Effects of 8-bromoguanosine 3':5'-cyclic monophosphate on phenylephrine-induced phosphatidylinositol hydrolysis and contraction in rat caudal artery.
1. The effects of 8-bromoguanosine 3':5'-cyclic monophosphate (8-bromo-cyclic GMP) on phenylephrine-induced contractions and phosphatidylinositol (PI) hydrolysis were investigated in rat isolated caudal artery. The effects of the nucleotide were compared to those of felodipine, a dihydropyridine Ca2+ channel antagonist and ryanodine, a putative depletor of intracellular Ca2+ stores. The purpose of this investigation was to examine the regulatory effects of cyclic GMP on receptor-mediated signal transduction in vascular smooth muscle. 2. Phenylephrine induced a concentration-dependent increase in PI hydrolysis that reached a maximum at 10 microM phenylephrine. Pre-incubation with felodipine (10 nM) significantly reduced PI turnover, but did not affect basal hydrolysis. Similarly, removal of extracellular Ca2+ (2 mM ethylene glycol-bis(beta-amino-ethyl ether) N, N, N', N'-tetraacetic acid (EGTA)) blocked phenylephrine-induced PI hydrolysis, but did not affect basal turnover. In contrast, 8-bromo-cyclic GMP (10 microM) did not affect phenylephrine-induced PI hydrolysis, nor did it affect basal turnover. 3. Phenylephrine induced concentration-dependent contractions that were inhibited by each of 8-bromo-cyclic GMP (10 microM), felodipine (1 nM and 10 nM) and ryanodine (3 microM and 10 microM). In addition, removal of Ca2+ from the physiological salt solution (2 mM EGTA) completely abolished contractions elicited by phenylephrine. 4. Phenylephrine-induced contractions were not further affected by felodipine and 8-bromo-cyclic GMP applied concomitantly than by equivalent concentrations of felodipine alone. However, ryanodine and 8-bromo-cyclic GMP applied together significantly inhibited phenylephrine-induced contractions in comparison to ryanodine alone. 5 These results suggest that phospholipase C-activated PI hydrolysis in the rat caudal artery is dependent on extracellular Ca2+, mediated, in part, through dihydropyridine-sensitive Ca2+ channels.Inhibition of contraction by felodipine may be brought about through indirect inhibition of IP3 production and subsequent attenuation of intracellular Ca2+ release. 8-Bromo-cyclic GMP does not inhibit PI hydrolysis; it may regulate vascular smooth muscle contraction by inhibition of Ca2+ release from IP3-mediated intracellular stores, but it is unlikely that 8-bromo-cyclic GMP affects ryanodine-sensitive stores.
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Department of Pharmacology & Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
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D000818:Animals; D001158:Arteries / Q000187:drug effects; D002021:Buffers; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004347:Drug Interactions; D015736:Felodipine / Q000494:pharmacology; D006868:Hydrolysis; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012433:Ryanodine / Q000494:pharmacology; D013623:Tail / Q000098:blood supply*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D002021:Buffers; D002121:Calcium Channel Blockers; D010716:Phosphatidylinositols; D014662:Vasoconstrictor Agents; D012433:Ryanodine; D010656:Phenylephrine; C016276:8-bromocyclic GMP; D006152:Cyclic GMP; D015736:Felodipine; D002118:Calcium