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Biomedical subjects

A D Fryer

Publications and source records attributed to A D Fryer.

At least 55 records · Page 3Linked to original sources
PubMed1992

M2 muscarinic receptors inhibit isoproterenol-induced relaxation of canine airway smooth muscle.

Classification of muscarinic receptors in the central airways has revealed the coexistence of M2 and M3 muscarinic receptors in this tissue, with the M2 subtype being predominant. Although M3 muscarinic receptors have been linked to airway smooth muscle contraction, a functional role for the M2 subtype in this tissue has been unclear. In nonairway smooth muscle, stimulation of the M2 muscarinic receptor has been shown to be associated with inhibition of adenylyl cyclase. In the present study, characterization of muscarinic receptors in canine tracheal smooth muscle confirmed that the majority of these muscarinic receptors were of the M2 subtype (89 +/- 3%), with a minor population of M3 receptors (11 +/- 3%). In functional studies, both isoproterenol and forskolin cause a dose-dependent relaxation of precontracted airway smooth muscle. In tissues precontracted with methacholine, 11-([[2-(diethylamino)methyl]-1-piperidinyl]acetyl)5,11- dihydro-6H-pyrido[2,3-6][1,4]benzodiazepine-6-one (AF-DX 116), a selective M2 antagonist, shifted dose-response curves to both isoproterenol and forskolin significantly to the left. In contrast, AF-DX 116 did not alter relaxation induced by the K+ channel opener BRL 38227. Furthermore, the ability of AF-DX 116 to enhance isoproterenol-induced relaxation appears to be limited to smooth muscle precontracted with muscarinic agonists because AF-DX 116 had no effect on isoproterenol dose-response curves in muscle strips precontracted with histamine. Hexahydrosiladifenidol (HHSiD), a selective antagonist for M3 receptors, did not shift the isoproterenol dose-response curve in muscle precontracted with methacholine. This study demonstrates that stimulation of M2 muscarinic receptors in canine airway smooth muscle plays an important role in functional antagonism by reducing the relaxation caused by agents such as isoproterenol and forskolin.

Animals↗
PubMed1991

Parainfluenza virus infection damages inhibitory M2 muscarinic receptors on pulmonary parasympathetic nerves in the guinea-pig.

1. The effect of viral infection on the function of neuronal M2 muscarinic autoreceptors in the lungs was studied in anaesthetized guinea-pigs. 2. Guinea-pigs were inoculated intranasally with either parainfluenza type 3 or with a vehicle control. Four days later the animals were anaesthetized, paralysed and artificially ventilated. Pulmonary inflation pressure, tidal volume, blood pressure, and heart rate were recorded. Both vagus nerves were cut and electrical stimulation of the distal portions caused bronchoconstriction (measured as an increase in pulmonary inflation pressure) and bradycardia. 3. In control animals, pilocarpine (1-100 micrograms kg-1, i.v.) attenuated vagally-induced bronchoconstriction by stimulating inhibitory M2 muscarinic receptors on parasympathetic nerves in the lungs. Conversely, blockade of these receptors with the antagonist gallamine (0.1-10 mg kg-1, i.v.) produced a marked potentiation of vagally-induced bronchoconstriction. These results confirm previous findings. 4. In guinea-pigs infected with parainfluenza virus, pilocarpine did not inhibit vagally-induced bronchoconstriction. Furthermore, gallamine did not potentiate vagally-induced bronchoconstriction to the same degree as in uninfected controls. 5. There was no increase in baseline pulmonary inflation pressure in the infected animals over the controls. Receptors on airway smooth muscle were unchanged by viral infection since large doses of pilocarpine caused equivalent bronchoconstriction in both groups of animals. Gallamine inhibited the vagally-induced fall in heart rate equally in both groups of animals indicating that virus-induced changes in M2 receptor function on pulmonary parasympathetic nerves are not part of a generalized decrease in M2 receptor function. 6. These results demonstrate that the M2 muscarinic receptor-mediated inhibition of acetylcholine release from parasympathetic nerves in the lungs is decreased in animals infected with parainfluenza virus. Loss of this inhibition would result in increased release of acetylcholine from the parasympathetic nerves and may explain virus-induced airway hyperresponsiveness.

