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Biomedical subjects

H W Mitchell

Publications and source records attributed to H W Mitchell.

At least 55 records · Page 3Linked to original sources
PubMed1990

Inhibitory and excitatory responses to field stimulation in fetal and adult pig airway.

The innervation in airway tissues from young adult (15-26 wk) and fetal (95/115 d gestation) pigs was compared in isolated tracheal and bronchial preparations subjected to electrical field stimulation. End-organ responsiveness to carbachol, substance P, isoprenaline, and VIP was present by 95 d gestation. Electrical field stimulation (0.5-20 Hz, 70 V, 0.5 ms) resulted in a frequency-dependent contraction that was blocked by atropine (10(-6) M) and TTX (10(-6) M) at both ages. However, there was a 10-fold increase in threshold in the fetal airways because contractions were evoked at frequencies of approximately 5 Hz in the fetus compared with 0.5 Hz in the young adult airways. In the young adult airways, there were atropine-resistant contractions at longer pulse durations (1-5 ms, 20 Hz), but not usually in the fetus. The atropine-resistant contractions were not blocked by TTX. Capsaicin (10(-6) M) produced no contraction in the pig airway. In tissues contracted using the ED50 of carbachol, electrical stimulation (1-20 Hz, 70 V, 1 ms) caused marked relaxation, however, compared with those in the young adult, fetal responses were weak or absent. Propranolol (10(-6) M) partially reduced the relaxation of the young adult bronchus (approximately 25%), but it had little effect on responses in the other young adult and fetal preparations. Therefore, the inhibitory innervation of pig airways was predominantly nonadrenergic and the excitatory component was cholinergic. Neither of these components was fully developed in the fetus close to term.

Animals↗
PubMed1989

The relevance of pharmacological dose--response curves to airway narrowing.

A defect in the smooth muscle of airways has been discarded as a possible cause of asthma in recent years because of the lack of correlation between airflow obstruction in patients and the contractile responsiveness of the isolated airway smooth muscle. Howard Mitchell and Malcolm Sparrow question the relevance of comparing parameters obtained from pharmacological dose-response curves (e.g. EC50) of strips of airways in vitro with those describing airways narrowing in vivo (e.g. resistance). They point out that in small airways the upper half of the dose-response curves seen in strips of airway wall is not represented in perfused tubular airway segments because they are fully constricted at or near the EC50 of the strip.

Animals↗
PubMed1989

Perfused bronchial segment and bronchial strip: narrowing vs. isometric force by mediators.

When bronchial segments were perfused with Krebs solution at a constant pressure (5-6 cmH2O), the resistance rose exponentially with increasing concentrations of either carbachol or histamine in the lumen. The pressure-flow relationship was linear. Histamine and carbachol caused 43 and 47% muscle shortening, respectively, and produced the same maximum effect (Emax) because they both stopped perfusion. In bronchial strips the maximum isometric force or isotonic shortening to carbachol was more than twice that of histamine and the responses showed a plateau. There were no significant differences in sensitivities [negative log of the concentration producing half-maximal response (EC50)] to either carbachol or histamine in the strips (isotonic and isometric) and the segments perfused at constant pressure. When airway segments were perfused at a constant flow, however, responses plateaued and the sensitivities to carbachol and histamine were reduced more than tenfold compared with the strips [4.71 +/- 0.20 and 6.22 +/- 0.08 (SE) for carbachol in segments and isometric strips, respectively, and 3.92 +/- 0.13 and 4.94 +/- 0.11 (SE) for histamine]. We conclude that when segments are perfused at a constant pressure, airway closure occurs before maximal pharmacological activation, as seen in airway strips.

Airway Resistance↗
PubMed1988

Effect of elastase instilled into the trachea on airways mechanics in guinea pigs.

Instilled elastase caused an inflammatory response in the lungs of guinea pigs which was observed at 6 h, 24 h, and 48 h post-treatment. The inflammation was most marked at 24 h and was characterised by a loss of epithelial cilia and detachment of epithelial cells from the basement membrane, a marked increase in polymorphonuclear leukocytes (PMNs) in blood vessels of the tracheal submucosa and an infiltration of macrophages into the parenchyma. Compared with controls, isolated tracheal preparations from 24 h and 48 h elastase pretreated animals were hyperreactive (Emax) to histamine and carbachol. This hyperreactivity persisted in tracheas from 48 h elastase pretreated animals after removal of the epithelial layer. Parenchymal strips were hyperreactive to histamine only. Tissue sensitivity (EC50) was little affected by elastase. Tracheal preparations incubated in 0.01% elastase for 3 h responded normally. In vivo responses of Raw and Cdyn to histamine were unaffected by elastase at 24 h and 48 h. However, the slope of the dose-response curve to acetylcholine was steepened 24 h after elastase instillation, but not at 48 h. In contrast to other models of inflammation elastase evokes in vitro but not in vivo hyperresponsiveness.

