Effects of dihydralazine on renal water and aquaporin-2 excretion in humans

Objective. Dihydralazine is a vasodilator that lowers blood pressure, but often also leads to significant water and sodium retention. To characterize the effect of dihydralazine on renal sodium and water handling, we tested the hypothesis that dihydralazine causes water retention parallel with an increase in urinary excretion of aquaporin-2 (u-AQP2) in healthy humans. Material and methods. The effect of intravenous infusion of dihydralazine in three doses (3.125 mg, 6.250 mg and 9.375 mg) on urinary AQP2, water and sodium excretion, heart rate (HR), blood pressure (BP) and vasoactive hormones was measured in a randomized, placebo-controlled, double-blind, crossover study in 17 healthy subjects. Glomerular filtration rate (GFR) and renal tubular function were determined with the continuous infusion clearance technique and vasoactive hormones with radioimmunoassays. Results. Dihydralazine compared to placebo had no impact of u-AQP2 (effect of dihydralazine versus placebo SE) (-0.0740.048 ng/min versus -0.0150.034 ng/min; p=0.42), despite significant reductions in urine output and free water clearance after 9.375 mg of dihydralazine. Dihydralazine significantly lowered BP and increased HR, plasma levels of angiotensin II and (except after 3.125 mg) atrial natriuretic peptide, while plasma levels of vasopressin, GFR and fractional excretions of sodium and lithium were not significantly changed. Conclusions. These findings suggest that dihydralazine increases water re-absorption in the distal tubules, independently of vasopressin and of sodium re-absorption. Furthermore, our study does not support an effect of the sympathetic nervous system, the renin-angiotensin system and the natriuretic peptide system on u-AQP2 regulation.