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Biomedical subjects

F Mitchelson

Publications and source records attributed to F Mitchelson.

At least 37 records · Page 2Linked to original sources
PubMed1996

Inhibition by endothelin-1 of cholinergic nerve-mediated acetylcholine release and contraction in sheep isolated trachea.

1. The relative roles of ETA and ETB receptor activation on cholinergic nerve-mediated contraction and acetylcholine (ACh) release were examined in sheep isolated tracheal smooth muscle. 2. Electrical field stimulation (EFS; 90 V, 0.5 ms duration, 1 Hz, 10 s train) applied to sheep isolated tracheal smooth muscle strips induced monophasic contractile responses that were abolished by either 1 microM tetrodotoxin or 0.1 microM atropine, but were insensitive to 10 microM hexamethonium and 100 microM L-NAME. Thus, EFS-induced contractions resulted from the spasmogenic actions of ACh released from parasympathetic, postganglionic nerves. 3. As expected, sheep isolated tracheal smooth muscle preparations did not contract in response to the ETB receptor-selective agonist, sarafotoxin S6c (0.1-100 nM). However, sarafotoxin S6c caused a concentration-dependent and transient inhibition of EFS-induced contractions. The inhibitory effect induced by a maximally effective concentration of sarafotoxin S6c (10 nM; 72.1 +/- 5.7%, n = 6) was abolished in the presence of the ETB receptor-selective antagonist BQ-788 (1 microM). Contractile responses to exogenously administered ACh (10 nM-0.3 mM) were not inhibited by sarafotoxin S6c (1 or 10 nM; n = 7). 4. In contrast to sarafotoxin S6c, endothelin-1 induced marked contractions in sheep isolated tracheal smooth muscle. These contractions were inhibited by BQ-123, consistent with an ETA receptor-mediated response. In the presence of BQ-123 (3 microM), endothelin-1 produced a concentration-dependent inhibition of EFS-induced contractions (30 nM endothelin-1, 68.9 +/- 10.2% inhibition, n = 5). These responses were inhibited by 1 microM BQ-788, indicative of an ETB receptor-mediated process. Endothelin-1 was about 3 fold less potent than sarafotoxin S6c. 5. EFS (90 V, 0.5 ms duration, 1 Hz, 15 min train) induced the release of endogenous ACh (1.94 +/- 0.28 pmol mg-1 tissue, n = 12), as assayed by h.p.l.c. with electrochemical detection. EFS-induced release of ACh was inhibited to a similar extent by 100 nM endothelin-1 (47 +/- 4%, n = 9) and 10 nM sarafotoxin S6c (46 +/- 9%, n = 3). These effects of endothelin-1 on ACh release were inhibited by 1 microM BQ-788 alone (n = 4), by BQ-788 in the presence of 3 microM BQ-123 (n = 4), but not by 3 microM BQ-123 alone (n = 5). 6. In summary, sheep isolated tracheal smooth muscle contains two anatomically and functionally distinct endothelin receptor populations. ETA receptors located on airway smooth muscle mediate contraction, whereas ETB receptors appear to exist on cholinergic nerves that innervate tracheal smooth muscle cells and mediate inhibition of ACh release. The inhibitory effect of ETB receptor stimulation on cholinergic neurotransmission is in stark contrast to the enhancing effects hitherto described in the airways.

Acetylcholine↗
PubMed1995

[3H]N-methylscopolamine dissociation from muscarine receptors affected by low concentrations of allosteric modulators.

The ability of allosteric ligands to modulate the dissociation rate of [3H]N-methylscopolamine from atrial muscarinic receptors in the presence of varying concentrations of unlabelled N-methylscopolamine or atropine was evaluated. Gallamine, at a concentration approximating its KD value, slowed the dissociation of [3H]N-methylscopolamine in the presence of ca. 30 x KD of both unlabelled NMS or atropine. This was less evident when concentrations of ca. 1000 x KD of the unlabelled antagonists were employed. Similar findings were made with another allosteric modulator. These results indicate that gallamine can act allosterically at low concentrations.

Allosteric Regulation↗
PubMed1995

Vagal nerve stimulation of the guinea-pig oesophagus.

