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Biomedical subjects

M Weinstock

Publications and source records attributed to M Weinstock.

At least 109 records · Page 6Linked to original sources
PubMed1978

Changes in brain catecholamine turnover and receptor sensitivity induced by social deprivation in rats.

Catecholamine turnover was compared in two brain areas of rats housed under different social conditions. Rats reared in isolation for 6-8 weeks had a significantly lower noradrenaline turnover in the brainstem and lower noradrenaline and dopamine turnover in a brain segment comprising all other areas except the cerebellum, pineal gland, thalamus, and subthalamus. In the open-field test, isolated rats were much more active than group-housed animals. Noradrenaline turnover increased in both brain areas of isolated rats but not in grouped animals after exposure to the open field. Hyperactivity was selectively reduced in isolated rats by chronic oral treatment with d-amphetamine, 5 mg/kg/24 h. It was also reduced 15 min after pretreatment with alpha-methyl-p-tyrosine 200 mg/kg. It is suggested that a prolonged period of reduced noradrenaline release may sensitise post synaptic receptors in isolated rats. Hyperactivity appears to be associated with an increase in transmitter release onto sensitised receptors.

Animals↗
PubMed1978

Beta-adrenoceptors modulate noradrenaline release from axonal sprouts in cultured rat superior cervical ganglia.

Superior cervical ganglia of rats grown in organ culture were used to study the effect of beta-receptor stimulants and antagonists on 3H-noradrenaline release in response to stimulation by KC1 (75 mM). (--)-Isoprenaline 1X 10(-9)--1 X 10(-7) M) increased 20--25% the release of 3H-noradrenaline from cultured ganglia exposed to KC1. Isoprenaline did not modify either the spontaneous (non-calcium dependent) release of 3H-noradrenaline from cultured ganglia, or the KC1-stimulated release from fresh ganglia. The effect of (--)-isoprenaline was blocked by (--)-propranolol 5 X 10(-9) -- 1 X 10(-8) M and by butoxamine 10(-6) M, but not by (+)-propranolol (1 -- 5 X 10(-8) M), practolol (1 X 10(-8) -- 1 X 10(-6) M), or sotalol (1 X 10(-7) -- 1 X 10(-6) M). Isoprenaline induced augmentation of 3H-noradrenaline release and its antagonism by (--)-propranolol still occurred in the presence of DMI. It is suggested that presynaptic beta-receptors in sympathetic nerve terminals may be involved in a positive feedback of noradrenaline release.

Adrenergic beta-Antagonists↗
PubMed1978

Cardioselectivity as a function of molecular structure in beta-adrenoceptor blocking agents of the 1-(para-substituted aryloxy)-3-(isopropylamino)propan-2-ol type.

The relationship between molecular structure and cardioselectivity is described in the 1-(para-substituted aryl-oxy)-3-(isoprophylamino)propan-2-ol type of beta-adrenoceptor blocking agents. Cardioselectivity in the aforementioned series requires that the aromatic substitution in the position para to the amino alcohol side chain will have a minimal linear length of 5.0 A. Highest cardioselectivity is obtained when this para substituent is a rigid group coplanar with the aromatic ring. This may result from steric hindrance for binding at the beta2-adrenoceptor subtype which does not occur in the beta1 subtype. Evidence in favor of this suggestion was obtained by the finding that the trans isomer of 1-[4-(1-propenyl)-2-methoxyphenoxy]-3-(isopropylamino)propan-2-ol is cardioselective (beta1/beta2 = 25), whereas the cis isomer is beta2 selective (beta1/beta2 = 0.1).

Adrenergic beta-Antagonists↗
PubMed1978

The role of peripheral catecholamines in oxotremorine tremor in the rat and its antagonism by beta adrenoceptor blocking agents.

Oxotremorine, 0.25 mg/kg, produces marked tremor in the rat, which is abolished by scopolamine, 0.5 mg/kg, and is substantially reduced in intensity and duration both by adrenalmedullectomy and by chemical sympathectomy with 6-hydroxydopamine. Oxotremorine increases plasma norepinephrine from 0.62 +/- 0.07 to 3.01 +/- 0.47 ng/ml and plasma epinephrine, from 0.82 +/- 0.14 to 3.42 +/- 0.48 ng/ml, in conscious unrestrained rats. l-Propranolol (0.5-2.5 mg/kg) reduces tremor, and at 2.5 mg/kg is more effective than either chemical sympathectomy or adrenal demedullation. d-Propranolol and sotalol are also active at 4 and 10 times the dose of l-propranolol, respectively. l-Propranolol does not prevent the rise in catecholamines induced by oxotremorine. It is suggested that stimulation of central muscarinic receptors causes tremor by a combination of two effects. There is an increase in cholinergic influence to motor efferents accompanied by an activation of the sympathoadrenal system to release catecholamines which augment tremor by stimulation of beta2 adrenoceptors.

Adrenal Medulla↗
PubMed1977

Nature of seasonal variation in development of acute tolerance to morphine.

Morphine inhibits contractions of coaxially stimulated guinea pig ileum. Acute tolerance to this effect occurs on continuous perfusion with morphine for 1.5 h. This is associated with an increase in the sensitivity of the tissue to acetylcholine. Acute tolerance does not always develop in spite of identical treatment, but shows a distinct seasonal incidence. It is significantly higher in the summer (May--Nov.) than winter (Dec.--April). This seasonal variation in development of tolerance does not appear to be related to changes in diet, environmental light or temperature, or to the sensitivity of the ileum to morphine. In the winter, the acetylcholine release from stimulated ilea is lower than in the summer. In addition to inhibiting acetylcholine release, morphine also has a non-specific blocking effect in the winter. This postjunctional effect could prevent the development of supersensitivity to acetylcholine during continuous morphine treatment so that acute tolerance cannot occur.

