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Biomedical subjects

H W Mitchell

Publications and source records attributed to H W Mitchell.

68 records · Page 4Linked to original sources
PubMed1982

Effect of ETYA and BW 755c on arachidonate-induced contractions in the guinea-pig isolated trachea.

1. Arachidonic acid caused larger contractions to indomethacin-tested guinea-pig trachea than in control tracheae. 2. No change in contractions was obtained in tracheae treated with 5,8, 11, 14, eicosatetraynoic acid (ETYA 10 micro M). 3. ETYA (100 micro M) blocked the effect of indomethacin on arachidonic acid-induced responses. Likewise BW 755c (113 micro M) reversed the effect of indomethacin. 4. The results show that arachidonate lipoxygenase products may be responsible for the contractile responses seen in the presence of indomethacin.

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

The effect of mixed inhibitors of cyclo-oxygenase and lipoxygenase on the indomethacin-induced hyper-reactivity in the isolated trachea of the pig.

1 Indomethacin enhances muscle contraction to histamine in the pig isolated trachea. The effect of three cyclo-oxygenase/lipoxygenase inhibitors on these potentiated histamine-induced responses was examined. 2 At the higher concentrations BW 755c (113-226 microM), 5, 8, 11, 14-eicosatetraynoic acid (ETYA, 10-100 microM) and phenidone (5-500 microM) abolished the effect of indomethacin on tracheal contractions to histamine (100 microM). 3 Each of the three inhibitors also reduced the slope of the histamine concentration-response curve obtained in the presence of indomethacin. However, the sensitivity (pD2) of the smooth muscle to histamine was not affected by BW 755c, ETYA or phenidone. 4 The results provide further support for a lipoxygenase-dependent component of indomethacin-induced hyper-reactivity in the pig trachea.

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

The effect of contraction and Ca2+ removal on the indomethacin-induced increase in tracheal smooth muscle reactivity.

The effect of contraction and Ca2+ on the indomethacin mediated increased tracheal reactivity to histamine was studied in swine isolated tracheal smooth muscle. The potentiating effect of indomethacin was not directly related to the size of muscle contraction. Histamine, but not acetylcholine-induced contractions were partially inhibited in a zero-Ca2+ Krebs solution and almost abolished in zero-Ca2+ Krebs solution containing 0.1 mM EGTA. Indomethacin potentiated histamine but not acetylcholine-induced contractions in the zero-Ca2+ medium. Re-addition of Ca2+ ions caused a further potentiation of the histamine-induced response. The histamine response with indomethacin when EGTA was present was further reduced. Indomethacin had no effect on Ca2+-contractures of tissues bathed in zero-Ca2+ solution containing 80 mM K+. The results demonstrate that histamine-induced tone is largely dependent on labile Ca2+, whereas its potentiation by indomethacin, is only partly dependent on this cation pool.

Animals↗
PubMed1979

In vitro action of combined salbutamol and theophylline on anaphylactic contractions, mediator release and cyclic 3',5'-adenosine monophosphate in lung parenchyma.

The mechanisms involved in the anti-asthmatic action of combined bronchodilator therapy was studied by determining the effects of combined salbutamol and theophylline on anaphylactic contractions, histamine release, prostaglandin (PG)F2 ALha release, cyclic 3',5'-adenosine monophosphate (c-AMP) and smooth muscle tone in guinea-pig peripheral airways in vitro. Combined, salbutamol (3 X 10(=8) M) and theophylline (3 X 10(-4) M) markedly inhibited anaphylactic contractions (85.8%) in lung strips. The inhibition of anaphylactic contractions was significantly greater than inhibition of histamine and PGF2 alpha-induced contractions. Histamine release was reduced by 66.1% but PGF2 alpha was not significantly altered. Increased c-AMP was observed with combined salbutamol (3 X 10(-8) M) and theophylline (3 X 10(-4) M) in the absence of antigen. The combined effect of salbutamol and theophylline was always greater than the sum of their individual effects. The results demonstrate that in peripheral airways theophylline potentiates the action of salbutamol both directly via smooth muscle relaxation and indirectly via inhibition in mediator release.

Albuterol↗
PubMed1979

Anaphylaxis in guinea-pig peripheral airways in vitro.

