Deficiency of T-type Ca²⁺ channels Ca_v3.1 and Ca_v3.2 has no effect on angiotensin II-induced hypertension but differential effect on plasma aldosterone in mice

Abstract

T-type Ca2+ channel Cav3.1 promotes microvessel contraction ex vivo. It was hypothesized that in vivo, functional deletion of Cav3.1, but not Cav3.2, protects mice against angiotensin II (ANG II)-induced hypertension. Mean arterial blood pressure (MAP) and heart rate were measured continuously with chronically indwelling catheters during infusion of ANG II (30 ng·kg−1·min−1, 7 days) in wild-type (WT), Cav3.1−/−, and Cav3.2−/− mice. Plasma aldosterone and renin concentrations were measured by radioimmunoassays. In a separate series, WT mice were infused with ANG II (100 ng·kg−1·min−1) with and without the mineralocorticoid receptor blocker canrenoate. Cav3.1−/− and Cav3.2−/− mice exhibited no baseline difference in MAP compared with WT mice, but day-night variation was blunted in both Cav3.1 and Cav3.2−/− mice. ANG II increased significantly MAP in WT, Cav3.1−/−, and Cav3.2−/− mice with no differences between genotypes. Heart rate was significantly lower in Cav3.1−/− and Cav3.2−/− mice compared with control mice. After ANG II infusion, plasma aldosterone concentration was significantly lower in Cav3.1−/− compared with Cav3.2−/− mice. In response to ANG II, fibrosis was observed in heart sections from both WT and Cav3.1−/− mice and while cardiac atrial natriuretic peptide mRNA was similar, the brain natriuretic peptide mRNA increase was mitigated in Cav3.1−/− mice ANG II at 100 ng/kg yielded elevated pressure and an increased heart weight-to-body weight ratio in WT mice. Cardiac hypertrophy, but not hypertension, was prevented by the mineralocorticoid receptor blocker canrenoate. In conclusion, T-type channels Cav3.1and Cav3.2 do not contribute to baseline blood pressure levels and ANG II-induced hypertension. Cav3.1, but not Cav3.2, contributes to aldosterone secretion. Aldosterone promotes cardiac hypertrophy during hypertension.

Endothelial mineralocorticoid receptor ablation confers protection towards endothelial dysfunction in experimental diabetes in mice

“…Our data showed that ECMR contributed to diabetes‐associated cardiac and renal hypertrophy. Interestingly, cardiac hypertrophy was attenuated by lower plasma aldosterone and by MR antagonists in mice with Ang‐II‐induced hypertension, despite unchanged, elevated, AngII concentration and hypertension 41 suggesting a significant independent aldosterone‐MR‐driven effect in mice. We have previously shown that ECMR‐KO mice do not have elevated blood pressure at baseline or following AngII infusion compared to WT 25 .…”

The mineralocorticoid receptor leads to increased expression of EGFR and T-type calcium channels that support HL-1 cell hypertrophy

“…In cardiomyocytes, EGFR transactivation by angiotensin II led to cellular hypertrophy, which could be prevented by the EGFR inhibitor AG1478 or by dominant negative Gαq 50 . The MR inhibitor canrenoate was also able to reduce cardiac hypertrophy that was induced by angiotensin II 51 . Although Messaoudi found that aldosterone-induced cardiac hypertrophy was not prevented in a heart-specific dominant negative EGFR transgenic mouse 50 others found that aldosterone can stimulate NHE1 via EGFR transactivation and thereby induce cardiac hypertrophy 52 .…”

Enhanced Ca2+signaling, mild primary aldosteronism, and hypertension in a familial hyperaldosteronism mouse model (Cacna1hM1560V/+)

“…Ca V 3.2 has been proposed to be essential for intrinsic voltage oscillatory activity in the zona glomerulosa ( 25 ), raising the question whether inhibition of Ca V 3.2 could be a useful mechanism to lower blood pressure or aldosterone levels in the general population. Prior studies of another Cacna1h −/− model argue against such an effect, with normal aldosterone and renin levels and normal blood pressure ( 45 ). Similarly, Mibefradil, a calcium channel inhibitor that preferentially blocks T-type channels [withdrawn from the market ( 46 )] does not have lasting effects on blood pressure or aldosterone levels ( 11 , 47 , 48 ) despite inhibitory effects in vitro ( 49 ).…”