Vagal nerve stimulation of the isolated guinea-pig oesophagus resulted in a triphasic contractile response which was abolished by tetrodotoxin. The mechanisms for each of the three responses were investigated. The first response was abolished by the neuromuscular blocking drug, tubocurarine, and was unaffected by atropine. The second response to vagal nerve stimulation was abolished by the ganglion blocking drug, hexamethonium, and by tubocurarine at a higher concentration than that required to block the first response. The second response was also abolished by atropine and was enhanced by physostigmine. It was concluded that this response was due to preganglionic stimulation of smooth muscle. omega-Conotoxin GVIA selectively inhibited the third response. This response was resistant to the neuromuscular and ganglion blocking drugs yet was abolished by atropine and was enhanced by physostigmine. This implicates the involvement of cholinergic neurones activated independently of nicotinic ganglionic receptors. The third response was also selectively abolished by capsaicin and enhanced by thiorphan. Contractile responses resulting from exogenous substance P were abolished by atropine and tetrodotoxin and enhanced by physostigmine. These findings suggest that the third response may be mediated by the action of a substance P-like neuropeptide released from sensory nerve endings which subsequently activate cholinergic neurones.

Animals↗
PubMed1995

Simultaneous comparison of nicotinic receptor antagonists on three nicotinic acetylcholine receptors.

The relative potencies of several nicotinic cholinoceptor antagonists in producing tetanic fade and reduction of striated muscle contraction were investigated in the isolated guinea-pig oesophagus as well as the guinea-pig and rat phrenic nerve-diaphragm preparations. Contractile smooth muscle responses to vagal stimulation, which involves ganglionic activation, were also measured simultaneously with striated muscle responses in the oesophagus. The relative potency for inhibiting the response of oesophageal smooth muscle to vagal stimulation (20 Hz) was trimetaphan > mecamylamine > hexamethonium > tubocurarine > pancuronium. For oesophageal striated muscle, production of tetanic fade at 100 Hz and reduction in peak tetanic tension at 20 or 100 Hz showed a similar relative potency; pancuronium > tubocurarine > mecamylamine > trimetaphan > hexamethonium and similar results were obtained in the guinea-pig diaphragm for the antagonists investigated (pancuronium, tubocurarine and mecamylamine). In the rat phrenic nerve-diaphragm preparation, production of tetanic fade at 50 Hz and reduction in twitch or tetanic tension all showed the relative potency; tubocurarine > pancuronium > mecamylamine > trimetaphan > hexamethonium. These findings indicate differences in the nicotinic cholinoceptor subtypes involved in vagal ganglionic responses and those in tetanic fade.

Animals↗
PubMed1994

Muscarinic receptors in rat uterus.

The aim of this study was to characterise the muscarinic receptor present in the uterus of the virgin rat. Homogenate binding studies were undertaken using [3H]quinuclidinyl benzilate as the radioligand and atropine (10 microM) to determine non-specific binding. [3H]Quinuclidinyl benzilate binding was saturable with a Kd of 63 pM and a Bmax of 3 fmol/mg protein. The pKi values obtained using antagonists with high affinity for differing muscarinic receptor subtypes were pirenzepine, 6.2; hexahydrosiladifenidol, 6.9; AF-DX 116 (11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]5,11-dihydro-6H - pyrido[2,3-b][1,4]benzodiazepine-6-one), 7.0; and himbacine, 7.8. These findings suggest that muscarinic M2 receptors are present in rat uterus.

Alkaloids↗
PubMed1994

Characterization of the muscarine receptor subtype on sympathetic nerve endings in the rat caudal artery.

The prejunctional muscarine receptor on sympathetic nerves in the rat caudal artery was characterized using several selective antagonists. The inhibitory response of carbachol on vasoconstriction elicited by sympathetic nerve stimulation was antagonized by benzhexol (trihexyphenidyl; pKB 7.1), heptane-1,7-bis(dimethyl-3'-phthalimidopropyl ammonium bromide) (C7/3-phth; pKB 6.5) and hexahydrosiladifenidol (HHSiD; apparent pKB 6.0). These pKB values suggest that the receptor most closely resembles the muscarine M2 receptor subtype rather than the muscarine M1, M3 or M4 receptor subtypes.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1994

Variation in the affinity of amitriptyline for muscarine receptor subtypes.

The affinity of amitriptyline for muscarine M1 receptors was studied in the rat cerebral cortex and rabbit vas deferens utilizing binding studies as well as inhibition of carbachol-induced phosphoinositide hydrolysis in the cerebral cortex and blockade of the muscarinic prejunctional inhibition of sympathetic nerve stimulation in the rabbit vas deferens. The inhibition constants (KI) or dissociation constants (KB) obtained were approximately 6- to 20-fold lower than those obtained at muscarine M2 receptors in rat atria (binding and negative inotropic response) indicating that amitriptyline exhibits a degree of muscarine M1 receptor selectivity.

