Muscarinic regulation of phosphatidylinositol turnover and cyclic nucleotide metabolism in the heart.
Stimulation of cardiac muscarinic receptors leads to increases in the synthesis and hydrolysis of the membrane phospholipid phosphatidylinositol (PI). Carbachol stimulates PI hydrolysis in right and left murine atria as well as in murine ventricule and dissociated embryonic chick heart cells. Muscarinic stimulation of PI hydrolysis is markedly attenuated in calcium-free medium, is not antagonized by isoproterenol, occurs after a latency of several minutes, and is half-maximally activated by approximately 10 microM carbachol. In contrast, muscarinic inhibition of cyclic AMP accumulation in the same preparations is calcium independent, is opposed by the effect of isoproterenol, is maximal in minutes, and is half-maximally activated by 0.1 microM carbachol. These differences demonstrate that the two muscarinic receptor-mediated events are probably unrelated and independent responses. The concentration of carbachol that causes half-maximal activation of PI hydrolysis is almost identical to that causing half muscarinic receptor occupancy as assessed by 3H-labeled (-)-quinuclidinyl benzilate binding. Thus activation of the PI response by carbachol appears to be closely linked to receptor occupancy, whereas cyclase inhibition may occur when only a small percentage of receptors are occupied. The possible role of the PI response in generating intracellular signals such as arachidonic acid release, cyclic GMP synthesis, or C-kinase activation is discussed.
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002645:Chickens; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D010277:Parasympathomimetics / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000502:physiology*
D010277:Parasympathomimetics; D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic; D002217:Carbachol; D000242:Cyclic AMP; D006152:Cyclic GMP; D007545:Isoproterenol; D000109:Acetylcholine; D002118:Calcium