Animals↗
PubMed1988

Inhibitory effect of sodium cromoglycate on pulmonary responses to histamine administered after indomethacin in anaesthetized guinea-pigs.

1. Histamine (2-4 micrograms kg-1 i.v.) increased airways resistance (Raw) and decreased dynamic lung compliance (Cdyn) in urethane-anaesthetized guinea-pigs. The effects on Raw were almost abolished by atropine (0.1 mg kg-1 i.v.) and reduced by vagal cooling (11-16 degrees C). 2. Histamine-induced changes in Raw and Cdyn were significantly (P less than 0.05) enhanced by indomethacin (1 mg kg-1 i.v.). 3. In animals not treated with indomethacin, exposure to an aerosol containing sodium cromoglycate (0.01-2% for 30 s) failed to affect subsequent (3 min) histamine-induced bronchoconstriction. 4. Administration of an aerosol containing low (0.01-0.2%) concentrations of sodium cromoglycate had no effect on the enhanced responses (i.e. hyperreactivity) seen after indomethacin. However, more concentrated sodium cromoglycate aerosols (greater than 0.2%) reduced or abolished the hyperreactivity to histamine seen after indomethacin. 5. It was concluded that sodium cromoglycate can prevent the development of hyperreactivity to histamine, possibly by interacting with some mechanism utilized by both histamine and indomethacin in this model.

Aerosols↗
PubMed1988

Vagal mechanisms and the effect of indomethacin on bronchoconstrictor stimuli in the guinea-pig.

1. In urethane-anaesthetized guinea-pigs, under spontaneous respiration, indomethacin (1 mg kg-1 i.v., 10-45 min) approximately doubled the bronchoconstrictor effect (increase in airways resistance, R(aw)) of equieffective doses of histamine and 5-hydroxytryptamine (5-HT), but not that of acetylcholine or leukotriene D4 (LTD4). 2. In mechanically ventilated guinea-pigs indomethacin increased R(aw) responses to histamine as well as increasing the fall in dynamic compliance (Cdyn) evoked by this agent. 3. Cooling the cervical vagi, to temperatures shown to block efferent and probably afferent pathways (approximately 9 degrees C), abolished the effect of indomethacin on airways responses. Inhibition of indomethacin-induced hyperreactivity was also observed after vagal section. 4. Electrical stimulation of the peripheral vagus (1-20 Hz, 0.75-5 ms pulses) increased R(aw) and decreased Cdyn but these responses were not markedly altered by indomethacin. 5. It was concluded that the indomethacin-induced hyperreactivity of tracheal smooth muscle, which was demonstrated in vitro, may not account for the airways hyperreactivity observed in the present in vivo experiments. The hyperreactivity to histamine induced by indomethacin in vivo depends on the functional integrity of vagal reflex pathways.

Airway Resistance↗
PubMed1987

Potency of several non-steroidal antiinflammatory drugs on airways responses to histamine.

The effects of four non-steroidal antiinflammatory drugs (NSAIDs, indomethacin, flufenamate, aspirin and phenylbutazone) were investigated in anesthetized guinea-pigs. Bronchoconstriction (increased airways resistance and decreased conductance and compliance) was obtained to histamine (1-3 micrograms/kg i.v.). Each of the NSAIDs (0.1-20 mg/kg i.v.) enhanced bronchoconstriction to histamine. Maximum effects were obtained 12-44 min after administration of the NSAID. The order of potency of the drugs in causing a 50% increase in resistance responses to histamine was indomethacin greater than flufenamate greater than aspirin greater than phenylbutazone.

Airway Resistance↗
PubMed1987

Electromechanical effects of tetraethylammonium and K+ on histamine-induced contraction in pig isolated tracheal smooth muscle.

The effect of tetraethylammonium (TEA) and K+ on contractions to histamine and acetylcholine have been compared in the pig isolated trachea using organ bath and sucrose-gap techniques. Histamine elicited weak contractions, compared with acetylcholine; however, these contractions were markedly potentiated by pretreatment with TEA (10 mM) or by raising the external KCl concentration to 30-50 mM. Neither TEA nor K+ increased the sustained depolarization evoked by histamine (or acetylcholine) although oscillatory depolarizations were often observed in the presence of TEA. Verapamil and a zero Ca2+ Krebs solution reduced contractions to histamine and reduced or abolished the effect of TEA and K+ on histamine-induced contractions. The results unmask different mechanisms of contraction for histamine and acetylcholine. Histamine-induced tone appears to be linked with mechanisms sensitive to TEA and high K+, possibly involving increased translocation of Ca2+ across the plasma membrane.

