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Biomedical subjects

J W Paterson

Publications and source records attributed to J W Paterson.

At least 37 records · Page 2Linked to original sources
PubMed1988

Epithelial dysfunction and airway hyperreactivity in asthma.

It is clear that the central airway epithelium plays an important role in restricting access of inhaled solutes to sub-epithelial airway wall structures. Non-specific airway hyperreactivity to spasmogens in asthma may result partly as a consequence of the compromise of the epithelium as a barrier to solute diffusion. However, impaired epithelial production and release of smooth muscle relaxant factor(s) may also contribute to airway hyperresponsiveness. Virally precipitated asthma also involves inflammation-induced epithelial damage. Beta-adrenoceptor hypofunction induced by respiratory viruses may also contribute to bronchial obstruction.

Adrenergic beta-Antagonists↗
PubMed1986

Autoradiographic localisation of ascorbic acid-dependent binding sites for [125I]iodocyanopindolol in guinea-pig trachea.

Light microscopic autoradiography showed that the supposedly beta-adrenoceptor-selective radioligand [125I]iodocyanopindolol (I-CYP) bound to sites in both the guinea-pig tracheal epithelium and smooth muscle that were sensitive to propranolol and isoprenaline. Low levels of binding were associated with sub-epithelial mucosal cells. Ascorbic acid caused a concentration-related increase in total I-CYP binding which was predominantly associated with the sub-epithelial mucosa, was not inhibited by propranolol, and was thus not associated with beta-adrenoceptors.

Animals↗
PubMed1986

An ultrastructural study of mast cells in the alveolar wall of normal and asthmatic lung.

Specimens of normal and asthmatic lungs were studied at the electron microscopic level and the frequency and ultrastructural features of mast cells and their granules within the alveolar wall were assessed with morphometric techniques. The numerical density of mast cells per square millimetre of alveolar wall was 299 (SD = 258) in normal and 366 (SD = 260) in asthmatic lung. The mean area of the mast cell nucleated profile was 25.7 microns2 (SD = 6.3) in normal lung and 29.8 (SD = 6.2) in asthmatic. The average number of secretory granules per single mast cell nucleated profile was 55 (SD = 13) in normal lung and 60 (SD = 12) in asthmatic lung. The diameter of the individual secretory granule was 338.9 nm (SD = 42.6) in normal and 345.6 (SD = 47.7) in asthmatic lung. The volume density of secretory granules in normal and asthmatic lung was 6.31 microns3 and 5.81 microns3, respectively. The mean diameter of the individual subunit ('scroll') inside the secretory granule was 88.8 nm for both normal and asthmatic lung. In normal lung 64.2% of granules were of 'scroll' and 'combined' type, and 35.8% of granules were 'particulate' or 'empty'. In specimens from asthmatic patients 40.3% of granules had 'scroll' or 'combined' structures and 59.7% were 'particulate' or 'empty'. Our data suggest that there is no difference between the number of mast cells in normal and asthmatic lung. However, in pulmonary mast cells from asthmatic lung, degranulation is more common than in normal lung.

Adolescent↗
PubMed1986

In vitro responsiveness of human asthmatic bronchus to carbachol, histamine, beta-adrenoceptor agonists and theophylline.

Responses of human bronchial strip preparations to contractile and relaxant agonists were measured in preparations from non-diseased and from asthmatic lung obtained 3-15 h post-mortem. The potencies of carbachol and histamine were approximately two times less in asthmatic than in non-diseased bronchi. This was statistically significant for carbachol (P less than 0.05), but not for histamine (P greater than 0.05). These results clearly indicate that the bronchial hyperreactivity to airway spasmogens observed in asthma is exclusively an in vivo phenomenon not involving increasing sensitivity of bronchial smooth muscle. The potencies of the beta-adrenoceptor agonists isoprenaline, fenoterol and terbutaline were significantly reduced by 4-5 fold in asthmatic bronchi compared with non-diseased airways. In contrast, theophylline was equipotent in the two populations of airway preparations. Thus, it appears that severe asthma is associated with decreased bronchial smooth muscle beta 2-adrenoceptor function.