Acetylcholine↗
PubMed1991

Dysfunction of M2-muscarinic receptors in pulmonary parasympathetic nerves after antigen challenge.

The effect of antigen challenge on the function of neuronal M2-muscarinic autoreceptors in the lungs was studied in anesthetized guinea pigs. Guinea pigs were injected intraperitoneally with saline (control group) or ovalbumin (10 mg/kg) on days 1, 3, and 5. One group of sensitized animals was challenged on days 20-25 with aerosolized ovalbumin for 5 min/day (challenged group), while another group of the sensitized animals was not challenged (sensitized group). On day 26 the animals were anesthetized, paralyzed, tracheostomized, and artificially ventilated. Pulmonary inflation pressure (Ppi), tidal volume, blood pressure, and heart rate were recorded. Both vagus nerves were cut, and electrical stimulation of the distal portions caused bronchoconstriction (measured as an increase in Ppi) and bradycardia. In the control group, pilocarpine (1-100 micrograms/kg iv) attenuated vagally induced bronchoconstriction by stimulating inhibitory M2-muscarinic receptors on parasympathetic nerves in the lungs. Conversely, blockade of these receptors with the antagonist gallamine (0.1-10 mg/kg iv) produced a marked potentiation of vagally induced bronchoconstriction. These results confirm previous findings. In the challenged guinea pigs, pilocarpine did not inhibit vagally induced bronchoconstriction. Furthermore, gallamine did not potentiate vagally induced bronchoconstriction to the same degree as in the controls. In the group of animals that was sensitized but not challenged, the potentiation of vagally induced bronchoconstriction by gallamine was identical to the controls. There was no increase in baseline Ppi in the sensitized or challenged animals compared with the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1990

Parainfluenza virus type 1 reduces the affinity of agonists for muscarinic receptors in guinea-pig lung and heart.

Membrane preparations of guinea-pig lung (containing multiple muscarinic receptor subtypes) and heart (containing M2 receptors only) were incubated with either neuraminidase, parainfluenza virus (which contains neuraminidase), or virus plus 2,3-dehydro-2-deoxy-N-acetylneuraminic acid, a neuraminidase inhibitor. None of these treatments affected [3H]quinuclidinyl benzilate [( 3H]QNB) binding. In the lung and heart, carbachol displaced 0.2 nM [3H]QNB from two sites. After treatment with either neuraminidase or virus the high affinity site was shifted to the right, and carbachol displaced QNB from one site with low affinity in the lung. In contrast, neuraminidase or virus decreased the affinity of carbachol for both sites in the heart. The neuraminidase inhibitor completely blocked virus-induced changes in carbachol affinity in both tissues. These results suggest that parainfluenza virus decreases the affinity of agonists for some of the muscarinic receptors in the lung, and for all of the muscarinic receptors in the heart due to its neuraminidase activity, which results in removal of sialic acid. The decreased agonist affinity in the lung may be responsible for the increased vagally induced bronchoconstriction seen in viral respiratory infections.

Animals↗
PubMed1990

Identification of three muscarinic receptor subtypes in rat lung using binding studies with selective antagonists.

