Importance of imidazoline-preferring receptors in the cardiovascular actions of chronically administered moxonidine, rilmenidine and clonidine in conscious rabbits.

OBJECTIVE

To determine the involvement of central imidazoline receptors in the cardiovascular actions of the chronically administered antihypertensive agents moxonidine, rilmenidine and clonidine.

DESIGN AND METHODS

In 21 rabbits with implanted fourth-ventricular catheters, we investigated the central effects of three cumulative doses of an I(1)-imidazoline/alpha(2)-adrenoceptor antagonist, efaroxan, and of an alpha(2)-adrenoceptor antagonist, 2-methoxyidazoxan (2-MI), on the changes in blood pressure and heart rate (HR) elicited by chronic subcutaneous administration of moxonidine, rilmenidine and clonidine, after 1 and 3 weeks of treatment. A low, medium and high dose of 2-MI was matched to three doses of efaroxan, such that each produced equal reversal of the hypotension induced by fourth-ventricular alpha-methyldopa and hence produced a similar degree of alpha(2)-adrenoceptor blockade.

RESULTS

Clonidine and moxonidine, at doses of 1 mg/kg per day, and rilmenidine at 5 mg/kg per day, produced sustained reductions in mean arterial pressure of 13 +/- 3, 15 +/- 2 and 13 +/- 2 mmHg, respectively over the 3-week treatment period, but did not alter HR. Central administration of efaroxan on day 9 and day 23 of treatment produced a greater increase in blood pressure than did 2-MI with all three antihypertensive agents. Blood pressure reached levels that were significantly above the original control values. By contrast, the alpha(2)-adrenoceptor antagonist 2-MI only induced a rebound blood pressure effect in clonidine- and to a lesser extent in rilmenidine-treated rabbits. Both efaroxan and 2-MI produced a similar degree of tachycardia in moxonidine-, rilmenidine- and clonidine-treated animals.(2)

CONCLUSIONS

The greater effect of efaroxan compared to the alpha(2)-adrenoceptor antagonist 2-MI suggests that the hypotension induced by chronic subcutaneous administration of moxonidine, rilmenidine and clonidine is mediated predominantly via an action on central imidazoline receptors. Furthermore, all agents showed a propensity to produce rebound hypertension with imidazoline receptor blockade. However, only clonidine showed a rebound phenomenon when challenged by acute central alpha(2)-adrenoceptor blockade