Amitriptyline↗
PubMed1994

Assessment of the allosteric interactions of the bisquaternary heptane-1,7-bis(dimethyl-3'-phthalimidopropyl)ammonium bromide at M1 and M2 muscarine receptors.

The interaction of the allosteric muscarine receptor antagonist heptane-1,7-bis(dimethyl-3'-phthalimidopropyl)ammonium bromide (C7/3-phth) with M1 muscarine receptors in rat cerebral cortex and rabbit vas deferens and M2 muscarine receptors in guinea pig atria was investigated. In atria, C7/3-phth completely inhibited the dissociation of N-[3H]methylscopolamine ([3H]NMS) in the presence of excess unlabeled NMS and slowed the washout of NMS in functional experiments. C7/3-phth also produced supra-additive inhibition of the negative inotropic effects of carbachol when combined with NMS. This latter phenomenon was less pronounced when pirenzepine (PZP) was used in place of NMS. Cooperativity factors for the interaction of C7/3-phth with other antagonists were obtained by fitting the data to a theoretical model for interaction between an agonist, a competitive antagonist, and an allosteric antagonist. The values obtained indicate that C7/3-phth exhibits a greater degree of negative heterotropic cooperativity with PZP than with NMS at the M2 muscarine receptor. In the rat cerebral cortex, C7/3-phth slowed the dissociation of [3H]NMS and [3H]quinuclidinyl benzilate from the M1 receptor to the same extent but appeared not to affect the dissociation of [3H]PZP. In rabbit vas deferens, the inhibitory effect of the combination of C7/3-phth and atropine on the responses to McN-A-343 at the M1 receptor was more pronounced than that of the combination of C7/3-phth and PZP. Comparison of the findings for both central and peripheral M1 receptors with those obtained for the cardiac M2 receptor suggests that the allosteric interaction of C7/3-phth is less evident at the M1 receptor, particularly in the case of PZP.

Allosteric Regulation↗
PubMed1993

The interaction of McN-A-343 with muscarine receptors in cardiac and smooth muscle.

The interaction of the muscarine receptor partial agonist (4-m-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343) was investigated at muscarine receptors in the atria and taenia caeci of the guinea-pig to compare its interaction at the muscarine M2 receptor in the two tissues. In the smooth muscle, the muscarine M3 receptor subtype is responsible for the contractile response but the major subtype detected in binding or antibody experiments is the M2 subtype. In guinea pig atria the dissociation constant of McN-A-343 at muscarine receptors was 15.2 microM determined in functional experiments on left atria in McEwen's solution or 14.8 microM in binding experiments with [3H]-(-)-quinuclidinyl benzilate ([3H]QNB) in the same medium containing 5'-guanylylimododiphosphate (50 microM). In the taenia caeci, the dissociation constant estimated for McN-A-343 at the M3 receptor from functional experiments based on the contractile response to the agonist in McEwen's solution was 4.6 microM. This value was similar to the dissociation constant (6.2 microM) estimated from binding studies versus [3H]QNB conducted in the same medium although studies with 11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H- pyrido[2,3-b][1,4]benzodiazepine 6-one (AF-DX 116) versus [3H]-(-)-N-methylscopolamine suggested that 70% of the receptors were the M2 subtype. The presence of the M2 subtype in the taenia caeci was also confirmed by the ability of oxotremorine to inhibit the increase in cAMP produced by isoprenaline (10 microM) since apparent pKB values for AF-DX 116 and hexahydrosiladiphenidol were 6.95 and 6.75, respectively. McN-A-343 (100 microM) failed to inhibit the response to isoprenaline and did not antagonize the inhibitory response to oxotremorine. It is concluded that the apparent affinity of McN-A-343 for muscarine M2 receptors in the atria and the taenia caeci differs and a number of explanations are discussed.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1993

Binding of the muscarine receptor antagonist heptane-1,7-bis(dimethyl-3'-phthalimidopropyl)ammonium bromide at cholinoceptor sites.

The binding of the bisquaternary muscarine receptor antagonist heptane-1,7-bis(dimethyl-3'-phthalimidopropyl)-ammonium bromide (C7/3-phth) was investigated at a number of cholinergic binding sites using (-)-[3H]nicotine, [3H]pirenzepine and (-)-[3H]quinuclidinyl benzilate ([3H]QNB) in both central and peripheral tissues. C7/3-phth displayed an affinity for muscarine M2 receptors in rat atria (70.1 nM) which was 1.6-fold greater than for putative M4 receptors in rabbit lung, and 4- to 5-fold greater than for M1 receptors in rat cerebral cortex. Its affinity for nicotine receptors in the cortex was low, being 808-fold lower than its affinity for the M2 receptor. Although the displacement of (-)-[3H]nicotine and [3H]pirenzepine binding in rat cortex by C7/3-phth was best described in terms of one-site modelling, low Hill coefficients were observed with C7/3-phth in displacement studies using [3H]QNB in this tissue. The possibility of allosteric interactions or multiple receptor subtype interactions is discussed.

