Abstract

The present study in conscious rabbits with intracisternal (i.c.) catheters sought to determine the relative contribution of the I1 subtype of imidazoline receptors (IR) and alpha 2 adrenoceptors to the hypotensive effects of rilmenidine, clonidine and moxonidine with an I1-IR/alpha 2 adrenoceptor antagonist efaroxan and a specific alpha 2 adrenoceptor antagonist 2-methoxyidazoxan (2-MI). The alpha 2 adrenoceptor antagonist effect of efaroxan was compared with 2-MI by performing cumulative dose-response curves in the presence of alpha-methyldopa (400 micrograms/kg i.c.). 2-MI was 5.6 times more potent than efaroxan at reversing 75% of the hypotension elicited by alpha-methyldopa (P < .025). This dose ratio was used to match doses of efaroxan and 2-MI for similar alpha 2 adrenoceptor blockade. The effects of efaroxan (4.1, 13, 41 micrograms/kg i.c.) and 2-MI (0.74, 2.3, 7.4 micrograms/kg i.c.) were investigated on a single i.c. dose of rilmenidine (12 micrograms/kg), clonidine (0.75 microgram/kg) and moxonidine (0.51 microgram/kg). These doses of the antihypertensive agents, which were determined from cumulative dose-response curves, produce 90% of the maximum hypotension. Efaroxan was more effective at reversing the hypotension induced by moxonidine and rilmenidine than was 2-MI (P < .01). These findings suggest that rilmenidine and moxonidine act predominantly via IR. By contrast, 2-MI was more effective at reversing the clonidine-induced hypotension than was efaroxan (P < .001), suggesting that clonidine acts mainly via alpha 2 adrenoceptors in conscious normotensive rabbits. Thus, a higher selectivity of the second generation agents moxonidine and rilmenidine for I1-IR over alpha 2 adrenoceptors, compared with the first generation agent clonidine, appears to be necessary for this effect to be manifested in their hypotensive actions.