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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.

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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.

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The role of opioid and histaminergic system in morphine induced emesis was investigated in dogs. Morphine (25 micrograms, icv) consistently evoked emesis with an average latency of 195 +/- 29 sec which was fully accounted for by an action on the chemoreceptor trigger zone (CTZ) as its ablation rendered animals refractory to vomiting. Intraventricular pretreatment with opioid antagonist naloxone, histamine H1 antagonist mepyramine and H2 antagonists metiamide and cimetidine afforded protection to icv morphine emesis. The CSF histamine concentration was significantly raised 5 min after icv morphine administration. The results suggest that both endogenous opioid and histamine are involved in morphine emesis. Naloxone in high doses (1600 micrograms, icv) elicited emesis which was not blocked by CTZ ablation confirming our earlier report.

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Far-field somatosensory evoked potentials were obtained by electrical stimulation of the volar surface of the forepaw and were recorded from the skull overlying the contralateral somatosensory area of the cerebral cortex. Three distinct peaks were discernable in the somatosensory evoked potentials prior to the first cortical component. Effects of different doses of morphine (0.5, 1.0, 2.5 and 5.0 mg/kg body weight), administered intravenously, were studied. Morphine selectively reduced the amplitude of component III in a dose-dependent manner. The maximum effect was obtained at a dose of 2.5 mg/kg. This effect was reversed within 2 min by intravenous administration of naloxone (0.25 mg/kg). The amplitudes of peaks I and II and the latencies of components I, II and III were not significantly affected by morphine. Infusion of morphine (25 micrograms/kg) into the thalamus showed effects on the far-field somatosensory evoked potentials similar to the maximal effect obtained on intravenous infusion. Therefore, the action of morphine on somatosensory evoked potentials could be attributed to its effect on the thalamic neurones.

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Serotonin (5-hydroxytryptamine, 5-HT) is implicated in the pathogenesis of migraine; however, its role in tension headache has not yet been studied. The uptake of 5-HT by platelets in patients of tension headache was significantly higher compared with migraineurs as well as controls. The basal platelet 5-HT levels did not show a significant difference. The study implicates the role of serotonin in tension headache.

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Isolated sheep ureteral ring suspended in an organ bath exhibits rhythmic contractions which are dose-dependently inhibited by indomethacin and revived by prostaglandin E2 or F2 alpha. Seven non-steroidal anti-inflammatory drugs (NSAID) belonging to different chemical groups were tested on the isolated ureteral ring model in molar concentrations of 10(-8)-10(-4) to determine the time elapsing from application of test drug to complete inhibition of ureteral contraction ("stop-time"). The descending order of potency of the NSAID was: flurbiprofen greater than indomethacin greater than flufenamic acid greater than tolmetin greater than aspirin greater than phenylbutazone greater than isoxicam. A parallelism was observed in the plot of log concentration of NSAID and "stop-time" amongst all compounds except aspirin and isoxicam. The sheep isolated ring preparation is a simple reproducible biological model for assessment of anti-inflammatory cyclo-oxygenase inhibitory activity of compounds.

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A double blind study in 25 patients with ischaemic heart disease and 20 matched healthy controls examined the effect of sulphinpyrazone on the uptake of serotonin by platelets and the basal concentrations of serotonin in platelets. Uptake was measured using tritium labelled serotonin and basal concentrations estimated spectrophotofluorometrically. Serotonin uptake was significantly increased both in the patients with chronic stable angina of effort and in those with a history of myocardial infarction six months or more previously. Sulphinpyrazone reduced serotonin uptake from 94.25 (SE 8.65) to 57.86 (5.37) cpm/10(8) platelets after 24 weeks of treatment in the group with stable angina and from 137.45 (16.26) to 68.08 (8.38) cpm/10(8) platelets in the myocardial infarction group. Raised basal concentrations in the two groups were also reduced by sulphinpyrazone. Placebo had no effect on serotonin uptake or basal concentrations in either group of patients. The ability of sulphinpyrazone to inhibit uptake and reduce basal concentrations of serotonin in patients with ischaemic heart disease may be yet another mechanism through which this drug exerts its beneficial antiplatelet effect.

