Biomedical subjects
M Weinstock
Publications and source records attributed to M Weinstock.
A pharmacological analysis of autonomic pathways mediating myocardial disturbances originating in a lateral hypothalamic area of the cat.
A study was made of the mechanisms mediating autonomic changes resulting from stimulation of a site in the lateral hypothalamic area (LHA). This site, when stimulated, induced angina-like ECG disturbances similar to those observed in some cases of brain traumas. These ECG changes were often associated with other autonomic changes, such as pressor response, tachycardia (in some cases bradycardia), nictitating membrane (NM) contraction and pupillary dilatation. Most symptoms were sympathetic: they were largely abolished by spinal cord section between C1 and C2, but were not affected by vagotomy, except that bradycardia was converted to tachycardia. Adrenal catecholamines were not involved since adrenal vein ligation was without effect. Hexamethonium (5-10 mg/kg) prevented pressor response and tachycardia in most cats but only partly protected against ECG changes and NM contractions. Atropine methyl nitrate (0.2 mg/kg) abolished the remaining ECG abnormalities and NM tension. The beta-receptor antagonists, propranolol and practolol (50 micrograms/kg) completely prevented the ECG changes induced either by isoprenaline or LHA stimulation. It is concluded that the symptoms induced by LHA stimulation result from noradrenaline release in the target organs.
Differential effects of 5-hydroxytryptamine antagonists on behaviors resulting from activation of different pathways arising from the raphe nuclei.
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Physostigmine antagonizes morphine-induced respiratory depression in human subjects.
The effect of physostigmine on the respiratory depression induced by morphine was studied in human subjects who received morphine as part of their preanesthetic medication. After pretreatment with droperidol (2.5-5 mg, iv) to prevent nausea, the change in minute ventilation was measured in 16 patients in response to increasing concentrations of inspired CO2 (CO2-response curve) by the rebreathing method. This was repeated 30 min after morphine (0.166 mg/kg, iv) in nine subjects and in seven controls who did not receive morphine and again 5-10 min after physostigmine (13-33 micrograms/kg, iv) in all subjects. All subjects were given N-butylhyoscine hydrobromide (5 mg, iv) to antagonize any peripheral cholinergic effects of physostigmine. Morphine decreased the mean slope of the CO2-response curve from 1.78 +/- 0.18 to 1.12 +/- 0.14 1 X min-1 X mmHg-1 (P less than 0.01) and increased the alveolar PCO2 for a fixed minute ventilation (position of curve) from 45.0 +/- 1.3 to 51.9 +/- 1.5 mmHg (P less than 0.001). Physostigmine restored the mean slope after morphine to control value, i.e., 1.79 +/- 0.231 X min-1 X mmHg-1, and position to 46.2 +/- 1.2 mmHg (P less than 0.001). Physostigmine did not increase the slope or alter the position of the CO2-response curves of subjects given droperidol alone. The authors conclude that physostigmine can reverse the respiratory depressant effect of morphine and restore the sensitivity of the respiratory center of CO2, presumably by raising acetylcholine levels in the brain after these have been reduced by morphine.
Vasodilator responses to cholinergic and adrenergic stimulants in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) normotensive rats.
The cardiovascular effects of isoprenaline, methacholine, and sodium nitroprusside were studied in spontaneously hypertensive (SHR) and in Wistar-Kyoto normotensive (WKY) rats. In conscious rats with chronic indwelling arterial cannulae, methacholine caused a much greater fall in mean arterial blood pressure (MAP) in SHR rats, abolishing the initial 30-40 mm Hg difference in MAP at a dose of 2.5 micrograms/kg. The hypotensive response to methacholine was accompanied by reflex tachycardia in WKY rats but by a dose-related bradycardia in SHR rats. Isoprenaline increased heart rate and reduced blood pressure to a similar extent in rats of both strains. Administration of sodium nitroprusside resulted in a hypotensive response that was of greater duration in SHR rats. In addition, the reflex tachycardia was more marked and of greater duration in WKY compared to SHR rats. This demonstrates that the baroreflex response to vasodilation is suppressed in SHR rats and that this may contribute to the increased vasodepressor response of these animals to methacholine. However, when baroreflexes but not initial MAP were suppressed with pentobarbital, methacholine caused a similar degree of bradycardia in SHR and WKY rats but a greater vasodepressor response in SHR rats. With isoprenaline, the MAP difference between strains was maintained at all doses up to 200 ng/kg. Although it is not yet clear what is responsible for the increased vascular constriction of SHR rats, our findings suggest that it can be removed by muscarinic receptor activation with methacholine but not by stimulation of beta-adrenoceptors.
