Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension

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.

Figures

Fig. 1.

Effects of oral DHEA on pulmonary and systemic circulation. DHEA (3-wk oral) decreases the PAP (A) and RV wall thickness (B) but does not affect systemic circulation (C) of CH-DHEA rats or cardiac function (D and E).

Fig. 2.

Effects of intravascular DHEA on mean PAP. Intravascular DHEA had no effect in both control and CH-DHEA-treated animals (A and C), whereas it induced a significant decrease in PAP in CH animals (B).

Fig. 3.

Effect of intravascular DHEA on mean PAP. Intravascular DHEA (3 μg to 3 mg/kg) decreased the PAP of CH rats in a dose-dependent manner.

Fig. 4.

Effects of oral DHEA on PA remodeling. CH induced a significant increase in the PA wall thickness. Oral DHEA for 3 or 1 wk prevented and reversed PA wall remodeling, respectively.

Fig. 5.

Effect of oral DHEA on [Ca2+]i of PASMCs. Oral DHEA for 3 or 1 wk induced a significant decrease in [Ca2+]i of PASMCs.

Fig. 6.

K channels and the mechanisms involved by in vitro DHEA administration on PASMCs. (A) DHEA (100 μM) induced a significant decrease in [Ca2+]i. IbTx (100 nM) blocked 65% of the DHEA-induced [Ca2+]i decrease, and combined IbTx and 4-AP (1 mM) was 100% efficient. Agitoxin-2 had no effect on the DHEA response. (B) DTT suppressed the DHEA-induced decrease in [Ca2+]i. The 1H-[1,2,4]oxadiazolol [4,3,-a]quinoxalin-1-one (ODQ), genistein, and a PKA inhibitor had no effect on DHEA-induced [Ca2+]i.

Fig. 7.

Effects of DHEA on PA reactivity to BKCa blockers and BKCa expression. (A) In vitro concentration–response curves for the effect of IbTx on the resting tension of IPA rings from CH and CH-DHEA rats. The amplitude of contraction is expressed as a percentage of the KCl (80 mM)-induced response obtained at the beginning of the experiments. Note the increase in the IbTx response in rings from CH-DHEA rats. Data points are mean ± SEM for CH (n = 11, N = 4) and CH-DHEA (n = 11, N = 4) rats. (B) Immunoblots of the BKCa α-subunit after 21 day of oral administration of DHEA. Each lane was loaded with 10 μg of protein. BKCa α-subunit was recognized by the Ab as a 125-kDa immunoreactive band. BKCa α-subunit is down-regulated in CH vs. control groups, whereas its expression was similar between control and CH-DHEA groups. No difference was observed in the 45-kDa β-actin bands used as an internal standard.