3-Methoxy-4-hydroxyphenylglycol in cerebrospinal fluid and vanillylmandelic acid in urine of humans with hypertension.

3-Methoxy-4-hydroxyphenylglycol (MHPG) was measured in lumbar spinal fluid of 20 subjects with hypertension of varied etiology and severity. There was a significant correlation between the concentration of MHPG and the severity of hypertension. However, changes in the concentration of vanillylmandelic acid in the urine of these subjects were insignificant. In six subjects, administration of clonidine or alpha-methyldopa, two centrally acting antihypertensive drugs, was associated with a significant lowering of MHPG concentrations. These data support the hypothesis that central catecholamines are involved in clinical hypertension.

Effect of morphine on far-field somatosensory evoked potentials in the rat.

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.

Role of the chemoreceptor trigger zone in histamine-induced emesis.

1. In unanaesthetized dogs, the emetic action of histamine was studied after its injection into the cerebral venricles through chronically implanted cannulae in order to elucidate the role of the chemoreceptor trigger zone (CT-zone), situated in the area postrema, for this emesis.2. On injection into the lateral cerebral ventricle, about 10 times larger doses of histamine (3 mg) were required regularly to produce emesis, and it occurred after a longer latency than on injection into the fourth ventricle. This is in accord with an action of histamine on the CT-zone.3. After bilateral ablation of the CT-zone, intraventricular injections of histamine no longer produced emesis even when injected in doses which were three to four times greater than those which regularly elicited vomiting in dogs with intact CT-zone. The emesis produced in dogs by intraventricular injections of histamine is thus fully accounted for by an action on the CT-zone.4. Injections of chlorpromazine intramuscularly or of the two antihistamines cyclizine and mepyramine, either intramuscularly or into the lateral ventricle, prevented the emesis caused by histamine injected into the lateral ventricle. This protective action of the antihistamines-which did not extend to the emesis produced by oral copper sulphate-suggests the presence of histaminergic receptors in the CT-zone.

Nature of histamine receptors concerned in capillary permeability.

1 Histamine and 2-methyl-histamine (H1-receptor agonist) caused dose-dependent increases in capillary permeability in albino mice, but 4-methyl-histamine (H2-receptor agonist) caused no significant increase. 2 Mepyramine (H1-receptor antagonist) blocked the histamine-induced increase in capillary permeability whereas burimamide (H2-receptor antagonist) produced no significant blockade of the histamine-response. 3 Combined mepyramine and burimamide pretreatment did not give any significantly greater protection than mepyramine alone. 4 The results indicate involvement of the H1-receptors in histamine-induced increase in capillary permeability.

Nature of histamine receptors in the emetic chemoreceptor trigger zone.

1 The protective effects of the intracerebroventicular (i.c.v.) administration of the H1-receptor antagonist, mepyramine and the H2-receptor antagonists, burimamide and metiamide on centrally induced histamine-emesis were studied in unanaesthetized dogs. 2 The PD50 values of intraventricular mepyramine, burimamide and metiamide against the 100% emetic dose of histamine (3.0 mg i.c.v.) were found to be approximately 200 mug, 20 mug and 20 mug respectively. 3 Although burimamide (i.c.v. or i.v.) afforded protection against histamine-induced emesis, there was no protection against intravenous apomorphine-or oral copper sulphate-induced emesis. 4 The results suggest that both H1- and H2-histamine receptors in the emetic chemoreceptor trigger zone of the area postrema are concerned in histamine-induced emesis.

An analysis of central adrenoceptors for control of cardiovascular function.

1. In dogs anaesthetized with pentobarbitone sodium, bradycardia with hypotension occurred on intracerebroventricular (i.c.v.) injection of noradrenaline (50-200 mug) or phenylephrine (100-400 mug), but tachycardia with hypotension occurred on i.c.v. injection of isoprenaline (100-200 mug).2. These cardiovascular responses were central effects, and from the results obtained after bilateral vagotomy, removal of both stellate ganglia and transection of the upper cervical cord, it was evident that the efferent nervous pathway for all these effects was the sympathetic nervous system.3. An i.c.v. injection of the alpha-adrenoceptor blocking agent phenoxybenzamine (10 mg) blocked the bradycardia and hypotension produced by noradrenaline or phenylephrine, and an i.c.v. injection of a beta-adrenoceptor blocking agent, either propranolol (2 mg) or N-isopropyl-p-nitrophenyl-ethanolamine (INPEA) (10 mg), blocked the tachycardia and hypotension produced by isoprenaline.4. The cardiovascular effects produced by i.c.v. injection of the three sympathomimetic amines could be reproduced in cross-circulation experiments in the recipient dog when the amines were injected into its head circulation, and the effects of noradrenaline and phenylephrine, but not those of isoprenaline, were abolished by the alpha-adrenoceptor blocking agent yohimbine (1 mg/kg) injected intravenously into the donor dog.5. It is concluded that the central alpha-adrenoceptors are concerned with bradycardia and the central beta-adrenoceptors with tachycardia, but that both receptors are concerned with hypotension.

