Prostaglandins mediate the stimulatory effects of endothelin-1 on cAMP accumulation and inositol-1,4,5-trisphosphate production and contraction in cat iris sphincter.
We previously reported that in the iris sphincter smooth muscle, endothelin-1 (ET-1) activates both adenylyl cyclase and the phosphoinositide cascade and that the changes in the levels of cAMP and inositol-1,4,5-trisphosphate (IP3) produced are species specific. In the present study, we examined the mechanism of the ET-1 effects in cat iris sphincter. In general, we found that ET-1 (0.1 microM) increased prostaglandin E2 (PGE2) release by 156%, cAMP accumulation by 310%, IP3 production by 88% and induced contraction; that PGE2 increased cAMP accumulation, IP3 production and contraction; and that the effects of ET-1 are inhibited by indomethacin (Indo), suggesting that arachidonic acid metabolites may mediate the responses to the peptide. Kinetic studies revealed the following: (1) The effect of ET-1 on cAMP accumulation is rapid (within 30 sec), dose dependent (EC50 = 5.8 nM) and completely abolished by Indo (Ki = 0.16 microM), a cyclooxygenase inhibitor, but not by nordihydroguairetic acid, a lipoxygenase inhibitor, implying the involvement of PGs. (2) ET-1 dose-dependently evoked PGe2 release (EC50 = 1.8 nM), IP3 production (EC50 = 4.5 nM) and contraction (EC50 = 5 nM) and that all of these responses were inhibited by Indo. (3) PGE2 increased cAMP accumulation in a dose-dependent manner with an EC50 of 1.5 x 10(-7) M, and PGD2 and PGF2 alpha had little effect on the cyclic nucleotide. (4) PGE2 (1 microM), increased IP3 production by 55% and induced muscle contraction in a dose-dependent manner (EC50 = 40 nM). We conclude from these data that in cat iris sphincter PGs may mediate ET-1-induced cAMP accumulation, IP3 production and smooth muscle contraction.
Yousufzai
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Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, USA.
Ye
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Abdel-Latif
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D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002415:Cats; D002417:Cattle; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism*; D015232:Dinoprostone / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis*; D007498:Iris / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D007700:Kinetics; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D011817:Rabbits
D016232:Endothelins; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D015232:Dinoprostone; D007213:Indomethacin