The 5-hydroxytryptamine content of mouse brain and whole mice after treatment with some drugs affecting the central nervous system

A number of drugs were examined for their ability to change the concentration of 5-hydroxytryptamine in mouse brain and in whole mice treated with 5-hydroxytryptophan. After β-phenylisopropylhydrazine or iproniazid, two inhibitors of monoamine oxidase, the brain 5-hydroxytryptamine rose to a maximum value in 8 hr., after which it declined, although a slight rise remained for as long as 6 days. Dose-effect relationships, determined 6 hr. after administration, showed β-phenyl-isopropylhydrazine to be approximately 60 times as effective as iproniazid in raising the brain 5-hydroxytryptamine. When mice were given 5-hydroxytryptophan and the amine content of the whole mice estimated, pretreatment with β-phenylisopropylhydrazine increased their 5-hydroxytryptamine content whereas pretreatment with iproniazid did not change it. The concentration of the amine in mouse brain and in whole mice was lower after reserpine, but was raised when reserpine and β-phenylisopropylhydrazine were given together. A small rise in brain 5-hydroxytryptamine was found after chlorpromazine; when chlorpromazine was given with iproniazid, however, the resulting increase was less than that found after iproniazid alone. Brain 5-hydroxytryptamine was unaltered after prolonged treatment with morphine.     

Restoration of the chronotropic effect of tyramine on rat atria after reserpine

1. The restoration by various sympathomimetic amines of the chronotropic response to tyramine was studied on the isolated atria of rats pretreated with reserpine. The atria were exposed to the "restorative" sympathomimetic amine for 10 min, washed over a period of 1 hr and then tested with 10 muM tyramine. The effect of noradrenaline, dopamine and norphenylephrine before and after inhibition of monoamine oxidase by 0.5 mM iproniazid were compared with their alpha-methyl and N-alkyl analogues in their ability to restore the chronotropic response to tyramine.2. Noradrenaline and adrenaline restored the chronotropic response to tyramine, the degree of restoration depending on the concentration of the restorative amine used. Noradrenaline after iproniazid and alpha-methylnoradrenaline were equipotent and were about 1,000 times more active than noradrenaline where monoamine oxidase was not inhibited. Dopamine, epinine, norphenylephrine, phenylephrine, octopamine, synephrine and isoprenaline in the absence of monoamine oxidase inhibition had no effect. Dopamine after iproniazid and alpha-methyldopamine were equipotent and were about 1/10 as active as alpha-methylnoradrenaline. Norphenylephrine after iproniazid and metaraminol were equipotent and were about 1/500 as active as alpha-methylnoradrenaline. Octopamine after iproniazid was even less active. The N-methylated analogues were about 1/10 as active as their nor-compounds but the N-isopropyl analogue, isoprenaline, was devoid of activity.3. Dopamine after iproniazid and alpha-methyldopamine were inactive if a dopamine-beta-hydroxylase inhibitor, disulphiram or sodium diethyldithiocarbamate, was present.4. It is concluded that, in atria of reserpinized rats, (a) protection from monoamine oxidase increases; (b) N-substitution decreases; and (c) hydroxyl groups at the beta-carbon and ring positions 3 and 4 increase the capabilities of a sympathomimetic amine to restore the chronotropic response to tyramine.     

The effect of iproniazid and imipramine on the blood platelet 5-hydroxytryptamine level in man

Observations are reported on the blood platelet 5-hydroxytryptamine content of six patients receiving imipramine, N-(γ-dimethylaminopropyl)-iminodibenzyl hydrochloride. The response was a fall to a level of one-sixth of the original in three weeks, with little change thereafter. This is in sharp contrast to the action of iproniazid which caused a rise of some 200% in the blood platelet 5-hydroxytryptamine level over the same period. Imipramine in a concentration of 1 mg./ml. had no inhibitory action on 5-hydroxytryptophan decarboxylase; 8.0 μg./ml. of imipramine suppressed two-thirds of the in vitro uptake of 5-hydroxytryptamine (2.5 μg./ml.) by normal human platelets.     

The mechanism of the depressor action of noradrenaline in the cat

In cats anaesthetized with pentobarbitone sodium or chloralose and injected with phenoxybenzamine or phentolamine, administration of (—)-noradrenaline (5 to 20 μg) produced a fall of blood pressure which resembled in onset and duration that produced by adrenaline under similar conditions. The depressor action of noradrenaline was due mainly to dilatation of the splanchnic blood vessels. This could be abolished by administration of pronethalol, a drug known to block sympathetic β-receptors.     

