Comparison of Mianserin With Desipramine, Maprotiline and Phentolamine on Cardiac Presynaptic and Vascular Postsynaptic Α‐adrenoceptors and Noradrenaline Reuptake in Pithed Normotensive Rats

Abstract

1 The cardiovascular effects of intravenous desipramine (0.03 and 0.1 mg/kg), maprotiline (0.5 mg/kg), mianserin (1.0 and 3.0 mg/kg) and phentolamine (0.25 mg/kg) were examined and compared in pithed rats. Several experimental procedures were used in order to distinguish between the effects of the compounds on cardiac presynaptic a-adrenoceptors and on neuronal noradrenaline reuptake, as inhibition of either mechanism produces an increase of neurotransmitter concentration within the sympathetic synapse and therefore results in a greater end organ response.2 Pressor responses elicited by noradrenaline were potentiated by desipramine and maprotiline, reduced by phentolamine and not significantly modified by mianserin. However, all four compounds inhibited the pressor action of tyramine. Furthermore, mianserin reduced the pressor response to adrenaline. 3 Desipramine, maprotiline and mianserin, but not phentolamine enhanced the positive chronotropic effects of noradrenaline, without affecting those of isoprenaline. 4 All four compounds abolished the clonidine-induced inhibition of heart rate responses to short term electrical stimulation of the spinal cord. Moreover, in rats with a persistent tachycardia (induced by continuous stimulation of the thoracic spinal cord) desipramine, maprotiline and mianserin further increased heart rate. This effect was also observed in animals pretreated with phentolamine, administered in order to inhibit cardiac presynaptic x-adrenoceptors. 5 In rats with a sustained tachycardia (100 beats/min produced by electrical stimulation of the spinal cord) both mianserin and phentolamine, in contrast to desipramine, shifted the clonidine heart rate dose-response curve to the right. Phentolamine was about 34 times more potent than mianserin in this respect. 6 In pithed, reserpine-treated rats, the pressor responses to clonidine were not significantly modified by desipramine. The dose-response curves were shifted to the right by phentolamine (0.25 mg/kg) and mianserin (3.0 mg/kg). 7 These results indicate that mianserin is an antagonist of both cardiac presynaptic and vascular postsynaptic a-adrenoceptors and also inhibits the neuronal reuptake of noradrenaline.

Effects of Mianserin, Desipramine and Maprotiline on Blood Pressure Responses Evoked by Acetylcholine, Histamine and 5‐hydroxytryptamine in Rats

“…The antidepressant drugs, desipramine, maprotiline and mianserin, in doses that significantly inhibit the neuronal uptake of noradrenaline in pithed rats (Cavero et al, 1980a), exhibited different spectra of peripheral autonomic receptor blocking properties. Whilst desipramine did not modify the blood pressure responses to acetylcholine, histamine or 5-HT, maprotiline and mianserin were histamine receptor antagonists and only mianserin inhibited the effects of 5-HT.…”

“…To facilitate the expression of the results of the three point dose-peak response curves (Figures 1 and 2), the areas under these curves (AUC) before (control) and after the treatment were calculated (Cavero et al, 1980a;Figure 4) and the effects of treatment expressed as a percentage of the control AUC response which was taken as 100%.…”

“…The maximal doses of the three antidepressant agents used in this study produce significant potentiations of the heart rate responses to exogenous and endogenously released noradrenaline, due to inhibition of the noradrenaline neuronal uptake mechanism (Cavero et al, 1980a).…”

“…were studied in atropine (0.5 mg/kg, i.v.) pretreated pithed rats under control conditions and after intravenous administration of saline, desip- (Cavero et al, 1980a).…”

“…In the cardiovascular system of the rat, mianserin possesses postsynaptic al-and presynaptic a2-adrenoceptor antagonist activity and like desipramine and maprotiline, inhibits the neuronal uptake mechanism for noradrenaline (Doxey, Everitt & Metcalf, 1978;Robson, Antonaccio, Saelens & Liebman, 1978;Cavero, Gomeni, Lefevre-Borg & Roach, 1980a;Docherty & McGrath, 1980). Furthermore, mianserin is an antagonist of responses mediated by 5-hydroxytryptamine (5-HT) in various preparations (Vargaftig, Coignet, De Vos, Grijsen & HU8 7DS 0007-1188/81/09 0143-06 $0 1.00 Bonta, 1971;Robson etal., 1978;Figge, Leonard & Richelson, 1979;Tang & Seeman, 1980).…”