Animals↗
PubMed1993

Multiple binding sites for nicotine receptor antagonists in inhibiting [3H](-)-nicotine binding in rat cortex.

The displacement of [3H](-)-nicotine from its binding site in rat cerebral cortex by a number of antagonists was investigated. [3H](-)-Nicotine appeared to bind to a single site with a dissociation constant (KD) of 5.5 nM; pancuronium, gallamine and trimetaphan displaced [3H](-)-nicotine with inhibition constants (KI) of 57, 99 and 621 microM, respectively, whereas mecamylamine only displaced 50% of nicotine binding in concentration > 1 mM. For hexamethonium and (+)-tubocurarine the displacement of [3H](-)-nicotine binding appeared to involve two sites; the higher affinity site comprising 30% of the total binding for hexamethonium but 76% of the sites for (+)-tubocurarine. In the presence of mecamylamine (100 microM) the displacement of [3H](-)-nicotine binding by (+)-tubocurarine appeared to involve only a single site with an affinity similar to that for the high affinity site in the absence of mecamylamine whereas that for hexamethonium still involved two sites. It is suggested that (+)-tubocurarine may act at both the binding site for [3H](-)-nicotine per se and also at an allosteric site. The failure of mecamylamine to influence the binding of hexamethonium suggests that there may be more than one allosteric site or that hexamethonium may distinguish between subtypes of nicotine receptors in the cortex.

Animals↗
PubMed1992

Prejunctional muscarine receptors in the rabbit ear artery differ from M1, M2 and M3 muscarine receptors.

The ability of several selective muscarine receptor antagonists to inhibit the effect of carbachol on prejunctional muscarine receptors on sympathetic nerve endings in the rabbit isolated ear artery was investigated to characterise the receptor subtype involved. Carbachol did not reduce responses to exogenous noradrenaline and the inhibitory effect of carbachol on responses to nerve stimulation was unaffected by hexamethonium (10 microM) indicating that the effect of the muscarine agonist was exerted prejunctionally and was not modulated by nicotine receptor stimulation. The dissociation constants or apparent dissociation constants obtained using (+/-)-benzhexol (pKB; 6.63), (R)-benzhexol methiodide (8.11), dicyclomine (5.86), (+/-)-telenzepine (7.34), AF-DX 116 (6.95), himbacine (7.60), (+/-)-hexahydrosiladiphenidol (5.39) and a bisquaternary ammonium compound, heptane-1,7-bis(dimethyl-3'-phthalimidopropyl ammonium bromide) (5.84), indicate that the muscarine receptor subtype involved is not of the M1, M2 or M3 subtype.

Animals↗
PubMed1992

Pharmacological agents affecting emesis. A review (Part I).

The availability of radiolabelled ligands selective for various putative neurotransmitter receptor sites and the development of quantitative autoradiography has led to a greater understanding of the neuronal pathway and receptor subtypes involved in the vomiting reflex induced by various mechanisms both within the central nervous system and the periphery. Receptors for acetylcholine, dopamine, histamine and serotonin have been detected in a number of brain regions associated with the vomiting reflex, and provide a rational basis for the antiemetic action of drugs that inhibit receptor subtypes for these neurotransmitters. The basis of the antiemetic action of other drugs such as dexamethasone and the cannabinoids is still obscure. Some drugs act on more than 1 receptor subtype. Metoclopramide may inhibit both dopamine D2- and 5-HT3 receptors in producing its antiemetic effect. Both metoclopramide and domperidone appear to have additional peripheral actions that contribute to their effectiveness. The cannabinoids are effective in cytotoxic-induced vomiting, perhaps acting via endorphin receptors or by inhibiting prostaglandin synthesis. The effectiveness of 5-HT3 receptor antagonists may depend on the block of both central and peripheral neuronal 5-HT3 receptors. Vomiting constitutes a major disadvantage to the use of many drugs; vomiting induced by aminoglycoside antibiotics appears to be due to ototoxicity and is relieved by histamine H1-receptor antagonists. The protracted vomiting associated with the use of some cytotoxics in cancer chemotherapy may involve psychic components, the chemoreceptor trigger zone and peripheral sensory neurons. Both 5-HT3 and dopamine D2-receptor antagonists exert some control, the former being more effective with cytotoxics of high emetogenic potential, such as cisplatin. Serotonin 5-HT3 receptor antagonists or high doses of metoclopramide in combination with anxiolytics and steroids as well as greater attention to pharmacokinetic profiles of the drugs involved would appear to offer improved control. The use of dopamine receptor antagonists in controlling emesis induced by dopamine agonists used in Parkinson's disease poses theoretical problems which can be overcome by using drugs with selectivity for the chemoreceptor trigger zone, such as domperidone or metoclopramide. However, higher doses of these drugs may produce some impairment of therapeutic responses to the agonists. Muscarinic and nicotinic agonists currently under investigation in Alzheimer's disease pose another therapeutic dilemma as emesis is due to a central action of these compounds. Several sites may be involved including the chemoreceptor trigger zone and frontal lobes. Opiates may act through dopamine receptors or mu-receptors on dopaminergic nerves, but serotonergic mechanisms may also be involved in the action of some opiates.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Pharmacological agents affecting emesis. A review (Part II).

