Importance of imidazoline receptors in the cardiovascular actions of centrally acting antihypertensive agents

Increasing evidence indicates that the hypotensive effect of centrally acting antihypertensive drugs is not due to stimulation of alpha 2-adrenoceptors but to action on imidazoline receptors (IR). This has led to the development and recent clinical use of second generation agents such as rilmenidine and moxonidine that possess a much greater selectivity toward these nonadrenergic receptors. However, relatively few studies have examined the role of these receptors in conscious Animals or have adequately accounted for the alpha 2-adrenoceptor antagonist properties of IR antagonists such as idazoxan. We have taken the approach of initially calibrating the alpha 2-adrenoceptor antagonist potency of intracisternally (ic) administered idazoxan and the IR-1 receptor antagonist efaroxan against 2-methoxyidazoxan, a highly selective alpha 2-adrenoceptor antagonist with little or no imidazoline antagonist effect. This was done using alpha-methyldopa, a hypotensive agent affecting only alpha 2-adrenoceptors. Thus, we chose doses of the antagonists with equal alpha 2-adrenoceptor blocking action such that differences in the ability of idazoxan or efaroxan compared to 2-methoxy-idazoxan to reverse the hypotension produced by rilmenidine, moxonidine, or clonidine indicate an interaction with IR. By this method we found that the hypotensive effects of rilmenidine and moxonidine at moderate intracisternal doses were more readily reversed by the imidazoline antagonists than by 2-methoxy-idazoxan, indicating that IR were largely responsible for their hypotensive actions. By contrast, clonidine's effects were equally reversed by all antagonists, suggesting interaction mainly with alpha 2-adrenoceptors. In conscious rabbits with chronic renal sympathetic nerve electrodes we examined the effect of rilmenidine and alpha-methyldopa on the renal sympathetic baroreflex. Both drugs reduced renal sympathetic nerve activity and sympathetic baroreflex responses, but only the effect of rilmenidine was preferentially reversed by idazoxan. Thus, both IR and central alpha 2-adrenoceptor receptors can influence the renal baroreflex, but the former are relatively more important for the actions of rilmenidine. We recently examined the possible sites of action of rilmenidine in anesthetized rabbits and showed that sixfold lower doses were required to reduce blood pressure when the drug was injected into the rostral ventrolateral medulla compared to intracisternal administration. At this site rilmenidine also reduced renal sympathetic tone and inhibited renal sympathetic baroreflex responses. By contrast, rilmenidine was relatively ineffective when injected into the nucleus of the solitary tract. These experiments support the view that rilmenidine acts primarily at IR in the rostral ventrolateral medulla to reduce sympathetic tone and modulate sympathetic baroreflexes.