Abstract P308: Leucine Rich Repeat Containing 8A Anion Channels Modulate Vasodilation In Angiotensin II-induced Hypertensive Mice

Abstract

Leucine Rich Repeat Containing 8 (LRRC8) family proteins (LRRC8A, B, C, D and E) comprise Volume-regulated anion channels (VRACs) which are activated by tumor necrosis factor alpha (TNFα) and angiotensin II (AngII). We have previously investigated vascular reactivity in mesenteric arteries from male wild type (WT) and smooth muscle-specific LRRC8A knockout (KO) mice. KO vessels displayed enhanced responsiveness to both endothelium-dependent (acetylcholine, ACh), and independent (sodium nitroprusside, SNP) vasodilators. We hypothesized that LRRC8A KO mice would be protected from AngII-induced hypertension. Blood pressure (BP) was measured by radiotelemetry. Resting BP was unaltered compared to WT and AngII infusion by osmotic minipump (alzet, 90 ng/min for 14 days) induced a similar degree of hypertension in awake mice (nighttime) but the difference between day and night pressures was significantly larger in KO mice. Mesenteric arteries were isolated from WT and KO mice after 14 days and vascular reactivity was quantified by wire myograph. Relaxation responses to both ACh and SNP relaxation were impaired in AngII hypertensive compared to normotensive WT mice. However, KO vessels relaxed better to both vasodilators in rings from both vehicle and AngII-treated mice (ACh LogEC 50 , WT+AngII -5.3 ± 0.27 vs. KO+AngII -6.5 ± 0.19, p < 0.05, n=4-6; SNP LogEC 50 , WT+AngII -7.4 ± 0.10 vs. KO+AngII -8.1 ± 0.10, p < 0.05, n=3-6). These results demonstrate a dissociation between elevated blood pressure and impaired vasodilator function. The data suggest that LRRC8A anion channels play a complex role in the development of AngII-induced hypertension.