Hypothermic effect of hydralazine in rodents

1. Hydralazine injected i.p. produced dosedependent hypothermia in mice and rats. 2. The hypothermic response to hydralazine was attenuated by a dose of the same drug given 24 h earlier. The attenuation could not be attributed to nonspecific experimental factors and indicates the development of tolerance. 3. Tolerance to hydralazine was dose-dependent and of long duration: a single i.p. administration of the drug produced tolerance 24, 48 or 72 h later. 4. Rapid development of tolerance to the hypothermic effect of another vasodilator, ethanol, was also observed. No cross tolerance between hydralazine and ethanol was found. 5. Tolerance did not develop to the blood pressure lowering effect of hydralazine. 6. Hydralazine similarly induced hypothermia when administered i.p. at thermoneutrals environmental temperature. Tolerance was not seen after a second administration of hydralazine at thermoneutrality, but was found when the second administration was given at room temperature. 7. Intracerebroventricular administration of hydralazine also produced hypothermia. Subsequent i.c.v. administration did not reveal tolerance but tolerance was seen when the second administration was given i. p. 8. A behavioral thermoregulatory study indicated that the hypothermic effect of hydralazine is, at least in part, peripherally mediated but a central contribution to the development of tolerance could not be excluded.