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 guanabenz 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 imidazoline I(1) receptors and low affinity for alpha(2)-adrenoceptors, lower sympathetic tone without causing an alpha(2)-adrenoceptor-mediated inhibition of cerebrocortical noradrenaline release. 2. In rats anaesthetized with urethane, blood pressure and heart rate were measured and the concentration of noradrenaline in arterial blood plasma was determined. The release of noradrenaline in the medial prefrontal cortex was estimated by microdialysis. Intravenous administration of rilmenidine (30, 100, 300 and 1000 microg kg(-1)), moxonidine (10, 30, 100 and 300 microg kg(-1)), clonidine (1, 3, 10 and 30 microg kg(-1)) and guanabenz (1, 3, 10 and 30 microg kg(-1)) led to dose-dependent hypotension and bradycardia; the plasma noradrenaline 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 noradrenaline release at doses similar to those which cause sympatho-inhibition. This effect was probably due to an alpha(2)-adrenoceptor-mediated inhibition of the firing of locus coeruleus neurons and, in addition, to presynaptic inhibition of noradrenaline release at the level of the axon terminals in the cortex. The results argue against the hypothesis that rilmenidine and moxonidine, due to their selectivity for sympatho-inhibitory I(1) imidazoline receptors, do not suppress noradrenergic neurons in the central nervous system.
Szabo
B
B
Institute of Experimental and Clinical Pharmacology and Toxicology, Albert Ludwigs University, Hermann-Herder-Strasse 5, D-79104 Freiburg i. Br., Germany. szabo@uni-freiburg.de
Fritz
T
T
Wedzony
K
K
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D006143:Guanabenz / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000077769:Rilmenidine; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology
D000959:Antihypertensive Agents; D007093:Imidazoles; D010080:Oxazoles; C043482:moxonidine; D006143:Guanabenz; D003000:Clonidine; D000077769:Rilmenidine; D009638:Norepinephrine