Effects of alpha-adrenoceptor antagonists administered intraventricularly on central hypotensive action of clonidine and on central hypertensive action of methoxamine in rabbits.

In urethane-anesthetized rabbits blood pressure was lowered by intraventricular clonidine (30 microgram) and increased by intraventricular methoxamine (1 mg). Clonidine is well known to cause hypotension by acting on central alpha-adrenoceptors. The hypertensive effect of intraventricular methoxamine was not observed in cord-sectioned rabbits, in guanethidine-treated adrenalectomized rabbits and in phentolamine-treated rabbits, indicating the effect was central in origin. These responses to intraventricularly administered clonidine and methoxamine were examined in rabbits pretreated intraventricularly with various alpha-adrenoceptor antagonists believed to exhibit preference for alpha 1- or alpha 2-adrenoceptors in the peripheral tissues. Pretreatment with 250 microgram of yohimbine and with 500 microgram of piperoxan inhibited the clonidine hypotension, but pretreatment even with 2 mg of either of these drugs did not affect the methoxamine hypertension. In contrast, pretreatment with 8 microgram of prazosin inhibited the methoxamine effect, whereas pretreatment even with 1 mg of prazosin did not affect the clonidine effect. Pretreatment with 8 microgram of thymoxamine inhibited the methoxamine effect, while it was necessary to increase the doses for each drug up to 4 to 8 times to oppose the clonidine effect. Pretreatment with 2 mg of labetalol inhibited the methoxamine effect but was ineffective against clonidine. Pretreatment with 500 microgram of phentolamine was effective in antagonizing the clonidine effect but twice the dose was needed to inhibit the methoxamine effect. From the findings that the hypertensive effect of methoxamine and the hypotensive effect of clonidine were inhibited differently by various alpha-adrenoceptor antagonists and that the selectivity of these antagonists for the methoxamine and clonidine effect is similar, respectively, to that for alpha 1- and alpha 2-adrenoceptors in the peripheral tissues, we concluded that the methoxamine hypertension and the clonidine hypotension are due to the stimulation of alpha 1- and alpha 2- adrenoceptors in the brain, respectively.