Endorphins and the hypotensive response to stimulation of alpha-receptors in the brainstem by alpha-methylnoradrenaline

Opioid peptide involvement in the fall in blood pressure resulting from stimulation of alpha-receptors in the brainstem has been investigated in the urethane-anaesthetised rat. Unilateral microinjection of alpha-methylnoradrenaline into the nucleus tractus solitarii (NTS) induced a doserelated fall in blood pressure and heart rate. The depressor response induced by the amine was prevented by pretreatment with naloxone, administered either subcutaneously or directly into the nucleus. Pretreatment with antiserum to beta-endorphin, applied locally, also blocked the depressor response, however a similar dilution of antiserum to met-enkephalin was ineffective in this respect. The local application of phentolamine into the n. tractus solitarii caused an initial fall in both blood pressure and heart rate, and blocked the cardiovascular changes induced by alpha-methylnoradrenaline for at least 90 min. Pretreatment with the alpha-receptor antagonist attenuated the fall in blood pressure produced by microinjection of beta-endorphin. These results suggest that the fall in blood pressure observed after administration of alpha-methylnoradrenaline involves a beta-endorphin-like peptide, a probable site of this interaction being the n. tractus solitarii.     

Biphasic blood pressure response to neuropeptide Y in anesthetized rats

The effects of neuropeptide Y (NPY) on systemic arterial blood pressure and heart rate were studied in anesthetized intact and pithed rats. I.v. doses of NPY (0.3-30 nmol/kg) raised the mean arterial blood pressure dose dependently. At doses of greater than or equal to 3.0 nmol/kg, the initial pressor response was followed by a dose-dependent fall in blood pressure in intact and pithed rats. The depressor response was accompanied 1-2 min after the NPY injection by a slight increase in heart rate in pithed rats but not in intact rats, and 10 min after the injection by a decrease in heart rate in intact rats. After repeated injections of NPY, the depressor effect vanished, whereas the integrated pressor response over time was markedly enhanced. After pretreatment with the histamine H1-receptor antagonist, mepyramine, or with the histamine liberator, compound 48/80, the pressor response to NPY remained but the depressor response disappeared. We suggest that the marked fall in blood pressure can be attributed to NPY-evoked histamine release from mast cells.     

The depressor action of dopamine and adrenaline

Dopamine is a pressor agent in the spinal cat, but causes a fall of blood pressure in the guinea-pig and rabbit under urethane anaesthesia. When guinea-pigs and rabbits are injected with reserpine, which depletes the vessel walls of noradrenaline, dopamine then becomes pressor. If an intravenous infusion of noradrenaline is given the depressor action returns. An intravenous infusion of vasopressin does not have this effect.

A strip of rabbit aorta is caused to contract by noradrenaline and by dopamine, but if dopamine is added at the height of a noradrenaline contraction it causes relaxation.

Adrenaline causes a fall of blood pressure in the cat under ether with vagi cut. However, in a reserpine-treated cat its action is pressor. The depressor action is restored during an infusion of noradrenaline. Noradrenaline has thus been shown to cause a vasomotor reversal of dopamine and of adrenaline.

     

Effect of α-alkylated tryptamine derivatives on 5-hydroxytryptamine metabolism in vivo

In rats, three α-alkylated tryptamine derivatives (α-methyl, α-ethyl, and αα-dimethyltryptamine) caused alterations of 5-hydroxytryptamine metabolism typical of monoamine-oxidase inhibitors with short duration of action, viz., an increase of endogenous 5-hydroxytryptamine in brain, enhancement of the increase of 5-hydroxytryptamine in brain and heart after 5-hydroxytryptophan administration, an inhibition of the decrease in 5-hydroxytryptamine in brain induced by a benzoquinolizine derivative and of the increase induced by iproniazid. The increase after iproniazid was antagonized to the same extent by all the tryptamine derivatives and by harmaline, whereas dexamphetamine showed less effect. In the other experiments with brain, the tryptamine derivatives were less potent than harmaline, but somewhat more active than dexamphetamine. α-Methyltryptamine and α-ethyltryptamine were relatively more effective in the heart than in the brain. Among the tryptamine derivatives αα-dimethyltryptamine had the weakest activity in brain and in heart.     

Responses of the cardiovascular system of the rat to noradrenaline infusions and their modification by adrenoceptor blocking agents.