Acetylcholine↗
PubMed1977

Prevention by drugs of tachyphylaxis at nicotinic receptors in the cat superior cervical ganglion in situ.

A new compound, AF3 (4-ethyl-6-oxa-1-azatricyclo)4.2.2.02,7)dodecan-5-one), and its 4-phenyl analogue, AF6, embodying the structural elements of acetylcholine in a highly rigid framework, were shown to evoke nicotine-like responses in the nictitating membrane (NM) and blood pressure when applied to the superior cervical ganglion in anaesthetized cats. In this respect, their equiactive molar ratio was (nicotine : 1),20-30. However, at doses that were too low to evoke any response, AF3 appeared to potentiate the responses to nicotine or tetra-methylammonium (TMA) by preventing or abolishing tachyphylaxis to the two latter drugs, the effect being dose-dependent with AF3. DMPP which produces much less tachyphylaxis, or preganglionic nerve stimulation, was little or not potentiated in presence of AF3. It is proposed that potentiation to nicotine or TMA occurs following occupancy by AF3 of a regulatory subsite, thereby preventing further access to it by nicotine or TMA. In this respect, AF3 plays the role of a "neutral" molecule.

Animals↗
PubMed1976

A new probe for heterogeneity in muscarinic receptors: 2-methyl-spiro-(1, 3-dioxolane-4, 3')-quinuclidine.

The title compound (MSDQ) is a new muscarinic agonist related to 3-acetoxyquinuclidine (3-AcQ) but also of a highly rigid structure. In view of this, it may constitute a probe for the detection of heterogeneity among muscarinic receptors. Indeed, equipotent molar ratios (EPMR) for ACh, 3-AcQ and MSDQ were as follows: guinea pig ileum, 1 : 14 : 240; vasodepressor effect in the cat, 1 : 6 : 188. But EPMR for 3-AcQ and MSDQ as stimulants of the superior cervical ganglion in the cat were 1 : 1 and for the induction of tremors in mice, 9 : 5. No such subtle differences in receptor specificity were detected when the probe used was the 2, 2-diphenyl analogue (DiPSDQ) of MSDQ which was a powerful competitive antagonist in all systems, more potent than atropine, but with a CNS/PNS activity of 1.1 compared to 26 for atropine. In view of this, the use of potent antagonists as probes for muscarinic receptor heterogeneity is questionable.

Animals↗
PubMed1976

Tricyclic antidepressant drugs as antagonists of muscarinic receptors in sympathetic ganglia.

Close arterial injection of McN-A-343 into the superior cervical ganglion of the cat resulted in contractions of the nictitating membrane. The ganglionic effects of McN-A-343 but not those of DMPP were antagonized in a dose-related manner by 2-10 mug of desipramine, imipramine, chlorimpramine, iprindole and viloxazine. No correlation was found between the dose of each drug which blocked the effects of McN-A-343 and that required to potentiate the responses of the nictitating membrane to intra-arterial administration of noradrenaline. It is concluded that clinically effective antidepressant agents can block muscarinic receptors in neural tissue, even if they do not do so in smooth muscle and gland cells.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1976

A study of muscarinic receptor heterogeneity with weak antagonists.

A study of heterogeneity among muscarinic receptors was carried out with new rigid molecules, comprising structures in the fused quinuclidine-valerolactone, quinuclidine-cyclohexenone, quinuclidine-cyclohexanone and quinuclidine-cyclohexane derivatives. These are structurally related to the potent muscarinic agent, 3-acetoxyquinuclidine but substantially different from in it conformation. All proved to antagonize acetylcholine-like activity, but to a different extent in different systems. The equipotent molar ratio with respect to atropine (as 1) was: isolated guinea pig ileum, 10,000-1,000; salivary gland (mouse), 1,000-100; superior cervical ganglion (cat), 100-10; CNS (mouse), approximately 10. It is suggested that the rigid structure induces a three-point constrained fit in the receptor (onium group, hydrophobic moiety and carbonyl group), but that not all muscarinic receptors are capable of responding equally. In this case, receptor specificity of the drug is a direct consequence of its graded departure from the preferred conformation of acetycholine and, therefore, is necessarily associated with partial loss of potency.

Animals↗
PubMed1976

Reduction by propranolol of raised urinary output of MHPG in hyperactive rats.

Prolonged isolation of rats resulted in hyperactivity in the open field and a significant increase in 24 hr urinary excretion of MHPG (3-methoxy-4-hydroxyphenylglycol). Exploratory activity of group-housed rats in open field was not associated with raised MHPG excretion, compared with that of rats remaining in home cages. Exposure of group-housed rats to 4 degrees C for 2 hr also increased urinary excretion of MHPG. Pretreatment of isolated rats with dl-, d-propranolol or practolol abolished hyperactivity of isolated rats and reduced MHPG output in these rats and in rats exposed to cold. dl-Propranolol did not reduce activity of group-housed rats in open field or their urinary excretion of MHPG. It is suggested that propranolol may have a selective inhibitory effect on stress-induced increases in noradrenaline turnover.

Animals↗