Effects of desipramine on neuronal responses to dopamine, noradrenaline, 5-hydroxytryptamine and acetylcholine in the caudate nucleus of the rat.

1 The sensitivity of single neurones to microelectrophoretically applied dopamine, noradrenaline (NA), 5-hydroxytryptamine (5-HT) and acetylcholing (ACh) was investigated in the caudate nucleus of the rat, anaesthetized with halothane. Both excitatory and depressant responses could be observed to each of the agonists. There was a high correlation between the direction of responses to dopamine and noradrenaline, whereas there was no significant correlation between the direction of responses to dopamine and ACh. 2 The effect of desipramine was studied on both excitatory and depressant responses to dopamine, NA and 5-HT, and on excitatory responses to ACh. Both potentiation and antagonism of neuronal responses to monoamines and ACh could be observed after a brief application of desipramine. 3 Excitatory responses to glutamate were not affected by desipramine. 4 The observation that responses to dopamine and NA can be potentiated by desipramine in the caudate nucleus suggests that uptake blockade is not a prerequisite for potentiation. 5 It is suggested that the potentiation of neuronal responses to dopamine by desipramine may be responsible for the therapeutic efficacy of desipramine in Parkinson's disease.     

Evaluation of antagonists of histamine, 5-hydroxytryptamine and acetylcholine in the guinea-pig

Changes in the resistance to entry of air into the lungs of anaesthetized guinea-pigs have been used to study the effects of histamine, 5-hydroxytryptamine, and acetylcholine. Some known antagonists of these bronchoconstrictor agents have been investigated. The degree of antagonism has been expressed in terms of the dose ratio, previously used only with in vitro preparations.     

Effects of imipramine and desipramine on responses of single cortical neurones to noradrenaline and 5-hydroxytryptamine

1 The technique of microelectrophoresis was used in order to study the effects of imipramine and desipramine on single neurones in the somatosensory cortex of the cat, anaesthetized with halothane.2 Imipramine and desipramine, when applied for a brief period, did not affect the firing rate of the vast majority of the neurones tested.3 Both potentiation and antagonism of excitatory responses to noradrenaline could be observed after a brief application of either of the antidepressants. Four drug-interaction patterns could be distinguished: potentiation of immediate onset; potentiation reaching its maximum after a delay; antagonism followed by potentiation; antagonism followed by recovery.4 When different doses of the same antidepressant were applied, it was found that the drug-interaction patterns were related to the dose of antidepressant applied, a lower dose causing potentiation, and a higher dose antagonism of the response.5 Both potentiation and antagonism of depressant responses to noradrenaline could be observed.6 Both excitatory and depressant responses to 5-hydroxytryptamine were modified by imipramine and desipramine: a smaller dose of the antidepressant potentiated, and a higher dose antagonized the responses.7 Excitatory responses to glutamate were not affected by imipramine and desipramine.     

Sensitization by caerulein of guinea-pig ileum to contractions by acetylcholine,histamine, 5-hydroxytryptamine and nicotine

Summary Low concentrations (0.63 and 1.25 ng/ml) of caerulein increase the submaximal contractions of the guinea-pig isolated ileum induced by several agonists and electrical stimulation. These effects of the polypeptide are due partly to neuronal pathways (i.c., a ganglionic stimulation) and partly to a non specific muscular sensitization. At higher concentrations of caerulein the effects of all the agonists were decreased. This seems related to the contractile effect of the peptide itself on the longitudinal muscle which interfers non specifically with the development of contractions induced by any other agonist.     

Effects of LM 5008, a selective inhibitor of 5-hydroxytryptamine uptake, on blood pressure and responses to sympathomimetic amines

LM 5008 (4-[2-(3-indolyl)ethyl]piperidine) (10, 20 and 50 mg kg-1) had no significant effect on pressor responses to noradrenaline or tyramine in rats anaesthetized with urethane. Desmethylimipramine (1 mg kg-1) blocked the response to tyramine but chlorimipramine (5 mg kg-1) had no significant effect on responses to noradrenaline or tyramine. In the rabbit, anaesthetized with chloralose, LM 5008 (5 mg kg-1) had no effect on pressor responses to noradrenaline, tyramine or angiotensin II, while desmethylimipramine (0.25 mg kg-1) inhibited responses to tyramine and potentiated those to noradrenaline. LM 5008 (10 mg kg-1) had no effect on resting blood pressure of conscious normotensive or DOCA-saline hypertensive rats. Tranylcypromine (5 mg kg-1) produced a fall in blood pressure in conscious normotensive and in DOCA hypertensive rats. Treatment with a combination of LM 5008 (10 mg kg-1) and tranylcypromine (5 mg kg-1) resulted in the appearance of a behavioural hyperactivity syndrome, but blood pressure was not different from that of animals treated with tranylcypromine alone. These results further demonstrate the selectivity of LM 5008 for 5-hydroxytryptamine as opposed to catecholamine uptake.     

