Positive inotropic effects of the beta 2-adrenoceptor agonist terbutaline in the human heart: effects of long-term beta 1-adrenoceptor antagonist treatment

Department of Internal Medicine, University of Essen, Germany.

OBJECTIVES. This study was conducted to determine whether activation of cardiac beta 2-adrenoceptors increases contractility in humans and whether this is affected by long-term beta 1-adrenoceptor antagonist treatment. BACKGROUND. Coexistence of beta 1- and beta 2-adrenoceptors in the human heart is generally accepted. The functional importance of cardiac beta 2-adrenoceptors for increases in contractility in humans, however, has not been completely established. METHODS. We studied 1) the beta-adrenoceptor subtype mediating positive inotropic effects of the beta 2-adrenoceptor agonist terbutaline in vitro (on right atrial and left ventricular preparations from nonfailing human hearts) and increases in contractility (by measurement of systolic time intervals) in vivo in seven healthy male volunteers; and 2) in vivo whether long-term treatment of volunteers with the beta 1-adrenoceptor antagonist bisoprolol affects terbutaline-induced increases in contractility. RESULTS. In vitro terbutaline caused a concentration-dependent increase in atrial and ventricular adenylate cyclase activity and force of contraction. Terbutaline effects were antagonized only by the beta 2-adrenoceptor antagonist ICI 118,551, indicating that they were mediated by beta 2-adrenoceptor stimulation. In vivo intravenous infusions of terbutaline (dose range 25 to 300 ng/kg body weight per min for 15 min) dose dependently increased heart rate and shortened the pre-ejection period and heart rate-corrected electromechanical systole (QS2) time. These effects are mediated predominantly by beta 2-adrenoceptor stimulation because they were only marginally affected by the beta 1-adrenoceptor antagonist bisoprolol (1 x 10 mg orally), either given 2 h before infusion or long term for 3 weeks. CONCLUSIONS. Stimulation of cardiac beta 2-adrenoceptors in humans causes not only in vitro but also in vivo positive inotropic effects. Long-term beta 1-adrenoceptor antagonist treatment does not considerably affect beta 2-adrenoceptor-mediated in vivo increases in contractility. Thus, it may be possible to treat patients with chronic heart failure and long-term beta 1-adrenoceptor antagonist therapy with beta 2-adrenoceptor agonists if immediate inotropic support is needed.

This article has been cited by other articles:

				J. C Coons, M. Shullo, K. Schonder, and R. Kormos Terbutaline for Chronotropic Support in Heart Transplantation Ann. Pharmacother., April 1, 2004; 38(4): 586 - 589. [Abstract] [Full Text] [PDF]

				H. Bruck, K. Leineweber, A. Ulrich, J. Radke, G. Heusch, T. Philipp, and O.-E. Brodde Thr164Ile polymorphism of the human {beta}2-adrenoceptor exhibits blunted desensitization of cardiac functional responses in vivo Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2034 - H2038. [Abstract] [Full Text] [PDF]

				D. H. Au, E. M. Udris, V. S. Fan, J. R. Curtis, M. B. McDonell, and S. D. Fihn Risk of Mortality and Heart Failure Exacerbations Associated With Inhaled {beta}-Adrenoceptor Agonists Among Patients With Known Left Ventricular Systolic Dysfunction Chest, June 1, 2003; 123(6): 1964 - 1969. [Abstract] [Full Text] [PDF]

				M D Lowe, E Rowland, M J Brown, and A A Grace {beta}2 Adrenergic receptors mediate important electrophysiological effects in human ventricular myocardium Heart, July 1, 2001; 86(1): 45 - 51. [Abstract] [Full Text] [PDF]

				S. Dhein, P. Rohnert, S. Markau, E. Kotchi-Kotchi, K. Becker, U. Poller, B. Osten, and O.-E. Brodde Cardiac beta-adrenoceptors in chronic uremia: studies in humans and rats J. Am. Coll. Cardiol., August 1, 2000; 36(2): 608 - 617. [Abstract] [Full Text] [PDF]

				O.-E. Brodde and M. C. Michel Adrenergic and Muscarinic Receptors in the Human Heart Pharmacol. Rev., December 1, 1999; 51(4): 651 - 690. [Abstract] [Full Text] [PDF]

				G. E. Newton, E. R. Azevedo, and J. D. Parker Inotropic and Sympathetic Responses to the Intracoronary Infusion of a ß2-Receptor Agonist : A Human In Vivo Study Circulation, May 11, 1999; 99(18): 2402 - 2407. [Abstract] [Full Text] [PDF]

				R. F. Schäfers, J. Nürnberger, B. Herrmann, R. R. Wenzel, T. Philipp, and M. C. Michel Adrenoceptors Mediating the Cardiovascular and Metabolic Effects of alpha -Methylnoradrenaline in Humans J. Pharmacol. Exp. Ther., May 1, 1999; 289(2): 918 - 925. [Abstract] [Full Text]

				U. Poller, B. Fuchs, A. Gorf, J. Jakubetz, J. Radke, K. Ponicke, and O.-E. Brodde Terbutaline-induced desensitization of human cardiac {beta}2-adrenoceptor-mediated positive inotropic effects: attenuation by ketotifen Cardiovasc Res, October 1, 1998; 40(1): 211 - 222. [Abstract] [Full Text] [PDF]