Differential Depressant Effects of General Anesthetics on the Cardiovascular Response to Cocaine in Mice

Abstract

In recent years, murine models have gained increasing importance for studies of cardiovascular physiology and pharmacology, largely due to the development of transgenic strains with specific alterations in phenotype. Differential effects of general anesthetic agents on the cardiovascular responses to cocaine have been reported in larger mammals; therefore, we studied the effects of commonly used anesthetics on heart function and on blood pressure responses to cocaine in Swiss Webster mice. We positioned a polyethylene catheter (PE-10) in the right carotid artery or left ventricle of mice anesthetized with equivalent anesthetic dose of either ketamine-xylazine (KX, 40 mg/kg + 5 mg/kg), pentobarbital (PEN, 40 mg/kg) or a-chloralose-urethane (CU, 80 mg/kg + 100 mg/kg). Cocaine (0.3 mg/kg, 1 mg/kg and 3 mg/kg) was administrated via the left jugular vein by bolus injection. In the KX group, the basal mean arterial pressure (MAP) and systolic left ventricular pressure (LVP) were 110 12 and 120 f 13 mmHg, respectively, close to conscious values. However, PEN and CU significantly decreased the basal parameters (P < 0.01 compared to the KX group). The lowest dose of cocaine (0.3 mg/kg) elicited minimal changes. Significant responses were obtained with a 1-mg/kg dose of cocaine ( P < 0.01 compared to baseline). However, at 3 mg/kg, a toxic effect of cocaine appeared in all three anesthetic groups. Compared to published conscious animal data, anesthetic agents attenuated the cardiovascular effects of cocaine. Taken together, our results indicate that minimally effective doses of general anesthetics may significantly alter the basal hemodynamic state and the responses to sympathomimetic agents in the murine model, as has been reported in larger mammalian species. We concluded that anesthesia with ketamine-xylazine provides baseline hemodynamic values close to reported values in conscious animals, but also attenuates the hemodynamic response to cocaine. [P.S.E.B.M. 1999[P.S.E.B.M. , Vol 2211 n recent years, there has been a dramatic increase in the number of patients with a history of cocaine abuse who I demonstrate various cardiovascular signs and symptoms, such as acute myocardial ischemia and infarction, arrhythmia and sudden death, contraction band necrosis, myocarditis, cardiomyopathy, and hypertension (1-3). Moreover, long-term exposure to cocaine has been shown to induce uterine and fetal blood flow disorders, fetal growth restriction, and hypoxia (4). Studies have reported a significant influence of cocaine administration on cardiovascular function in pigs, dogs, ferrets and rats (5-7). Nunez and Morgan (8, 9) reported that acute or chronic cocaine exposure induced microvascular vasoconstriction and produced myocardial ischemia and infarction. Stambler et al. (10) reported that, in conscious dogs, cocaine showed a biphasic effect on blood pressure, first causing transient depression followed by enhanced left ventricular function. The changes in cardiovascular function caused by cocaine were associated with catecho...