Role of gap junctions in endothelium-derived hyperpolarizing factor responses and mechanisms of K+-relaxation

Harris, David, Martin, Patricia E. M., Evans, William Howard, Kendall, David A, Griffith, Tudor M. and Randall, Michael D 2000. Role of gap junctions in endothelium-derived hyperpolarizing factor responses and mechanisms of K+-relaxation. European Journal of Pharmacology 402 (1-2) , pp. 119-128. 10.1016/S0014-2999(00)00512-4

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Abstract

We have examined the effects of ouabain (1 mM), the gap junction inhibitors, 18α-glycyrrhetinic acid (100 μM), N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A; 10 μM) and palmitoleic acid (50 μM), and clotrimazole (10 μM) against endothelium-derived hyperpolarizing factor (EDHF)-mediated and K+-induced vasorelaxations in the rat mesentery. In the presence of indomethacin (10 μM) and 300-μM NGnitro-l-arginine methyl ester (l-NAME), carbachol caused EDHF-mediated relaxations (Rmax=85.3±4.0%). In the presence of ouabain, these responses were substantially reduced (Rmax=11.0±2.3%). 18α-glycyrrhetinic acid, SR141716A, palmitoleic acid and clotrimazole also significantly inhibited these EDHF-mediated responses. K+ caused vasorelaxation of preparations perfused with K+-free buffer (Rmax=73.7±2.4%), which were reduced by 10-μM indomethacin (Rmax=56.4±6.2%). K+ vasorelaxation was essentially abolished by endothelial denudation. Both ouabain and 18α-glycyrrhetinic acid opposed K+ relaxations, however, neither SR141716A, clotrimazole nor palmitoleic acid had any effect. Direct cell–cell coupling via gap junctions was attenuated by ouabain, clotrimazole and palmitoleic acid. We conclude that: (i) that gap junctional communication plays a major role in EDHF-mediated relaxations, (ii) that K+-vasorelaxation is endothelium-dependent (thus, K+ is unlikely to represent an EDHF), and (iii) that the inhibitory actions of ouabain and clotrimazole on gap junctions might contribute towards their effects against EDHF.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	Elsevier
ISSN:	0014-2999
Last Modified:	17 Mar 2021 02:51
URI:	https://orca.cardiff.ac.uk/id/eprint/65813

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