Author + information
- Received April 27, 1992
- Revision received July 15, 1992
- Accepted July 16, 1992
- Published online February 1, 1993.
- Jeffrey A. Breall, MD, PhD,
- Jun Watanabe, MD, PhD and
- William Grossman, MD, FACC∗
- ↵∗Address for correspondence: William Grossman, MD, Cardiovascular Division, Beth Israel Hospital, 330 Brookline Avenue, Boston, Massachusetts 02215.
Objectives. The purpose of this study was to compare the effects of zatebradine on heart rate, contractility and relaxation with those of its structural analog verapamil. We used isoproterenol, a potent beta-agonist, to see how these effects were modulated by sympathetic activation. We also compared the effects of zatebradine and verapamil on coronary blood flow and coronary blood flow reserve.
Background. Zatebradine, previously called UL-FS 49, is a new bradycardic agent believed to act selectively at the sinoatrial node.
Methods. Isolated isovolumetric pig hearts were prepared and left ventricular pressure, its first derivative (dP/dt), tau and heart rate were measured both before and after administration of either 0.975 mg of zatebradine (Group I, n = 8) or 125 μg of verapamil (Group II, n = 8). After the effects of each drug reached a plateau, a continuous infusion of isoproterenol was started and measurements were obtained again and compared with a third group of measurements from control hearts infused with isoproterenol after receiving only saline solution (n = 8). We also assessed the effects of zatebradine and verapamil on coronary vascular tone by measuring flow in the left anterior descending coronary artery in intact anesthetized open chest pigs both before and after the Intracoronary administration of these drugs (n = 8 for each). All preparations were atrially paced to negate any bradycardic effects of the drugs.
Results. In the group that received zatebradine, mean (±SE) heart rate decreased from 143 ± 8 to 99 ± 4 beats/min (p < 0.01) and there was no significant change in either peak left veatricular systolic pressure, dP/dt or tau. In contrast, verapamil produced a lesser decrease in heart rate (136 ± 7 to 120 ± 7 beats/min, p < 0.05) but produced substantial decreases in peak left ventricular pressure (100 ± 3 to 45 ± 4 mm Hg, p < 0.01) and dP/dt (68% decrease, p < 0.01) and an increase in tau (+26%, p < 0.05). Isoproterenol restored these variables toward normal values in the hearts treated with verapamil, although left vestricular systolic pressure and dP/dt were restored to control values only at the highest isoproterenol concentrations. In the hearts treated with zatebradine, isoproterenol sagnificantly increased left ventricular pressure and contractility and decreased tau; however, beast rate remained unchanged at peak effect. Zatebradine had no effect on coronary blood flow and there was a 100% increase in flow with reactive heyperemia, Conversely, verapamil increased coromry flow by 100%, with no subsequent further increase by reactive hyperemia compared with control values.
Conclusions. Although structurally similar to verapamil, zatebradine is a nighty specific bradycardic agent. It has little direct effect on left ventricular developed pressare, contractility, relaxation and coronary vascular tone. Furthermore, the bradycardic effect of zatebradine unlike that of verapamil, is not overcome by doses of isoproterenol that increase developed pressure and contractility and improve relaxation. Because of its highly specific bradycardic effect, this drug may potentially be useful in treating patients with ischemic heart disease or congestive heart failure.
☆ This study was supported in part by Cardiovascular Research Training Grant HL 07374 from the National Institutes of Health, Bethesda, Maryland. It was presented in part at the 40th Annual Scientific Session of the American College of Cardiology, Atlanta. Georgia, March 1991. Zatebradine was generously supplied by Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
- Received April 27, 1992.
- Revision received July 15, 1992.
- Accepted July 16, 1992.