Zinc pyrithione induces endothelium-dependent hyperpolarization-mediated mesenteric vasorelaxation in healthy and colitic mice

Abstract

Background: Although Zinc pyrithione (ZPT) could lower blood pressure by inducing vasorelaxation, it is unclear if it is able to induce vasorelaxation of mesenteric arterioles in health and ulcerative colitis (UC) to exert anti-colitic action.

Methods: The vasorelaxation of the second-order branch of the mesenteric artery from wide type (WT) mice, TRPV1^-/-(KO) mice, and TRPV4^-/-(KO) mice was determined using a Mulvany-style wire myograph. Calcium imaging and patch clamp were applied to analyze the actions of ZPT in human vascular endothelial cells. Mouse model of UC was used to evaluate the anti-colitic action of ZPT.

Results: ZPT dose-dependently induced mesenteric vasorelaxation predominately through endothelium-dependent hyperpolarization (EDH), which could be attenuated by intracellular Zn²⁺ and Ca²⁺ chelators TPEN and BAPTA-AM. The ZPT/EDH-mediated vasorelaxation via TRPV1, TRPV4 and TRPA1 channels was verified by a combination of selective pharmacological inhibitors and TRPV1-KO and TRPV4-KO mice. Moreover. ZPT induced Ca²⁺ entry via vascular endothelial TRPV1/4 and TRPA1 channels and enhanced membrane non-selective currents through these channels. Notably, ZPT exerted anti-colitic effects by rescuing the impaired acetylcholine (ACh)-induced mesenteric vasorelaxation in colitic mice.

Conclusions: ZPT/Zn²⁺ induces EDH-mediated mesenteric vasorelaxation through activating endothelial multiple TRPV1/4 and TPPA1 channels in health, and rescues the impaired ACh-induced vasorelaxation to exert anti-colitic action. Our study may open a new avenue of potential vessel-specific targeted therapy for UC.

Keywords: Endothelium-dependent hyperpolarization; TRPA1; TRPV1; TRPV4; Ulcerative colitis; ZPT.