Premium
Acute activation of endothelial AMPK surprisingly inhibits endothelium‐dependent hyperpolarization‐like relaxations in rat mesenteric arteries
Author(s) -
Chen Hui,
Vanhoutte Paul M.,
Leung Susan W.S.
Publication year - 2019
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.14716
Subject(s) - ampk , hyperpolarization (physics) , activator (genetics) , endothelium , mesenteric arteries , endocrinology , chemistry , medicine , microbiology and biotechnology , vascular smooth muscle , vasodilation , protein kinase a , biochemistry , biology , phosphorylation , artery , smooth muscle , receptor , organic chemistry , nuclear magnetic resonance spectroscopy
Background and Purpose Endothelium‐dependent hyperpolarizations (EDHs) contribute to the regulation of peripheral resistance. They are initiated through opening of endothelial calcium‐activated potassium channels (K Ca ); the potassium ions released then diffuse to the underlying smooth muscle cells, causing hyperpolarization and thus relaxation. The present study aimed to examine whether or not AMPK modulates EDH‐like relaxations in rat mesenteric arteries. Experimental Approach Arterial rings were isolated for isometric tension recording. AMPK activity and protein level were measured by ELISA and western blotting respectively. Key Results The AMPK activator, AICAR, reduced ACh‐induced EDH‐like relaxations and increased AMPK activity in preparations with endothelium; these responses were prevented by compound C, an AMPK inhibitor. AICAR inhibited relaxations induced by SKA‐31 (opener of endothelial K Ca ) but did not affect potassium‐induced, hyperpolarization‐attributable relaxations or increase AMPK activity in preparations without endothelium. A769662, another AMPK activator, not only caused a similar inhibition of relaxations to ACh and SKA‐31 in preparations with endothelium but also inhibited hyperpolarization‐attributable relaxations and augmented AMPK activity in rings without endothelium. Protein levels of total AMPKα, AMPKα1, or AMPKβ1/2 were comparable between preparations with and without endothelium. Conclusions and Implications Activation of endothelial AMPK, by either AICAR or A769662, acutely inhibits EDH‐like relaxations of rat mesenteric arteries. Furthermore, A769662 inhibits signalling downstream of smooth muscle hyperpolarization. In view of the major blunting effect of AMPK activation on EDH‐like relaxations, caution should be applied when administering therapeutic agents that activate AMPK in patients with endothelial dysfunction characterized by reduced production and/or bioavailability of NO.