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Biomedical subjects

D Raeburn

Publications and source records attributed to D Raeburn.

At least 55 records · Page 3Linked to original sources
PubMed1988

Bronchodilator therapy in cystic fibrosis: for better or worse?

As one approach to the management of the respiratory manifestations of cystic fibrosis, bronchodilators have been used to try to alleviate symptomatology. Several bronchodilators have been tested with varying degrees of success depending on the parameters measured, the method of patient selection for trials and the time of the study. In some instances the use of bronchodilators has proven detrimental to lung function. In general, it appears that bronchodilator therapy may be beneficial or hazardous and must be evaluated on an individual patient basis. Repeated assessments of respiratory function are necessary and the patient's management must be frequently re-evaluated.

Age Factors↗
PubMed1988

Peripheral type benzodiazepine receptor and airway smooth muscle relaxation.

It has been postulated that a benzodiazepine receptor with a micromolar affinity may be associated with Ca++ channels in peripheral organs. We examined the actions of Ro5-4684 (parachlorodiazepam) and midazolam on guinea pig tracheal smooth muscle contraction. Binding studies using [3H]Ro5-4684 indicate the presence of a "peripheral" type binding site with a Kd of approximately 4 nM and maximum binding of 1 pmol/mg of protein. Midazolam did not displace radioligand. In tension studies no activity was seen for Ro5-4684 or midazolam at concentrations below 1 microM. Higher concentrations relaxed the airway smooth muscle under basal tone, the effect was augmented significantly by epithelium removal. Similar results were obtained in tissues precontracted with methacholine or KCl. Midazolam (1 or 100 microM) significantly (P less than .05) attenuated the response to Ca++ in K+-depolarized tracheal strips, the effect was greater at low Ca++ concentrations. The compounds appear to function as Ca++ antagonists in airway smooth muscle but ar not typical as shown by their ability to reduce basal tone in airway smooth muscle.

Animals↗
PubMed1987

Regional differences in reactivity and in the influence of the epithelium on canine intrapulmonary bronchial smooth muscle responsiveness.

Differences in the reactivity and in the influence of the epithelium on responsiveness of canine 2nd and 3rd generation airway smooth muscle were examined. Epithelium-containing 3rd generation airways produced a greater maximum contraction and were more sensitive to methacholine and histamine, but not to KCl, than corresponding 2nd generation airways. Mechanical removal of the epithelium increased the sensitivity to methacholine and histamine in 2nd generation airways; there was also an increase in the maximum response elicited by histamine, but not by methacholine, in epithelium-free preparations. In contrast, there was no significant difference in the sensitivity to or the maximum response elicited by histamine or methacholine in epithelium-containing and epithelium-free 3rd generation airways. Epithelium removal had no effect on KCl-induced responses in either airway region. The inhibitory effects of verapamil (1 microM) against KCl- and methacholine-induced responses were identical in preparations containing and lacking the epithelium. The results support the postulate of an epithelium-derived inhibitory factor modulating airway smooth muscle reactivity. Furthermore, the influence of the epithelium exhibits regional differences, being greater in larger airways.

Animals↗
PubMed1987

Demonstration of the release of an epithelium-derived inhibitory factor from a novel preparation of guinea-pig trachea.

Using a novel preparation of guinea-pig trachea, direct evidence was obtained for the release of an epithelium-derived inhibitory factor modulating contractions elicited by antigen. Thus, epithelium removal produced a 6.1-fold leftward shift in ovalbumin concentration-response curves in tracheal strips from ovalbumin-sensitized guinea-pigs. This increase in sensitivity to ovalbumin was not evident when a tracheal portion containing epithelium was positioned in close proximity to the tissue from which tension was recorded.

Airway Resistance↗
PubMed1987

The development of tone in the smooth muscle of guinea-pig isolated tracheal preparations may be influenced by prostanoids released from the adjacent airway cartilage.

Guinea-pig tracheal strip preparations containing cartilage, placed under an applied load in vitro, develop tone spontaneously. The finding that spontaneous tone is reduced by indomethacin suggests that one or more prostanoids are involved in the development of spontaneous tone in this species. In this study we examined the effects of removing the cartilage component of the preparations on changes in tone induced by indomethacin and isoproterenol. In contrast to preparations containing cartilage, tissues devoid of cartilage, did not develop tone after the application of an initial 1 g resting load. Indomethacin (1 microM) reduced resting tone by 0.62 +/- 0.14 g in cartilage-containing tissues but, in contrast, reduced tone by only 0.03 +/- 0.01 g in tissues devoid of cartilage. Furthermore, relaxation responses (0.38 +/- 0.05 g) to isoproterenol (1 microM) could be produced in cartilage-containing preparations but not in cartilage-free preparations. Radioimmunoassays indicated that the release of PGE2, PGF2 alpha and 6-keto PGF1 alpha, the end-product of PGI2 breakdown, was diminished in preparations lacking cartilage. Thus, in guinea-pig airway preparations cartilage is apparently a source of sufficient prostanoids to induce spontaneous tone.