1 The effects of noradrenaline upon the cardiovascular system of the rat, anaesthetized with pentobarbitone, have been investigated.2 Noradrenaline produces a dose-dependent increase in mean arterial blood pressure (MABP) which is due entirely to an increase in cardiac output; total peripheral vascular resistance (TPR) remains unchanged.3 Following β-adrenoceptor blockade the pressor response to infused noradrenaline is enhanced and is now due mainly to an increase in TPR; the increment in cardiac output is reduced.4 After α-adrenoceptor blockade the pressor response is greatly reduced; the residual increase in MABP is due solely to an increase in cardiac output.5 After ganglion blockade resting cardiac output and TPR both fall, resulting in a reduction in MABP. The pressor response to noradrenaline is enhanced and is now due to increases in both TPR and in cardiac output.6 The cardiovascular response of the anaesthetized rat to noradrenaline can be explained in terms of classical α- and β-adrenoceptor stimulation by the amine; the unusual form of the response may be due to an effective predominance of β-adrenoceptor-mediated effects in this species.7 It is suggested that the failure of exogenous noradrenaline to produce a rise in TPR results from a balance between the α-adrenoceptor-mediated increase and β-adrenoceptor-mediated decrease in this variable. However, this proposed balance is lost if resting vasoconstrictor tone is reduced by ganglion blockade.     

Effects of clonidine and yohimbine on a C-fibre-evoked blood pressure reflex in the rat.

1. The involvement of alpha 2-adrenoceptors in a capsaicin-induced depressor reflex in the rat has been investigated. 2. The reflex fall in blood pressure following an intra-arterial injection of capsaicin was partially blocked by an intrathecal infusion of clonidine (1 microgram) at the spinal cord level L4-L5, an effect which was abolished by the prior intrathecal infusion of yohimbine (5 micrograms). 3. Clonidine (1 microgram) given intracisternally blocked the depressor reflex almost completely; however, it also produced a gradual, prolonged fall in mean carotid pressure. 4. Yohimbine (20 micrograms) given intracisternally did not change mean blood pressure but had a dual effect on the depressor reflex in response to the capsaicin injection: a short period of enhanced reflex response was followed by a long lasting inhibition of the response. 5. It was concluded that alpha 2-adrenoceptors in the spinal cord inhibit the capsaicin-evoked depressor reflex and that pre- and postsynaptic alpha 2-adrenoceptors in the brain stem modulate this reflex.     

Blockade of the dopamine depressor response by molindone, a newly introduced neuroleptic

Pretreatment with the neuroleptics, haloperidol and molindone, significantly antagonized the dopamine-induced depressor response in the anaesthetized dogs. The depressor response to dopamine was however, not significantly affected by propranolol, atropine or antazoline pretreatment. The results suggest that molindone like haloperidol, is capable of blocking the vascular dopamine receptors responsible for mediating dopamine-induced vasodilatation in the coeliac, mesenteric and renal vascular bed and fall in blood pressure.     

Effect of bulbocapnine as a peripheral dopamine receptor antagonists in the anesthetized cat

Summary We have found bulbocapnine to be an effective, apparently competitive inhibitor of dopamine depressor responses in the anesthetized, phenoxybenzamine-treated cat. The duration of action of the compound as a dopaminergic antagonist exceeded 3 hrs after an intravenous dose of 8 mg/kg. In the same preparation, however, bulbocapnine did not at all inhibit the depressor responses to acetylcholine, histamine and isoproterenol, indicating a selectivity of action. Although administration of a high dose of propranolol (2 mg/kg, i.v.) did not alter the response of the alpha-receptor blocked cat to dopamine, the subsequent infusion of bulbocapnine remained effective. These results suggest that dopamine is acting as a blood pressure depressor agent via a unique receptor mechanism.     

Some observations on the pharmacology of α-methyldopa

α-Methyldopa in high concentrations impaired the responses of rabbit isolated ileum and guinea-pig isolated vas deferens to stimulation of the sympathetic nerves and to noradrenaline, but these preparations taken from animals previously treated with α-methyldopa showed no sign of impairment. Contractions of the cat nictitating membrane were reduced but not abolished by α-methyldopa. In cats, dogs and rats, pressor responses to noradrenaline were usually slightly increased by α-methyldopa. Pressor responses to tyramine were not affected consistently. α-Methyldopa, α-methyldopamine and α-methylnoradrenaline behaved like dopa, dopamine and noradrenaline respectively in restoring the responses of tissues from reserpine-treated animals to stimulation of the sympathetic nerves to the rabbit ileum, the guinea-pig vas deferens and the cat nictitating membrane and in restoring responses to tyramine of the cat blood pressure and nictitating membrane, and the rat blood pressure. The potency of α-methylnoradrenaline relative to noradrenaline ranged from one-half to one-ninth on various preparations. The results are discussed in relation to the antihypertensive action of α-methyldopa.     