Part I of this article reviewed the pathophysiology of emesis, and its pharmacological treatment. Drug-induced vomiting was also discussed. In the second part of the review, other common causes of vomiting are considered. The basis of the use of antiemetics in morning sickness and migraine is still obscure; for the latter, serotonin 5-HT1 receptor agonists, 5-HT3 receptor antagonists and dopamine D2 receptor antagonists are effective. For motion sickness, control can be achieved with various antagonists of muscarinic or histamine H1-receptors. Centrally active adrenoceptor agonists in combination with a muscarinic antagonist or H1-receptor antagonist may offer better control of motion sickness and its associated symptoms than either antagonist alone; based on clinical studies, postoperative vomiting after opiate administration appears to be controlled by blocking dopamine D2, histamine H1- or muscarinic receptors. Radiation therapy appears to be similar to cytotoxic therapy in that the mediators produced or released by radiation activate both peripheral and central sites involved in the vomiting reflex. Blockade of dopamine D2 and 5-HT3 receptors may be effective.

Antiemetics↗
PubMed1991

Effect of temperature reduction on responsiveness to cholinomimetics in the taenia caeci of the guinea-pig.

1. The effect of temperature reduction on the interaction of carbachol (CCh) and McN-A-343 (McN) with muscarinic receptors in the guinea-pig taenia caeci was investigated. 2. McN, a partial agonist, acted on the smooth muscle to produce contraction. The response was unaffected by tetrodotoxin and the pKB for inhibition by pirenzepine was 6.8, indicating that ganglionic M1 receptors were not involved in the response. 3. Reduction in temperature from 37 degrees C to 18 degrees C for 3 h led to a marked reduction in the contractile response to McN (2-200 microM) but no reduction in the response to CCh (0.1-3 microM). 4. The reduction in temperature was not accompanied by any change in the affinity of McN or CCh for muscarine receptors in binding experiments with [3H]-QNB. 5. The KA value for CCh determined after irreversible receptor inactivation with propylbenzilylcholine mustard followed by ca 60-min wash-out was 7.6 microM, a value similar to that obtained in binding experiments. 6. The EC50 for McN in producing contraction at 37 degrees C (2.1 microM) was similar to the KA value for the partial agonist obtained in experiments with the irreversible antagonist phenoxybenzamine (2.5 microM). It was also similar to the KB value determined at 18 degrees C (3.4 microM) when McN could be used as an antagonist of contractions to CCh. 7. At 18 degrees C, phosphatidylinositol (PI) hydrolysis by CCh was reduced to 23% of that at 37 degrees C. 8. It is concluded that reduction of muscarinic receptor activation of the PI pathway by cholinomimetics with lowering of the temperature could account for the findings with McN on contractility.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1990

Structure-activity relationships of some Galbulimima alkaloids related to himbacine.

Himbacine, himbeline, N-methylhimandravine and himandravine together with their dihydro-derivatives were evaluated as antagonists of muscarinic receptors in guinea-pig ileal longitudinal muscle and electrically stimulated left atrium. Himbacine was the most potent compound and the 15-fold selectivity exhibited for the M2 muscarinic receptor was greater than that found with any of the other compounds examined. Reduction of the double bond linking the decalin ring system and the piperidine ring almost abolished selectivity in dihydrohimbacine. Removal of the N-methyl group in himbacine to form himbeline was associated with reduced selectivity. However the corresponding change in converting N-methylhimandravine to himandravine was not associated with any change in selectivity suggesting that orientation of the 2-methyl group in the piperidine ring may be important for selectivity.

Alkaloids↗