Central adrenoceptors concerned in the release of adrenocorticotrophic hormone.

The effect of injecting the alpha-adrenoceptor stimulating drugs adrenaline, noradrenaline and phenylephrine and the beta-adrenoceptor stimulating drug, isoprenaline into the lateral ventricles (i.c.v.) of the brains of dogs on the plasma cortisol concentration was investigated. Adrenaline, noradrenaline and phenylephrine produced a significant rise in the plasma cortisol concentration. Isoprenaline had no effect on the plasma cortisol concentration. The effect of noradrenaline and phenylephrine on the plasma cortisol concentration was completely blocked by yohimbine (i.c.v.). This indicates that the stimulation of central alpha-adrenoceptors can cause the release of adrenocorticotrophic hormone.

Central GABA-ergic mechanism in stress-induced gastric ulceration.

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.

Enkephalin receptors in the emetic chemoreceptor trigger zone of the dog.

1 The emetic action of Met-enkephalin, morphine and naloxone was studied following their administration into the cerebral ventricles of dogs through chronically implanted cannulae and the effect on the responses of ablating the chemorceptor trigger zone (CTZ) was investigated. The opiate antagonist, naloxone, was used to determine the role of enkephalin receptors in emetic responses.2 Administration of Met-enkephalin (1.0 mug/kg) into the IVth ventricle regularly evoked emesis with an average latency of 35 s. A dose of morphine (2.5 mug/kg) which was five times larger was required for a consistent emetic response when introduced into the lateral cerebral ventricle (i.c.v.) as compared to the dose required by the IVth ventricular route. The latency of emetic responses by the latter route of injection of morphine was shorter. This is in accord with an action of morphine on the emetic CTZ.3 After bilateral ablation of the CTZ, intraventricular injections of Met-enkephalin and morphine failed to produce emesis even when given in doses that were 5 to 10 times the dose which regularly elicited emesis in animals with intact CTZ. The emesis produced in dogs by intraventricular Met-enkephalin and morphine is thus fully accounted for by an action on the CTZ.4 Naloxone (i.c.v.) in doses up to 10.0 mug/kg did not cause emesis. However, higher doses of naloxone elicited dose-dependent emesis in dogs. The 100% emetic dose of naloxone was found to be 160 mug/kg and the latency of emesis was 180 s. Unlike Met-enkephalin and morphine, naloxone continued to elicit emesis in CTZ-ablated animals.5 Pretreatment with intraventricular naloxone (1 to 8 mug/kg) blocked the emetic responses induced by intraventricular Met-enkephalin and morphine but not that to apomorphine. The selective protective action of the opiate antagonist against Met-enkephalin and morphine supports the presence of enkephalin receptors in the emetic CTZ.

Role of catecholamines in centrogenic cardiac arrhythmia induced by aconitine.

1. Injection of 20 mug of aconitine into the lateral ventricle of dogs anaesthetized with pentobarbitone regularly induced cardiac irregularities and hypertension. The cardiovascular changes appeared within 5 min and lasted for about 90 min. Tachyphylaxis to the aconitine-induced cardiovascular effects was observed.2. The aconitine-induced arrhythmia and hypertension were centrogenic, for they were abolished or prevented by spinal transection (C(2)) or ganglionic blockade.3. Bilateral vagotomy as well as bilateral stellate ganglionectomy merely raised the threshold for arrhythmia without affecting the blood pressure response. The neural supply to the heart, therefore, does not seem to be the major pathway concerned in the genesis of the centrogenic cardiovascular effects of aconitine.4. The centrally evoked release of endogenous catecholamines from the adrenal glands was responsible for the aconitine-induced arrhythmia, since the arrhythmia could be blocked or prevented by prior reserpinization, bilateral adrenalectomy or thoracic splanchnic nerve section.5. alpha- and beta-adrenoceptive receptor blocking agents prevented or abolished the aconitine-induced arrhythmia in a manner similar to the catecholamine-induced arrhythmia.

Study of central neurotransmitters in stress-induced gastric ulceration in albino rats.

