timulated release of a hyperpolarizing factor (ADHF) from mesenteric artery perivascular adipose tissue: involvement of myocyte BKCa channels and adiponectin

Weston, A. H., Egner, Iris, Dong, Y., Porter, E. L., Heagerty, A. M. and Edwards, G. 2013. timulated release of a hyperpolarizing factor (ADHF) from mesenteric artery perivascular adipose tissue: involvement of myocyte BKCa channels and adiponectin. British Journal of Pharmacology 169 (7) , pp. 1500-1509. 10.1111/bph.12157

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Abstract

Background and Purpose Perivascular adipose tissue (PVAT) releases adipocyte-derived hyperpolarizing factors (ADHFs) that may partly act by opening myocyte K+ channels. The present study in rat and mouse mesenteric arteries aimed to identify the myocyte K+ channel activated by PVAT and to determine whether adiponectin contributed to the hyperpolarizing effects of PVAT. Experimental Approach Myocyte membrane potential was recorded from de-endothelialized, non-contracted rat and mouse mesenteric arteries in the presence and absence of PVAT. Key Results The β3-adrenoceptor agonist, CL-316,243 (10 μM), generated PVAT-dependent, iberiotoxin-sensitive myocyte hyperpolarizations resulting from BKCa channel opening and which were partially blocked by L-NMMA (100 μM). Adiponectin (5 μg·mL−1) also produced iberiotoxin-sensitive hyperpolarizations in PVAT-denuded arterioles. Activation of myocyte AMP-activated protein kinase (AMPK) using 5 μM A-769662 also induced BKCa-mediated hyperpolarizations. Dorsomorphin abolished hyperpolarizations to CL-316,243, adiponectin and A-769662. In vessels from Adipo−/− mice, hyperpolarizations to CL-316,243 were absent whereas those to A-769662 and adiponectin were normal. In rat vessels, adipocyte-dependent hyperpolarizations were blocked by glibenclamide and clotrimazole but those to NS1619 (33 μM) were unaltered. Conclusions and Implications Under basal, non-contracted conditions, β3-adrenoceptor stimulation of PVAT releases an ADHF, which is probably adiponectin. This activates AMPK to open myocyte BKCa channels indirectly and additionally liberates NO, which also contributes to the observed PVAT-dependent myocyte hyperpolarizations. Clotrimazole and glibenclamide each reversed hyperpolarizations to adiponectin and A-769662, suggesting the involvement of myocyte TRPM4 channels in the ADHF-induced myocyte electrical changes mediated via the opening of BKCa channels.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	Nature Publishing Group
ISSN:	0007-1188
Date of Acceptance:	3 March 2013
Last Modified:	03 Mar 2020 02:51
URI:	https://orca.cardiff.ac.uk/id/eprint/96922

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