Abstract 115: Hydrochlorothiazide Lowers Systemic Blood Pressure Predominantly Through Vasodilation in Conditions Associated with Vasoconstriction
Thiazide derivatives 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 hypertension. The mechanism by which thiazides reduce the blood pressure (i.e. renal vs. extra renal) is not well understood. The blood pressure response to thiazides requires an initial volume loss (averaging about 1.5 kg) since it is not observed in individuals who are ingesting a high-salt diet. The objective of this study was to elucidate the renal and extra renal effects of thiazides. Using NCC deficient mice, we demonstrate that hydrochlorothiazide (HCTZ), a commonly used thiazide derivative, reduces blood pressure in the presence of volume-depletion and augmentation of circulating angiotensin levels but not in mice with normal vascular volume (NCC KO at baseline = 131.6 ± 4.4 vs. NCC KO with HCTZ = 125.8 ± 3.7 mm Hg) vs. (volume depleted NCC KO at baseline = 118.2 ± 4.1 vs. volume depleted NCC KO with HCTZ= 96.37± 4.5 mm Hg; p <0.05). The reduction in blood pressure by HCTZ occurs in the absence of increased salt excretion or urine output, indicating its extra-renal mechanism. Echocardiography demonstrated no significant changes in cardiac index in response to the drop in blood pressure by HCTZ (WT at baseline = 0.639 ± 0.05 vs. WT with HCTZ = 0.590 ± 0.01 ml/min/g) vs. (volume depleted NCC KO at baseline = 0.617± 0.07 vs. volume depleted NCC KO with HCTZ = 0.509 ± 0.04 ml/min/g). The antihypertensive effects of HCTZ were abrogated in the presence of paxilline, a specific blocker of large conductance calcium activated potassium channels (BK channels) in the vascular smooth muscle cell. Western blotting demonstrated enhanced expression of BK channels in vascular system of volume depleted NCC deficient mice vs. WT mice. Our results indicate that systemic vasoconstriction, as observed in volume depleted states, will amplify the extra-renal effects of HCTZ to lower blood pressure through vasodilation irrespective of the status of its renal target NCC.
Patients with congestive heart failure who are on a combination of a loop diuretic and HCTZ are at increased risk of significant hypotension subsequent to the activation of extra-renal effects of HCTZ, specifically when they become volume depleted.
Author Disclosures: S. Alshahrani: None. J. Rubinstein: None. M. Jiang: None. S. Barone: None. J. Xu: None. K. Zahedi: None. M. Soleimani: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Modest; principal investigator.
- © 2015 by American Heart Association, Inc.