Dissociation of negative inotropic effect of carbachol from changes in camp and camp-dependent protein kinase in isolated perfused rat hearts. Zhang, Jack Zhen, and Kathleen M. Macleod. Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, B.C. V6T 1Z3, Canada
APStracts 3:0035H, 1996.
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) cAMP, since this appears to lead to translocation of particulate cAMP-dependent protein kinase (PKA) to the soluble fraction and the positive inotropic response. Perfusion of hearts with carbachol and isoproterenol concurrently for 1.5 min prevented the increase in left ventricular pressure (LVP) found with isoproterenol 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 then with isoproterenol and carbachol for 1.5 min abolished the isoproterenol-induced increase in LVP and in total and particulate cAMP levels, although changes in total and particulate PKA activity were only partially attenuated. Perfusion of hearts with carbachol for 1 min then carbachol plus forskolin for 2 or 5 min also completely prevented the forskolin-induced increase in LVP, without affecting the changes in either total or particulate cAMP levels or soluble or particulate PKA activity produced by this agent. Therefore, muscarinic receptors do not appear 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 ventricular muscle to cAMP-generating agents. 

Received 30 June 1995; accepted in final form 11 January 1996.
APS Manuscript Number H603-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 29 January 96