The contributions made by histamine, prostaglandins (PG) and slow reacting substance (SRS-A) to anaphylactic contractions in isolated guinea-pig lung were investigated. Histamine, PGF2alpha and SRS-A induced isometric contractions in lung parenchymal strips and in tracheal smooth muscle. The effective concentrations of the autacoids were the same in lung strips and tracheas. Anaphylactic contractions in lung strips from bovine serum albumin sensitised animals were not affected by mepyramine (5 X 10(-6)M), or indomethacin (3 X 10(-5)M) but were markedly reduced by FPL 55712 (5 X 10(-5)M) suggesting that SRS-A plays a major role in the anaphylactic response. The effect of isoprenaline on anaphylactic histamine release and contractions was also examined. Anaphylactic contractions in lung strips were inhibited by isoprenaline (10(-10)--10(-7)M). Isoprenaline also inhibited anaphylactic histamine release from lung parenchyma. 10(-7)M isoprenaline inhibited contractions by 85.6% and reduced histamine release by 27.9%. The results suggest that histamine release does not contribute markedly to anaphylaxis in peripheral airways.

Anaphylaxis↗
PubMed1977

The effect of catecholamines on the in vivo and in vitro responses of the cat lung during anaphylaxis.

1. Anaphylaxis in the lung of cats actively sensitized to Ascaris antigen has been investigated in vivo and in vitro. 2. In vivo there was a 100% increase in airways resistance and a 50% decrease in dynamic lung compliance following intravenous challenge with Ascaris antigen. Prostaglandin F2alpha induced similar changes but with histamine only dynamic lung compliance was affected. (-)-Isoprenaline prevented these prostaglandin F2alpha- and histamine-induced changes and caused a delay of about 2 min in the onset of the mechanical changes following anaphylactic challenge. 3. In vitro the isolated lung strip contracted within seconds of challenge whereas there was a delay of 2 to 3 min in the onset of the tracheal anaphylactic response. (-)-Isoprenaline, (-)-adrenaline and (+/-)-noradrenaline reduced the magnitude of anaphylactic contractions of the isolated trachea but did not significantly affect those of the isolated lung strip. This indicated lack of inhibition of mediator release from the lung parenchyma. 4. Histamine was released from sensitized lung fragments following challenge with the Ascaris extract. This release constituted 6.3% of the total tissue histamine and was not inhibited by (-)-isoprenaline (1 micrometer). 5. (-)-Isoprenaline abolished 5-hydroxytryptamine (5-HT)-induced contractions of the isolated trachea but not those elicited in response to acetylcholine. The isolated lung strip responses to histamine, prostaglandin F2alpha and 5-HT were highly resistant to inhibition by (-)-isoprenaline.

Airway Resistance↗
PubMed1976

The cat lung strip as an in vitro preparation of peripheral airways: a comparison of beta-adrenoceptor agonists, autacoids and anaphylactic challenge on the lung strip and trachea.

1 A new in vitro preparation, the isolated lung strip of the cat, is described for investigating the direct effect of drugs on the smooth muscle of the peripheral airways of the lung. The preparation comprises a thin strip of lung parenchyma which can be mounted in a conventional organ bath for isometric tension recording. Its pharmacological responses have been characterized and compared with the isolated tracheal preparation of the cat. 2 The lung strip exhibited an intrinsic tone which was relaxed by catecholamines, aminophylline and flufenamate. It was contracted strongly by histamine, prostaglandin F2alpha, acetylcholine, compound 48/80, potassium depolarizing solution and alternating current field stimulation. In contrast, the cat trachea was unresponsive to histamine and prostaglandin F2alpha and did not exhibit an intrinsic tone. 3 (-)-Isoprenaline and (-)-adrenaline were much more potent in relaxing the lung strip than the trachea. The potency order of relaxation responses to isoprenaline, adrenaline and (+/-)-noradrenaline in the lung strip was isoprenaline greater than adrenaline greater than noradrenaline but in the trachea was isoprenaline greater than noradrenaline greater than or equal to adrenaline. 4 beta2-Adrenoceptor selective agonists salbutamol and terbutaline were more potent in the lung strip than the trachea, suggesting beta2-adrenoceptors predominated in the lung strip. Propranolol was equipotent in inhibiting isoprenaline relexations of the lung strip and trachea, whereas practolol was much less effective in inhibiting lung strip than trachea, further supporting a predominance of beta2-adrenoceptors in lung strip and beta1-adrenoceptors in trachea. 5 Strong Schultz-Dale type contractions were elicited in both lung strips and trachea by Ascaris lumbricoides antigen in actively sensitized cats. The initial phase of the contractile response of the lung strip following challenge was shown to be due to histamine release and was absent in the trachea. The delayed phase of the contraction which took several minutes to develop in both the mepyramine-treated lung strip and trachea was not due to prostaglandins E1, F2alpha or bradykinin, the probable mediator being slow reacting substance of anaphylaxis (SRS-A). 6 It is concluded that the isolated lung strip of the cat is useful as an in vitro model for investigating the effect of drugs on the smooth muscle of the peripheral airways of the lungs.