1 Restraint when combined with cold (4 degrees C) consistently induces gastric ulceration in rats at 2 h. The cold-restraint ulcer (CRU) technique provides a suitable model for acute studies. 2 The peripheral mechanisms in CRU seem to be increased sympathetic and parasympathetic outflow since CRU was significantly reduced by prior spinal transection or vagotomy or by appropriate blocking agents. Since metiamide significantly reduced CRU, H2-histamine receptors are also involved. 3 Central catecholaminergic as well as cholinergic mechanisms seem to be responsible for the activation of peripheral sympathetic and parasympathetic outflow in CRU, since central administration of dibenamine, propranolol, 6-hydroxydopamine and atropine prevented the CRU. 4 Exogenous administration of putative neurotransmitters (adrenaline, noradrenaline and acetylcholine) into the cerebroventricular system produced gastric ulceration similar to CRU. However, dopamine, histamine and 5-hydroxytryptamine failed to induce gastric ulceration. 5 The results with intracerebroventricular adrenaline and acetylcholine indicate a central cholinergic link distal to adrenergic activation in the ulcerogenesis. 6 Intracerebroventricular adrenaline-induced gastric ulceration appears to be most akin to CRU. However, other central neurotransmitter mechanisms may also be involved.

Central mechanism of vasopressin-induced changes in antidiuretic hormone release.

1. Intracerebroventricularly (i.c.v.) administered vasopressin (0.001-1.0 u) in dogs anaesthetized with chloralose produced adose-dependent increase in urine flow with a concomitant decrease in the levels of antidiuretic hormone (ADH) in jugular vein blood. 2. Higher doses of vasopressin (1.5-2.0 u, i.c.v) on the other hand had an antidiuretic effect and produced an increase in blood ADH level. 3. Pretreatment (i.c.v.) with a beta-adrenoceptor antagonist completely blocked the diuretic response of low doses of vasopressin (i.c.v.) but did not influence the antidiuretic response obtained with high doses. 4. Repeated administration of vasopressin (1.0 u, i.c.v.) induced tachyphylaxis; central catecholamine depletion with tetrabenazine significantly inhibited the vasopressin-induced diuretic response. 5. It is concluded that intracerebroventricular vasopressin-induced changes in ADH secretion are mediated through the release of catecholamines in the central nervous system.

Central cholinergic and adrenergic mechanisms in the release of antidiuretic hormone.

1. Studies on the urine outflow, blood ADH concentration and electrolyte excretion were carried out in alpha-chloralose anaesthetized hydrated dogs; the agonists and antagonists of specific cholinoceptors and adrenoceptors were injected by the intracerebroventricular technique, to delineate the role of the C.N.S. receptors in the control of ADH secretion.2. Central injection of acetylcholine elicited a dose-dependent antidiuretic response which was associated with an increase in the blood ADH titre. Central atropinization partially blocked the antidiuretic response. The remaining antidiuretic response was reversed to a diuretic one by further pretreatment with phenoxybenzamine. The diuretic response thus obtained could be blocked by propranolol.3. The alpha-adrenoceptor agonists, phenylephrine and noradrenaline, induced dose-dependent antidiuretic responses with a concomitant rise in blood ADH concentration. Their effect could be blocked by pretreatment centrally with phenoxybenzamine. Low doses of adrenaline induced a diuretic response and a decrease in blood ADH concentration, higher doses elicited a dose-dependent antidiuretic response and increase in the titre of ADH in blood. Central phenoxybenzamine pretreatment reversed the antidiuretic effect of high doses of adrenaline to a diuretic effect which could be blocked by propranolol.4. Isoprenaline elicited a dose-dependent diuretic response and a decrease in blood ADH titre and propranolol competitively blocked the effect of isoprenaline.5. It is concluded that central muscarinic cholinoceptors and the alpha-adrenoceptors are concerned in the release of ADH, whereas the beta-adrenoceptors are concerned with inhibition of ADH release.

The muscle relaxant activity of methaqualone and its methyl congener.

Studies with methaqualone and dimethylquinazolone showed them to possess both central and peripheral muscle relaxant activity, the latter only at high dose levels. They selectively inhibited polysynaptic reflexes and were more potent than mephenesin.

Mechanism of histamine-induced antidiuretic response.

