LAUSR

&NA; Augmented vasoconstriction is a hallmark of hypertension and is mediated partly by hyper‐stimulation of G protein couple receptors (GPCRs) and downstream signaling components. Although GPCR blockade is a key component of current anti‐hypertensive strategies, whether hypertension is better managed by directly targeting G proteins has not been thoroughly investigated. Here, we tested whether inhibiting Gq/11 proteins in vivo and ex vivo using natural cyclic depsipeptide, FR900359 (FR) from the ornamental plant, Ardisia crenata, and YM‐254890 (YM) from Chromobacterium sp. QS3666, or it's synthetic analog, WU‐07047 (WU), was sufficient to reverse hypertension in mice. All three inhibitors blocked G protein‐dependent vasoconstriction, but to our surprise YM and WU and not FR inhibited K+‐induced Ca2+ transients and vasoconstriction of intact vessels. However, each inhibitor blocked whole‐cell L‐type Ca2+ channel current in vascular smooth muscle cells. Subcutaneous injection of FR or YM (0.3 mg/kg, s.c.) in normotensive and hypertensive mice elicited bradycardia and marked blood pressure decrease, which was more severe and long lasting after the injection of FR relative to YM (FRt1/2 ≌ 12 h vs. YMt1/2 ≌ 4 h). In deoxycorticosterone acetate (DOCA)‐salt hypertension mice, chronic injection of FR (0.3 mg/kg, s.c., daily for seven days) reversed hypertension (vehicle SBP: 149 ± 5 vs. FR SBP: 117 ± 7 mmHg), without any effect on heart rate. Our results together support the hypothesis that increased LTCC and Gq/11 activity is involved in the pathogenesis of hypertension, and that dual targeting of both proteins can reverse hypertension and associated cardiovascular disorders.