Heterogeneity of the muscarinic receptor population in the rat central and peripheral lung was found in competition binding experiments against [3H]quinuclidinyl benzilate [( 3H]QNB) using the selective antagonists pirenzepine, AF-DX 116 and hexahydrosiladifenidol (HHSiD). Pirenzepine displaced [3H]QNB with low affinity from preparations of central airways indicating the absence of M1 receptors in the trachea and bronchi. Muscarinic receptors in the central airways are comprised of both M2 and M3 receptors since AF-DX 116, an M2-selective antagonist, bound with high affinity to 70% of the available sites while HHSiD, an M3-selective antagonist bound with high affinity to the remaining binding sites. In the peripheral lung, pirenzepine bound with high affinity to 14% of the receptor population, AF-DX 116 bound with high affinity to 79% of the binding sites while HHSiD bound with high affinity to 18% of the binding sites. The presence of M1 receptors in the peripheral airways but not in the central airways was confirmed using [3H]telenzepine, an M1 receptor ligand. [3H]Telenzepine showed specific saturable binding to 8% of [3H]QNB labeled binding sites in homogenates of rat peripheral lung, while there was no detectable specific binding in homogenates of rat trachea or heart. The results presented here demonstrate that there are three muscarinic receptor subtypes in rat lungs, and that the distribution of the different subtypes varies within the lungs. Throughout the airways, the dominant muscarinic receptor subtype is M2. In the trachea and bronchi the remaining receptors are M3, while in the peripheral lungs, the remaining receptors are both M1 and M3.

Animals↗
PubMed1989

Identification of M1 muscarinic receptors in pulmonary sympathetic nerves in the guinea-pig by use of pirenzepine.

1. The effect of pirenzepine, a muscarinic antagonist considered to be selective for M1 receptors, was studied on bronchoconstriction and bradycardia elicited by preganglionic stimulation of the parasympathetic vagal nerves and by i.v. injections of acetylcholine (ACh) in anaesthetized guinea-pigs. 2. Pirenzepine was equipotent in the heart and lung as an antagonist of the effects of i.v. ACh at postjunctional muscarinic receptors. Doses of pirenzepine in excess of 1 mumol kg-1 abolished all muscarinic responses consistent with non-selective blockade of M3 receptors on airway smooth muscle and M2 receptors on atrial cells. 3. In the lung, low doses of pirenzepine (1-100 nmol kg-1) increased vagally-induced bronchoconstriction despite concurrent partial blockade of the postjunctional receptors. This suggests blockade of neuronal muscarinic receptors. 4. Propranolol (1 mg kg-1) increased control bronchoconstrictor responses elicited by ACh and vagal stimulation but did not alter the potency of pirenzepine for postjunctional receptors in heart or lung. However, pirenzepine-induced enhancement of vagally-induced bronchoconstriction was abolished by propranolol, suggesting that pirenzepine may be an antagonist for muscarinic receptors located in the sympathetic nerves innervating airway smooth muscle. 5. These results confirm that bronchoconstrictor stimuli indirectly initiate activation of an opposing sympathetic reflex in the guinea-pig lung. This response is facilitated by muscarinic receptors located in the sympathetic nervous pathway. 6. The high potency of pirenzepine for the neuronal receptors in the sympathetic nerves suggests that these are M1 receptors. In contrast, the parasympathetic nerves innervating airway smooth muscle in this species contain M2 receptors which inhibit neurotransmission.

Animals↗
PubMed1989

An endogenous factor induces heterogeneity of binding sites of selective muscarinic receptor antagonists in rat heart.

According to molecular biological and pharmacological criteria, rat heart membranes normally express only one muscarinic receptor subtype. The selective antagonists pirenzepine and AF-DX 116 bind to this receptor with a single affinity: low and high, respectively. We report here that an endogenous, intracellular factor alters the affinity of selective antagonists for muscarinic receptors in the heart. Thus, when the intracellular fluid is added back to rat heart membranes, both pirenzepine and AF-DX 116 bind to two receptor sites. Approximately 30% of the receptors bind pirenzepine with high affinity and AF-DX 116 with low affinity. Thus, while cardiac muscarinic receptors are coded for by a single mRNA and are therefore genetically homogeneous, the resulting receptor protein might behave like a mixture of receptor subtypes in intact tissues due to the influence of intracellular factors on receptor conformation.