Mechanism of action of guanethidine

The early hypotensive action of intravenous guanethidine in rabbits, rats and cats anaesthetized with urethane is reversed after pretreatment with iproniazid. The fall in blood pressure following injection of guanethidine in rabbits is reduced after previous administration of reserpine. Reserpine, like adrenalectomy and splenectomy, suppresses the early pressor effect of guanethidine in cats anaesthetized with chloralose. Guanethidine inhibits the action of tyramine and nicotine, but potentiates the effect of noradrenaline on isolated rabbit atria. Guanethidine is also a weak inhibitor of monoamine oxidase activity. The results are discussed and compared with those shown by reserpine. It is concluded that the early effects of guanethidine are mainly due to the release of endogenous catechol amines.     

Blockade of spinal dopamine D2 receptors enhances the pressor effect of intravenous quinpirole in normotensive,conscious rats

The present investigation was undertaken to examine whether in conscious intact rats blockade of spinal dopamine D2 receptors enhances the pressor effect of intravenous quinpirole. In saline-pretreated rats, intravenous quinpirole (1 mg/kg) induced a significant pressor effect, which reached a maximum (17.71+/-0.60 mmHg) within the first min. after injection. Pretreatment with intravenous (0.5 mg/kg) or intrathecal (40 microg/rat at T9-T10) domperidone, a dopamine D2 receptor antagonist that does not cross the blood-brain barrier, significantly enhanced the maximal pressor response to quinpirole (25.60+/-1.52 and 24.00+/-1.72 mmHg, respectively). The pressor effect of quinpirole was also significantly enhanced after combined pretreatment with intravenous and intrathecal domperidone, and its maximum (31.60+/-2.31 mmHg) was significantly higher than that recorded in animals pretreated with intrathecal or intravenous domperidone alone. Intravenous pretreatment with metoclopramide (5 mg/kg) fully abolished the quinpirole-induced pressor effect. These results show that in conscious intact rats, blockade of spinal dopamine D2 receptors enhances the pressor response to systemic quinpirole, suggesting that this agonist can decrease blood pressure through a spinal dopaminergic mechanism. Thus, our previous hypothesis that the entire effect of intravenous quinpirole on blood pressure in conscious rats can be composed of a central pressor action, a peripheral sympathoinhibitory depressor effect and also a spinal depressor effect is strongly supported by the present findings.     

Blockade of Spinal Dopamine D2 Receptors Enhances the Pressor Effect of Intravenous Quinpirole in Normotensive,Conscious Rats

Abstract: The present investigation was undertaken to examine whether in conscious intact rats blockade of spinal dopamine D₂ receptors enhances the pressor effect of intravenous quinpirole. In saline‐pretreated rats, intravenous quinpirole (1 mg/kg) induced a significant pressor effect, which reached a maximum (17.71±0.60 mmHg) within the first min. after injection. Pretreatment with intravenous (0.5 mg/kg) or intrathecal (40 μg/rat at T₉‐T₁₀) domperidone, a dopamine D₂ receptor antagonist that does not cross the blood‐brain barrier, significantly enhanced the maximal pressor response to quinpirole (25.60±1.52 and 24.00±1.72 mmHg, respectively). The pressor effect of quinpirole was also significantly enhanced after combined pretreatment with intravenous and intrathecal domperidone, and its maximum (31.60±2.31 mmHg) was significantly higher than that recorded in animals pretreated with intrathecal or intravenous domperidone alone. Intravenous pretreatment with metoclopramide (5 mg/kg) fully abolished the quinpirole‐induced pressor effect. These results show that in conscious intact rats, blockade of spinal dopamine D₂ receptors enhances the pressor response to systemic quinpirole, suggesting that this agonist can decrease blood pressure through a spinal dopaminergic mechanism. Thus, our previous hypothesis that the entire effect of intravenous quinpirole on blood pressure in conscious rats can be composed of a central pressor action, a peripheral sympathoinhibitory depressor effect and also a spinal depressor effect is strongly supported by the present findings.     

Changes in the 5-hydroxytryptamine content of rat, rabbit and human brain after death

The fall in 5-hydroxytryptamine concentration which occurs in brain tissues in the first 48 hr after death varies in different areas of the brain and is of the same order of magnitude in those areas of the rat and rabbit in which it was estimated, namely, hypothalamus, hippocampal gyrus and frontal cortex, and also in human frontal cortex. The loss of 5-hydroxytryptamine is greater in the hypothalamus than in the cerebral cortex. The extent of this change depends on the temperature and conditions of storage of tissues. It is least in tissues which remain within the skull after death before chemical extraction and in tissues stored at —17° C. Comparison of cerebral 5-hydroxytryptamine content in control animals and animals pretreated with iproniazid suggests that the differences are for the greater part due to the action of mono-amine oxidase.     

