Myosin phosphorylation and cyclic adenosine 3',5'-monophosphate in relaxation of arterial smooth muscle by vasodilators.
Recent evidence indicates that contraction of vascular smooth muscle may be regulated by two calcium-dependent mechanisms: activation of myosin kinase, and calcium binding to a second, unknown regulatory site. This hypothesis implies that vasodilators could modify vascular tone by several mechanisms, including inactivation of myosin kinase. Since relaxation of the carotid artery following agonist removal may occur when myosin phosphorylation is at resting levels, we could determine whether dephosphorylation of myosin is necessarily involved in the molecular mechanisms mediating relaxation in response to vasodilators. The relaxant effects of adenosine, 3-isobutyl-1-methylxanthine, forskolin, sodium nitroprusside, and 8-bromo-cGMP were tested under conditions where myosin phosphorylation was at basal levels (0.08 +/- 0.02 mol Pi/mol light chain). All of these agents increased the rate of relaxation in nonsteady state experiments where relaxation was induced by stimulus washout. Steady state dose-response curves were obtained for forskolin and 8-bromo-cGMP in the presence of basal myosin phosphorylation. Forskolin caused a dose-dependent increase in cAMP levels at a rate consistent with a cause and effect relationship between relaxation and total tissue cAMP content. Both drugs relaxed the muscles, with no detectable change in myosin phosphorylation. Therefore, dephosphorylation of myosin is not a necessary event in the molecular mechanism of several vasodilators, including some which presumably act via cyclic nucleotides.
D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism / Q000502:physiology; D005576:Colforsin; D000242:Cyclic AMP / Q000378:metabolism*; D004224:Diterpenes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology*; D009218:Myosins / Q000378:metabolism*; D010766:Phosphorylation; D013552:Swine; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology*
D004224:Diterpenes; D014665:Vasodilator Agents; D005576:Colforsin; D000242:Cyclic AMP; D009218:Myosins