Background: Recently, hydrochlorothiazide has been shown to relax vascular smooth muscle in vitro in clinically relevant concentrations by the opening of calcium-activated potassium channels, leading to hyperpolarization and consequent closing of voltage-operated calcium channels. Long-term administration of hydrochlorothiazide reduces peripheral vascular resistance in vivo in man. These results indicate that hydrochlorothiazide has hemodynamic activity, and we therefore examined the direct vascular action of this drug in vivo.
Subjects and methods: Forearm vasodilator responses to the infusion of a placebo and five increasing doses of hydrochlorothiazide into the brachial artery were recorded by venous occlusion strain-gauge plethysmography (perfused forearm technique) in eight normotensive male volunteers. Venous samples were taken from an ipsilateral antecubital vein at the end of each infusion period to measure the hydrochlorothiazide concentration.
Results and discussion: Plasma concentrations of hydrochlorothiazide averaged 3.5 +/- 0.3 mu g/ml at the highest infusion rate. This concentration leads to a 60 +/- 10% relaxation in vitro and is more than 10 times the therapeutic plasma concentration. Despite these supratherapeutic levels, we were unable to demonstrate a change in forearm blood flow and vascular resistance. Also, no significant changes were observed in blood pressure and heart rate.
Conclusion: In contrast to in vitro results, hydrochlorothiazide does not exert any direct vasoactivity in the forearm vascular bed of healthy normotensive male volunteers at (supra)therapeutic plasma concentrations.