Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension.
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.
Bonnet
Sébastien
S
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.
Dumas-de-La-Roque
Eric
E
Bégueret
Hugues
H
Marthan
Roger
R
Fayon
Michael
M
Dos Santos
Pierre
P
Savineau
Jean-Pierre
JP
Baulieu
Etienne-Emile
EE
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D000860:Hypoxia; D008168:Lung / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction; D015221:Potassium Channels / Q000378:metabolism; D011312:Pressure; D051381:Rats; D017208:Rats, Wistar
D000276:Adjuvants, Immunologic; D015220:Calcium Channels; D015221:Potassium Channels; D003687:Dehydroepiandrosterone; D002118:Calcium