Hypersensitivity of morphine-tolerant rabbits to the respiratory stimulant effect of a cholinergic agonist.
The effect of morphine and oxotremorine, a centrally acting cholinergic agonist on the respiratory rate and arterial blood gases, was studied in rabbits given saline, increasing doses of morphine (5 mg/kg, 2 days; 10 mg/kg, 2 days; and 20 mg/kg, 3 days) injected at 12-hr intervals for 1 week. Care was taken to ensure that the chronically morphine-treated rabbits were neither under the influence of a previous dose of morphine nor in a phase of withdrawal when the response to test doses was measured. Tolerance to the respiratory depressant effect of morphine was demonstrated by the finding that a 5 times greater dose of morphine was needed to decrease respiration rate and raise arteriolar pCO2 than that given to saline-treated rabbits. The respiratory stimulant effect of oxotremorine, as demonstrated by an increase in respiration rate and decrease in PaCO2, was significantly greater in morphine-tolerant rabbits. It is concluded that chronic opiate treatment can induce supersensitivity of the cholinergic systems subserving control of respiration.
Effect of physostigmine on morphine-induced postoperative pain and somnolence.
The effects of physostigmine 1 mg i.v. were studied on the analgesia, sedation and reduction in respiratory rate induced by morphine 10 mg/60 kg i.v. in 10 patients recovering from surgery. Within 5-10 min, physostigmine abolished the somnolent effect of morphine and restored the respiratory rate to pre-drug values. Analgesia, assessed by an independent observer and by the patient was, if anything, increased by physostigmine. The analeptic effect of physostigmine lasted 40-60 min.
Activation of central muscarinic receptors causes respiratory stimulation in conscious animals.
1 Oxotremorine (10 microgram/kg) injected intravenously into conscious rabbits pretreated with atropine-methyl-nitrate (ATMN, 0.5 mg/kg) caused significant increases in respiration rate from 94 to 131 per min, and in PaO2 from 13.8 to 15.4 kPa, and a decrease in PaCO2 from 3.30 to 2.09 pKa within 15 min. Blood pH fell from 7.44 to 7.16. 2 Blood pressure increased by 11.6%, 5 min after oxotremorine injection. 3 The acidosis was shown to be due to an increase in blood lactic acid from 41 to 132 mg/100 ml. 4 Pretreatment with propranolol (5 mg/kg s.c.) prevented the lactic acidosis and fall in pH but did not alter the respiratory stimulation induced by oxotremorine. 5 It is suggested that the lactic acidosis induced by oxotremorine results from stimulation of beta-adrenoceptors in skeletal muscle by catecholamines released from the adrenal medulla and sympathetic nerves. 6 Since all the above effects of oxotremorine are antagonized by hyoscine (5 mg/kg) but not by ATMN (0.5 mg/kg), it is concluded that oxotremorine can stimulate respiration by a direct action on muscarinic receptors in the central nervous system.
Antagonism of the cardiovascular and respiratory depressant effects of morphine in the conscious rabbit by physostigmine.
