Thiazide-induced vasodilation in humans is mediated by potassium channel activation

Hydrochlorothiazide and indapamide are thought to exert their hypotensive e fficacy through a combined vasodilator and diuretic effect, but in vivo evi dence for a direct vascular effect is lacking. The presence and mechanism o f a direct vascular action of hydrochlorothiazide in vivo in humans were ex amined and compared with those of the thiazide-like drug indapamide. Forear m vasodilator responses to infusion of placebo and increasing doses of hydr ochlorothiazide (8, 25, and 75 mu g . min(-1) . dL(-1)) into the brachial a rtery were recorded by venous occlusion plethysmography. Dose-response curv es were repeated after local tetraethylammonium (TEA) administration to det ermine the role of potassium channel activation and, in patients with the G itelman syndrome, to determine the role of the thiazide-sensitive Na-Cl cot ransporter in the vasodilator effect of hydrochlorothiazide. Vascular effec ts of hydrochlorothiazide were compared with those of indapamide in both no rmotensive (mean arterial pressure, 85+/-7 mm Hg) and hypertensive (mean ar terial pressure, 124+/-16 mm Hg) subjects. At the highest infusion rate, lo cal plasma concentrations of hydrochlorothiazide averaged 11.0+/-1.6 mu g/m L, and those of indapamide averaged 7.2+/-1.5 mu g/mL. In contrast to indap amide, hydrochlorothiazide showed a direct vascular effect (maximal vasodil ation, 55+/-14%; P=0.013), which was inhibited by TEA (maximal vasodilation after TEA, 13+/-10%; P=0.02). The response was not dependent on blood pres sure and was similar in patients with Gitelman syndrome, indicating that ab sence of the Na-CI cotransporter does not alter the vasodilatory effect of hydrochlorothiazide. The vasodilator effect of hydrochlorothiazide in the h uman forearm is small and only occurs at high concentrations. The mechanism of action is not mediated by inhibition of vascular Na-Cl cotransport but involves vascular potassium channel activation. In contrast, indapamide doe s not exert any direct vasoactivity in the forearm vascular bed.