Introduction: It is well accepted that centrally acting antihypertensive agents such as rilmenidine reduce blood pressure through inhibition of the sympathetic nervous system. The central receptor involved, be it a central imidazoline receptor or an alpha2-adrenoceptor and its location, is less certain.
Methods and results: The present paper reviews studies from our laboratory examining these questions by using antagonists with differing affinity for imidazoline receptors and alpha2-adrenoceptors. In addition, we have used various routes of administration in conscious and anaesthetized normotensive rabbits. We found that rilmenidine was more potent in its hypotensive action when administered into the fourth ventricle than when given intravenously and considerably more potent when injected into the rostroventrolateral medulla (RVLM) compared to the nucleus of the solitary tract (NTS). By contrast, alpha-methylnoradrenaline, which acts solely through alpha2-adrenoceptors to produce hypotension, was similarly potent in both the NTS and RVLM. Injections of rilmenidine into the RVLM reduced renal sympathetic tone and produced a marked inhibition of renal sympathetic baroreflex responses. The pattern of renal sympathetic baroreflex effects of rilmenidine administered into the RVLM was similar to the effects of the fourth ventricular or intravenous administration. These studies together support the view that the RVLM is the major site of action. We have determined the relative importance of imidazoline receptors and alpha2-adrenoceptors in the inhibition of renal sympathetic nerve activity produced by rilmenidine administered into the RVLM, the fourth ventricle or intravenously. Initial studies in conscious rabbits showed that intravenous or fourth ventricular administration of rilmenidine induced renal sympatho-inhibition which was preferentially reversed by idazoxan or efaroxan (imidazoline/alpha2-adrenoceptor antagonist) compared to 2-methoxyidazoxan (alpha2-adrenoceptor antagonist). In anaesthetized rabbits, administration of idazoxan into the RVLM reversed the inhibition of the renal sympathetic activity induced by RVLM or intravenous administration of rilmenidine. In contrast, idazoxan had no effect on the responses produced by the alpha2-adrenoceptor agonist alpha-methylnoradrenaline.
Conclusion: Our studies suggest that rilmenidine given systemically acts primarily on imidazoline receptors in the RVLM to reduce sympathetic tone and to modulate sympathetic baroreflexes.