Cardiovascular responses in rats with glycerol-induced acute renal failure

Autonomic and cardiovascular function were assessed in rats with glycerol-induced acute renal failure (ARF). Rats with ARF had significantly lower mean arterial blood pressure and heart rates and significantly elevated plasma noradrenaline concentrations. The chronotropic responses to right cervical sympathetic and vagal stimulation were diminished in rats with ARF. The pressor and depressor responses to noradrenaline and nitroprusside respectively when expressed as a change in mmHg pressure were significantly reduced in rats with ARF when compared to controls. However, when the depressor responses to nitroprusside were expressed as a percentage fall in basal mean arterial pressure, with the exception of the response to a dose of 10 micrograms kg-1, there were no significant differences between control and uraemic rats. The present findings show that in the rat, changes in cardiovascular responsiveness occur after a brief period of uraemia which are similar to those observed in patients and rats with chronic renal failure.     

Dopamine in the conscious dog with chronic heart-block

Summary The chronotropic effects of dopamine were studied in the conscious dog with chronic A-V block. Dopamine at 12.5–200 g/kg and 12.5–50 g/kg/min lowered atrial rate independently of dose. After blockade of muscarine receptors or alpha-adrenoceptors, it raised atrial rate. After blockade of dopamine receptors, dopamine still lowered atrial rate, and did so dose-relatedly after blockade of beta-adrenoceptors. It raised ventricular rate, and at high doses also induced ventricular rhythm disorders. Blockade of muscarine receptors enhanced the ventricular cardioaccelerator effect of dopamine (P<0.025) at 100 g/kg, while blockade of alpha-adrenoceptors reduced it (P<0.05). Blockade of dopamine receptors did not modify this effect, but blockade of beta-adrenoceptors reversed it. Dopamine at 25–200 g/kg raised mean blood pressure. This effect was enhanced by blockade of muscarine receptors, reversed by blockade of alpha-adrenoceptors, and was unaffected by blockade of beta-adrenoceptors or dopamine receptors. These results show that the atrial cardiomoderator effect of dopamine is a vagal reflex response to its hypertensive action, and that it is limited by its direct beta-adrenergic stimulating action. They also show that the ventricular cardioaccelerator effect of dopamine is attenuated by a reflex vagal depressor effect consequent to the induced hypertension. No evidence was found for the existence of positive chronotropic dopamine receptors in either atria or ventricles.A preliminary report of these findings was presented at the Symposium on Peripheral Dopaminergic Receptors, July 1978, in Strasbourg, France (Boucher et al. 1979b)     

Analysis of the action of m-tyrosine on blood pressure in the conscious rat: evidence for a central hypotensive effect

Mean arterial blood pressure was recorded through indwelling arterial catheters in conscious normotensive rats. dl -m-Tyrosine, 400 mg/kg, was given intraperitoneally alone and after pretreatment with two inhibitors of dopa decarboxylase [dl -α-hydrazino-α-methyl-β-(3,4-dihydroxyphenyl) propionic acid (MK 485) or N¹-(dl -seryl)-N²-(2,3,4-trihydroxybenzyl)hydrazine (Ro 4–4602)]. dl -m-Tyrosine alone produced a hypertensive response, but after MK 485 it caused a significant lowering of blood pressure after 5–7 min and after Ro 4–4602 (400 + 200 mg/kg) it had no significant influence on blood pressure. The hypotensive response to dl -m-tyrosine was not influenced by the central dopamine receptor blocking agent spiroperidol (0·1 mg/kg) or by pretreatment with the tyrosine hydroxylase inhibitor H 44/68 (250 mg/kg). However, the depressor action could be completely inhibited after depletion of central catecholamines by α-methyl-m-tyrosine, 400 + 400 + 200 mg/kg, in combination with H 44/68, 250 mg/kg. Further, the depressor action was abolished by the dopamine β-hydroxylase inhibitor bis (4-methyl-1-homo-piperazinyl-thiocarbonyl) disulphide (FLA-63) 40 mg/kg. In correlative biochemical experiments the concentrations of the decarboxylation products of m-tyrosine were measured in brain and heart. dl -m-Tyrosine alone produced an accumulation of m-tyramine and m-octopamine in these tissues. MK 485 + m-tyrosine substantially reduced the levels of m-tyramine and m-octopamine in the heart, but their accumulation in brain was largely unaltered. The results suggest that when decarboxylation of dl -m-tyrosine occurs in both the central and peripheral nervous system, there is a pressor action. When decarboxylation occurs mainly in the central nervous system there is a hypotensive response which is associated with accumulation of decarboxylation products of m-tyrosine.