A study of effects of putative neurotransmitters injected into the lateral cerebral ventricle of man.

1. The study was carried out in adult patients having normal cardiovascular reflexes and no brain stem lesions. They were exposed to ambient temperature of 72-74 degrees F. Injections of agonists and antagonists of receptors were made into the lateral cerebral ventricles of these patients through diagnostic burr hole in the skull. 2. Noradrenaline, adrenaline and dopamine evoked hypotension and bradycardia. While the core temperature was reduced by nor-adrenaline and adrenaline, dopamine evoked hyperthermia. Isoprenaline elicited hypertension, tachycardia and hyperthermia. Opposite cardiovascular and thermal effects were observed with blockade of alpha 1-, beta-and dopamine receptors with prazosin, propranolol and haloperidol respectively. 3. Injection of 5-hydroxytryptamine resulted in hypertension, tachycardia and hyperthermia but hypotension, bradycardia and hypothermia were seen with methysergide. 4. Similarly, carbachol injection caused initial excitatory followed by inhibitory cardiovascular responses. These were associated with hypothermia. On the contrary atropine per se elicited hypertension, tachycardia and hyperthermia. 5. Thus, alpha 1- and beta-adrenoceptors, dopaminergic, serotonergic and muscarinic cholinergic receptors are present in human brain which appear to modulate cardiovascular activity and core temperature.

Serotonergic modulation of spinal cord sympathetic preganglionic neurone activity in cardiovascular regulation.

The present study demonstrates the effect of activation of spinal serotonergic receptors on heart rate, blood pressure and cardiac arrhythmia induced by coronary artery ligation in cervical spinal cord transected and bilaterally vagotomized dogs. Intrathecal injection of serotonin (5-HT) evoked a fall in blood pressure (mean decrease, 16 +/- 3) and a decrease in heart rate (mean change, 24 +/- 6) and these effects were blocked by intrathecal pretreatment with methysergide. The magnitude of ventricular ectopics evoked by coronary artery ligation was decreased by serotonin (mean decrease, 31 +/- 5%), and this effect of serotonin was blocked by methysergide pretreatment intrathecally (mean change, 7 +/- 5%). Methysergide per se, increased the magnitude of ventricular ectopics (mean increase, 24 +/- 5%). The serotonergic receptors of the spinal cord appear to have an inhibitory influence on the cardiovascular functions.

Evidence for the inhibitory effect of 5-hydroxytryptamine at central and peripheral sites on ovulation in rabbits.

1. The effect of 5-hydroxytryptamine (5-HT) has been investigated on ovulation per se as well as on induced ovulation in rabbits. 2. 5-HT administered intracerebroventricularly (i.c.v.) did not induce ovulation per se. 3. The ovulation was induced by coitus, subcutaneous administration of progesterone and intravenous administration of cupric acetate. 4. Postcoital and progesterone induced ovulation was found to be blocked by i.c.v. administered 5-HT. 5. Cupric acetate induced ovulation was, however, not found to be blocked by i.c.v. administered 5-HT. 6. Intraperitoneal administration of 5-HT was found to block cupric acetate induced ovulation. 7. It is concluded that 5-HT exerts an inhibitory control over ovulation by acting at central as well as at peripheral sites in rabbits.

Role of histamine receptor in mesencephalic nucleus dorsalis raphe in cardiovascular regulation.

The effects of microinjection of histamine and its antagonists into mesencephalic nucleus dorsalis raphe, were investigated on mean arterial pressure and heart rate in cats to elucidate the nature and role of histaminergic receptors in cardiovascular regulation. Microinjection of histamine (5 and 10 micrograms) into nucleus dorsalis raphe elicited both inhibitory and excitatory cardiovascular responses respectively. On the other hand, microinjection of H2-receptor blocker, cimetidine (10 micrograms) resulted in hypertension and tachycardia while H1-receptor antagonist, mepyramine (10 micrograms) microinjection evoked hypotension and bradycardia. Furthermore, local pretreatment with cimetidine and mepyramine blocked the inhibitory and excitatory cardiovascular responses of graded doses of histamine microinjection. These H1 and H2 receptors are localized in nucleus dorsalis raphe since microinjection of histamine into adjoining neural structures did not evoke any cardiovascular change. Furthermore, both the inhibitory and excitatory cardiovascular responses to histamine microinjection could not be observed in animals with spinal cord transection and in animals pretreated with p-chlorophenylalanine while they could be observed in bilateral cervical vagotomized animals. Thus, it appears that these cardiovascular responses to microinjection of histamine into nucleus dorsalis raphe, are due to modulation of serotonergic bulbospinal influence on sympathetic preganglionic neurones in the spinal cord. Moreover, the excitatory cardiovascular responses of high dose of histamine (10 micrograms) seem to result from a local release of noradrenaline since they were blocked by prior microinjection of guanethidine and piperoxan into nucleus dorsalis raphe. A release of noradrenaline in turn, modulates the activity of the neurones of the nucleus by acting on alpha adrenoceptors and thereby alters the activity of sympathetic preganglionic neurones.(ABSTRACT TRUNCATED AT 250 WORDS)

