Calcium gated potassium channel activator, dehydroepiandrosterone sulfate, reduces hypoxic pulmonary hypertension in rats

J. Bíbová, J. Herget, V. Hampl

Department of Physiology, Second Medical School, Charles University, Prague, Czech Republic

Sustained depolarization of pulmonary arterial smooth muscle cells participates in the mechanism of chronic hypoxia-induced pulmonary hypertension (1). Membrane potential in vascular smooth muscle cells is mostly governed by potassium (K+) channels. Chronic hypoxia and pulmonary hypertension depress the activity of various types of K+ channels, including the calcium-gated K+ (KCa) channels (1). The normal function of the KCa channels is believed to be restoration of membrane potential following depolarization. We hypothesized that reduced KCa channel activity is causative in the mechanism of chronic hypoxic pulmonary hypertension. We reasoned that if this hypothesis is correct, than treatment of rats with an activator of KCa channels should reduce pulmonary hypertension.

To test this hypothesis, we treated rats exposed to chronic hypoxia (10% O2, 4 weeks) with a KCa channel activator, dehydroepiandrosterone sulfate (DHEA; 1 mg/ml in drinking water) (2). DHEA was administered either for the entire duration of the hypoxic exposure or for its second half only. Mean pulmonary artery blood pressure (PAP), measured by catheterization in rats anesthetized with thiopental (40 mg/kg BW), was elevated by the hypoxic exposure. DHEA treatment reduced PAP in chronically hypoxic, but not normoxic rats (Table). DHEA also diminished the hypoxia-induced right ventricular hypertrophy. Systemic blood pressure and cardiac index were not affected by the DHEA treatment.

Hypoxia 4 weeks
4 weeks
2 weeks
4 weeks
PAP (mmHg)
16 ± 1
15 ± 1
29 ± 3*
24 ± 1*+
24 ± 1*+

*P < 0.01 vs. Normoxia; +P < 0.01 vs. Hypoxia without DHEA

We conclude that the KCa channel activator, DHEA, selectively reduces hypoxic pulmonary hypertension in rats. This finding might be of therapeutic interest because the safety of administering DHEA to humans is well established.

(1) Peng W., et al.: Am. J. Physiol. 272:C1271-1278,1997.

(2) Farrukh I.S., et al.: Am. J. Physiol. 274:L186-L195,1998.

Supported by the Grant Agency of the Czech Republic grant # 306/97/0854.