Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. V. Role of pharmacokinetics and the autonomic nervous system in the interactions between verapamil and inhalational anesthetics

To assess the role of both pharmacokinetics and the autonomic nervous system in the interaction between inhalational anesthetics and verapamil, dogs were chronically instrumented to measure heart rate, PR interval, dP/dt, cardiac ouput, and aortic blood pressure. In a first group of seven dogs, studied awake and during halothane (1.2%), enflurane (2.5%), and isoflurane anesthesia (1.6%), verapamil was infused for 30 min in doses calculated to obtain similar plasma concentrations (83 ± 10, 82 ± 6, 81 ± 10, and 77 ± 9 ng · ml^-a1, respectively). For the latter purpose, the infusion dose was 3 and 2 μg · kg^-1 · min^-1 awake and during anesthesia, respectively, preceded by a loading dose of 200, 150, and 100 μg · kg^-1, awake, during isoflurane, and halothane and enflurane, respectively. In awake dogs, verapamil induced an increase in heart rate (24 ± 5 bpm) and PR interval (35 ± 9 msec) and a decrease in mean arterial pressure (-5 ± 2 mmHg) and dP/dt (-494 ± 116 mmHg/s). Although plasma concentrations were similar in awake and in anesthetized dogs, the only statistically significant changes induced by verapamil were an increase in heart rate and a decrease in dP/dt during halothane and enflurane, while left atrial pressure increased only with enflurane. In a second group of six dogs, verapamil pharmacokinetics were determined in the presence and absence of a ganglionic blocking drug (chlorisondamine, 2 mg · kg^-1 iv). Blockade of ganglionic transmission resulted in a decrease in both initial volume of distribution and total clearance of verapamil - changes similar to those previously reported with inhalational anesthetics. The authors' data demonstrate the importance of pharmacokinetics in the interaction between verapamil and inhalational anesthetics. Also demonstrated is the importance of autonomic nervous transmission blockade on the inhalational anesthetic-induced effects of verapamil properties.