β-Blocking and Hemodynamic Effects of ASL-8052

The hemodynamic and cardiac β-blocking effects of ASL-8052 (esmolol), an ultrashort-acting β-blocker, were examined in pentobarbital-anesthetized dogs. The compound produced dose-dependent reductions in heart rate, left ventricular dP/dt, right ventricular contractile force, and diastolic arterial blood pressure in dogs with intact autonomic function. ASL-8052 was devoid of any hemodynamic effects in ganglion-blocked animals. Responses to isoproterenol (except for diastolic blood pressure) were blocked by ASL-8052 in qualitatively similar fashion in both groups of animals. The compound reduced the rate-pressure product and decreased diastolic coronary blood flow. The reactive hyperemic response to a 10-s occlusion of the left circumflex coronary artery was not modified by ASL-8052. Heart rate and contractile force dose-response curves to isoproterenol were equally shifted to the right in a dose-dependent, parallel fashion by constant infusion of ASL-8052. During infusion of large doses in reserpinized dogs, the compound decreased heart rate, contractility, and arterial blood pressure, while left ventricular end-diastolic pressure increased. No intrinsic sympathomimetic effect was observed. Tachycardia induced by either stimulation of the right ansa subclavia or intravenous injection of isoproterenol was blocked to an equivalent degree by ASL-8052. These data indicate that ASL-8052 produces hemodynamic effects that are characteristic of and explained by β-adrenergic receptor blockade. However, direct cardiac depression is observed at extremely high doses.