Animals↗
PubMed1989

Different mechanisms of antagonism by methoctramine of two neuronal muscarinic receptor-mediated second messenger responses.

The allosteric effects and subtype selectivity of methoctramine on neuronal muscarinic receptors in N1E-115 cells and two different rat brain regions (cerebral cortex and striatum) were assessed. Saturation isotherms of [3H]N-methylscopolamine binding, performed in N1E-115 cells and dissociated cerebral cortex, showed that methoctramine reduced the Bmax in a concentration-dependent manner. Furthermore, this compound slowed the rate of dissociation of bound [3H]N-methylscopolamine in the same tissue preparations. Low concentrations of methoctramine (less than or equal to 1 microM) antagonized the M1-linked phosphoinositide response in N1E-115 cells and dissociated cerebral cortex in an apparent competitive mechanism. However, methoctramine exhibited noncompetitive effects at higher concentrations in N1E-115 cells. Observation of a similar effect in cerebrocortical cells was precluded since methoctramine by itself, at concentrations higher than 1 microM, stimulated inositol phosphate formation. The stimulatory effect of methoctramine on phosphoinositide hydrolysis was not blocked by atropine. A solely competitive mode of antagonism by methoctramine was observed for the inhibition of cAMP formation (a noncardiac-M2 coupled response) in N1E-115 cells and dissociated striatum. This antagonism was evident even at concentrations of methoctramine that noncompetitively antagonized the M1 response. Anomalously, methoctramine alone inhibited cAMP formation in dissociated striatum at concentrations of greater than or equal to 30 microM. Atropine was ineffective at blocking this effect. Methoctramine failed to demonstrate muscarinic receptor subtype selectively in blocking these two second messenger responses. This nonselectivity was supported by indirect binding experiments involving methoctramine and [3H]N-methylscopolamine. The data presented here demonstrate that methoctramine binds to a secondary site(s) associated with neuronal muscarinic receptors. Furthermore, methoctramine exhibits different mechanisms of antagonism and displays poor selectivity for the M1-linked phosphoinositide and noncardiac-M2 linked cAMP responses.

Animals↗
PubMed1987

Ipratropium bromide potentiates bronchoconstriction induced by vagal nerve stimulation in the guinea-pig.

In anaesthetised guinea-pigs, bronchoconstriction induced by vagal nerve stimulation was potentiated by low doses of the antimuscarinic bronchodilator drug, ipratropium (0.01-1.0 microgram/kg); the maximum effect was obtained with 1.0 microgram/kg which doubled the bronchoconstriction. When the dose was increased above 1.0 microgram/kg potentiation no longer occurred; instead the vagally induced bronchoconstriction was antagonised. This was accompanied by reduction in the bronchoconstriction and bradycardia induced by i.v. acetylcholine, due to blockade of post-junctional muscarinic receptors in the airways and heart. With 10 micrograms/kg ipratropium responses elicited both by vagal stimulation and by exogenous acetylcholine were abolished. The results show that ipratropium is an antagonist for pre-junctional muscarinic inhibitory receptors on pulmonary parasympathetic nerves and also confirm its potent antagonist actions on post-junctional muscarinic receptors in the airway smooth muscle. The effect of ipratropium in the lung depends, therefore, on the balance between the pre- and post-junctional effects.

Animals↗
PubMed1987

Pancuronium and gallamine are antagonists for pre- and post-junctional muscarinic receptors in the guinea-pig lung.

