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.