Acetylcholine↗
PubMed1987

Airways hyperreactivity and bronchoconstriction induced by vanadate in the guinea-pig.

1 The characteristics of vanadate-induced bronchoconstriction and airways hyperreactivity were observed in spontaneously breathing anaesthetized guinea-pigs by measurement of airways resistance (Raw) and dynamic lung compliance (Cdyn). Vanadate (0.3-3 mg kg-1 i.v. over 25 min) increased Raw and decreased Cdyn in a reversible, dose-related manner. This action (1 mg kg-1 vanadate) was not inhibited by atropine (1 mg kg-1 i.v.), propranolol (1 mg kg-1 i.v.) or bilateral vagotomy, suggesting a direct effect on the airways smooth muscle. 2 An aerosol of vanadate (10% w/v in H2O) for 3 min decreased Cdyn by 19.5% (P less than 0.05, n = 6) but caused no change in Raw. 3 Histamine (3 micrograms kg-1 i.v.) caused a bronchoconstriction which was enhanced by vanadate in a dose-related manner. This hyperreactivity (after 1 mg kg-1 i.v. vanadate) was unchanged after propranolol or bilateral vagotomy, but was partly blocked by atropine (enhancement by vanadate of the Cdyn change to histamine was diminished, P less than 0.02, n = 3). 4 Bronchoconstrictor responses to acetylcholine (6 micrograms kg-1 i.v.) and 5-hydroxytryptamine (6 micrograms kg-1 i.v.) were also enhanced by vanadate (1 mg kg-1 i.v.) Hyperreactivity after vanadate to the three bronchoconstrictors tested continued during vanadate infusion and was reversed 45 min after cessation of infusion. 5 Histamine (3 ;Lgkg-' i.v.) caused a transient tachypnoea which was also enhanced by vanadate (0.3-3mgkg-'i.v.), in a dose-related manner, in association with the increased reactivity of the airways (r = 0.66, n = 11). 6 It is concluded that vanadate-induced airways hyperreactivity is non-vagal (efferent) and largely non-cholinergic in origin and appears to involve an action of vanadate within the lung itself.

Acetylcholine↗
PubMed1986

Smooth muscle contractility and changes in histaminergic mechanisms in the pig trachea during development.

Maximal contractile reactivity was compared in isolated tracheas from different sized (aged) pigs. Maximum force and tension to histamine declined by approximately 10-fold in tracheas from 150-200 kg pigs compared to 30 kg animals, whereas acetylcholine-induced contractions were little changed. Furthermore, contractions to Ca2+ in chemically skinned muscle were not different in different sized animals. The effect of maturation on the reactivity to histamine was unaltered in preparations from which superficial connective tissue had been dissected but it was reduced or abolished by preincubation with indomethacin. The data indicate that maturation affects histaminergic mechanisms of contraction selectively, with respect to acetylcholine, rather than the intrinsic contractile properties of the muscle.

Animals↗
PubMed1985

Attenuation of tracheal smooth muscle contraction by connective tissue.

Removing the fibroelastic connective tissue, which surrounds the smooth muscle of the pig trachea, enhanced contractions and decreased desensitization in vitro in response to histamine. There were no differences between the preparations in the presence of indomethacin. The magnitude of contraction to acetylcholine was not significantly different. Incubation of the connective tissue in histamine solution caused the appearance of a substance(s) which relaxed other, precontracted tracheal muscles. Propranolol did not block this relaxation. Intact connective tissue appears to reduce the reactivity of the tracheal smooth muscle to histamine.

Acetylcholine↗
PubMed1985

Analysis by microcomputer of the effect of capsaicin on pulmonary mechanics in the rat and guinea-pig.

Analysis of airways resistance and lung compliance in anaesthetized rats and guinea-pigs was accomplished on-line by microcomputer. In spontaneously respiring guinea-pigs capsaicin (0.5-2.5 microgram/kg i.v.) increased both resistance by 0.33 +/- 0.13 cmH20/ml/sec and the end-expiratory lung volume and it decreased compliance by 0.24 +/- 0.09 ml/cmH2O. These effects of capsaicin were resistant to vagotomy. In the rat, doses of capsaicin (40-80 micrograms/kg i.v. and i.a.) which produced respiratory apnoea had no effect on resistance or compliance in artificially ventilated animals but it did cause a decrease of end-expiratory volume, an effect which was abolished by vagotomy. The results confirm that reduction in tidal volume seen in spontaneously respiring rats following capsaicin (Mitchell et al., 1984) appears to be due to an action other than one on the bronchial calibre.

Airway Resistance↗
PubMed1984

Pharmacological studies into cyclo-oxygenase, lipoxygenase and phospholipase in smooth muscle contraction in the isolated trachea.

