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Evidence that inward rectifier K+ channels mediate relaxation by the PGI(2) receptor agonist cicaprost via a cyclic AMP-independent mechanism

Orie, NN; Fry, CH; Clapp, LH; (2006) Evidence that inward rectifier K+ channels mediate relaxation by the PGI(2) receptor agonist cicaprost via a cyclic AMP-independent mechanism. CARDIOVASC RES , 69 (1) 107 - 115. 10.1016/j.cardiores.2005.08.004.

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Abstract

Objective: We investigated the role of the inward rectifier potassium (K-IR) channel and the cyclic AMP-dependent pathway in mediating vasorelaxation induced by the prostacyclin analogue cicaprost.Methods: Small vessel myography was used to assess responses to cicaprost in segments of rat tail artery contracted with phenylephline. Microelectrode recordings were made from helical strips to assess effects on membrane potential.Results: Cicaprost caused relaxation and hyperpolarisation that were significantly inhibited by Ba2+ (30-100 mu M), a known blocker of K-IR channels. Raising extracellular K+ from 5 to 15 mM elicited membrane hyperpolarisation and an endothelium-independent relaxation that was blocked by Ba2+ (30-100 mu M), suggesting the existence of functional KIR channels on the smooth muscle. In contrast, neither glibenclamide (10 mu M), a blocker of ATP-sensitive K+ channels, nor fluoxetine hydrochloride (100 mu M), a blocker of G-protein-gated inward rectifier K+ channels, nor pertussis toxin (PTX; 1 mu g/ml), which irreversibly inhibits G(i)/G(o), reduced relaxation to cicaprost. Indeed, PTX significantly potentiated responses. Relaxation to cicaprost was not mediated by NO but was partially endothelium-dependent, consistent with a similar inhibition by a combination of charybdotoxin (0.1 mu M) and apamin (0.5 mu M), blockers of endothelium-derived hyperpolarising factor (EDHF). However, relaxation was unaffected by adenylyl cyclase (SQ22536, dideoxyadenosine) or protein kinase A (Rp-2-O-monobutyryl-cAMP) inhibitors, consistent also with Ba2+ only weakly inhibiting relaxation to the adenylyl cyclase activator forskolin.Conclusion: We conclude that cicaprost relaxes rat tail artery by activating K-IR channels with some involvement from EDHF. The mechanism appears to be largely independent of cyclic AMP and G(i)/G(0), although the latter appears to counteract relaxation through an unknown pathway and/or receptor. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Type: Article
Title: Evidence that inward rectifier K+ channels mediate relaxation by the PGI(2) receptor agonist cicaprost via a cyclic AMP-independent mechanism
DOI: 10.1016/j.cardiores.2005.08.004
Keywords: prostacyclin analogue, vascular smooth muscle, inward rectifier potassium channels, relaxation, EDHF, ARTERIAL SMOOTH-MUSCLE, GUINEA-PIG AORTA, POTASSIUM CHANNELS, NITRIC-OXIDE, PROSTANOID RECEPTORS, BLOOD-VESSELS, G-PROTEINS, RAT, PROSTACYCLIN, CORONARY
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Pre-clinical and Fundamental Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
URI: http://discovery.ucl.ac.uk/id/eprint/8308
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