The cardiovascular and adrenergic actions of verapamil or diltiazem in combination with propranolol during halothane anesthesia in the dog

Abstract

Continuous infusions of verapamil and diltiazem were established in halothane-anesthetized dogs (1.15-1.35% end tidal concentration) with or without a concomitant propranolol infusion to investigate changes: in cardiovascular function, in reflex activation as reflected in circulating catecholamine levels, and in the chronotropic response to the exogenously administered beta agonist, isoproterenol. Verapamil plasma levels of approximately 100 and 250 ng·ml-1, diltiazem plasma levels of approximately 140 and 325 ng·ml-1, and propranolol levels of approximately 70 ng·ml-1 were tolerated individually in the presence of halothane, although atrioventricular conduction was prolonged in the verapamil and diltiazem groups. Catecholamine levels were increased in the high verapamil group. However, when propranolol was combined with the lower levels of verapamil or diltiazem, the result was decreased heart rate, blood pressure, left ventricular maximum rate of tension development (dP/dt), and cardiac index with increased systemic vascular resistance. When the attempt was made to proceed to the increased plasma levels of verapamil or diltiazem in the presence of propranolol, 6/6 animals in the verapamil-propranolol group and 4/6 animals in the diltiazem-propranolol group were unable to maintain a mean arterial blood pressure of greater than 50 mmHg, and many development 2° or higher heart block. Analysis of the plots of the logarithms of the doses of isoproterenol versus changes in heart rate revealed that larger amounts of isoproterenol were required to achieve the same increase in heart rate as with halothane alone if these plasma levels of propranolol, verapamil, or diltiazem individually were present, and that very much larger doses of isoproterenol were required to increase heart rate to the same level as with halothane alone when a combined block with verapamil or diltiazem plus propranolol was present.