Presence of opioid receptors in mesencephalic nucleus dorsalis raphe concerned in cardiovascular regulation in cats.

The effects of microinjection of opioid receptor agonist and antagonist into mesencephalic nucleus dorsalis raphe, were studied on mean arterial pressure and heart rate to elucidate the nature and role of these opioid receptors in cardiovascular regulation. Microinjection of morphine (5 micrograms and 10 micrograms) into nucleus dorsalis raphe elicited both inhibitory and excitatory cardiovascular responses respectively, while microinjection of opioid receptor antagonist, naloxone (10 micrograms) failed to produce any significant cardiovascular responses. However, local pretreatment with naloxone blocked both inhibitory and excitatory responses of graded doses of morphine. These opioid receptors seem to be localised in the neurons of the nucleus since microinjection of morphine into neural structures adjoining nucleus dorsalis raphe failed to induce any cardiovascular responses. Furthermore, the dose or morphine (2 micrograms) which was ineffective when microinjected into nucleus dorsalis raphe, produced inhibitory cardiovascular responses after pretreatment with LM5008, a 5-HT uptake blocker. Similarly, the excitatory cardiovascular responses of morphine microinjection were blocked by spinal cord transection (C1) and p-CPA, guanethidine and piperoxan pretreatments, while bilateral cervical vagotomy failed to do so. Thus, it is likely that the inhibitory cardiovascular responses of morphine are mediated directly through stimulation of opioid receptors present in the neurons of nucleus dorsalis raphe while the excitatory responses to higher dose of morphine, appear to be due to a release of noradrenaline which in turn modulates the activity of neurons by acting on alpha adrenoceptors.

Cardiovascular responses elicited by microinjection of monoamines into mesencephalic nucleus dorsalis raphe in cats.

The effect of monoaminergic agonists and antagonists microinjected into mesencephalic nucleus dorsalis raphe has been studied on blood pressure and heart rate to elucidate the nature and role of these monoaminergic receptors in cardiovascular regulation. Microinjection of monoamines, noradrenaline, phenylephrine and 5-hydroxytryptamine (5-HT) into nucleus dorsalis raphe elicited hypertension and tachycardia which could be blocked by local pretreatment with piperoxan (an alpha-adrenoceptor blocker) and methysergide (a 5-HT receptor blocker) respectively. However, isoprenaline microinjections failed to evoke any response. Bilateral vagotomy did not prevent these cardiovascular responses evoked by monoamines microinjection, while cervical spinal cord (C1) transection with bilateral vagotomy prevented these responses. These monoaminergic receptors seem to be localized in nucleus dorsalis raphe since microinjection of monoamines into neural structures adjoining nucleus dorsalis raphe, failed to induce any cardiovascular response. Monoaminergic receptors are present in nucleus dorsalis raphe which modulate cardiovascular activity by influencing sympathetic preganglionic neurons in the intermediolateral columns of the spinal cord.

Substituted triazoles as anti-inflammatory agents.

Newly synthesized triazoles were evaluated for their anti-inflammatory and antiproteolytic activities. These derivatives possessed potent anti-inflammatory and antiproteolytic activities. In addition, these compounds were relatively less toxic.

Spinal site of antiarrhythmic action of morphine and pethidine in normal and spinal cord transected dogs.