Animals↗
PubMed1987

Calcium uptake into guinea-pig trachealis: the effect of epithelium removal.

Removal of the epithelium from preparations of guinea-pig airways in vitro increases the responsiveness of the smooth muscle of normal and ovalbumin-sensitized animals to a number of contractile agents. To determine if epithelium removal results in an increase in Ca2+ entry into the smooth muscle, the effect of removing the epithelium on Ca2+ uptake into the trachealis smooth muscle was studied using a modified La3+-technique. KCl increased Ca2+ uptake in the presence and absence of the epithelium in control and sensitized animals. Methacholine did not promote Ca2+ uptake, whether or not the epithelium was present, in either control or sensitized animals. Ovalbumin did not stimulate Ca2+ uptake into the trachealis of sensitized animals. These results indicate that the increase in responsiveness of airway smooth muscle seen on epithelium removal is not a consequence of a facilitation of Ca2+ entry into the muscle. The increased responsiveness to methacholine in control animals, and to ovalbumin in preparations in tension studies in epithelium-free tissues from sensitized animals, cannot be explained by an increased availability of extracellular Ca2+ into the muscle, but, rather may reflect some other effect of the epithelium-derived modulatory factor.

Animals↗
PubMed1987

Sr2+ may differentiate high and low affinity Ca2+ stores in guinea-pig trachealis.

1. In guinea-pig trachealis Ca2+ are mobilized from different stores to produce the contractions to various agents. 2. Sr2+ can substitute for Ca2+ and maintain responses to KC1 but not responses to A23187 or agents acting via drug-receptor interaction. 3. Resting tone and responses to KC1 are supported by low affinity Ca2+. 4. Responses to the other agents are supported by high affinity Ca2+.

Animals↗
PubMed1987

Relaxation of guinea-pig tracheal smooth muscle to arachidonate is converted to contraction following epithelium removal.

1 The effect of epithelium removal on responses of guinea-pig isolated trachealis to sodium arachidonate has been examined. 2 Arachidonate (100 microM) caused relaxation of epithelium-intact preparations, but following epithelium removal, the response to arachidonate was converted to contraction. In the presence of indomethacin (1 microM), arachidonate caused contraction in intact and denuded trachea. 3 Arachidonate also produced concentration-dependent effects, the qualitative nature of which varied with the presence or absence of the epithelium. In the presence of indomethacin, tracheal strips contracted in a concentration-dependent manner whether or not the epithelium had been removed. 4 Nordihydroguaiaretic acid (NDGA; 10 microM) markedly inhibited the contractile response of denuded strips to arachidonate. In intact tissues this lipoxygenase inhibitor converted the arachidonate-induced relaxation to a concentration-dependent contraction. The contraction to arachidonate, in the presence of NDGA, was epithelium-dependent. In the presence of both indomethacin and NDGA, responses to arachidonate were abolished. 5 It is concluded that the relaxation of guinea-pig trachea to arachidonic acid is epithelium-dependent and is mediated by an inhibitory product of the cyclo-oxygenase metabolic pathway. The contraction in denuded trachea, and trachea in the presence of indomethacin, may be mediated by lipoxygenase products of arachidonic acid metabolism, i.e. peptidoleukotrienes. The mediator of the epithelium-dependent contraction in NDGA-treated tissues is unknown.

Animals↗
PubMed1987

Differential effects of epithelium removal on the responsiveness of guinea-pig tracheal smooth muscle to bronchoconstrictors.

