Pharmacological Research | 2019
Anti‐hypertensive mechanisms of cyclic depsipeptide inhibitor ligands for Gq/11 class G proteins
Abstract
&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.