Circulation Research, Vol 59, 297-309, Copyright © 1986 by American Heart Association

ARTICLES

Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down- regulation in heart failure

MR Bristow, R Ginsburg, V Umans, M Fowler, W Minobe, R Rasmussen, P Zera, R Menlove, P Shah and S Jamieson

We used radioligand binding techniques and measurement of beta-agonist- mediated positive inotropic responses in isolated cardiac tissue to examine beta-adrenergic-receptor subpopulations in nonfailing and failing human left and right ventricular myocardium. In tissue derived from 48 human hearts the receptor subtypes identified in nonfailing ventricle by radioligand binding were beta 1 (77%) and beta 2 (23%), with no evidence of an "atypical" beta-adrenergic receptor. In failing left ventricle the beta 1:beta 2 ratio was markedly different, i.e., 60:38. This decrease in the beta 1 proportion and increase in the beta 2 proportion in the failing ventricles were due to a 62%, "selective" down-regulation of the beta 1 subpopulation, with little or no change in beta 2 receptors. In muscle bath experiments in isolated trabeculae derived from nonfailing and failing right ventricles, both beta 1- and beta 2-adrenergic receptors were coupled to a positive inotropic response. In nonfailing myocardium, beta 1 responses predominated, as the selective beta 1 agonist denopamine produced a response that was 66% of the total contractile response of isoproterenol. In heart failure the beta 1 component was markedly decreased, while the beta 2 component was not significantly diminished. Moreover, in heart failure the beta 2 component increased in prominence, as the contractile response to the selective beta 2 agonist zinterol increased from a minority (39%) to a majority (60%) of the total response generated by isoproterenol. We conclude that failing human ventricular myocardium contains a relatively high proportion of beta 2 receptors, due to selective down-regulation of beta 1 receptors. As a result, in the failing human heart the beta 2-receptor subpopulation is a relatively important mediator of inotropic support in response to nonselective beta-agonist stimulation and is available for inotropic stimulation by selective beta 2 agonists.

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				M. Jain, C. C. Lim, K. Nagata, V. M. Davis, D. S. Milstone, R. Liao, and R. M. Mortensen Targeted inactivation of G{alpha}i does not alter cardiac function or {beta}-adrenergic sensitivity Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H569 - H575. [Abstract] [Full Text] [PDF]

				R Schulz and G Heusch Hibernating myocardium Heart, December 1, 2000; 84(6): 587 - 594. [Full Text]

				N.G. Mahon and W.J. Mckenna Genes and acquired disease: beta-adrenoceptor polymorphisms and heart failure Eur. Heart J., November 2, 2000; 21(22): 1810 - 1812. [PDF]

				E. A. Sosunov, R. Z. Gainullin, N.S. Moise, S. F. Steinberg, P. Danilo Jr., and M. R. Rosen {beta}1 and {beta}2-adrenergic receptor subtype effects in German shepherd dogs with inherited lethal ventricular arrhythmias Cardiovasc Res, November 1, 2000; 48(2): 211 - 219. [Abstract] [Full Text] [PDF]

				R.-P. Xiao Cell Logic for Dual Coupling of a Single Class of Receptors to Gs and Gi Proteins Circ. Res., October 13, 2000; 87(8): 635 - 637. [Full Text] [PDF]

				Y. G. Wang, A. M Samarel, and S. L Lipsius Laminin binding to {beta}1-integrins selectively alters {beta}1- and {beta}2-adrenoceptor signalling in cat atrial myocytes J. Physiol., August 15, 2000; 527(1): 3 - 9. [Abstract] [Full Text] [PDF]

				M. Zaugg, W. Xu, E. Lucchinetti, S. A. Shafiq, N. Z. Jamali, and M. A. Q. Siddiqui {beta}-Adrenergic Receptor Subtypes Differentially Affect Apoptosis in Adult Rat Ventricular Myocytes Circulation, July 18, 2000; 102(3): 344 - 350. [Abstract] [Full Text] [PDF]

				H. K. Ranu, J. C. W. Mak, P. J. Barnes, and S. E. Harding Gi-dependent suppression of beta 1-adrenoceptor effects in ventricular myocytes from NE-treated guinea pigs Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1807 - H1814. [Abstract] [Full Text] [PDF]