Adolescent↗
PubMed1986

Influence of the epithelium on responsiveness of guinea-pig isolated trachea to contractile and relaxant agonists.

The potency (pD2) and maximal contractile effect (Emax) of histamine, acetylcholine, carbachol and K+ were assessed from cumulative concentration-effect curves in guinea-pig isolated tracheal ring preparations with and without an intact epithelium. Estimates of Emax were not significantly different in epithelium-denuded preparations compared with those measured in intact preparations; pD2 values for acetylcholine, carbachol and K+ were not significantly altered. In contrast, the potency of histamine was significantly increased by about 4 fold in preparations devoid of epithelial cells. Estimates of potency and Emax were also determined for the smooth muscle relaxants isoprenaline, forskolin and theophylline (which increase intracellular cyclic AMP) and for nitroglycerin (which increases cyclic GMP) in both intact and epithelium-stripped tracheal rings. The pD2 values for these relaxants were not significantly altered by the removal of the epithelium. However, with the exception of nitroglycerin, Emax values for these relaxants were significantly lower in stripped than in intact tracheal rings that had been maximally precontracted with carbachol. The autoradiographic localisation of binding sites for the non-selective beta-adrenoceptor ligand [125I]-iodocyanopindolol (I-CYP) showed that the epithelium of the guinea-pig trachea had a 75 +/- 16% greater density of beta-adrenoceptors than the smooth muscle. Removing the epithelium did not significantly alter either the density of smooth muscle binding sites or the affinity of I-CYP binding. It was concluded that the reduced functional response of guinea-pig trachea to isoprenaline was probably not due to smooth muscle beta-adrenoceptor dysfunction. Results indicate that the epithelium plays an important role in the modulation of responsiveness of guinea-pig trachea to histamine and relaxants that mediate their effects by selectively increasing intracellular cyclic AMP levels.

Acetylcholine↗
PubMed1986

Autoradiographic localization of beta-adrenoceptors in pig lung using [125I]-iodocyanopindolol.

The binding of the beta-adrenoceptor radioligand [125I]-iodocyanopindolol (I-CYP) has been studied in pig lung parenchyma and the distribution of binding sites visualised by light microscopic autoradiography. I-CYP binding was saturable (maximum binding capacity Bmax = 51 +/- 3 fmol mg-1 protein), involving sites with high affinity (dissociation constant KD = 73 +/- 10 pM). Specific I-CYP binding was displaceable both by beta-adrenoceptor agonists ((-)-isoprenaline greater than (-)-adrenaline greater than (+/-)-fenoterol greater than (-)-noradrenaline greater than (+)-isoprenaline greater than (+/-)-RO363) and antagonists ((+/-)-propranolol greater than ICI-118551 greater than atenolol), indicating a predominance of beta 2-adrenoceptors. Further analysis showed that displacement data for the beta 1-selective antagonist atenolol and the beta 2-selective antagonist ICI-118551 were fitted best to a 2 binding site model and that both beta 1- and beta 2-adrenoceptors were present in pig lung in the ratio 28:72 respectively. Autoradiographic grains were localized over tissue and were most dense over alveolar walls greater than vascular endothelium greater than vascular smooth muscle greater than bronchial smooth muscle = bronchial epithelium. Atenolol (10(-5) M) caused a 31% reduction in specific grain density over alveolar wall tissue, while a 10 fold lower concentration of ICI-118551 (10(-6) M) caused a 50% decrease. These results are consistent with binding data in pig lung parenchyma demonstrating a mixed population of beta-adrenoceptors with a predominance of the beta 2 subtype. 6 It is possible that the previously described relaxant responses of the pig lung parenchyma strip to beta-agonists, mediated via beta 2-adrenoceptors, resulted from the sum of reactivities in airway and vascular smooth muscle together with relaxation of alveolar interstitial cells.

Animals↗
PubMed1986

Beta agonist-induced desensitization in pig bronchus.

