Rilmenidine is one of the lead compounds of the second generation of centrally acting antihypertensive drugs. In the first part of this study, 2 routes of administration of chronic treatment (1 month) with rilmenidine were compared. In conscious and pentobarbital-anesthetized spontaneously hypertensive rats (SHR), rilmenidine was delivered intraperitoneally either 250 microg/kg b.i.d. or 500 microg/kg/d infusion by means of minipumps. The possibility of rilmenidine-induced desensitization of central (brain cortex) and/or peripheral (kidney) alpha2-adrenoreceptors was studied in saturation experiments with the classic alpha2-adrenergic antagonist [H]rauwolscine. In the second part of this study, the cardiovascular and cardiac antihypertrophic effects of the most efficient procedure were investigated. The discontinuous administration of the drug was more effective than infusion. In rats treated with rilmenidine b.i.d., mean blood pressure was reduced by nearly 15% when no reduction occurred in SHRs treated with minipumps. With the first schedule of administration, plasma concentration of the drug reached a maximum of approximately 30 ng/ml when it was only 12 ng/ml with the continuous infusion of the same dose. Anesthesia with pentobarbital potentiated the antihypertensive effect of rilmenidine in rats treated discontinuously and unmasked an antihypertensive action in rats receiving the drug with minipumps. In saturation binding experiments, no significant changes in adrenergic receptors were observed in kidney membrane preparations. In contrast, in brain cortical membranes a reduction by about 50% of the Bmax of [H]rauwolscine value was observed in rats treated discontinuously with rilmenidine. In contrast, a 400% increase of the Bmax was observed in the brain of rats treated with minipumps. Over the one-month period of the second study, the discontinuous treatment with the 500 microg/kg/d dose of rilmenidine was still able to reduce blood pressure, at least at the peak concentration time, but did not induce any significant reduction of the ventricular mass. In conclusion, rilmenidine has only weak antihypertensive effects in conscious SHRs, even at doses higher than those that are active in rabbits and humans. As a consequence, it lacks significant cardiac antihypertrophic effects in this species. Pharmacokinetic data show that the rapid plasma withdrawal of this drug may explain this particular feature in rats.