1 The influence of the epithelium on contractions produced by the peptidoleukotrienes, 5-hydroxytryptamine (5-HT) and the thromboxane mimetic, U-44069, was examined in trachea from control and ovalbumin-sensitized guinea-pigs. 2 In control tissues removal of the epithelium produced an approximately 2 to 4 fold leftward shift in leukotriene C4 (LTC4) and LTD4 concentration-response curves, but no effect on LTE4-induced contractions. Similar results were obtained in preparations from ovalbumin-sensitized animals. 3 Responses produced by 5-HT or U-44069 were similar in the presence and absence of the epithelium in control guinea-pigs. 4 Indomethacin produced contrasting effects on leukotriene-induced contractions in control guinea-pigs: an increase in sensitivity to LTC4 in the presence but not absence of the epithelium, no effect on LTD4-induced contractions and a decrease in sensitivity to LTE4 in both epithelium-containing and epithelium-free preparations. 5 These results indicate that there is selectivity in the effects of epithelium removal on agonist-induced contractions of the guinea-pig trachea. This provides further evidence for the modulatory influence of the epithelium on the reactivity of mammalian airway smooth muscle and supports the postulated existence of an epithelium-derived inhibitory factor. The observation that in intact trachea indomethacin mimics the effects of epithelium removal on LTC4-induced responses, suggests the involvement of a prostanoid(s) in this phenomenon.

Animals↗
PubMed1987

Influence of cartilage on reactivity and on the effectiveness of verapamil in guinea pig isolated airway smooth muscle.

The authors have examined the effects of cartilage removal on smooth muscle reactivity and the action of verapamil in guinea pig trachealis. In preparations devoid of cartilage, smooth muscle reactivity to both histamine and KCl was reduced. Reactivity to methacholine was unaffected by cartilage removal. In the absence of cartilage, verapamil had a greater depressant effect on the maximum responses to histamine and methacholine than in intact tissues. Similarly, verapamil was more potent against histamine- and methacholine-induced responses in the absence of cartilage where a greater shift to the right was seen in the concentration-response curves when compared with cartilage-containing controls. The spasmolytic action of verapamil on methacholine-induced responses was greater in the absence of cartilage and was greater than its antispasmogenic activity against methacholine (whether or not cartilage was present). Thus, cartilage removal reduces muscle reactivity and increases the potency of verapamil in guinea pig trachealis.

Animals↗
PubMed1986

Airway epithelium modulates the reactivity of guinea-pig respiratory smooth muscle.

The influence of the epithelium on the reactivity of guinea-pig tracheal smooth muscle in vitro was investigated. Mechanical removal of the epithelium produced contrasting effects on methacholine-, histamine- and K+-induced contractions of tracheal strips. Epithelium removal resulted in 2.1-fold shifts to the left of histamine and methacholine concentration-response curves, and an increase in the maximum response to histamine; the maximum response to methacholine was unaffected. Epithelium removal had little effect on the sensitivity, but decreased the maximum response to K+. The results suggest that inhibitory and excitatory factor(s) are released from epithelial cells, and that these factors modulate the reactivity of the smooth muscle. Indomethacin (1 microM) produced in epithelium-containing preparations qualitatively identical effects on the sensitivity to methacholine and on the maximum response to histamine as removal of the epithelium. However, indomethacin was without effect on the sensitivity to histamine in the presence or absence of the epithelium. Alterations in the production or release of epithelial cell-derived factors may contribute to the airway hyperreactivity observed in respiratory disorders.

Airway Resistance↗
PubMed1986

Epithelium modulates the reactivity of ovalbumin-sensitized guinea-pig airway smooth muscle.

Mechanical removal of the airway epithelium alters the in vitro reactivity of airway smooth muscle. The modulation of reactivity may involve the release of inhibitory and excitatory factors from epithelial cells. Guinea pigs sensitized with ovalbumin have been used as an animal model of airway hyperreactivity. We evaluated the influence of the epithelium on the reactivity of in vitro tracheal smooth muscle from control and ovalbumin-sensitized guinea pigs, and the extent to which the presence of the epithelium affects the contractile response to in vitro challenge with ovalbumin. In both control and ovalbumin-sensitized tissues, epithelium removal increased the sensitivity of the preparations to histamine, methacholine and isoproterenol to a similar extent, i.e., 2- to 2.5-fold. Epithelium removal resulted in an 8.1-fold increase in sensitivity to ovalbumin in sensitized tissues. The epithelium appears not only to modulate the reactivity of the tissues to bronchoactive agents, but it also influences the magnitude of the contractile response following antigen challenge.

Animals↗
PubMed1986

Epithelium removal increases the reactivity of human isolated tracheal muscle to methacholine and reduces the effect of verapamil.

Removal of the epithelium increased the sensitivity of human isolated tracheal smooth muscle to methacholine, producing a greater than 2-fold leftward shift in the concentration-response curve. Concomitantly, the ability of verpamil to lower the maximum contractile response was reduced in tissues without an intact epithelium. These findings suggest a role for the epithelium in modulating the reactivity of human and extend the findings of similar studies in experimental animals.

Adult↗
PubMed1986

The dependence of airway smooth muscle on extracellular Ca2+ for contraction is influenced by the presence of cartilage.

