BETA(1)-ADRENERGIC AND BETA(2)-ADRENERGIC RECEPTORS EXHIBIT DIFFERINGSUSCEPTIBILITY TO MUSCARINIC ACCENTUATED ANTAGONISM

Neonatal rat ventricular myocytes express both beta(1)- and beta(2)-ad renergic receptors linked to enhanced intracellular adenosine 3',5'-cy clic monophosphate (cAMP) accumulation and the modulation of contracti le function. This study tests the hypothesis that muscarinic agonists act via distinct mechanisms to interfere with beta(1)- and beta(2)-adr energic receptor actions. The beta(2)-selective agonist zinterol(10(-7 ) M) elicits approximately a fourfold increase in cAMP accumulation, w hich is mimicked, both in magnitude and kinetics, by 10(-9) M of the m ixed beta(1)-receptor agonist/beta(2)-receptor agonist isoproterenol. At these concentrations, isoproterenol and zinterol elicit equivalent inotropic and lusitropic (i.e., enhanced relaxation) responses. Carbac hol inhibits all three responses (cAMP, inotropic, and lusitropic) eli cited by isoproterenol. In contrast, carbachol does not interfere with the effect of zinterol to augment cAMP accumulation or to induce a po sitive inotropic response. However, carbachol inhibits the lusitropic response to zinterol via an action at an M-2-muscarinic receptor linke d to a pertussis toxin-sensitive pathway. Additional studies indicate that beta(2)-receptor-dependent phosphorylation of troponin I and phos pholamban is substantially attenuated by carbachol. We conclude that c arbachol interferes with beta(1)-receptor actions by reducing cAMP acc umulation. In contrast, the anti-beta(2)-receptor actions of carbachol are mediated by a mechanism that is distinct from inhibition of cAMP accumulation, involving an M-2-muscarinic receptor coupled to a pertus sis toxin-sensitive G protein, which leads to inhibition of troponin I and phospholamban phosphorylation and inhibition of the beta(2)-recep tor-dependent lusitropic response.