The influence of physostigmine was studied on the effect of morphine on the cardiovascular and respiratory systems in conscious rabbits. Morphine (4 mg/kg i.v.) caused analgesia, bradycardia, hypotension and respiratory depression, as indicated by a fall in respiratory rate of 50%, a rise in blood PaCO2 from 25.1 to 37.2 mm Hg and a fall in pH from 7.40 to 7.24. These effects lasted 2 to 3 hr and were completely antagonized by naloxone. Physostigmine (2.5 or 5 microgram/kg/min) given by constant i.v. infusion did not significantly alter blood pressure or heart rate, but decreased blood PaCO2 from 25.1 to 19 mm Hg and increased pH from 7.40 to 7.46. Pretreatment of rabbits with physostigmine (5 microgram/kg/min) completely prevented both the fall in blood pressure and blood pH and the rise in PaCO2 induced by morphine (4 mg/kg) and also significantly reduced both the intensity and duration of bradycardia. Analgesics activity of morphine remained unimpaired by physostigmine. Neostigmine (2.5 microgram/kg/min) potentiated the bradycardia induced by morphine and did not antagonize its hypotensive and respiratory depressant effects. The results support the hypothesis that the respiratory and cardiovascular depressant effects of morphine, but not the analgesia, results from an inhibition of acetylcholine release from neurons in the central nervous system.
Evidence that noradrenaline modulates the increase in striatal dopamine metabolism induced by muscarinic receptor stimulation.
The effect of oxotremorine was studied on the concentration of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylethylglycol (MHPG) in the corpus striatum of rats. At a dose of 1 mg/kg oxotremorine increased HVA levels by 68% and MHPG, by 51%. MHPG was also increased in the nucl. accumbens (58%) and neocortex (42%). Pretreatment with clonidine, 0.1 mg/kg abolished the increase in MHPG in the striatum and significantly inhibited the rise in HVA. 1-Propranolol 2.5 mg/kg, but not d-propranolol, had an effect similar to that of clonidine. A lower dose of oxotremorine (0.5 mg/kg) increased striatal HVA by 36% but did not alter MHPG levels. This increase in HVA was not reduced by 1-propranolol. Eight days after bilateral lesions of the locus coeruleus, there was a reduction in the basal concentrations of noradrenaline (41%) and MHPG (57%) in the striatum. The data suggest that at higher doses of oxotremorine (1 mg/kg), but not a lower dose (0.5 mg/kg), a noradrenergic pathway is stimulated to increase the rate of metabolism of noradrenaline in the striatum. Oxotremorine also appears to increase dopamine metabolism in the striatum by at least two separate mechanisms, one of which involves the mediation of noradrenaline.
Antagonism by propranolol of isolation-induced aggression in mice: correlation with 5-hydroxytryptamine receptor blockade.
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Ventricular self-defibrillation in mammals: age and drug dependence.
Ventricular fibrillation (VF) was electrically induced in cats, rabbits, guinea pigs and rats. In young animals of all species and also in old rats short transient VF (TVF) was followed by spontaneous reversion to normal sinus rhythm. Old cats, rabbits and guinea pigs had episodes of sustained VF (SVF) which did not terminate spontaneously; artificial electro-defibrillation was required. Dibenzepin converted the sustained response of old animals to a transient one. Verapamil antagonized the effect of dibenzepin in old animals and also changed the TVF in young animals to SVF. The effect of calcie age of the animal is an important factor in determining whether the fibrillatory red to an alteration in the properties of the cell membrane.
Physostigmine antagonizes morphine-induced respiratory depression but not analgesia in dogs and rabbits.
The ability of physostigmine to antagonize the respiratory depressant effect of morphine was studied in conscious rabbits and ketamine-anaesthetized dogs pretreated with atropine methyl nitrate. Morphine 4 mg kg-1 increased PaCO2 in the rabbit from 3.43 +/- 0.16 to 4.95 +/- 0.28 kPa, decreased arterial pH from 7.45 +/- 0.01 to 7.31 +/- 0.01 and decreased respiratory frequency by 36%. Physostigmine 0.1 mg kg-1 reduced PaCO2 to control values within 10 min and significantly increased arterial pH and respiratory frequency. There was no antagonism of the analgesic effect of morphine. Neostigmine 0.1 mg kg-1 did not reverse the respiratory depressant effect of morphine. In dogs anaesthetized with ketamine, morphine 15 mg kg-1 caused loss of consciousness and marked analgesia, decreased the respiratory frequency by 47%, and increased PaCO2 by 47%. Physostigmine 0.1 mg kg-1 antagonized the effect of morphine on respiration and restored consciousness in the dogs, but did not impair analgesia. It is concluded that physostigmine reverses morphine-induced respiratory depression by prolonging the effect of acetylcholine released from brain-stem neurones. The possibility should be considered of replacing opiate antagonists by physostigmine to reverse postoperative respiratory depression and drowsiness induced by opiates.
