Effects of imidazoline antihypertensive drugs on sympathetic tone and noradrenaline release in the prefrontal cortex

1 The aim of the present study was to compare the effects of the centrally acting antihypertensive drugs rilmenidine, moxonidine, clonidine and guanab enz on sympathetic tone with their effects on noradrenaline release in the cerebral cortex. In particular, the hypothesis was tested that rilmenidine and moxonidine, due to their high affinity for sympatho-inhibitory imidazol ine I-1 receptors and low affinity for alpha (2)-adrenoceptors, lower sympa thetic tone without causing an alpha (2)-adrenoceptor-mediated inhibition o f cerebrocortical noradrenaline release. 2 In rats anaesthetized with urethane, blood pressure and heart rate were m easured and the concentration of noradrenaline in arterial blood plasma was determined, The release of noradrenaline in the medial prefrontal cortex w as estimated by microdialysis. Intravenous administration of rilmenidine (3 0, 100, 300 and 1000 mug kg(-1)), moxonidine (10, 30, 100 and 300 mug kg(-1 )), clonidine (1, 3, 10 and 30 mug kg(-1)) and guanabenz (1, 3, 10 and 30 m ug kg(-1)) led to dose-dependent hypotension and bradycardia; the plasma no radrenaline concentration also decreased. After the two highest doses, all four drugs lowered noradrenaline release in the prefrontal cortex. At doses eliciting equal hypotensive and sympatho-inhibitory responses, rilmenidine and moxonidine inhibited cerebral cortical noradrenaline release at least as much as clonidine and guanabenz. 3 The results show that rilmenidine and moxonidine lower cerebrocortical no radrenaline release at doses similar to those which cause sympatho-inhibiti on. This effect was probably due to an alpha (2)-adrenoceptor-mediated inhi bition of the firing of locus coeruleus neurons and, in addition, to presyn aptic inhibition of noradrenaline release at the level of the axon terminal s in the cortex. The results argue against the hypothesis that rilmenidine and moxonidine, due to their selectivity for sympatho-inhibitory I-1 imidaz oline receptors, do not suppress noradrenergic neurons in the central nervo us system.