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Biomedical subjects

J T Hamilton

Publications and source records attributed to J T Hamilton.

At least 55 records · Page 3Linked to original sources
PubMed1982

The effect of a benzodiazepine, flurazepam, on the response of in vitro skeletal muscle preparations to muscle relaxants: are purines or their receptors involved?

Changing trends in the use of anxiolytic agents and recent reassessment of their neuropharmacological activity has prompted this evaluation of the peripheral neuromuscular activity of the benzodiazepine, flurazepam. In previous reports we have documented peripheral neuromuscular activity of chlordiazepoxide and diazepam on the rat phrenic nerve diaphragm preparation. The water soluble benzodiazepine, flurazepam, has been studied on the rat phrenic nerve diaphragm and frog rectus abdominis in vitro. On the former preparation flurazepam enhanced and then blocked the response to indirect electrical stimulation (0.2 Hz) and readily blocked posttetanic potentiation and prevented the preparation from sustaining a tetanic contracture (30 Hz). On the later preparation, flurazepam blocked in a noncompetitive manner the response of the frog muscle to applied cholinergic agonists. Studies on the rat preparation with the neuromuscular blocking drug succinylcholine have shown an unexpected protection against blockade in preparations pretreated with low concentrations of flurazepam. This was not observed when flurazepam was given prior to d-tubocurarine. The application of adenosine to rat diaphragms during steady-state partial blockade caused by flurazepam or d-tubocurarine showed an inhibiting action of adenosine which was reversed by theophylline. Pretreatment of rat preparations with dipyridamole significantly enhanced the blocking action of standard concentrations of succinylcholine. These results, along with those in the literature, encourage a reassessment of the action of purines and benzodiazepines on skeletal muscle and encourage a consideration of a possible involvement of purinergic neuromodulation of transmission which is unmasked when the safety factor for transmission is altered by muscle relaxants. The possible clinical significance of protection against succinylcholine by benzodiazepines is noted.

Adenosine↗
PubMed1982

Flunitrazepam binding sites in rat diaphragm. Receptors for direct neuromuscular effects of benzodiazepines?

The evidence for direct muscle relaxant effects of benzodiazepines is controversial. We now show that a crude membrane preparation of rat diaphragm possesses binding sites for [3H]flunitrazepam (FNZ). Scatchard analysis gave a binding site density of 1689 +/- 143 fmol/mg protein (Kd = 25.6 +/- 2.6 nM). These sites are of the "peripheral" type since clonazepam fails to displace [3H]FNZ as effectively as R05-4864 (IC50 values: 7.5 x 10(-6) M and 8 x 10(-9) M, respectively). Diazepam is almost as effective as R05-4864 and potently displaces [3H]FNZ binding (IC50 = 3 x 10(-8) M). We propose that the previously described effects of diazepam on rat diaphragm are mediated through high-affinity binding sites.

Animals↗
PubMed1980

Studies of the action of nicotine in guinea-pig tracheal smooth muscle: interaction with beta-adrenoceptor antagonists.

Nicotine produced cholinergic excitatory and adrenergic and non-adrenergic inhibitory responses in isolated guinea-pig trachea. Responses were blocked by hexamethonium (10 micro M), lidocaine (85 micro M) or tetrodotoxin (0.01 micro M) demonstrating that nicotinic receptors in nervous tissue were being activated. In the presence of atropine (0.1 micro M), inhibitory responses to nicotine were partially blocked by specific, experimentally determined, beta-blocking concentrations of pindolol or sotalol or by pretreatment with 6-hydroxydopamine or reserpine but were completely blocked by the less specific beta-blocking drugs 1- and dl-propranolol. Parallel experiments on guinea pig ileum revealed a marked attenuation by dl-propranolol of the atropine sensitive, cholinergic excitatory response to applied nicotine. The non-beta-adrenoceptor blocking agent d-propranolol, produced qualitatively similar attenuation of all excitatory and inhibitory responses to nicotine on both preparations. The remarkable susceptibility of nicotine-induced, neurally mediated responses to low, beta-blocking concentrations of dl-propranolol and to low concentrations of both of its racemates suggests that the non-specific actions of these compounds may have much more significance than is customarily believed. Such studies on the interaction between nicotine and some beta-adrenoceptor blocking drugs are consistent with the hypothesis that non-beta-blocking so-called 'non-specific membrane depressant actions' of dl-propranolol may in concentrations previously considered 'sub-local anaesthetic', significantly depress physiological transmission induced by activation of nicotinic receptors.

Adrenergic beta-Antagonists↗
PubMed1976

The effect of metoclopramide on intestinal muscle responses and the peristaltic reflex in vitro.

