Attenuation of muscarinic cholinergic inhibition by islet-activating protein in the heart.

Experiments were carried out to investigate the influence of islet-activating protein (IAP), a pertussis toxin, on the autonomic regulation of cardiac function. In atria isolated from rats given intravenous IAP (0.125-1.0 micrograms/100 g body wt) 12-72 h prior to experiments, the negative chronotropic and inotropic actions of carbachol were attenuated in a dose- and time-dependent manner. The inhibitory action of carbachol in the absence of isoproterenol and its attenuation by IAP were not associated with any changes in tissue adenosine 3',5'-cyclic monophosphate (cAMP) levels. In addition, carbachol decreased the isoproterenol-induced elevation of cAMP levels and inhibited the positive chronotropic and inotropic responses to isoproterenol. The inhibitory action of carbachol on the isoproterenol-induced functional and cAMP responses was also reduced by the IAP treatment. The increase in tissue guanosine 3',5'-cyclic monophosphate (cGMP) levels produced by carbachol was likewise abolished by the IAP treatment. These results indicate that IAP treatment attenuates the inhibitory actions of carbachol elicited via muscarinic receptors through both cAMP-dependent and cAMP-independent subcellular processes.