The effects of atropine, pancuronium and gallamine were tested on pre- and post-junctional muscarinic receptors in the lung. Inhibition of bronchoconstriction induced by intravenous injection of acetylcholine (ACh) was used as a measure of post-junctional receptor blockade. All three antagonists reduced ACh-induced bronchoconstriction. The effects were dose-related for atropine and pancuronium and complete inhibition was obtained with 0.01 mg/kg and 10 mg/kg respectively. Gallamine was much less potent than the other two drugs; the inhibitory effect was not dose-related and never exceeded 50% even at a dose of 10 mg/kg. In contrast, blockade of pre-junctional inhibitory muscarinic receptors in pulmonary parasympathetic nerves by these three antagonists, produced potentiation of bronchoconstriction induced by vagal-nerve stimulation. Consequently, the effect of the three antagonists on vagally-induced bronchoconstriction is dependent on the balance between their pre- and post-junctional blocking activity. Gallamine was the most effective and atropine the least effective antagonist for potentiating nerve-induced bronchoconstriction. At doses which produce 100% neuromuscular blockade, both pancuronium (0.04 mg/kg) and gallamine (4 mg/kg) potentiated vagally-induced bronchoconstriction. At these doses, pancuronium doubled and gallamine caused a four-fold increase in vagally-induced bronchoconstriction, despite partial concurrent blockade of muscarinic receptors in the smooth muscle of the airways.

Acetylcholine↗
PubMed1986

Postganglionic muscarinic inhibitory receptors in pulmonary parasympathetic nerves in the guinea-pig.

The location of neuronal inhibitory muscarinic receptors in pulmonary parasympathetic nerves was investigated in vivo and in vitro. The effects of an agonist for neuronal muscarinic receptors (pilocarpine) and an antagonist (gallamine) were tested on contractions of airway smooth muscle induced by pre- and postganglionic cholinergic nerve stimulation. In anaesthetized guinea-pigs, gallamine potentiated constriction of the tracheal tube and smaller airways induced by preganglionic stimulation. Gallamine also potentiated postganglionic stimulation induced by transmural stimulation of the tracheal tube and by 1-1-dimethyl-4-phenylpiperazinium iodide in the rest of the lung. Bronchoconstriction and contraction of the tracheal tube induced by intravenous acetylcholine were not potentiated by gallamine, indicating that postjunctional muscarinic receptors in airway smooth muscle were not involved in the potentiation. The muscarinic agonist, pilocarpine, had the opposite effect to gallamine and inhibited contractions of the tracheal tube induced by both types of nerve stimulation. In vitro, the inhibitory effect of pilocarpine was demonstrated in the tracheal tube preparation stimulated both pre- and postganglionically. The effect of pilocarpine was antagonized by gallamine. Because gallamine and pilocarpine affected the responses to postganglionic stimulation, the inhibitory muscarinic receptors must be located on the postganglionic neurones of the parasympathetic nerves innervating the trachea and the smaller airways. However, these experiments cannot exclude the possibility that muscarinic receptors may also be located on the soma of the ganglion cells.

Acetylcholine↗
PubMed1985

Neuronal muscarinic receptors attenuate vagally-induced contraction of feline bronchial smooth muscle.

In anaesthetized cats, stimulation of the vagus nerves produced bradycardia and a bronchoconstriction which was measured as an increase in lung resistance (RL) and a fall in dynamic lung compliance (Cdyn); these effects were abolished by atropine. Gallamine potentiated vagally-mediated changes in RL and Cdyn at doses that blocked muscarinic receptors in the heart and inhibited neuromuscular transmission. (+)-Tubocurarine and suxamethonium did not affect the response of the lung or the heart to vagal stimulation. Bronchoconstriction induced by intravenous acetylcholine was not potentiated by gallamine, indicating that postsynaptic muscarinic receptors in the lung and changes in muscle tone were not involved. Potentiation of vagally-induced bronchoconstriction appears to be due to blockade of inhibitory muscarinic receptors located in the pulmonary parasympathetic nerves innervating both central and peripheral airways. Pilocarpine was an agonist for these neuronal receptors as it inhibited vagally-induced bronchoconstriction at low doses (10 ng to 1 microgram kg-1). The results demonstrate that gallamine is an antagonist and pilocarpine an agonist at neuronal muscarinic receptors which attenuate parasympathetic nerve activity in feline lung.