Metoclopramide (Mcp) is known to facilitate gastrointestinal emptying in vivo and to stimulate various isolated intestinal muscle preparations. On the guinea pig ileum, taenia coli, rabbit ileum and rat duodenum, Mcp increased the tone and responses to acetylcholine, carbachol and nicotine; had no effect on responses to histamine, potassium chloride and prostaglandin E1; decreased responses to 5-hydroxytryptamine (5-HT). Atropine, methysergide, morphine, and tetrodotoxin, alone or in combination, partially blocked the stimulatory responses to Mcp, but hexamethonium, mepyramine and indomethacin did not. Mcp (1.0 muM) lowered the threshold for elicitation of the peristaltic reflex to a sub-threshold intraluminal pressure (2.5 cm water), facilitated the peristaltic response to threshold pressures (3-4 cm water) and restored the reflex in fatigued preparations, but not that depressed by cooling to 24 degrees C. During block of peristalsis by atropine, hexamethonium or methysergide (applied serosally) 5-HT (0.25 muM) but not Mcp (1.0 muM)) effectively restored the peristaltic reflex, but neither antagonized the inhibition by morphine or procaine acting serosally. However, Mcp (1.0 muM) re-established peristalsis inhibited by a high concentration of 5-HT ((4 X 10 muM). These results do not support the hypotheses that the stimulatory action of Mcp is entirely dependent on either peripheral sensitization of muscarinic receptors or an action on tryptaminergic mechanisms but are consistent with our previous conclusion that an additional component may be a blockade of some intrinsic inhibitory (possibly purinergic) substance normally restraining intestinal motility or tone.

Animals↗
PubMed1975

The effect of cocaine on the responses of the differently innervated laryngeal and bronchial ends of the guinea pig trachea in vitro to clinically used bronchodilators.

Fluorescent histochemical studies indicate that guinea pig tracheal smooth muscle has sparse adrenergic innervation with the greatest nerve density being located at the laryngeal end. In the present study, log dose-response lines were obtained for dl-isoprenaline (ISO), l-adrenaline (ADR) l-noradrenaline (NOR), salbutamol (SALB), and orciprenaline on isolated tracheal chains prepared from both the laryngeal (L) and bronchial (B) ends of the trachea. Responses were obtained in the absence and presence of the Uptake1 blocker, cocaine (0.67 and 6.7 muM) which markedly potentiated responses to NOR and ADR but failed to significantly alter responses to ISO and SALB on L preparations. The degree of potentiation obtained on B preparations was significantly less for NOR and ADR and was not significant for the other agents. In addition, experiments were carried out on tracheal chains which developed their normal tone in the absence of carbachol, and also on preparations obtained from 6-hydroxydopamine treated animals. The present findings, based on selective potentiation of NOR and ADR, support evidence that the degree of adrenergic innervation to the guinea pig trachea is greater at the laryngeal end, and the results obtained with cocaine strengthen the argument that it has a pre-synaptic site of action.

Albuterol↗
PubMed1975

The effect of metoclopramide on inhibition induced by purine nucleotides, noradrenaline, and theophylline ethylenediamine on intestinal muscle and on peristalsis in vitro.

Metoclopramide (N-(diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide) (Mcp) at concentrations of 0.1 and 1.0 muM partially and significantly reduced the relaxations induced by adenosine 5'-triphosphate (ATP), adenosine diphosphate (ADP), and adenosine, was without effect on theophylline ethylenediamine whilst significantly potentiating noradrenaline on the atropine-pretreated (0.1 muM) taenia coli, rabbit ileum, and rat duodenum. Mcp (1.0 muM) decreased the inhibitory effects of ATP, ADP, and adenosine on peristalsis induced in the isolated guinea-pig ileum by a constant increase in intraluminal pressure, did not affect inhibition due to theophylline ethylenediamine, whilst it potentiated inhibition of peristalsis due to noradrenaline. It is proposed that this effect of Mcp may be a specific antagonistic action on receptors sensitive to the putative purinergic transmitter, ATP and ADP, and may be partly responsible for its observed facilitatatory action on peristalsis.

Adenosine↗
PubMed1975

The effect of methyl paraben on tracheal smooth muscle in vitro.

The widely used bacteriostatic preservative methyl paraben (M.P.) produced a concentration-dependent relaxation of the carbachol-contracted guinea pig trachea and the isolated rabbit jejunum. The relaxant effects on the trachea were not blocked by dl-propranolol and the responses on the rabbit jejunum were not blocked by bretylium tosylate which abolished the responses to sympathetic nerve stimulation. Sub-threshold concentrations of M.P. (130 muM) produced a marked and significant enhancement of the responses of the trachea to the three catecholamines dl-isoprenaline (I), 1-noradrenaline (N), 1-adrenaline (A), a slight but significant enhancement of the responses of the trachea to the two non-catechol beta sympathomimetics salbutamol (S), and orciprenaline (O), but no significant enhancement of the responses to aminophylline (AM). It is concluded that the relaxant effect of M.P. is characteristic of a "non-specific" spasmolytic and this is consistent with its reported local anaesthetic activity. In addition, the specific ability of M.P. to enhance responses to catecholamines suggests that it may be interacting with a mechanism responsible for catecholamine removal (i.e., tissue uptake or uptake 2). In view of the widespread use of M.P. in pharmaceutical preparations in concentrations often equivalent to or greater than those employed in the present investigation, the fact should be stressed that its presence should not be overlooked in the interpretation of experimental and clinical studies.

Animals↗