Abstract 119: Anti-hypertensive Effect of Thiazides Shifts From Salt Excretion to Vasorelaxation During Salt Restriction or Volume Depletion

Abstract

Thiazide derivatives, including hydrochlorothiazide (HCTZ), are specific inhibitors of the Na+-Cl- Co-transporter (NCC) in the kidney distal tubules, and the most commonly used diuretic for the treatment of mild to moderate hypertension. Both renal (natriuretis) and extra renal (vasorelaxation) mechanisms have been proposed as major mediators of blood pressure reduction by HCTZ but the circumstances under which the renal or extra renal mechanism predominates remain unknown . To address these issues, systemic blood pressure was monitored by intra-arterial catheter and computerized tail cuff in transgenic mice lacking NCC under varying conditions. For comparison, mice with pendrin ablation or double deletion of pendrin and NCC were used to ascertain the compensatory role of pendrin in salt reabsorption in response to HCTZ. Pendrin KO mice were the only group which showed enhanced salt excretion in response to HCTZ, with salt excretion increasing by ~30% in pendrin KO vs. WT mice (p<0.05). In mice lacking NCC, HCTZ significantly reduced the systemic blood pressure only during salt restriction and without enhancing salt excretion. In volume depleted but not in volume resuscitated NCC/pendrin dKO mice, HCTZ caused dramatic reduction in systemic blood pressure, with systolic blood pressure decreasing from 72.13± 5.1 at baseline to 51.06 ± 6.6 mm Hg in dKO mice within 20 minutes of HCTZ administration (p<0.01 vs. baseline) with no significant effect in WT mice (p>0.5 vs. baseline) or in salt resuscitated NCC/pendrin dKO mice. There was no enhancement in salt excretion and no reduction in echocardiography-monitored cardiac output in pendrin/NCC dKO mice in response to HCTZ. The antihypertensive effects of HCTZ were abrogated in the presence of paxilline, a specific blocker of BK channel, which is upregulated in arterial vasculature of volume depleted mutant mice. We propose that thiazides reduce blood pressure predominantly via vasorelaxation during salt restriction/volume depletion; whereas, they enhance salt excretion during salt replete state and specifically in conditions associated with pendrin downregulation/inactivation.