Tranilast increases vasodilator response to acetylcholine in rat mesenteric resistance arteries through increased EDHF participation.

Christopher Torrens,Fabiano E Xavier,Gloria Balfagón,Esther Sastre,Laura Caracuel,Javier Blanco-Rivero,María Callejo

doi:10.1371/journal.pone.0100356

Abstract

Background and PurposeTranilast, in addition to its capacity to inhibit mast cell degranulation, has other biological effects, including inhibition of reactive oxygen species, cytokines, leukotrienes and prostaglandin release. In the current study, we analyzed whether tranilast could alter endothelial function in rat mesenteric resistance arteries (MRA).Experimental ApproachAcetylcholine-induced relaxation was analyzed in MRA (untreated and 1-hour tranilast treatment) from 6 month-old Wistar rats. To assess the possible participation of endothelial nitric oxide or prostanoids, acetylcholine-induced relaxation was analyzed in the presence of L-NAME or indomethacin. The participation of endothelium-derived hyperpolarizing factor (EDHF) in acetylcholine-induced response was analyzed by preincubation with TRAM-34 plus apamin or by precontraction with a high K+ solution. Nitric oxide (NO) and superoxide anion levels were measured, as well as vasomotor responses to NO donor DEA-NO and to large conductance calcium-activated potassium channel opener NS1619.Key ResultsAcetylcholine-induced relaxation was greater in tranilast-incubated MRA. Acetylcholine-induced vasodilation was decreased by L-NAME in a similar manner in both experimental groups. Indomethacin did not modify vasodilation. Preincubation with a high K+ solution or TRAM-34 plus apamin reduced the vasodilation to ACh more markedly in tranilast-incubated segments. NO and superoxide anion production, and vasodilator responses to DEA-NO or NS1619 remained unmodified in the presence of tranilast.Conclusions and ImplicationsTranilast increased the endothelium-dependent relaxation to acetylcholine in rat MRA. This effect is independent of the nitric oxide and cyclooxygenase pathways but involves EDHF, and is mediated by an increased role of small conductance calcium-activated K+ channels.

Highlights

Mesenteric blood flow can constitute up to 20–30% of total cardiac output [1] and is regulated by different mechanisms in which endothelial factors like nitric oxide (NO), prostanoids and endothelium-derived hyperpolarizing factor (EDHF) play a pivotal role
Tranilast increased the endothelium-dependent relaxation to acetylcholine in rat mesenteric resistance arteries (MRA)
This effect is independent of the nitric oxide and cyclooxygenase pathways but involves EDHF, and is mediated by an increased role of small conductance calcium-activated K+ channels

Summary

Introduction

Mesenteric blood flow can constitute up to 20–30% of total cardiac output [1] and is regulated by different mechanisms in which endothelial factors like nitric oxide (NO), prostanoids and endothelium-derived hyperpolarizing factor (EDHF) play a pivotal role. Mast cells secrete numerous vasoactive and proinflammatory mediators, such as histamine, serotonin, bradykinin, endothelin, NO, leukotrienes, prostaglandins, or cytokines [5], which could alter vascular endothelial and smooth muscle function [6]. These consequences are highly interesting, aspects of hemodynamic changes when mast cells are stabilized. Nitric oxide (NO) and superoxide anion levels were measured, as well as vasomotor responses to NO donor DEA-NO and to large conductance calcium-activated potassium channel opener NS1619

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Results

Conclusion