1. In dogs anaesthetized with alpha-chloralose, intracerebroventricular (i.c.v.) injection of histamine induced antidiuresis and increase in jugular vein blood antidiuretic hormone (ADH) level but no change in urinary electrolytes. The mechanism of the histamine-induced antidiuretic response was analysed by the use of pharmacological agents.2. Histamine (i.c.v.) in 1-20 mug doses produced a variable effect on urine outflow as well as on the blood ADH concentration; however, higher doses (25-500 mug) of histamine elicited a dose-dependent antidiuretic response with concomitant rise in blood ADH titre.3. Repeated administration of high doses of i.c.v. histamine (400 mug) elicited a diminishing antidiuretic response which was not observable after the fourth dose, thus exhibiting tachyphylaxis. The antidiuretic response to histamine could be restored by central administration of noradrenaline (500 mug).4. Central pretreatment with mepyramine (5 mg) prevented the histamine-induced antidiuresis. Atropine (2 mg i.c.v.) was ineffective in blocking the antidiuretic effect of histamine. A diuretic response to histamine (400 mug i.c.v.) was obtained in phenoxybenzamine (i.c.v.) pretreated animals; this response could be blocked by i.c.v. injection of propranolol. Tetrabenazine pretreatment prevented the antidiuretic response to histamine.5. The results of the study lead us to conclude that histamine releases central catecholamines which activate the central adrenergic mechanism for the release of antidiuretic hormone.

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.

Role of the chemoreceptor trigger zone in cyclopropane induced emesis in dogs.

Inhalation of cyclopropane in dogs, by the closed circuit method, for a fixed period, produced an emetic response during recovery from anaesthesia. Bilateral surgical ablation of the emetic chemoreceptor trigger zone of the area postrema rendered the dogs refractory to several times (3-6) the threshold emetic dose of cyclopropane.

Involvement of central cholinoceptors in Metrazol-induced convulsions.

Atropine sulphate (10 mg/kg IP) afforded 90% protection against clonic convulsions induced by standard doses of metrazol (80 mg/kg SC) in mice, whereas atropine methonitrate (10 mg/kg IP) did not offer any protection. Furthermore, physostigmine (1 mg/kg IP) caused recurrence of convulsions in atropinzed metrazol-treated mice and converted the subconvulsive dose of metrazol (40 mg/kg SC) into a 100% convulsive dose. However, neostigmine (1 mg/kg IP) did not antagonize the protection afforded by atropine sulphate against metrazol. The results of the study suggest an involvement of central cholinergic mechanisms in metrazol-induced convulsions.

Evidence for central histaminergic mechanism in foot shock aggression.

The role of central histaminergic system in foot shock induced aggression was studied in mice. Histamine administered by intracerebral (IC) injection (25-200 micrograms) produced a significant increase in fighting episodes in a dose dependent manner. It was observed that mepyramine (H1 blocker) given intraperitoneally (IP) significantly increased and metiamide (H2 blocker) given IC decreased significantly the fighting response. To determine the nature of receptors involved in histamine induced facilitation of aggressive behaviour, histamine was administered IC in mice pretreated with mepyramine or metiamide. Mepyramine pretreatment further increased the facilitatory effect of histamine while metiamide blocked the enhancement of aggressiveness by histamine. Combined pretreatment with metiamide and mepyramine decreased significantly the fighting counts which remained unaffected after histamine. Haloperidol did not block the enhancement of aggression by histamine or mepyramine. However, atropine pretreatment partially inhibited the histamine induced increase in the fighting counts. Results of pretreatment with metiamide and atropine were similar to those obtained with pretreatment of metiamide and mepyramine. Metiamide alone or in combination with atropine failed to affect the facilitatory effect of amphetamine on the foot-shock aggression. It is concluded that central histamine H2 receptors have a facilitatory role and H1 receptors an inhibitory role on aggressive behaviour in mice induced by foot-shock. Since histamine per se had a facilitatory effect on foot-shock induced aggression, the central H2 receptors seem to dominate over the H1 receptors.

An investigation into the mechanism of cardiovascular responses elicited by electrical stimulation of locus coeruleus and subcoeruleus in the cat.

Electrical stimulation of locus coeruleus (LC) and subcoeruleus (SC) elicited an increase in heart rate (HR) and blood pressure (BP). Adrenergic neurone blockade in the posterior hypothalamus with guanethidine and also bilateral adrenalectomy completely blocked the LC stimulation induced cardiovascular responses. The cardiovascular responses elicited by electrical stimulation of SC were, however, unaffected by the former and only partially inhibited by the latter. It is suggested that the LC stimulation-evoked rise in HR and BP is mediated by catecholamine release from the adrenal medulla due to an activation of the hypothalamic-adrenal axis. The cardiovascular responses elicited by stimulation of SC are mainly due to activation of the sympathetic preganglionic neurones and are further augmented by the adrenal catecholamine release.