Adrenergic beta-Agonists↗
PubMedDate not supplied

Different ratio of myosin heavy chain isoforms in arterial smooth muscle of spontaneously hypertensive rats.

The relative proportion of the two putative heavy chains of smooth muscle myosin (MHC1 and MHC2) was determined in the caudal and femoral arteries of spontaneously hypertensive rats (SHR) and normotensive (WKY) rats at 16 weeks of age. The heavy chain polypeptides with Mr 204,000 and 200,000 were resolved electrophoretically under denaturing conditions in porous polyacrylamide gels. Both proteins reacted strongly with a monoclonal antibody (2C4) to smooth muscle MHC. In caudal arteries the ratio of MHC1/MHC2 was 3.1:1 in SHR rats compared with 1.8:1 in WKY rats (p less than 0.005) and similarly in femoral arteries, 2.8:1 vs 1.5:1 (p less than 0.001). In the portal vein there was no significant difference, 1.7:1 vs 1.5:1. The possibility that the higher MHC ratio in the SHR is the genetically mediated defect in arterial smooth muscle cells leading to the hypertension is discussed as an alternative to the elevated systemic blood pressure causing the altered MHC ratio.

Animals↗
PubMedDate not supplied

Drug interactions in cat isolated tracheal smooth muscle.

1. The interactions between some drugs that contract and relax airways smooth muscle have been investigated in the cat isolated trachea. 2. Isoprenaline and theophylline inhibited serotonin-elicited contractions more than acetylcholine-mediated responses. This was observed both in terms of the degree of inhibition and the concentration of the relaxant drug producing this inhibition. 3. The acetylcholine- and serotonin-induced contractions were inhibited more by theophylline than by isoprenaline displaced acetylcholine and serotonin response curves to the right whereas theophylline caused a flattening of the curves. 4. Isoprenaline was more effective in hibiting serotonin contractions than acetylcholine contractions when the tracheas were bathed in K+ depolarizing solution, suggesting that the difference in the suscepbibility of serotonin and acetylcholine contractions to isoprenaline was not dependent on the electrical membrane potential. 5. Isoprenaline inhibited the tonic component of acetylcholine contractions more than the phasic component. 6. The differences in the pharmacological responses to the contractile and relaxant drugs in cat tracheal preparations provide further examples in smooth muscle of different mechanisms by which acetylcholine and serotonin induce contraction and isoprenaline and theophylline relaxation.

Acetylcholine↗
PubMedDate not supplied

Physiology of airway narrowing.

1. Responsiveness of the bronchial tree is measured at the mouth in vivo and represents narrowing responses of multiple airways in the lung. Responsiveness of individual bronchi has not been adequately investigated and the dynamic changes associated with airway narrowing are largely undefined. 2. Responsiveness to cholinergic drugs was determined in bronchial segments in vitro, from lumen flow and narrowing, and from the force and shortening of the smooth muscle producing these responses. 3. Maximum flow reduction was produced by submaximum smooth muscle force and shortening. In 2 mm inner diameter bronchi, flow was abolished by acetylcholine but the lumen was not physically closed. Flow sensitivity was increased more in small diameter bronchi than in large, but this was not associated with differences in force by smooth muscle. Smooth muscle contraction increased the thickness of the total airway wall via a tensioning and expansion of mural elastic fibres. Flow responses were more sensitive to drugs placed adventitially than luminally. 4. Results define a major role for airway geometry and location, the epithelial barrier and the intercellular matrix, which couples the smooth muscle to the cartilaginous airway adventitia, in determining responsiveness of intact airways.

Acetylcholine↗