Analysis of the receptor involved in the central hypotensive effect of rilmenidine and moxonidine.

The aim of this study was to determine whether alpha2-adrenoceptors or imidazoline I1-receptors are responsible for the central sympathoinhibition produced by rilmenidine and moxonidine, two clonidine-like antihypertensive drugs. Rilmenidine and moxonidine were compared with the indirectly acting alpha2-adrenoceptor agonist alpha-methyldopa. Three antagonists were used. Yohimbine and SK&F86466 were used as selective alpha2-adrenoceptor antagonists. They were compared with efaroxan which is also an alpha2-adrenoceptor antagonist, but, in addition, possesses affinity for imidazoline I1-receptors. According to some but not all studies, the affinity of efaroxan for I1-receptors is much higher than its affinity for alpha2-adrenoceptors. Drugs were administered into the cisterna cerebellomedullaris of conscious rabbits by a catheter implanted previously under halothane anaesthesia. Rilmenidine (10 microg kg(-1)), moxonidine (0.3 microg kg(-1)) and alpha-methyldopa (0.4 mg kg(-1)) lowered blood pressure and the plasma noradrenaline concentration; the degree of sympathoinhibition produced by the three agonists was very similar. When injected after the agonists, efaroxan (0.1-14 microg kg(-1); cumulative doses), yohimbine (0.4-14 microg kg(-1)) and SK&F86466 (0.4-44 microg kg(-1)) counteracted the effects of the agonists on blood pressure and the plasma noradrenaline concentration. Efaroxan was about tenfold more potent than yohimbine and SK&F86466 at antagonizing the hypotensive effects of alpha-methyldopa. Similarly, efaroxan was two- to tenfold more potent than yohimbine and SK&F86466 against rilmenidine and moxonidine. Finally, efaroxan was about as potent against alpha-methyldopa as against rilmenidine and moxonidine. The results confirm previous observations that selective alpha2-adrenoceptor antagonists are capable of completely antagonizing effects of rilmenidine and moxonidine. The effects of the alpha2-adrenoceptor antagonist with an additional high affinity for imidazoline I1-receptors, efaroxan, can also be explained by blockade of alpha2-adrenoceptors. Efaroxan was more potent against rilmenidine and moxonidine than the selective alpha2-adrenoceptor antagonists. This was probably due to the fact that the affinity of efaroxan for alpha2-adrenoceptors is higher than the affinity of yohimbine and SK&F86466, since efaroxan was also the most potent of the three antagonists against the indirectly acting alpha2adrenoceptor agonist alpha-methyldopa. The observation that efaroxan was equally potent against rilmenidine and moxonidine and against alpha-methyldopa suggests that the same receptors were involved in the effects of the three agonists, alpha2-adrenoceptors; this observation is not compatible with the high I1/alpha2 selectivity of efaroxan and the hypothesis that rilmenidine and moxonidine activate I1-receptors, whereas alpha-methyldopa activates alpha2-adrenoceptors. Thus, the data do not indicate involvement of I1 imidazoline receptors in the central sympathoinhibition elicited by rilmenidine and moxonidine in rabbits. It is likely that rilmenidine and moxonidine produce sympathoinhibition by activating the same receptors which are activated by the indirectly acting catecholamine alpha-methyldopa, namely alpha2-adrenoceptors.