In coronary artery ligated conscious dogs, intravenous (i.v.) injection of both morphine (8.0 mg/kg) and pethidine (12.0 and 24.0 mg/kg) inhibited the cardiac arrhythmia while naloxone (1.0 mg/kg) facilitated it. Intravenous pretreatment with naloxone completely blocked the morphine induced inhibition of the arrhythmia. Pethidine, however, elicited significant inhibition of the arrhythmia in the naloxone pretreated animals but its duration of action was markedly reduced. The temporal effect of i.v. injection of xylocaine (24.0 mg/kg) was parallel to that of pethidine (24.0 mg/kg) injected i.v. in the naloxone pretreated animals. In cervical spinal cord transected and bilaterally vagotomized dogs, i.v. injection of only 50.0 micrograms/kg of morphine elicited significant inhibition of the arrhythmia which was completely blocked by intrathecal pretreatment with a small dose (1.0 micrograms/kg) of naloxone. The same dose of naloxone, when given intravenously, failed to block the effect of morphine. The antiarrhythmic activity of morphine against the cardiac arrhythmia induced by coronary artery ligation appears to be due to activation of spinal opioid receptors. The local anaesthetic activity of pethidine contributes towards its early phase of antiarrhythmic activity.

Presence of cholinoceptors in mesencephalic raphe nuclei concerned in thermoregulation in rabbits.

The thermal effects of cholinomimetics and cholinoceptor blocking agents microinjected into mesencephalic nucleus raphe medianus (NRM) were investigated in rabbits to determine the nature and role of these cholinoceptors in thermoregulation. Microinjection of cholinoceptor agonists, carbachol and pilocarpine, into NRM resulted in significant hyperthermia which could be blocked by local pretreatment with chlorisondamine (a nicotinic receptor blocker) as well as by ethybenztropine (a muscarinic receptor blocker). Intracerebroventricular pretreatment with LM 5008 (serotonin reuptake blocker) significantly inhibited the carbachol-induced hyperthermia. Both nicotinic and muscarinic cholinoceptors are present in mesencephalic NRM which may be involved in thermoregulation in rabbits. Activation of these cholinoceptors in NRM results in hyperthermia which seems to be due to an inhibition of a serotonin sensitive hypothalamic heat loss mechanism.

Newer indolyl imidazolones as anti-inflammatory agents.

Sixteen new 1,2-disubstituted-4-(indol-3'-yl)methylene imidazol-5-ones were synthesized by the condensation of oxazolone with different aryl amines and evaluated as to their anti-inflammatory and antiproteolytic activities. These derivatives showed 2-38% protection against carrageenin-induced paw oedema in albino rats at a dose of 100 mg/kg p.o. All compounds showed antiproteolytic activity. The degree of inhibition against trypsin-induced hydrolysis of casein ranged from 10 to 75% at a concentration of 4 X 10(-4) mol/l. Furthermore, active compounds of the series were also screened for their analgesic activity against aconitine-induced writhing in albino mice. The toxicity of the compounds was reflected by their approximate LD50 values.

Adrenergic influences on the spinal cardiovascular neurones.

In cervical spinal cord transected and bilaterally vagotomized dogs, intrathecal (i.t.) injection of clonidine decreased the resting heart rate and mean arterial pressure (MAP) while isoprenaline increased the heart rate. The clonidine induced bradycardia and hypotension were antagonized by piperoxan pretreatment. Similarly, the isoprenaline induced tachycardia was antagonized by pretreatment (i.t.) with atenolol. Intrathecal atenolol per se decreased the heart rate and MAP while piperoxan had no effect. The post-coronary artery ligation cardiac arrhythmia, in the cervical spinal cord transected and bilaterally vagotomized dogs, was inhibited by clonidine, phenylephrine and methoxamine and facilitated by isoprenaline. beta-Adrenoreceptor antagonists propranolol, atenolol and acebutolol, given intrathecally, inhibited while piperoxan facilitated the cardiac arrhythmia. The clonidine and isoprenaline induced changes in the arrhythmia were antagonized by i.t. pretreatment with piperoxan and atenolol respectively. It appears that the alpha-adrenoreceptors are inhibitory while beta-adrenoreceptors are facilitatory for spinal control of heart rate and blood pressure and for post-coronary artery ligation cardiac arrhythmia.

Cardiovascular responses elicited by microinjection of cholinergic agents into nucleus dorsalis raphe in cats.

The effect of cholinomimetics and cholinoceptor blocking agents microinjected into nucleus dorsalis raphe (NDR) has been studied on heart rate and blood pressure to identify the nature and role of these cholinoceptors in cardiovascular regulation. Microinjection of the cholinoceptor agonists, pilocarpine and carbachol into NDR elicited bradycardia and hypotension accompanied by salivation which could be blocked by local pretreatment with ethybenztropine (a muscarinic receptor blocker), but not by chlorisondamine (a nicotinic receptor blocker). Pretreatment with atropine methylnitrate (i.v.), which blocks only peripheral muscarinic receptors, did not prevent these cardiovascular responses evoked by carbachol microinjection. These cholinergic receptors seem to be localized in NDR since, microinjection of carbachol into neural structures adjoining NDR, failed to induce any cardiovascular responses. Muscarinic cholinoceptors are present in NDR which modulate cardiovascular activity by influencing sympathetic preganglionic neurons in the intermediolateral columns of the spinal cord.

