ejp ELSEVIER European Journal of Pharmacology 316 (1996) 237-244 Increases in inotropic state without change in heart rate" Combined use of dobutamine and zatebradine in conscious dogs Douglas A. Hettrick, Paul S. Pagel, Dermot Lowe, John P. Tessmer, David C. Warltier * Departments of Anesthesiology, Pharmacology and Medicine (Dicision of Cardiot,ascular Diseases), Medical College of Wisconsin, and Zablocki VA Medical Center, Milwaukee, W153226, USA Received 9 May 1996; revised 20 August 1996; accepted 23 August 1996 Abstract The cardiovascular and left ventricular functional effects of dobutamine (5, 10 and 20 Ixg kg-~ rain J) were examined in conscious, chronically instrumented dogs in the presence and absence of control of heart rate with the specific bradycardic agent, zatebradine. Dobutamine increased heart rate, cardiac output, stroke volume, diastolic coronary blood flow velocity and pressure-work index (calculated myocardial oxygen consumption) and decreased systemic vascular resistance and diastolic coronary vascular resistance. Mean arterial pressure and left ventricular systolic and end-diastolic pressures were unchanged. Dobutamine-induced increases in heart rate and pressure-work index were attenuated by zatebradine. Dobutamine alone increased preload recruitable stroke work slope (63 _+ 6 to 116 _+ 11 mmHg) and + d P/d t. These positive inotropic effects were unaffected by zatebradine. Dobutamine decreased the time constant of isovolumic relaxation (30 _+ 3 to 25 -t- 2 ms). Dobutamine-induced decreases in the time constant of isovolumic relaxation were not altered by zatebradine, indicating that changes in the time constant occurred independent of heart rate. Dobutamine also increased the maximal segment lengthening velocity to a similar degree in zatebradine-treated versus untreated dogs. Control of dobutamine-induced tachycardia by zatebradine decreases myocardial oxygen consumption but does not alter the positive inotropic and lusitropic effects of dobutamine. Keywords: lsovolumic relaxalion; Ventricular filling; Myocardial contractility; Preload recruitable stroke work; Inotropes; Dobutamine; Bradycardic agents, specific; Zatebradine 1. Introduction Dobutamine has been shown to enhance myocardial contractility, produce beneficial effects on left ventricular diastolic function and reduce afterload in the failing heart (Ruffolo, 1987; Sonnenblick et al., 1979). However, tachy- cardia produced by dobutamine may adversely affect my- ocardial oxygen supply-demand relations in this setting despite concomitant improvements in ventricular loading conditions. The heart rate-dependence of dobutamine-in- duced enhancement of left ventricular systolic and dias- tolic function has not been established. This investigation examined the effects of dobutamine on systemic and coro- nary hemodynamics and left ventricular function in con- scious dogs in the presence and absence of zatebradine (UL FS-49), a specific bradycardic agent. Zatebradine has been shown to reduce heart rate by specifically decreasing * Corresponding author. Tel.: (1-414) 456-5735; Fax: (1-414) 266-8541. the rate of sinoatrial node discharge by inhibiting the hyperpolarizing-activated current in sinoatrial tissue (Van Bogaert et al., 1990) without directly altering inotropic and lusitropic state or peripheral vascular tone (Breall et al., 1993; Johnston et al., 1991; Pagel et al., 1995; Riley et al., 1987). The present investigation tested the hypothesis that dobutamine-induced enhancement of left ventricular sys- tolic and diastolic function occurs independent of increases in heart rate produced by this drug. 2. Materials and methods All experimental procedures and protocols used in this investigation were reviewed and approved by the Animal Care and Use Committee of the Medical College of Wis- consin. All procedures conformed to the 'Guiding Princi- ples of the Care and Use of Animals' of the American Physiologic Society and were in accordance with the 'Guide for the Care and Use of Laboratory Animals' (DHEW (DHHS) publication (NIH) 85-23, revised 1985). 0014-2999/96/$15.00 Copyright © 1996 Elsevier Science B.V. All rights reserved. PII S00 14-2999(96)0068 8-7