Evidence that inward rectifier K+ channels mediate relaxation by the PGI2 receptor agonist cicaprost via a cyclic AMP-independent mechanism.
OBJECTIVE
We investigated the role of the inward rectifier potassium (KIR) 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 phenylephrine. 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 microM), a known blocker of KIR channels. Raising extracellular K+ from 5 to 15 mM elicited membrane hyperpolarisation and an endothelium-independent relaxation that was blocked by Ba2+ (30-100 microM), suggesting the existence of functional KIR channels on the smooth muscle. In contrast, neither glibenclamide (10 microM), a blocker of ATP-sensitive K+ channels, nor fluoxetine hydrochloride (100 microM), a blocker of G-protein-gated inward rectifier K+ channels, nor pertussis toxin (PTX; 1 microg/ml), which irreversibly inhibits Gi/Go, 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 microM) and apamin (0.5 microM), 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.


CONCLUSIONS
We conclude that cicaprost relaxes rat tail artery by activating KIR channels with some involvement from EDHF. The mechanism appears to be largely independent of cyclic AMP and Gi/Go, although the latter appears to counteract relaxation through an unknown pathway and/or receptor.
Orie
Nelson N
NN
BHF Laboratories, Department of Medicine, University College London, WC1E 6JF, United Kingdom.
Fry
Chris H
CH
Clapp
Lucie H
LH
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D017609:Barium Compounds / Q000494:pharmacology; D018999:Charybdotoxin / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D019806:Cromakalim / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D003634:DDT / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044006:Receptors, Epoprostenol / Q000819:agonists*; D014665:Vasodilator Agents / Q000494:pharmacology*
D000067956:Adenylyl Cyclase Inhibitors; D017609:Barium Compounds; D002712:Chlorides; D009498:Neurotoxins; D024661:Potassium Channels, Inwardly Rectifying; D044006:Receptors, Epoprostenol; D014665:Vasodilator Agents; D005473:Fluoxetine; D019806:Cromakalim; C024986:barium chloride; D018999:Charybdotoxin; C017759:9-(tetrahydro-2-furyl)-adenine; D010656:Phenylephrine; D001030:Apamin; C000849:bis(p-chlorophenyl)acetic acid; D003634:DDT; D011464:Epoprostenol; D000242:Cyclic AMP; D000225:Adenine; C043867:cicaprost; D005905:Glyburide