Pretreatment of pig isolated bronchial preparations with isoproterenol (Iso) caused a time and concentration-related decrease in both the relaxant potency (pD2) and maximal relaxant effect (Emax) of Iso. Exposure to Iso (5 microM) caused an apparent reduction in the Iso pD2 at 6 hr of approximately 74-fold with a concomitant decrease in Iso Emax from 108 +/- 2 (n = 43) to 55 +/- 6% (n = 11). Responsiveness to the relaxant effects of Iso recovered spontaneously but slowly, being still incomplete 4 hr after desensitization with Iso (1 microM, 3 hr). Responsiveness to norepinephrine and fenoterol was also reduced markedly after exposure to Iso (5 microM), although the relaxant effects of the nonbeta agonists theophylline and forskolin were not reduced. Indeed, the potency of forskolin, was increased 4-fold. The beta antagonists propranolol (nonselective) and atenolol (beta-1 selective) protected bronchi from Iso-induced desensitization, whereas ICI-118551 (beta-2 selective) did not. Furthermore, the dextro (+)-isomer of Iso was virtually inactive as a desensitizing agent. Pretreatment with norepinephrine and fenoterol also decreased the relaxant effects of Iso, although they were at least 100 times less potent than Iso in desensitizing pig bronchi. These results indicate that desensitization was specifically mediated via beta-1 adrenoceptors which predominate in pig bronchus. Alpha adrenoceptor activity mediating increased bronchial tone was apparent in Iso-desensitized bronchi but not in nondesensitized preparations even in the presence of beta adrenoceptor blockade. Neither the cyclooxygenase inhibitor indomethacin, nor the phospholipase A2 inhibitor mepacrine had any significant effect on the extent of Iso-induced desensitization in pig bronchus.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1985

Experimental testing of Mackay's model for functional antagonism in the isolated costo-uterus of the rat.

Several key predictions of a recently developed model for functional antagonism (Mackay, 1981) were experimentally tested using the rat isolated costo-uterine preparation. In the presence of the functional antagonist fenoterol (Fen), the functional constants (KAF) for carbachol and oxotremorine (Oxo) were respectively 9.9 and 3.4 fold greater than their corresponding affinity constants (KA). According to Mackay's model for functional antagonism, the higher KAF/KA ratio for carbachol indicates that this cholinoceptor agonist has a greater efficacy than Oxo. This was confirmed by using conventional pharmacological methods. As predicted from the model of functional antagonism, the plot of KAF/KA-1 against the fraction of cholinoceptors not irreversibly blocked by phenoxybenzamine (Pbz) was linear for both carbachol and Oxo and the lines of best fit crossed the axes at a point not significantly different from the origin. The value of 4.6 for the relative efficacy of carbachol to Oxo estimated from functional antagonism studies was comparable to the value of 5.6 calculated using the method of irreversible antagonism proposed by Furchgott (1966).

Animals↗
PubMed1984

Effects of adrenaline and carbachol on the morphology of alveolar contractile cells in the lung of the toad (Bufo marinus).

Smooth muscle-like interstitial cells in toad (Bufo marinus) lung strips were examined by light and electron microscopy and subjected to morphometric analysis in an attempt to assess the effect of spasmogenic and relaxant agonists on contractile cells in peripheral airways. Carbachol (12.8 microM) caused a 43.6% reduction in contractile cell length compared to control, while adrenaline (100 microM) caused a 21.3% increase. The mean transverse and longitudinal-sectional area and perimeter of cell profiles were significantly greater in carbachol treated preparations than in control. In tissue that had relaxed after exposure to adrenaline, the mean area of longitudinally sectioned cells and the perimeter of cell profiles were significantly reduced.

Animals↗
PubMed1984

Classification of beta-adrenoceptors in human isolated bronchus.

