HEMODYNAMIC EFFECTS OF Gq/11‐SPECIFIC CYCLIC DEPSIPEPTIDE INHIBITOR LIGANDS IN NORMOTENSIVE AND HYPERTENSIVE MICE

Abstract

Augmented vasoconstriction is a hallmark of hypertension and is mediated partly by hyper‐stimulation of G protein‐coupled 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 or ex vivo using cyclic depsipeptides, YM‐254890 (YM), FR‐900359 (FR) and WU‐07047 (WU) is sufficient to reduce vasoconstriction and reverse hypertension in mice. FR, YM and WU markedly reduced vasoconstriction evoked with Gq/11‐coupled GPCRs. YM and WU but not FR inhibited vasoconstriction through G protein‐dependent and independent pathways by blocking L‐type calcium channel‐mediated Ca2+ influx. Acute subcutaneous injection of FR and YM (0.3 mg/kg, s.c.) in normotensive and hypertension mice elicited marked hypotension, which was more severe and long lasting (FRt1/2 □ 12 hr vs. YMt1/2 □ 4 hr) after the injection of FR relative to YM. In 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). Incubation of cells with YM or FR caused cellular redistribution of Gq from the plasma membrane. Our results together support the hypothesis that increased vascular Gq/11 activity is involved in the pathogenesis of hypertension, and that direct systemic blockade of Gq/11 can reverse hypertension. The findings provide clear evidence for targeting Gq/11 in the cardiovascular system as an effective therapy for treating hypertension.Support or Funding InformationThis study is supported by grants from Pennsylvania Department of Health (CURE), Margaret Q. Landenberger Foundation, American Heart Association (16SDG27260276) and NIH (HL139754) to P. Osei‐Owusu.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.