Peripheral catecholamines mediate certain responses to central cholinergic receptor stimulation by oxotremorine.
The role of peripheral catecholamines in mediating the pressor and tremorigenic effects of oxotremorine were investigated in conscious rats. At time of peak tremor intensity induced by oxotremorine, plasma adrenaline and noradrenaline were increased 3--4-fold. Tremor intensity was substantially reduced by either adrenal medullectomy, chemical sympathectomy with 6-hydroxydopamine, or injection of 2.5 mg/kg L-propranolol. The pressor response to oxotremorine was not reduced by adrenal denervation, which however prevented the usual rise in plasma adrenaline but not that of noradrenaline. It is concluded that central cholinergic receptor stimulation activates the sympatho-adrenal system. While both adrenaline and intact sympathetic nerves are necessary for the mediation of the full tremorigenic effect, the pressor response to oxotremorine is mainly due to the effect of noradrenaline on vascular alpha-receptors.
Differential effects of d- and l-propranolol on dopamine turnover stimulated by oxotremorine in striatal and mesolimbic areas of rat brain.
The effects of l-propranolol, d-propranolol and clonidine on homovanillic acid (HVA) concentrations in the corpus striatum and nucleus accumbens of rats were studied under normal conditions and after treatment with oxotremorine or haloperidol. Thile propranolol and clonidine given alone had no significant effect on HVA levels in either area, l-propranolol (1--10 mg/kg) and clonidine (0.1 mg/kg), both significantly inhibited the elevation of striatal HVA, found 60 min after oxotremorine administration. Both l- and d-propranolol (2.5 mg/kg), reduced the effect of oxotremorine in the nucleus accumbens. Neither l-propranolol no clonidine affected the rise in HVA in either brain area seen after haloperidol. Our results suggest that propranolol may reduce cholinergic activation of dopaminergic pathways by two different mechanisms. One is stereospecific for the l-isomer and operates in the striatum and another, which is shared by both isomers, occurs in the nucleus accumbens.
Radioautographic visualization of 3H-fucose incorporation into glycoprotein by osteoblasts and its deposition into bone matrix.
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The effect of oxotremorine on blood pressure and plasma catecholamines in conscious and anesthetized rats.
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Effects of procaine and extracellular calcium concentration on response of rat stomach fundus muscle to acetylcholine and 5-hydroxytryptamine.
1. When rat stomach fundus muscle was incubated for 30 min in Tyrode solution from which calcium chloride had been omitted, there was an almost complete abolition of the contractile response to 5-hydroxytryptamine (5-HT) while that to acetylcholine (ACh) was still present. 2. The maximum tension obtainable with ACh remained the same in external calcium concentrations ranging from 0.45 to 3.6 mM, but the pD2 value increased. 3. A concentration of at least 0.9 mM calcium was needed to maintain a maximum contraction with 5-HT, and the pD2 for this agent also increased significantly with increase in calcium content of the medium. 4. The effects of procaine on the responses of the muscle to 5-HT and ACh were similar to the respective changes induced by lowering the calcium concentration, and were reduced by the addition of calcium. 5. Concentrations of 2.2 x 10(-7) to 3.6 x 10(-5) M procaine reduced the effects of both 5-HT and KCl and suppressed the maximum responses. 6. The maximum responses to KCl and 5-HT were restored at higher concentrations of procaine (greater than 3.6 x 10(-4) M), while the effect of ACh was reduced. 7. It is suggested that 5-HT, like KCl, is almost entirely dependent on extracellular calcium for inducing muscle contraction, while ACh may utilize calcium from bound stores.