[Mode of action of clonidine, a central hypotensive agent, analyzed by the interaction with various sympathomimetic...

Injection of a low dose of clonidine showed the biphasic blood pressure response which comprises a delayed onset of long lasting hypotension and a quick onset of hypertension of short duration followed by the former, in the alpha-chloralose-urethanized rat. A second injection of low dose of clonidine administered 90 min after the first showed only two peaks of pressor response, no longer a depressor one, and tachyphylaxis occurred with repeated injections of the same dose of clonidine, together with a gradual elevation of blood pressure level. Furthermore, the depressor action was inhibited by pretreatment with cocaine or imipramine. In contrast, injection of a high dose of clonidine exhibited pressor response with only two peaks, duration of which was markedly potentiated by pretreatment with cocaine or imipramine, and also by guanethidine, but inhibited in reserpinized and spinal rats. While the blood pressure was sustained at a high level after the injection of a high dose os clonidine, blood pressure reversal was produced by tyramine, due to possible beta-mimetic action of much greater amounts of catecholamines released by tyramine. The isolated guinea-pig vas deferens contracted when treated with clonidine, and this contraction was inhibited in the reserpinized preparation. This inhibition was recovered by incubation with norepinephrine. Interaction between tyramine and clonidine was also seen in vitro, but it disappeared in the reserpinized, denervated or propranolol-pretreated guinea-pig vas deferens. The contraction of the vas deferens induced by clonidine was potentiated by pretreatment with cocaine, but not by pretreatment with guanethidine, ans was inhibited by treatment with alpha-adrenergic blocking agents phentolamine and phentolame and phenoxybenzamine, but not by tolazoline.