DISSOCIATION OF NEGATIVE INOTROPIC EFFECT OF CARBACHOL FROM CHANGES IN CAMP AND PKA IN PERFUSED RAT HEARTS

The purpose of this investigation was to determine whether muscarinic receptors are selectively coupled to the pool of adenylyl cyclase that is responsible for the elevation of particulate (membrane-bound) aden osine 3',5'-cyclic monophosphate (cAMP), because this appears to lead to translocation of particulate cAMP-dependent protein kinase A (PKA) to the soluble fraction and the positive inotropic response. Perfusion of hearts with carbachol and isoproterenol concurrently for 1.5 min p revented the increase in left ventricular pressure (LVP) found with is oproterenol alone, although isoproterenol-induced changes in total and particulate cAMP levels and soluble and particulate PKA activity were unaffected. However, perfusion of hearts with carbachol for 1 min the n with isoproterenol and carbachol for 1.5 min abolished the isoproter enol-induced increase in LVP and in total and particulate cAMP levels, although changes in total and particulate PKA. activity were only par tially attenuated. Perfusion of hearts with carbachol for 1 min then c arbachol plus forskolin for 2 or 5 min also completely prevented the f orskolin-induced increase in LVP without affecting the changes in eith er total or particulate cAMP levels or soluble or particulate PKA acti vity produced by this agent. Therefore, muscarinic receptors do not ap pear to selectively couple to the pool of adenylyl cyclase responsible for elevation of particulate cAMP levels. These data provide further evidence that antagonism of adenylyl cyclase activity is not required for the inhibition by carbachol of positive inotropic responses of ven tricular muscle to cAMP generating agents.