Mianserin — An analysis of its peripheral autonomic actions

The effects of mianserin on the accumulation of (−)‐[3H]‐noradrenaline and on contractile responses to field stimulation, exogenously applied (−)‐noradrenaline, and to tyramine were studied in the rat anococcygeus muscle. Mianserin (10−9to 10−5m) and nortriptyline (10−9to 10−5m) inhibited the accumulation of (−)‐[3H]‐noradrenaline. In this aspect mianserin had a similar potency to nortriptyline, the most potent tricyclic antidepressant in inhibiting noradrenaline accumulation in this tissue. Mianserin 10−9or 10−8m alone had no effect on contractile responses to field stimulation and to (−)‐noradrenaline but inhibited the responses to tyramine. The responses to field stimulation at low frequencies and to (−)‐noradrenaline were potentiated by 10−7and 10−6m mianserin. It is suggested that the inhibitory effect mianserin has on neuronal accumulation is primarily responsible for these effects. Mianserin 10−5m inhibited responses to field stimulation and to (−)‐noradrenaline. In the presence of nortriptyline (10−6m), the contractile responses to field stimulations were potentiated by mianserin (10−8, 10−7and 10−6m), 10−8m being the most potent in this aspect. Mianserin 10−8, 10−7, 10−6and 10−5m had a similar inhibitory effect on responses to (−)‐noradrenaline. In the absence of neuronal uptake, the potentiating effect of mianserin on responses to field stimulation may be due to antagonism at presynaptic α‐adrenoceptors. In the presence of 10−6m nortriptyline, 10−5m mianserin abolished responses to field stimulation. Following incubation of the tissue in the presence of 6‐hydroxydopamine (10−3m for 3 h), mianserin (10−7, 10−6and 10−5m) nortriptyline (10−7and 10−6m) and phentolamine (5 × 10−8and 5 × 10−7m) inhibited contractile responses to (−)‐noradrenaline. This illustrates the ability of these agents to inhibit the responses to noradrenaline at a postsynaptic site. The inhibitory effect was dose‐related with nortriptyline and phentolamine; this illustrates the ability of these agents to antagonize postsynaptic α‐adrenoceptors. The inhibitory effect observed with mianserin was not dose‐related. This suggests that in addition to its reported ability to antagonize postsynaptic α‐adrenoceptors, mianserin may have another post‐synaptic action at the level of, or distal to, the α‐adrenoceptor. These results illustrate that, in the rat anococcygeus muscle, mianserin is a potent inhibitor of noradrenaline accumulation and may be an antagonist at presynaptic α‐adrenoceptors. Mianserin also inhibits the responses to exogenously applied noradrenaline in this tissue by an action or actions at the level of, or distal to, the postsynaptic α‐adrenoceptor.

Section: Discussionmentioning

confidence: 68%

“…The postsynaptic a-adrenoceptor blocking activity of mianserin (Borowski et al, 1976;Doxey et al, 1978) may be responsible for this effect. Low concentrations of mianserin (10-9 and 10-8 M) had no effect on responses to noradrenaline.…”

Section: Discussionmentioning

confidence: 99%

Effect of Mianserin on Noradrenergic Transmission in the Rat Anococcygeus Muscle

Doggrell

1980

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Cavero¹,

Lefèvre-Borg²,

Roach³

1981

1 In rats anaesthetized with pentobarbitone, intravenous administration of desipramine (0.1 mg/kg), maprotiline (0.5 mg/kg) or mianserin (0.3 -3.0 mg/kg) did not modify the blood pressure lowering effects of acetylcholine (0.25-1.0 pg/kg, i.v.) which were significantly reduced by atropine (3.0 pg/kg, i.v.). 4 In syrosingopine pretreated rats given mianserin 0.1 mg/kg, intravenously, 5-HT (20.0jpg/kg, i.v.) produced a significant fall in blood pressure which could be reduced by a large dose of mianserin (10.0 mg/kg, i.v.). 5 In conclusion, desipramine, maptrotiline and mianserin, in doses previously found to inhibit noradrenaline neuronal reuptake in the rat cardiovascular system, lack muscarinic receptor antagonist properties. Whilst maprotiline and mianserin blocked vascular histamine receptors, only mianserin, like cyproheptadine, was a potent antagonist of the 5-HT receptors that mediate increases in blood pressure in rats. Finally, the vasodepressor effects of 5-HT in syrosingopine pretreated rats given a small dose of mianserin were antagonized by a large dose of mianserin, suggesting that 5-HT may activate two distinct types of receptors in the rat.

“…Such a mechanism enhances the availability at P-adrenoceptor sites of endogenously released or exogenously injected noradrenaline. This action of mianserin has been demonstrated by studing blood pressure responses to tyramine in the pithed rat (Goodlet & Sugrue, 1974;Doxey et al, 1978) and by biochemically assessing noradrenaline reuptake into the rat (Baumann & Maitre, 1975; and rabbit (Harper & Hughes, 1977) heart and into synaptosomes and slices from rat brain (Goodlet & Sugrue, 1974;Raiteri et al, 1976;Goodlet et al, 1977;Baumann & Maitre, 1975;.…”

Section: Discussionmentioning

confidence: 99%

“…The latter experiment is necessary to verify whether an action of mianserin on noradrenaline reuptake could possibly account for some of their findings, since either the latter mechanism or inhibition of presynaptic a-adrenoceptors increase the concentration of the neurotransmitter within the sympathetic synaptic gap. Mianserin has been reported to inhibit noradrenaline reuptake in rat brain (Baumann & Maitre, 1975;Raiteri, Angelini & Bertollini, 1976) and rabbit heart (Goodlet, Mireylees & Sugrue, 1977) as well as in the rat cardiovascular system (Goodlet & Sugrue, 1974;Doxey, Everitt & Metcalf, 1978). Mianserin also possesses vascular postsynaptic a-adrenoceptor blocking properties in the rat (Van Zwieten, 1975;Doxey et al, 1978) and dog (Vargaftig, Coignet, De Vos, Grijsen & Bonta, 1971).…”

Section: Introductionmentioning

confidence: 99%

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

Cavero¹,

Goméni²,

Lefèvre-Borg³

et al. 1980

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.