Cholinergic influences on the spinal cardiovascular neurones.

1 In bilaterally vagotomized and spinal cord (C1) transected dogs, intrathecal (i.t.) injection of pilocarpine decreased while DMPP increased the blood pressure. These responses were antagonized by i.t. pretreatment with ethylbenztropine and chlorisondamine respectively. 2 No change in the resting heart rate occurred after intrathecal injection of cholinergic drugs in these animals. 3 The post-coronary artery ligation cardiac arrhythmia, in bilaterally vagotomized and spinal (C1) transected dogs, was inhibited by i.t. pilocarpine and chlorisondamine and facilitated by ethylbenztropine and DMPP. 4 The effects of muscarinic and nicotinic receptor agonists on the arrhythmia were blocked by their respective blockers. 5 It appears that the muscarinic receptors are inhibitory while nicotinic receptors are facilitatory for spinal control of vasomotor tone and the post-coronary artery ligation cardiac arrhythmia. However, the spinal muscarinic and nicotinic receptors do not appear to have a significant role in the regulation of normal heart rate.

Anticonvulsant and monoamine oxidase inhibitory activity of substituted oxadiazol-thiones.

Several 1,3,4-oxadiazol-thiones were synthesised and characterized by their melting points elemental analysis and I.R. spectra. All the oxadiazol-thiones possessed anticonvulsant activity which was reflected by protection upto 80% against pentylenetetrazole induced seizures and 40% protection against maximal electroshock induced seizures. Substantiations at position-3 of oxadiazol-thiones have shown marked effect on MAO inhibitory activity. No definite correlation between monoamine oxidase inhibitory and anticonvulsant activity could be established. It was observed that by the substitution of one, two and three methyl groups in the phenyl ring of 2-arylamino methyl side chain anticonvulsant activity against both maximal electroshock induced convulsions and pentylenetetrazol induced convulsions decreases i.e. the order of activity was found to be unsubstituted greater than monomethyl greater than dimethyl greater than trimethyl.

Central adrenoceptors and cholinoceptors in cardiovascular control.

1. In cats anaesthetized with chloralose, adrenoceptor and cholinoceptor agonists and antagonists were localized to the posterior hypothalamus (PH), lateral medullary pressor area (LMPA) and spinal autonomic loci to delineate the role of central cholinoceptors and adrenoceptors in cardiovascular control. 2 All along the neuroaxis, the alpha-adrenoceptors seem to subserve an inhibitory and the beta-adrenoceptors a facilitatory role in cardiovascular control. There appear to be a predominance of alpha-adrenoceptors at the medullary level and beta-adrenoceptors at the hypothalamic level. 3 The nicotinic cholinoceptors at the hypothalamic, medullary and spinal levels were facilitatory, whereas muscarinic cholinoceptors were inhibitory for cardiovascular control. However, muscarinic receptors were undetectable at the posterior hypothalamus. 4 The central cardiovascular effects of nicotine are attributed to nicotinic receptor activation and release of central catecholamines. 5 There appears to be a relationship between central cholinergic and adrenergic mechanisms in cardiovascular control.

Mechanism of cardiovascular effects of clonidine in conscious and anesthetized rabbits.

The actions of intravenous clonidine [2-(2,6 dichlorophenylamino)-2-imidazoline hydrochloride] on blood pressure and heart rate were examined in conscious rabbits. Complete transection of thecervical spinal cord increased the intensity and duration of the hypertensive effect of 30 microgram/kg of clonidine and completely abolished the fall in blood pressure. Heart rate slowing by clonidine was reduced. Result were similar 1 hour, 24 hours and 7 days after cord transection. Bilateral aortic sinus nerve section (baroreceptor deafferentation) increased both the hypertensive and hypotensive action of clonidine but reduced the bradycardia. When cervical cord transection was combined with batensive action, were abolished. We conclude that whereas the hypertensive action results from a direct effect on peripheral adrenoceptors, the fall in blood pressure is related to a reduction in sympathetic tone mediated at the level of the brain stem or more rostrally. The heart rate slowing results from both a reduction in sympathetic tone and also an enhanced vagal outflow. The increase in vagal tone seems to be dependent on the intergrity of baroreceptor afferent pathways.