Comparison of mianserin with desipramine, maprotiline and phentolamine on cardiac presynaptic and vascular postsynaptic α-adrenoceptors and noradrenaline reuptake in pithed normotensive rats

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 alpha-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 alpha-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 alpha-adrenoceptors and also inhibits the neuronal reuptake of noradrenaline.     

Protection against burn, tourniquet and endotoxin shock by histamine, 5-hydroxytryptamine and 5-hydroxytryptamine derivatives

1. 5-Hydroxytryptamine (5-HT), tryptamine, 5-methyltryptamine, 5-methoxytryptamine, N-methyltryptamine, 5-hydroxy-N,N-dimethyltryptamine, and histamine markedly protect mice subjected to burn, tourniquet and endotoxin shock. All of these compounds protect when given 30 min before the production of shock, but not when administered afterwards.2. The above compounds, as well as purines and purine derivatives have a similar chemical structure. Protection requires the compounds to contain a 5-membered ring with one unsubstituted N atom and a side chain with a basic N atom three atoms from the ring.3. All other biological amines tested without this chemical structure did not protect.4. Since the simplest compounds containing all the prerequisites for protection is histamine, this compound may play the key role in protection, for both 5-HT and purines release histamine from tissues.5. Protective doses of 5-HT and histamine prevent swelling of the injured area after tourniquet trauma and produce an increased bleeding volume and lower haematocrit value after burning. These actions of the drugs on the circulation may account for the increased survival after thermal trauma.     

Involvement of 5-hydroxytryptamine in the blood pressure changes evoked by electrical stimulation of the median raphe nucleus

Electrical stimulation of the median raphe nucleus (MRN) in urethane-anaesthetised rats decreased systemic blood pressure at low intensities of stimulation (5–25 μA) and increased it with higher intensities (20–150 μA). Prazosin (0-5-5.0 μg/Kg i.v.) dose-dependently attenuated pressor responses concurrently with a reduction in the responsiveness of peripheral alpha-adrenoceptors to phenylephrine (500ng i.V.). Methlothepin (5–10 μg/Kg i.v.) abolished depressor responses and reduced the pressor effects without altering the response to phenylephrine. Ketanserin (5–10 μg/Kg i.v.) abolished depressor changes and potentiated pressor responses. High doses (20–200 μg/Kg) produced a decrease in pressor responses but correspondingly lowered BP and reduced the response to phenylephrlne.

The results suggest the presence of 5-HT-containlng links between the MRN and the peripheral cardiovascular effector systems.     

Inhibition by tetrahydroharmane compounds of 5-hydroxytryptamine and histamine uptake in rabbit blood platelets

Summary The effect of 5-hydroxytryptamine (5-HT), tryptamine (T), 6-hydroxy-1,2,3,4-tetrahydroharmane (6-HTH), and 1,2,3,4-tetrahydroharmane (TH) on the accumulation of radioactive 5-HT and histamine, was studied in rabbit blood platelets. 6-HTH and TH inhibited the uptake of the labelled amine, but they were weaker inhibitors than 5-HT or T. All four compounds inhibited the accumulation of radioactive histamine in the granules as well as in the whole cells, but the latter effect is not the consequence of inhibition of granular accumulation.It is concluded that the methylene bridge, which is the most important structural difference between the harmanes and the tryptamines, does not abolish the affinity of the molecule to the uptake receptor at the platelet membrane. However, since the inhibitory potency was lower than that of the parent amines, one cannot be certain as to whether or not the conformation present in the harmane derivatives offers the best fit for the receptor.     

Relative acute cardiovascular toxicity induced by maprotiline, mianserin and nomifensine in conscious rabbits

The relative acute cardiovascular toxicity among three novel antidepressants: maprotiline, mianserin and nomifensine, has been assessed in conscious rabbits ip injected at 50 mg/kg, throughout a 150 min observation period. No death was observed in mianserin rabbits (n = 6), but 3 in the maprotiline rabbits (n = 8) and 1 death in the nomifensine group (n = 8), within the 2 hours. Cardiac output and renal blood flow were determined by the radioactive Sephadex microspheres method. Cardiac output values were significantly lowered (-29%) at 120 min only in mianserin rabbits, whereas renal blood flow values were reduced by 46.8% (mianserin, 35.8% (maprotiline) and 28% (nomifensine) at 120 min. In mianserin and maprotiline rabbits left ventricular pressure and mean arterial pressure fell significantly, but remained unchanged in nomifensine group. ECG disturbances consisting of ventricular and supraventricular extrasystoles were seen in all the injected rabbits, but QRS widening and right bundle branch block were solely observed after maprotiline and mianserin. Nomifensine rabbits experienced severe seizures with hypocapnia and metabolic acidosis. The drug myocardial/plasma ratio ranged between 59.3 (maprotiline) 13.25 (mianserin) and 0.92 (nomifensine). A rise in plasma catecholamines (epinephrine) was documented after mianserin but not after nomifensin and maprotiline. Nomifensine exhibited much lesser cardiotoxicity than mianserin and maprotiline at this dose (50 mg/kg), but induced more convulsions.     

