Premium
Stimulated release of a hyperpolarizing factor ( ADHF ) from mesenteric artery perivascular adipose tissue: involvement of myocyte BK Ca channels and adiponectin
Author(s) -
Weston A H,
Egner I,
Dong Y,
Porter E L,
Heagerty A M,
Edwards G
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12157
Subject(s) - iberiotoxin , endocrinology , medicine , myocyte , glibenclamide , adipocyte , adiponectin , mesenteric arteries , ampk , potassium channel , adipose tissue , chemistry , biology , microbiology and biotechnology , protein kinase a , artery , kinase , insulin resistance , insulin , diabetes mellitus
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 β 3 ‐adrenoceptor agonist, CL ‐316,243 (10 μM), generated PVAT ‐dependent, iberiotoxin‐sensitive myocyte hyperpolarizations resulting from BK Ca 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 BK Ca ‐mediated hyperpolarizations. Dorsomorphin abolished hyperpolarizations to CL ‐316,243, adiponectin and A ‐769662. In vessels from A dipo −/− 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 NS 1619 (33 μM) were unaltered. Conclusions and Implications Under basal, non‐contracted conditions, β 3 ‐adrenoceptor stimulation of PVAT releases an ADHF , which is probably adiponectin. This activates AMPK to open myocyte BK Ca 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 TRPM 4 channels in the ADHF ‐induced myocyte electrical changes mediated via the opening of BK Ca channels.