Acetylcholine↗
PubMed1985

The response of cat airways to histamine in vivo and in vitro.

The effects of histamine have been examined in anaesthetized cats and on cat cat isolated lung parenchyma strip. Histamine infused intravenously for 2 min produced a small and inconsistent effect on central airways and a small but consistent constriction of peripheral airways. Histamine bronchoconstriction of the central airways was unmasked by non-selective and beta 2-adrenoceptor blockade but not by beta 1-adrenoceptor blockade. This bronchoconstriction was antagonized by atropine but not by cimetidine or prazosin. Bronchoconstriction of the peripheral airways was not affected in a dose-related manner by beta-adrenoceptor blockade. The bronchoconstriction was antagonized by mepyramine but not by atropine or prazosin. beta-Adrenoceptor antagonists produced a bell-shaped dose-response curve on histamine contractions in cat isolated lung parenchyma strip. Strips of lung parenchyma obtained from reserpine-treated cats produced a larger contraction to histamine which was not potentiated by propranolol. It is concluded that in the central airways, histamine bronchoconstriction produced by an action on irritant receptors is masked by an action on beta 2-adrenoceptors of catecholamines released locally and from the adrenal glands. In the peripheral airways, histamine bronchoconstriction is mediated by H1-receptors and beta 2-adrenoceptor blockade may either potentiate or antagonize the histamine response depending on the concentration.

Adrenergic beta-Antagonists↗
PubMed1984

Muscarinic inhibitory receptors in pulmonary parasympathetic nerves in the guinea-pig.

In anaesthetized guinea-pigs, gallamine produced a dose-related potentiation of the bronchoconstriction induced by electrical stimulation of the cervical vagus nerves; (+)-tubocurarine and suxamethonium lacked this effect. The bronchoconstriction produced by intravenous injection of acetylcholine or histamine, however, was not potentiated by gallamine. Vagally-induced bradycardia was abolished by gallamine, confirming antagonism of the effect of acetylcholine on muscarinic receptors in the heart. The muscarinic receptor agonist pilocarpine, had the opposite effect to gallamine in the lung as it inhibited vagally-mediated bronchoconstriction. Pretreatment of guinea-pigs with either guanethidine or propranolol did not affect the gallamine-induced potentiation of vagally-mediated bronchoconstriction. The potentiating effect of gallamine in the lung can be explained by blockade of inhibitory, muscarinic receptors located in the parasympathetic nerves supplying the lungs.

Animals↗
PubMed1984

Severe superior vena cava syndrome and hydrocephalus after the Mustard procedure: findings and a new surgical approach.

Some degree of obstruction of the superior vena cava is common after the Mustard operation for transposition of the great arteries. This can cause superior vena cava syndrome, which in extreme cases may lead to hydrocephalus in young children. While revision of the intra-atrial baffle can be performed, this procedure is associated with significant morbidity and mortality and may not resolve the problem. We describe an alternative operative approach in a group of patients who had superior vena cava syndrome after the Mustard procedure: anastomosis of the innominate vein to the left atrial appendage. This procedure is not complicated to perform and is safe; symptoms were relieved in all patients.

Acute Disease↗
PubMed1983

beta 1-selective adrenoceptor antagonists. 2. 4-ether-linked phenoxypropanolamines.

A series of 4-substituted phenoxypropanolamines was prepared and examined for beta-adrenoceptor activity. Some of the compounds, especially the [4-[2-[[2-(4-fluorophenyl)ethyl] oxy]ethoxy]phenoxy]propanolamines (14, 15, and 24), showed potent beta 1-blockade with virtually no beta 2-blockade at doses over a 1000 times greater. The compounds also possessed partial agonist activity. Structure-activity relationships are discussed, and conclusions are drawn about the binding sites on beta-adrenoceptors.

Adrenergic beta-Agonists↗