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Cholinergic receptors present in three medullary nuclei namely, the nucleus tractus solitarii (NTS), nucleus ambiguous (AMB) and the dorsal motor nucleus of the vagus nerve (DMV) have been studied with regard to their role in regulation of heart rate (HR), blood pressure (BP) and baroreceptor reflex activation induced bradycardia in cats. Microinjection of carbachol into NTS was without effect while administration of carbachol or pilocarpine into AMB and DMV elicited dose related decrease in HR without affecting BP. These effects were completely antagonized by ethylbenztropine. Bilateral muscarinic cholinoceptor blockade of either AMB or DMV, with ethylbenztropine, produced a partial inhibition of the baroreflex bradycardia while intracisternal ethylbenztropine completely abolished this reflex response. Involvement of muscarinic cholinoceptors of AMB or DMV in baroreflex mediated adjustments of HR is therefore suggested.

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Microinjection of noradrenaline and clonidine into lateral medullary pressor area (LMPA) of chloralose anaesthetized cats produced dose dependent decrease in blood pressure without affecting heart rate, while phenylephrine did not elicit any cardiovascular response. Selective alpha 2-adrenoceptor antagonists idazoxan and piperoxan, microinjected locally, blocked the effects of the agonists but prazosin and phenoxybenzamine, which are relatively selective for alpha 1-adrenoceptors, failed to do so. Clonidine did not elicit any response in guanethidine pretreated cats but noradrenaline microinjected into LMPA of these animals induced a pressor response which was blocked by prazosin pretreatment. It is concluded that catecholaminergic fibres impinging upon this area inhibit the activity of the inhibitory second order baroreceptor neurone by activating alpha 1-adrenoceptors while alpha 2-adrenoceptors situated presynaptically on these inhibitory catecholaminergic nerve terminals are responsible for the manifestation of the hypotensive effect of clonidine and exogenously administered noradrenaline.

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Lumber cerebrospinal fluid (CSF) concentrations of metabolites of noradrenaline, adrenaline and serotonin were estimated in patients of sustained hypertension (n = 20), and healthy controls (n = 15). Platelet uptake of serotonin and its basal contents were also estimated in the same individuals. CSF 5-hydroxy indole acetic acid level (5-HIAA) (major metabolite of serotonin) was significantly higher in hypertensives than controls (p less than .01). CSF 3-methoxy, 5-hydroxy phenyl glycol (MHPG) (major metabolite of adrenaline and noradrenaline) level was also raised significantly in cases of hypertension (p less than .01). However, platelet uptake of serotonin as well as its basal contents in hypertension were significantly lower than controls (p less than .01). It can thus be postulated that there exists an increased central serotonergic and catecholaminergic activity in hypertension. Furthermore, alterations observed in platelet serotonin uptake and its basal content suggest the involvement of platelet serotonergic system in hypertension.

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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.

