Pathogenesis of pulmonary hypertension includes a reduction of potassium (K) channel activity. K channel closure causes depolarization, which stimulates calcium (Ca) entry through voltage gated Ca channels. The resulting increase in intracellular Ca concentration stimulates both vasoconstriction and vascular smooth muscle proliferation, which together create the syndrome of pulmonary hypertension. Therefore, we hypothesized that pharmacological augmentation of K channel activity should reduce pulmonary hypertension. We used a chronic hypoxic model of pulmonary hypertension in rats. Some of the rats were given a recently described activator of Ca-gated K channels, dehydroepiandrosterone sulfate (DHEA), in drinking water (1 mg/ml). Pulmonary arterial blood pressure, increased by 4 weeks of hypoxia (29 ±3 vs. 16 ±1 mmHg in normoxic controls), was significantly attenuated both in rats treated with DHEA for the whole duration of the hypoxic exposure (24 ±1 mmHg) and in rats given DHEA only during the last 2 weeks of hypoxia (24 ±1 mmHg). Cardiac index and systemic arterial blood pressure did not differ among the groups. We conclude that both a preventive and therapeutic application of a Ca-gated K channel activator, DHEA, known to be well tolerated by humans, reduces hypoxic pulmonary hypertension in rats.
Supported by GACR # 306/97/0854 and 305/97/S070.