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The effects of clonidine, a potent central alpha-adrenergic agonist, and of tolazoline, an alpha-adrenergic antagonist, on the minimal anesthetic concentration (MAC) of halothane were studied in male mongrel dogs. Control halothane MAC was 0.8 +/- 0.04 vol% (determined in each dog by gas chromatography of arterial blood, n = 30). Clonidine, 5 microgram/kg (n = 10) and 20 microgram/kg (n = 10), give slowly intravenously, maximally reduced MAC by 42% (at 2.3 hours after clonidine) and 48% (at 2.6 hours after clonidine) for each dose. In another set of animals (n = 5) an alpha-adrenergic antagonist, tolazoline, 5 mg/kg IV, reversed the clonidine-induced reduction in halothane MAC rapidly and completely. Tolazoline alone, 5 mg/kg, (n = 5) had no significant effect on halothane MAC. Thus, the administration of the central alpha-adrenergic agonist clonidine decreased the required anesthetic concentration of halothane, as defined by MAC, by almost half. This effect, as it is reversed by tolazoline, is likely to be mediated through a central alpha-adrenergic receptor mechanism.

The effect of verapamil, 0.2 mg/kg i.v. over 30 s, on the amount of epinephrine required to elicit a reproducible ventricular arrhythmia during 0.9% halothane in oxygen anesthesia was investigated in two groups of dogs after three consecutive doses of verapamil given at 90 (group I) and 120 min (group II) intervals, respectively. Verapamil caused a stepwise cumulative increase in the arrhythmogenic dose of epinephrine in both groups despite plasma verapamil levels that declined to low levels (28 and 22 ng/ml, respectively) between doses. Control epinephrine arrhythmogenic doses were 2.89 +/- 0.54 and 2.74 +/- 0.19 microgram/kg/min (mean +/- SEM), respectively, for groups I and II, and rose to 4.58 +/- 0.72 and 4.55 +/- 0.30 microgram/kg/min after the first verapamil dose, to 6.20 +/- 0.74 and 6.13 +/- 0.40 microgram/kg/min after the second verapamil dose, and 8.16 +/- 0.85 and 8.09 +/- 0.95 microgram/kg/min after the third verapamil dose, respectively. All postverapamil epinephrine arrhythmogenic dose values were significantly elevated above control and above the preceding values, although there was no significant difference between the two groups. Changes in heart rate or blood pressure were similar among the three doses of verapamil in each group. These results can be interpreted to indicate that, unlike hemodynamic effects that appear to parallel plasma verapamil concentrations, the protective effects of verapamil against halothane--epinephrine ventricular arrhythmias may not be accurately reflected by plasma verapamil levels and may be significantly present when plasma levels are too low to cause measurable hemodynamic effects.

The cardiovascular responses to increasing infusion rates of the slow calcium channel inhibitor, verapamil, were studied in three groups of dogs during either enflurane, isoflurane, or halothane anesthesia. Control hemodynamic values and plasma samples were taken after 2 h of anesthesia with the given agent. Increasing infusion rates of verapamil were given to achieve a range of plasma verapamil levels up to approximately 500 ng X ml-1. Each infusion rate was administered for 30 min, at which time repeat measurements and plasma samples for verapamil were taken. Mean arterial blood pressure, cardiac index, and left ventricular dP/dt decreased with increasing plasma verapamil levels in the enflurane and isoflurane groups compared with the control values. The values for the enflurane-verapamil combination were significantly lower than those for the other anesthetics at comparable verapamil levels. Compared with enflurane, higher verapamil levels were required with isoflurane to achieve the equivalent degree of hemodynamic depression. A higher incidence of conduction abnormalities also was noted in the enflurane group. In the halothane group, the only significant change observed at these verapamil levels, achieved by continuous infusion, was a prolongation of the PR interval of the ECG. In this animal model, verapamil was least well tolerated by the cardiovascular system during enflurane anesthesia.

The relationship between halothane concentration and tachyphylaxis to sodium nitroprusside (SNP) was studied in a rabbit model. Three groups of six rabbits (groups A, B, and C) were anesthetized with halothane at 0.75, 1.0, and 1.25 vol% end-tidal, respectively. SNP-induced hypotension was maintained for 135 min or until a cumulative total dose of 12 mg/kg had been infused (defined as "marked tachyphylaxis"). Plasma norepinephrine (NE), epinephrine (EPI) levels, and plasma renin activity (PRA) were measured. Initial mean arterial pressure (MAP) (72 +/- 2 mm Hg), heart rate (325 +/- 12 beats/min), and the amount of SNP required to induce 40% hypotension (19 +/- 4 micrograms/kg/min) did not differ significantly among the three groups. In group A, five out of six animals exhibited "marked tachyphylaxis." In group B, only one animal showed "marked tachyphylaxis"; the remaining five required a dose rate of 104 +/- 38 micrograms/kg/min at 135 min to maintain a 40% reduction in MAP. In group C, none of the animals showed "marked tachyphylaxis"; the dose rate of SNP required after 135 min was 29 +/- 14 micrograms/kg/min. In all groups, SNP dose rate was found to best correlate (p less than 0.0005, r = 0.79) with NE levels and not with PRA or arterial blood pH. This implies that reflex sympathetic activation is the measured mediator of SNP tachyphylaxis. Halothane blunted the tachyphylaxis (sympathetic response) to SNP-induced hypotension at higher concentrations.