To determine the potential role of prostaglandins in mediating the hypotensive action of the new antihypertensive agent pinacidil, we measured the blood pressure, regional blood flow and neurohumoral responses to pinacidil in thirteen hypertensive patients randomly assigned to receive pretreatment with either indomethacin (75 mg) or placebo. After baseline measurements had been obtained, each patient received an oral dose of pinacidil to which he had previously demonstrated a therapeutic response. The doses of pinacidil administered between the two groups did not differ. Serial measurements of blood pressure and heart rate over two hours revealed no attenuation of the hypotensive effect of pinacidil in the indomethacin-pretreated patients (-12.7 +/- 4.1 mm Hg) compared to the placebo group (-9.3 +/- 3.2 mm Hg). While significant vasodilation was not observed in the forearm, renal vasodilation occurred and was not different between the two groups. Pinacidil had no effect on glomerular filtration rate. Neither did pinacidil significantly increase plasma catecholamines or renin activity. The results indicate that prostaglandins probably do not play a major role in the vasodilator action of pinacidil, and that therapeutic doses of the drug have a differential effect on regional blood flows that result in hypotension, but not significant neurohumoral stimulation, in patients with mild to moderate hypertension.