Abstract 562: Differential Effects of Renin Inhibitors and Ca2+ Channel Blockers on Blood Pressure and Vascular Function in Caveolin-1 Null Mice

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Abstract

Caveolin-1 (cav-1) is a transmembrane protein identified in plasma membrane caveolae, and a potential modulator of renal and vascular function and insulin sensitivity. We have shown that cav-1 gene variants are associated with insulin resistance (IR) in hypertensive humans, and that cav-1 deficiency in mice leads to increased blood pressure (BP) and IR. To test whether these changes in the cav-1 KO involve renal or vascular abnormalities, we treated WT and cav-1 KO mice for 14 days with placebo, the renin inhibitor aliskiren (50 mg/kg/day), or the Ca2+ channel blocker amlodipine (6 mg/kg/day) and assessed BP, fasting blood glucose, HOMA-IR, plasma aldosterone (ALDO), and vascular function.

Cav-1 KO mice, as compared with WT, showed increased BP (131±7 vs. 110±2 mm Hg), blood glucose (112±4 vs. 83±4 mg/dl), HOMA-IR (1.9±1.1 vs. 1.1±0.4), lower plasma ALDO (97±10 vs. 131±42 ng/dl), and altered vascular reactivity--reduced Phe-induced vasoconstriction (0.6±0.2 vs. 1.1±0.2g), enhanced acetylcholine (ACh)-induced relaxation (65±11 vs 23±7%), and enhanced relaxation in response to exogenous NO. Endothelium removal, NOS inhibition, or guanylate cyclase inhibition abolished ACh-induced relaxation, suggesting changes in endothelium-dependent NO-cGMP pathway in cav-1 KO mice. In cav-1 KO mice aliskiren significantly reduced BP to 113±4 mm Hg, ALDO levels by 40%, and HOMA-IR to 0.9±0.1, but had no significant effects on blood glucose, Phe-induced vasoconstriction, ACh- or exogenous NO-induced vasorelaxation. In contrast, amlodipine reduced BP to 117±4 mmHg (this effect did not reach significance), had no effect on ALDO levels, and showed a trend for increased IR. Importantly, amlodipine enhanced the sensitivity to Phe in both WT and cav-1 KO, and reduced the ACh-induced relaxation in cav-1 KO mice to 47±11%.

Thus aliskiren treatment in cav-1 KO mice reduced BP possibly through suppression of RAAS and improved insulin sensitivity, but did not affect vascular function. In contrast, amlodipine treatment showed small changes in BP and IR but had adverse effects on vascular reactivity in cav-1 KO mice, raising the concern that it could have similar adverse effects on vascular function in hypertensive individuals that carry the cav-1 minor allele gene variants.

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