(+/-)-Isoprenaline (Iso), (-)-adrenaline (Ad), (-)-noradrenaline (NA), (+/-)-phenylephrine (Phe) and the beta 2-selective adrenoceptor agonist (+/-)-fenoterol (Fen) caused a concentration-dependent relaxation of human isolated bronchial preparations. Iso, Ad and NA caused complete relaxation of both spontaneous and carbachol-induced bronchial tone. Fen, which was only tested in preparations where tone was induced with carbachol, also caused complete relaxation. However, Phe was a partial agonist in all preparations tested. When relaxation responses to these amines were calculated as a % of their maximal effects, comparison of EC50 values showed that the order of potency was Iso greater than Ad = Fen greater than NA greater than Phe (92:27:25:1:0.2) in preparations with carbachol-induced tone and Iso greater than Ad greater than NA greater than Phe (112:38:1:0.3) in preparations with spontaneous tone. pA2 values determined for the beta-adrenoceptor antagonists propranolol (non-selective), atenolol (beta-selective) and ICI-118, 551 (beta 2-selective), using Iso as an agonist were, 9.3, 5.3 and 9.1 respectively. These results indicate that beta 2-adrenoceptors mediate relaxation of human isolated bronchus to sympathomimetic amines in preparations obtained 4-14 h post-mortem from non-diseased lung. alpha-Adrenoceptors were apparently sparse or absent in this tissue.

Adolescent↗
PubMed1984

Ethanol- and isoprenaline-induced responses in pig parenchymal lung tissue.

Ethanol (8.7-34.8 mM; 0.5-0.20% v/v) had no significant effect on spontaneously developed tension in pig lung parenchyma strips, although higher cumulative concentrations caused relaxation (at 34.8-174 mM) and contraction (at 348-1392 mM). Ethanol-induced effects were not caused by activation of adrenoceptors or of cholinoceptors, since blockade of these receptors did not alter those effects. Single low concentrations of ethanol (8.7-34.8 mM) which can occur in-vivo in man, caused increases in the relaxant potency of isoprenaline in pig lung strips, although the sizes of these increases varied widely. In addition, ethanol-induced potentiation of isoprenaline was not concentration-related. This effect was not caused by inhibition of isoprenaline uptake since [3H]isoprenaline transport was found not to be significantly altered in the presence of ethanol (8.7-34.8 mM).

Acetylcholine↗
PubMed1983

Evaluation of ketotifen (HC20-511) in bronchial asthma.

Ketotifen 1 mg b.d. (oral) and sodium cromoglycate 20 mg q.i.d. (inhalation) were compared in a double-blind crossover trial in 43 asthmatic outpatients. Comparison of diary card scores and pulmonary function tests showed significant improvement over a 12 week period on each drug. Comparison of the diary card scores and pulmonary function tests showed no significant difference between the drugs after 12 weeks of treatment. Twenty-six patients experienced sedation and/or lethargy whilst on ketotifen and 11 patients had similar side effects whilst on cromoglycate. Physician preferences based on diary card and pulmonary function data showed an approximately equal number of preferences for each medication and also a small group of patients in which no preference could be made. The present trial suggests that both ketotifen and cromoglycate are effective in the management of outpatient asthma. When all the patients are considered as a group no distinction can be made between the two drugs; on the basis of physician assessment of each patient, it appears that some patients may do better on ketotifen and others on cromoglycate.

Adolescent↗
PubMed1983

A pharmacological and ultrastructural study of alveolar contractile tissue in toad (Bu fo marinus) lung.

The structure of the wall of the lung from the toad (Bufo marinus) has been examined using scanning and transmission electron microscopy and the presence of smooth muscle cells in the septal-alveolar walls detected. Responses of toad isolated lung parenchyma strip to agonists causing relaxation and contraction were measured and the potencies of adrenoceptor and 5-hydroxytryptamine receptor antagonists were determined. Results indicated the presence of populations of alpha- and beta-adrenoceptors in toad lung alveoli, both of which mediate relaxation responses. Stimulation of both alpha- and beta-adrenoceptors was required to cause complete relaxation. 5-Hydroxytryptamine also caused complete relaxation. A population of alpha-adrenoceptors mediating contraction may also exist in pulmonary vascular and or septal edge smooth muscle.

Adrenergic alpha-Antagonists↗