cAMP-dependent reduction in membrane fluxes during relaxation of arterial smooth muscle.
Forskolin, an activator of adenylate cyclase, inhibited contractures induced in rat aorta by norepinephrine (NE) and angiotensin II and by KCl depolarization. The concentration of forskolin required to inhibit NE-induced contractures was significantly lower than required to inhibit KCl-induced contractures (IC50 0.18 +/- 0.01 vs. 2.2 +/- 0.2 microM). Forskolin effectively relaxed NE-induced contractures when active Na+-K+ transport was inhibited. Stimulation of 42K and 36Cl effluxes by NE was inhibited by low concentrations of forskolin. The IC50 for forskolin inhibition of 42K efflux, 0.17 +/- 0.02 M, was similar to that for relaxation of NE contraction. The time course for forskolin-induced increases in adenosine 3',5'-cyclic monophosphate (cAMP) was consistent with that for forskolin-mediated relaxation and its maintenance. Fifty percent inhibition of both NE-induced contractures and NE-stimulated 42K effluxes occurred at levels of cAMP that were 1.4 times basal, and 90% inhibition of both processes was associated with a two to threefold increase in cAMP content. In sharp contrast, the level of tissue cAMP associated with inhibition of KCl contractures was 6-10 times higher than that associated with inhibition of NE-induced contractures. We postulate that cAMP-dependent regulation of membrane fluxes stimulated by receptor occupancy represents a primary mechanism for relaxation of a NE contracture, whereas the processes that regulate depolarization-dependent channels and the phosphorylation of myosin light chain kinase occur at much higher cAMP content and apparently function in a secondary capacity.
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000502:physiology*; D005576:Colforsin; D000242:Cyclic AMP / Q000502:physiology*; D004224:Diterpenes / Q000494:pharmacology; D008297:Male; D008566:Membranes / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D011197:Potassium Radioisotopes / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D004224:Diterpenes; D011197:Potassium Radioisotopes; D000804:Angiotensin II; D005576:Colforsin; D000242:Cyclic AMP; D009638:Norepinephrine