Indomethacin (1 microM) enhanced histamine-induced contractions in pig and guinea-pig isolated tracheae. Mepacrine (30-50 microM) abolished this effect of indomethacin suggesting that contractile metabolites of arachidonate are involved in the response to indomethacin. Mepacrine (100 microM) in the absence of indomethacin also markedly reduced histamine-induced contractions (81.2% inhibition) in the pig trachea, without affecting responses to acetylcholine. Histamine-induced responses in the guinea-pig trachea were similarly reduced, but with a higher concentration of mepacrine (300 microM). BW755c (226 microM) enhanced histamine-induced contractions in some pig tracheal preparations and caused inhibition in others. These effects of BW755c were negatively correlated to the initial reactivity of the muscle to histamine such that weak contractions were potentiated and strong contractions were inhibited. A similar effect was seen with phenidone (100 microM). The results with BW755c and phenidone suggest that muscle reactivity (to histamine) may be partly determined by the balance between the release of inhibitory and contractile arachidonate metabolites. Mepacrine exerts a different effect indicating that histamine-induced contractions are regulated by a mepacrine-sensitive process which appears to be separate from the metabolism of arachidonate.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1983

Indomethacin enhances the effect of histamine on airways resistance in the anaesthetized guinea-pig.

In anaesthetized guinea-pigs intravenous histamine caused an increase in airways resistance (RA) and a fall in dynamic compliance (CDyn). Indomethacin (1 mg kg-1, i.v.) significantly enhanced the effect of histamine on RA. Indomethacin also increased the basal RA and the RA response to a histamine infusion. The effect of indomethacin on CDyn was less consistent but here also there was a trend for an increased response to histamine. Sodium carbonate (the vehicle for indomethacin, 0.05 ml 100 mM solution) had no effect on RA or CDyn in control experiments. Propranolol (0.1 mg kg-1, i.v.) enhanced the effect of histamine on RA in animals pretreated with either indomethacin or Na2CO3 vehicle, but the effect was more consistent in indomethacin pretreated animals. Indomethacin also tended to enhance the effect of histamine on RA in animals pretreated with reserpine or BW755c but it had little effect on the CDyn response to histamine. The results show that indomethacin augments the responsiveness of the airways to histamine in the anaesthetized guinea-pig. The results with propranolol and reserpine suggest that an operational beta-adrenergic system is not required for the effect of indomethacin on RA. No confirmation for lipoxygenase involvement was obtained with the lipoxygenase inhibitor, BW755.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1982

Non-atropinic anticholinergic action of quinidine on the ferret stomach.

1 The effect of quinidine on the cholinergic response of the ferret gastric corpus was investigated in vivo and in vitro. 2 In vivo, the atropine sensitive contractions of the gastric corpus evoked by stimulation of the cervical vagus in the anaesthetized ferret were antagonized by quinidine (10-30 mg/kg). 3 In vitro, quinidine (10 micrograms/ml) antagonized the contractile response elicited by transmural stimulation (T.M.) of strips of corpus. At this dose of quinidine, the response to acetylcholine at doses adjusted to match the response to T.M. stimulation were unaffected. At higher doses of quinidine (50 micrograms/ml) the response to stimulation of the non-cholinergic, non-adrenergic inhibitory neurones was also antagonized. 4 These results indicate that, at low doses, quinidine has an inhibitory effect on the cholinergic neurones.

Acetylcholine↗
PubMed1982

The effect of inhibitors of arachidonic acid metabolism on drug-induced contractions in isolated tracheal smooth muscle of the pig.

1 The regulation of drug-induced tone in airways smooth muscle was examined in an isolated preparation of swine tracheal smooth muscle. 2 The trachea contracted (isometric) to histamine, 2-pyridylethylamine (2-PEA), acetylcholine and K+ but no response to histamine H2-receptor agonists were observed. 3 Histamine-induced contractions (100 microM) were potentiated by 213.3% by indomethacin (1 microM) and by 126.9% by sodium salicylate (250 microM). These inhibitors had only slight or no effects on acetylcholine-induced tone. 2-PEA responses were also potentiated by indomethacin but there were no changes in the response to H2-receptor agonists in the presence of indomethacin. The indomethacin-mediated potentiation of histamine was blocked by 5, 8, 11, 14-eicosatetraynoic acid (10 microM). FPL 55712 had no effect on these responses. 4 Mepacrine (100 microM) inhibited responses to histamine but not those to acetylcholine. No effect was observed with dexamethasone (up to 100 microM). 5 Prostaglandin E2 caused relaxation but arachidonic acid did not. 6 The possibility that histamine H1-agonist-induced contractions are regulated by contractile products of the arachidonic acid lipoxygenase pathway is discussed.

5,8,11,14-Eicosatetraynoic Acid↗