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Importance of Central Noradrenergic and Serotonergic Pathways in the Cardiovascular Actions of Rilmenidine and Clonidine

We examined the role of central monoamine neurotransmitters noradrenaline and serotonin in the cardiovascular actions of the α2-adrenoceptor agonist rilmenidine in the conscious rabbit and compared it toclonidine.Rilmenidine and clonidine were equieffective in producing a maximum 24% reduction in blood pressure and heart rate whengiven intracisternally (i.c.), but rilmenidine was ∼20–30 times lesspotent than clonidine. The effective i c. doses of both drugs were 25–30 times lower than those required peripherally (i.v.). Comparison of the time course of an equieffective dose of rilmenidine and clonidine showed that the time to reach maximum effect was 10 min for both drugs but time to recovery was greater for rilmenidine (2:5–3 h vs. 1:5 h for clonidine). Destruction of central noradrenergic neuron pathways with i.c. 6-hydroxydopamine attenuated the hypotensive and bradycardic actions of both rilmenidine and clonidine at 2, 4, and 8 weeks after treatment. The maximum observed attenuation of the hypotension was at 8 weeks (40% of control for rilmenidine and 29% for clonidine), while for the bradycardia this was at 2 weeks (9 and 2% of control, respectively) with some recovery by 8 weeks (29 and 50% of control). Destruction of the central serotonergic neurons with i.c. 5, 6-dihydroxytryptamine also attenuated the hypotension and bradycardia to rilmenidine and clonidine but was slower in onset, needing the full 8 weeks to reach its maximum effect. At this time the hypotension and bradycardia to rilmenidine and clonidine were reduced to between 35 and 48% of control There were no significant changes over the 8 weeks in theresponses to rilmenidine and clonidine in animals treated with i.c. vehicle. These findings suggest that at least half of the hypotension and bradycardia following central rilmenidine and clonidine is dependent on the integrity of central noradrenergic and serotonergic pathways.