ROLE OF IMIDAZOLINE RECEPTORS IN THE CARDIOVASCULAR ACTIONS OF MOXONIDINE, RILMENIDINE AND CLONIDINE IN CONSCIOUS RABBITS

The present study in conscious rabbits with intracisternal (i.c.) cath eters sought to determine the relative contribution of the I, subtype of imidazoline receptors (IR) and alpha(2) adrenoceptors to the hypote nsive effects of rilmenidine, clonidine and moxonidine with an I-1-IR/ alpha(2) adrenoceptor antagonist efaroxan and a specific alpha, adreno ceptor antagonist 2-methoxyidazoxan (2-MI). The alpha(2) adrenoceptor antagonist effect of efaroxan was compared with 2-MI by performing cum ulative dose-response curves in the presence of alpha-methyldopa (400 mu g/kg i.c.). 2-MI was 5.6 times more potent than efaroxan at reversi ng 75% of the hypotension elicited by alpha-methyldopa (P < .025). Thi s dose ratio was used to match doses of efaroxan and 2-MI for similar alpha, adrenoceptor blockade. The effects of efaroxan (4.1, 13, 41 mu g/kg i.c.) and 2-MI (0.74, 2.3, 7.4 mu g/kg i.c.) were investigated on a single i.c. dose of rilmenidine (12 mu g/kg), clonidine (0.75 mu g/ kg) and moxonidine (0.51 mu g/kg). These doses of the antihypertensive agents, which were determined from cumulative dose-response curves, p roduce 90% of the maximum hypotension. Efaroxan was more effective at reversing the hypotension induced by moxonidine and rilmenidine than w as 2-MI (P < .01). These findings suggest that rilmenidine and moxonid ine act predominantly via IR. By contrast, 2-MI was more effective at reversing the clonidine-induced hypotension than was efaroxan (P < .00 1), suggesting that clonidine acts mainly via alpha, adrenoceptors in conscious normotensive rabbits. Thus, a higher selectivity of the seco nd generation agents moxonidine and rilmenidine for I-1-IR over alpha, adrenoceptors, compared with the first generation agent clonidine, ap pears to be necessary for this effect to be manifested in their hypote nsive actions.