Functional Mechanisms of Novel G Protein Inhibitor Ligands As Vasodilators

Abstract

G‐protein coupled receptor (GPCR) signaling plays an essential role in physiologic homeostasis and cardiovascular health. Dysfunction of GPCR pathway is implicated in hypertension, a leading risk factor for cardiovascular diseases. Here, we examined the functional properties of novel Gq inhibitor ligands, YM‐254890, FR900359, and WU‐07047, and determined their effectiveness at blocking GPCR signaling in the resistance vasculature. Under ex‐vivo pressurized vessel preparation, we measured vascular reactivity of small mesenteric arteries isolated from 3–4 month old wild type mice. Vasoconstriction of mesenteric arteries was evoked by applying increasing concentrations of the α1‐adrenergic receptor agonist, phenylephrine (PE), in the presence or absence of Gq inhibitors. We found that WU‐07047 had the least effect on maximal contractile response to PE (FR[0.01 μM]: 0.8 ± 0.6% vs. YM[0.01 μM]: 12.8 ± 2.8% vs. WU[10 μM]: 34.8 ± 3.2% %), whereas FR was the most potent (FR[0.01uM]: LogIC50 −0.008 ± 0 vs. YM[0.01uM]: LogIC50 −0.49 ± 0 vs. WU: LogIC50 −64.95 ± 6.4). WU‐07047 and YM‐254890 inhibited vasoconstriction through G protein‐independent pathway by blocking L‐type calcium channels (LTCCs). Bioinformatics analysis revealed a high sequence similarity between binding sites for dihydropyridines in the pore‐forming subunit of LTCCs and the binding pocket for the novel Gq inhibitor ligands in Gqα subunit. We conclude that the novel Gq inhibitors decrease vascular tone by blocking G protein‐dependent and G protein‐independent signaling mechanisms mediating resistance artery vasoconstriction. These findings suggest that targeting signaling downstream of GPCRs may be a more effective therapeutic approach to managing hypertension and associated cardiovascular diseases.Support or Funding InformationPennsylvania Dept. of Health (CURE) Grant (PO)Margaret Q. Landenberger Research Grant (PO)AHA Scientist Development Grant (PO)National Science Foundation (CBET 1262176) (KDM)