Isolated guinea-pig and rabbit airway smooth muscle preparations lacking cartilage are less able to contract, in response to methacholine, histamine and K+, in the absence of extracellular Ca2+ than cartilage-containing preparations removed from the same animal. Cartilage apparently provides utilizable Ca2+ for contraction of airway smooth muscle. The presence of cartilage, therefore, affects the apparent dependence of the isolated smooth muscle on extracellular Ca2+ for contraction.

Animals↗
PubMed1986

The effect of verapamil is reduced in isolated airway smooth muscle preparations lacking the epithelium.

The effect of epithelium removal on the reactivity of rabbit airway smooth muscle to bronchoactive agents and on the effect of verapamil was studied in vitro using preparations from several levels within the respiratory tree, i.e., trachea, primary (10) and secondary (20) bronchus. Methacholine contracted tissues from all three levels of airway. Histamine contracted strips from 20 bronchus, had an inconsistent action in strips from 10 bronchus and was without effect in tracheal preparations. K+ contracted tissues from the trachea and 10 bronchus, and had a mixed action in 20 bronchial strips. Removal of the epithelial cell layer variably affected the reactivity of the smooth muscle to the three agents studied. In 20 bronchus, epithelium removal potentiated responses to histamine and methacholine. In 10 bronchus, only responses to methacholine were consistently augmented. In tracheal preparations epithelium removal did not alter the reactivity of the tissue to any agent examined. Verapamil (1 microM) attenuated responses to all agents and increased in its potency from tracheal through 10 to 20 bronchial preparations. Following epithelium removal, verapamil was substantially less effective in 20 bronchi, yet its effects were unchanged in the trachea. The results indicate that the epithelial cell layer modulates airway smooth muscle reactivity; this phenomenon is apparently widespread in mammals, the modulatory effect is more prominent in the smaller airways, and the magnitude of the effect of verapamil on airway smooth muscle is, in part, related to the presence of the epithelium.

Animals↗
PubMed1986

Agonist-induced contractile responses of human bronchial muscle in vitro: effects of Ca2+ removal, La3+ and PY108068.

The effects of reducing the extracellular Ca2+ concentration ([Ca2+]0), the effects of La3+ and the dihydropyridine Ca2+ entry blocker PY108068 on contractile responses in human isolated bronchial strips have been compared. Reducing [Ca2+]0 or the presence of La3+ (1 mM) caused a reduction in basal tone, whereas PY108068 (1 microM) had no effect on unstimulated preparations. Response to KCl and A23187 were, in general, more markedly depressed by reducing the entry of extracellular Ca2+, with La3+ or PY108068 than were those to histamine, methacholine and LTD4. The effects of reducing [Ca2+]0, La3+ and PY108068 on responses to the receptor-mediated agents suggest that intracellular Ca2+ may be mobilized upon receptor activation, whereas responses to KCl and A23187 appear to be dependent upon the influx of extracellular Ca2+. More than one source of activator Ca2+ can therefore be involved in the development of contractions in human airway smooth muscle. These findings are in accord with those observed for in vitro airways preparations from experimental animals.

Bronchi↗
PubMed1986

The effects of epithelium removal on the sensitivity of guinea-pig isolated trachealis to bronchodilator drugs.

Mechanical removal of the epithelium increased the sensitivity of tracheal strips to isoprenaline, sodium nitroprusside, and to adenosine (only in the presence of inhibitors of its uptake and metabolism). Epithelium removal was without effect on sensitivity to salbutamol or papaverine. Preincubation of tracheal strips with an inhibitor of extraneuronal uptake, corticosterone (50 microM), had no effect on tissue sensitivity to either salbutamol or papaverine. However, the steroid both increased sensitivity to isoprenaline, and abolished the effect of epithelium removal on sensitivity to this catecholamine. These results suggest that in the guinea-pig, the tracheal epithelium is a major source of extraneuronal uptake for catecholamines. Furthermore, the increase in trachealis sensitivity to isoprenaline following epithelium removal is probably due to loss of these sites of extraneuronal uptake. The fact that sensitivity to salbutamol, papaverine and adenosine (in the absence of metabolic inhibitors) was not increased by denuding the epithelium indicates that loss of a diffusion barrier to drugs is not the mechanism of increased sensitivity. Adenosine (and possibly nitroprusside) may cause the epithelium to release a smooth muscle excitatory factor. Thus, removal of the epithelium attenuates this excitatory influence and enhances smooth muscle responsiveness to adenosine. These results provide further evidence that the epithelium has an important role in modulating the sensitivity of guinea-pig trachealis to drugs.

Adenosine↗