Effects of NG-nitro-L-arginine methyl ester on vasodilator responses to acetylcholine, 5''-N-ethylcarboxamidoadenosine or salbutamol in conscious rats.

1. Conscious, Long Evans rats (n = 16), chronically instrumented for the measurement of regional haemodynamics were given 3 min, randomized infusions of two doses of sodium nitroprusside (1.5 and 15 micrograms min-1), acetylcholine (0.4 and 4 micrograms min-1), 5'-N-ethylcarboxamidoadenosine (NECA; 45 and 450 ng min-1), and salbutamol (24 and 240 ng min-1) in the absence and in the presence of NG-nitro-L-arginine methyl ester (L-NAME; 1 mg kg-1 h-1), a potent inhibitor of nitric oxide biosynthesis. 2. Sodium nitroprusside caused hyperaemic vasodilatation in the mesenteric, and common carotid vascular beds. These effects were enhanced in the presence of L-NAME, as was the hypotension. 3. Acetylcholine caused hyperaemic vasodilation inp6he renal, internal carotid and common carotid vascular beds. These effects were attenuated in the presence of L-NAME, but the hypotension was unaffected. 4. NECA caused hyperaemic vasodiltation in the renal, mesenteric, hindquarters, internal carotid and common carotid vascular beds. However, only the hindquarters and internal carotid responses were diminished in the presence of L-NAME and the hypotension was unchanged. 5. Salbutamol caused hyperaemic vasodilatation in the hindquarters vascular bed only. This effect was reduced in the presence of L-NAME, but the hypotension was unchanged. 6. The results indicate marked regional variations in the sensitivity of vasodilator responses to L-NAME that can depend on the vasodilator agent chosen and the dose employed. It is clear from these findings also that measurement of mean arterial blood pressure alone cannot provide adequate information on which to judge the involvement of L-NAME-sensitive mechanisms in vasodilator responses in vivo.     

Interactions between alinidine and responses to acetylcholine, dopamine and 5-hydroxytryptamine of specific Helix central neurones.

Intracellular recordings were made from identified neurones in the brain of the snail, Helix aspersa. The effect of alinidine on the excitatory and inhibitory responses to acetylcholine and dopamine and on the excitatory response to 5-hydroxytryptamine (5-HT) was investigated. Alinidine was found to reduce the responses to acetylcholine and 5-HT and the excitatory response to dopamine but had no effect on the dopamine inhibitory response. pA2 values were determined for alinidine antagonism to indicate relative potency. The pA2 values against the excitatory responses of acetylcholine, dopamine and 5-HT were 5.8, 5.6 and 5.5 respectively. The pA2 value against acetylcholine inhibition was 3.5. From these studies it is suggested that alinidine interacts preferentially with the sodium inonophore, to a lesser degree with the chloride ionophore and not at all with the potassium ionophore on Helix central neurones.     

Effects of local anaesthetics on responses of human saphenous vein and bovine coronary artery to neurotransmitters, acetylcholine, noradrenaline and 5-hydroxytryptamine

The effects of 5 different local anaesthetics, lignocaine, etidocaine, prilocaine, mepivacaine, bupivacaine, and 3 different neurotransmitters, acetylcholine (ACh), noradrenaline (NA), 5-hydroxytryptamine (5-HT) on tone and contractility of human saphenous vein and bovine coronary artery were studied and compared in vitro. The experiments were carried out to see if there were species or tissue differences in the action of local anaesthetics and neurotransmitters at vascular smooth muscle, i.e. saphenous vein and coronary artery. Another important aspect was to see if local anaesthetics modified cholinergic (ACh), adrenergic (NA) and serotoninergic (5-HT) responses in vascular smooth muscle. Among the local anaesthetics studied, lignocaine and etidocaine produced prolonged relaxations, whereas prilocaine, mepivacaine, bupivacaine produced contractions in the saphenous vein and coronary artery. High concentrations of the latter drugs produced relaxations in the blood vessels. Among the local anaesthetics, lignocaine produced differential effects on saphenous vein and coronary artery, its effect on the latter was 3 times larger than on the saphenous vein. ACh, NA and 5-HT contracted the saphenous vein. In the coronary artery, ACh and 5-HT contracted whereas NA relaxed the vessel. On a molar basis, ACh was less effective than NA in contracting the saphenous vein. 5-HT was equipotent on both the saphenous vein and coronary artery. Lignocaine reduced ACh, NA and 5-HT-induced contractions in the saphenous vein and those of ACh and 5-HT in the coronary artery, and shifted the control curves, non-competitively, to the right. The relaxation produced by NA in the coronary artery was enhanced by lignocaine.(ABSTRACT TRUNCATED AT 250 WORDS)