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

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 Ba(2+) (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 Ba(2+) (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 Ba(2+) 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.