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 pro stacyclin analogues was investigated in guinea-pig aorta. Iloprost cau sed substantial relaxation of tissues contracted with phenylephrine or 25 mM K+ but not 60 mM K+. In endothelial-denuded tissues, maximal re laxations to iloprost, cicaprost or isoprenaline were inhibited by sim ilar to 40-50% with tetraethylammonium or iberiotoxin, both blockers o f large conductance Ca2+-activated KS (BKCA) channels. In contrast, th e response to forskolin, an activator of adenylate cyclase was margina lly inhibited by tetraethylammonium. The K-ATP channel blocker, gliben clamide significantly augmented the response to iloprost but not cicap rost. These effects were largely inhibited by the EP1 receptor antagon ist, 8-chlorodibenz[b,f ][1,4]oxazepine-10(11 H)-carboxylic acid 2-[1- oxo-3(4-pyridinyl)propyl]hydrazide, monohydrochloride (SC-51089) and p artially by indomethacin, suggesting that iloprost relaxation is count erbalanced by activation of EP1 receptors,in part through a constricto r prostaglandin. We conclude that BKCA channels play an important role in mediating the effects of iloprost and cicaprost and raises the pos sibility that cyclic AMP-independent pathways might be involved. (C) 1 998 Elsevier Science B.V. All rights reserved.