Evidence that Ca2+-activated K+ channels play a major role in mediating the vascular effects of iloprost and cicaprost.
The role of K+ channels in mediating vasorelaxation induced by two prostacyclin analogues was investigated in guinea-pig aorta. Iloprost caused substantial relaxation of tissues contracted with phenylephrine or 25 mM K+ but not 60 mM K+. In endothelial-denuded tissues, maximal relaxations to iloprost, cicaprost or isoprenaline were inhibited by approximately 40-50% with tetraethylammonium or iberiotoxin, both blockers of large conductance Ca2+-activated K+ (BKCa) channels. In contrast, the response to forskolin, an activator of adenylate cyclase was marginally inhibited by tetraethylammonium. The K(ATP) channel blocker, glibenclamide significantly augmented the response to iloprost but not cicaprost. These effects were largely inhibited by the EP1 receptor antagonist, 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid 2-[1-oxo-3(4-pyridinyl)propyl]hydrazide, monohydrochloride (SC-51089) and partially by indomethacin, suggesting that iloprost relaxation is counterbalanced by activation of EP1 receptors, in part through a constrictor prostaglandin. We conclude that BKCa channels play an important role in mediating the effects of iloprost and cicaprost and raises the possibility that cyclic AMP-independent pathways might be involved.
Centre for Clinical Pharmacology, Wolfson Institute for Biomedical Research, Department of Medicine, UCL, London, UK. l.clapp@ucl.ac.uk
L H
LH
Clapp
S
S
Turcato
S
S
Hall
M
M
Baloch
D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006834:Hydrazines / Q000494:pharmacology; D016285:Iloprost / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010077:Oxazepines / Q000494:pharmacology; D010656:Phenylephrine / Q000037:antagonists & inhibitors; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D019789:Tetraethylammonium / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D000970:Antineoplastic Agents; D006834:Hydrazines; D010077:Oxazepines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011448:Prostaglandin Antagonists; D014665:Vasodilator Agents; C086836:SC 51089; D010656:Phenylephrine; D019789:Tetraethylammonium; D011464:Epoprostenol; D016285:Iloprost; D007545:Isoproterenol; C043867:cicaprost; D002118:Calcium