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The effect of exogenous administration of central amino acid neurotransmitters gamma-aminobutyric acid (GABA), glycine, glutamic acid and aspartic acid) into the cerebroventricular system was studied on gastric ulceration induced in albino rats either by 2 h restraint at 4 degrees C or by 6 h restraint at room temperature (30 +/- 2 degrees C). GABA (5, 10, 20 and 50 micrograms) injected intracerebroventricularly (i.c.v.) showed a dose-dependent reduction of gastric ulceration induced by 2 h restraint at 4 degrees C (CRU), whereas glycine (5, 10 and 20 micrograms i.c.v.) failed to alter this response. Muscimol (5 and 10 micrograms i.c.v.), a GABA agonist, and sodium valproate (400 mg kg-1 p.o.), which increases the concentration of GABA in the CNS, significantly reduced CRU. Pretreatment with the GABA antagonists, bicuculline (40 micrograms i.c.v.) or picrotoxin (5 micrograms i.c.v.) reversed the anti-ulcerogenic effects of GABA (50 micrograms i.c.v.) and sodium valproate (400 mg kg-1 p.o.). Bicuculline (20 and 40 micrograms i.c.v.) and picrotoxin (5 and 10 micrograms i.c.v.) per se did not induce gastric ulceration in normal rats but significantly enhanced the minimal ulcerogenic response induced by 6 h restraint at room temperature. Pretreatment with GABA (i.c.v.) significantly reduced the gastric ulceration induced by i.c.v. administration of acetylcholine and adrenaline or pylorus ligation. Glutamic acid (20 micrograms i.c.v.) and aspartic acid (20 micrograms i.c.v.) did not significantly enhance the minimal ulcerogenic response induced by 6 h restraint at room temperature. These observations show that GABA in the CNS exerts an inhibitory effect on stress-induced ulcerogenesis.

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Anti-ulcer and sedative effects of tranquillosedatives viz. benzodiazepines (diazepam, oxazepam and nitrazepam), barbiturate (phenobarbitone), phenothiazines (chlorpromazine, trifluoperazine and thioridazine) and butyrophenone (haloperidol) were compared in albino rats. Ulceration of the glandular stomach was induced by 2 h restraint at 4 degrees C. Sedation was measured using the rotarod test. These tranquillosedatives showed dose dependent anti-ulcer and sedative effects. The relative potency and therapeutic index (ratio between rotarod ED50 and anti-ulcer ED50) of each drug were determined. Diazepam showed the highest therapeutic index (1.88). Diazepam significantly reduced the volume of gastric secretion, raised its pH and prevented the gastric ulcer formation in pylorus ligated rats but failed to prevent the acute duodenal ulceration induced by intramuscular injection of histamine or carbachol in guinea-pigs and rats, respectively. These observations suggest that benzodiazepines (diazepam) are more suitable anti-ulcer agents compared to barbiturate, phenothiazines and butyrophenone. The anti-ulcer effect of diazepam is possibly due to a combination of sedative, anti-anxiety and antisecretory actions.

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Effect of alcohols on the permeability of blood-brain barrier was studied in anaesthetised dogs using sodium fluorescein as circulant. Entry of sodium fluorescein in the cerebrospinal fluid (CSF) was measured spectrophotofluorometrically. Methyl, ethyl, propyl and butyl alcohols were used in the study. Methyl alcohol did not increase the entry of sodium fluorescein in CSF compared to control. However, ethyl, propyl and butyl alcohols significantly increased the entry of sodium fluorescein. The increase was dependent upon the length of alkyl chain of alcohols. Longer was the aliphatic chain more marked was the effect. The increase in permeability was also dependent upon the concentration of the alcohol. Thus 90% ethyl alcohol was more effective than 30% and this effect was concentration-dependent. The increase in permeability of blood-brain barrier could be correlated to the lipid solubility of alcohols.

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Serotonin (5-hydroxytryptamine) contents of maternal blood, fetal cord blood, and placenta from thirty-five patients with toxaemia of pregnancy and forty normal pregnant subjects were estimated. Placental monoamine oxidase activity from ten normal and ten toxaemic cases were also estimated. An increased content and uptake of serotonin by platelets in maternal blood from toxaemic patients were observed and there was a concomitant reduction in platelet count. Raised levels of serotonin and a decrease in monoamine oxidase levels were observed in placentas of the toxaemic group. The levels of serotonin in fetal cord blood were significantly higher than those in normal maternal blood. It is suggested that the fetus could be the source of increased serotonin in this syndrome, due to the decrease in monoamine oxidase activity in the toxaemic placenta. An abnormality in indole amine metabolism may contribute to the pathology associated with toxaemia of pregnancy.

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