AJP - Heart and Circulatory Physiology, Vol 272, Issue 6 2726-H2735, Copyright © 1997 by American Physiological Society

ARTICLES

beta 1-and beta 2-adrenergic receptors exhibit differing susceptibility to muscarinic accentuated antagonism

O. Aprigliano, V. O. Rybin, E. Pak, R. B. Robinson and S. F. Steinberg
Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.

Neonatal rat ventricular myocytes express both beta 1-and beta 2-adrenergic receptors linked to enhanced intracellular adenosine 3',5'-cyclic monophosphate (cAMP) accumulation and the modulation of contractile function. This study tests the hypothesis that muscarinic agonists act via distinct mechanisms to interfere with beta 1-and beta 2-adrenergic receptor actions. The beta 2-selective agonist zinterol (10(-7) M) elicits approximately a fourfold increase in cAMP accumulation, which is mimicked, both in magnitude and kinetics, by 10(-9) M of the mixed 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. Carbachol inhibits all three responses (cAMP, inotropic, and lusitropic) elicited by isoproterenol. In contrast, carbachol does not interfere with the effect of zinterol to augment cAMP accumulation or to induce a positive inotropic response. However, carbachol inhibits the lusitropic response to zinterol via an action at an M2-muscarinic receptor linked to a pertussis toxin-sensitive pathway. Additional studies indicate that beta 2-receptor-dependent phosphorylation of troponin I and phospholamban is substantially attenuated by carbachol. We conclude that carbachol interferes with beta 1-receptor actions by reducing cAMP accumulation. 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 M2-muscarinic receptor coupled to a pertussis toxin-sensitive G protein, which leads to inhibition of troponin I and phospholamban phosphorylation and inhibition of the beta 2-receptor-dependent lusitropic response.

This article has been cited by other articles:

				P. M. Ecker, C.-C. Lin, J. Powers, B. K. Kobilka, A. M. Dubin, and D. Bernstein Effect of targeted deletions of {beta}1- and {beta}2-adrenergic-receptor subtypes on heart rate variability Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H192 - H199. [Abstract] [Full Text] [PDF]

				P. McConville, R. G. Spencer, and E. G. Lakatta Temporal dynamics of inotropic, chronotropic, and metabolic responses during {beta}1- and {beta}2-AR stimulation in the isolated, perfused rat heart Am J Physiol Endocrinol Metab, September 1, 2005; 289(3): E412 - E418. [Abstract] [Full Text] [PDF]

				Y. Xiang, E. Devic, and B. Kobilka The PDZ Binding Motif of the beta 1 Adrenergic Receptor Modulates Receptor Trafficking and Signaling in Cardiac Myocytes J. Biol. Chem., September 6, 2002; 277(37): 33783 - 33790. [Abstract] [Full Text] [PDF]

				Y. Xiang, V. O. Rybin, S. F. Steinberg, and B. Kobilka Caveolar Localization Dictates Physiologic Signaling of beta 2-Adrenoceptors in Neonatal Cardiac Myocytes J. Biol. Chem., September 6, 2002; 277(37): 34280 - 34286. [Abstract] [Full Text] [PDF]

				E. Devic, Y. Xiang, D. Gould, and B. Kobilka beta -Adrenergic Receptor Subtype-Specific Signaling in Cardiac Myocytes from beta 1 and beta 2 Adrenoceptor Knockout Mice Mol. Pharmacol., September 1, 2001; 60(3): 577 - 583. [Abstract] [Full Text] [PDF]

				D. M. Bers and M. T. Ziolo When Is cAMP Not cAMP?: Effects of Compartmentalization Circ. Res., August 31, 2001; 89(5): 373 - 375. [Full Text] [PDF]

				T. J. Kamp and J. W. Hell Regulation of Cardiac L-Type Calcium Channels by Protein Kinase A and Protein Kinase C Circ. Res., December 8, 2000; 87(12): 1095 - 1102. [Abstract] [Full Text] [PDF]

				Z. Nagykaldi, D. Kem, R. Lazzara, and B. Szabo Conditioning of beta 1-adrenoceptor effect via beta 2-subtype on L-type Ca2+ current in canine ventricular myocytes Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1329 - H1337. [Abstract] [Full Text] [PDF]

				S. F. Steinberg The Molecular Basis for Distinct {beta}-Adrenergic Receptor Subtype Actions in Cardiomyocytes Circ. Res., November 26, 1999; 85(11): 1101 - 1111. [Full Text] [PDF]

				V. O. Rybin, X. Xu, M. P. Lisanti, and S. F. Steinberg Differential Targeting of beta -Adrenergic Receptor Subtypes and Adenylyl Cyclase to Cardiomyocyte Caveolae. A MECHANISM TO FUNCTIONALLY REGULATE THE cAMP SIGNALING PATHWAY J. Biol. Chem., December 22, 2000; 275(52): 41447 - 41457. [Abstract] [Full Text] [PDF]

				S.-J. Zhang, H. Cheng, Y.-Y. Zhou, D.-J. Wang, W. Zhu, B. Ziman, H. Spurgoen, R. J. Lefkowitz, E. G. Lakatta, W. J. Koch, et al. Inhibition of Spontaneous beta 2-Adrenergic Activation Rescues beta 1-Adrenergic Contractile Response in Cardiomyocytes Overexpressing beta 2-Adrenoceptor J. Biol. Chem., July 7, 2000; 275(28): 21773 - 21779. [Abstract] [Full Text] [PDF]