				W. W. Brooks, O. H. L. Bing, M. O. Boluyt, A. Malhotra, J. P. Morgan, N. Satoh, W. S. Colucci, and C. H. Conrad Altered Inotropic Responsiveness and Gene Expression of Hypertrophied Myocardium With Captopril Hypertension, June 1, 2000; 35(6): 1203 - 1209. [Abstract] [Full Text] [PDF]

				H.-J. Weig, K.-L. Laugwitz, A. Moretti, K. Kronsbein, C. Stadele, S. Bruning, M. Seyfarth, T. Brill, A. Schomig, and M. Ungerer Enhanced Cardiac Contractility After Gene Transfer of V2 Vasopressin Receptors In Vivo by Ultrasound-Guided Injection or Transcoronary Delivery Circulation, April 4, 2000; 101(13): 1578 - 1585. [Abstract] [Full Text] [PDF]

				J. S. Danetz, R. D. Davies, H. F. Clemo, and C. M. Baumgarten RABBIT VENTRICULAR MYOCYTE VOLUME CHANGES AS A DIRECT RESULT OF CRYSTALLOID CARDIOPLEGIA IN CONGESTIVE HEART FAILURE INDUCED BY AORTIC REGURGITATION J. Thorac. Cardiovasc. Surg., April 1, 2000; 119(4): 826 - 833. [Abstract] [Full Text] [PDF]

				S. F. Vatner, D. E. Vatner, and C. J. Homcy {beta}-Adrenergic Receptor Signaling: An Acute Compensatory Adjustment--Inappropriate for the Chronic Stress of Heart Failure? : Insights from Gs{alpha} Overexpression and Other Genetically Engineered Animal Models Circ. Res., March 17, 2000; 86(5): 502 - 506. [Full Text] [PDF]

				M. R. Bristow {beta}-Adrenergic Receptor Blockade in Chronic Heart Failure Circulation, February 8, 2000; 101(5): 558 - 569. [Full Text] [PDF]

				C. A. Walker, F. A. Crawford Jr, and F. G. Spinale MYOCYTE CONTRACTILE DYSFUNCTION WITH HYPERTROPHY AND FAILURE: RELEVANCE TO CARDIAC SURGERY J. Thorac. Cardiovasc. Surg., February 1, 2000; 119(2): 388 - 400. [Full Text] [PDF]

				T. Tanigawa, M. Yano, M. Kohno, T. Yamamoto, T. Hisaoka, K. Ono, T. Ueyama, S. Kobayashi, Y. Hisamatsu, T. Ohkusa, et al. Mechanism of preserved positive lusitropy by cAMP-dependent drugs in heart failure Am J Physiol Heart Circ Physiol, February 1, 2000; 278(2): H313 - H320. [Abstract] [Full Text] [PDF]

				K. M. Burrell, P. Molenaar, P. J. Dawson, and A. J. Kaumann Contractile and Arrhythmic Effects of Endothelin Receptor Agonists in Human Heart In Vitro: Blockade with SB 209670 J. Pharmacol. Exp. Ther., January 1, 2000; 292(1): 449 - 459. [Abstract] [Full Text]

				R.-P. Xiao, H. Cheng, Y.-Y. Zhou, M. Kuschel, and E. G. Lakatta Recent Advances in Cardiac {beta}2-Adrenergic Signal Transduction Circ. Res., November 26, 1999; 85(11): 1092 - 1100. [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]

				C. K. Billington, I. P. Hall, S. J. Mundell, J.-L. Parent, R. A. Panettieri Jr., J. L. Benovic, and R. B. Penn Inflammatory and Contractile Agents Sensitize Specific Adenylyl Cyclase Isoforms in Human Airway Smooth Muscle Am. J. Respir. Cell Mol. Biol., November 1, 1999; 21(5): 597 - 606. [Abstract] [Full Text]

				M. M Borst, P. Szalai, N. Herzog, W. Kubler, and R. H Strasser Transregulation of adenylyl-cyclase-coupled inhibitory receptors in heart failure enhances anti-adrenergic effects on adult rat cardiomyocytes Cardiovasc Res, October 1, 1999; 44(1): 113 - 120. [Abstract] [Full Text] [PDF]