries. In addition, the effect of DHEA on [Ca]i and the possible involvement of the potassium channels were measured by microspectrofluorimetry, isometric contraction measurement, and Western blot analysis.

Acknowledgments

We thank Professor Michel Lazdunski (Nice) and Professor Emmanuel Weitzenblum (Strasbourg) for commenting on the manuscript. We also thank Anne-Marie Lomenech, Pierre Techoueyre (Bordeaux), and Bernard Eychenne (Bicêtre) for technical assistance and Dominique Diop for editorial help. This study has been supported in part by the Centre de Recherche de l'Hôpital des Enfants de Bordeaux (CEDRE) laboratory of the Pediatric Hospital of Bordeaux and a grant of Artemis to the Baulieu-Fondation Nationale de Gérontologie (FNG) program.

Acknowledgments

Notes

Abbreviations: DHEA, dehydroepiandrosterone; Kv, voltage-gated K+ channels; HT, hypertension; PA, pulmonary artery; BKCa, large conductance Ca-activated channels; [Ca2+]i, intracellular Ca2+; CH-PHT, chronic hypoxic-pulmonary HT; IPA, intrapulmonary artery; PAP, PA pressure; RV, right ventricular; 4-AP, 4-amino-pyridine; PASMC, PA small muscle cell; IbTx, iberiotoxin.

Notes
Abbreviations: DHEA, dehydroepiandrosterone; Kv, voltage-gated K+ channels; HT, hypertension; PA, pulmonary artery; BKCa, large conductance Ca-activated channels; [Ca2+]i, intracellular Ca2+; CH-PHT, chronic hypoxic-pulmonary HT; IPA, intrapulmonary artery; PAP, PA pressure; RV, right ventricular; 4-AP, 4-amino-pyridine; PASMC, PA small muscle cell; IbTx, iberiotoxin.

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