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Biomedical subjects

D Raeburn

Publications and source records attributed to D Raeburn.

At least 37 records · Page 2Linked to original sources
PubMed1992

RP 59227, a novel PAF receptor antagonist: effects in guinea pig models of airway hyperreactivity.

The PAF antagonists RP 59227 and WEB 2086 (100 micrograms.kg-1 i.v., 10 min prior to platelet-activating factor (PAF) infusion) abolished or reduced (P less than 0.05) hyperreactivity to bombesin measured at 1 h. Similarly, RP 59227 and WEB 2086 (10 mg.kg-1 p.o., 1 h prior to PAF aerosol) abolished or reduced (P less than 0.01) hyperreactivity to bombesin measured at 24 h. Lower concentrations of RP 59227 and WEB 2086 (3 mg.kg-1 p.o.) were without effect. RP 59227 or WEB 2086 (3 or 10 mg.kg-1 p.o., 1 h prior to antigen aerosol) did not protect against antigen-induced hyperreactivity to histamine measured at 24 h. Antigen-(but not PAF)-induced hyperreactivity was accompanied by an increase in total cell number and, specifically, eosinophil number in bronchoalveolar lavage fluid. The PAF antagonists did not affect BALF cell populations. It is concluded that RP 59227 and WEB 2086 are potent PAF antagonists which inhibit PAF-but not antigen-induced airway hyperreactivity. These data suggest that endogenous PAF may not be involved in antigen-induced hyperreactivity in the guinea pig.

Animals↗
PubMed1992

RP 58802B, a long-acting beta 2-adrenoceptor agonist: assessment of antiasthma activity in the guinea-pig in vivo.

We have examined the protective actions of RP 58802B, a novel beta 2-adrenoceptor agonist, administered by the inhaled and oral routes in the anaesthetized and conscious guinea-pig against bronchospasm induced by histamine or antigen (ovalbumin). We have also examined the effects of RP 58802B on airway reactivity and inflammatory cell infiltration in platelet-activating factor (PAF) (aerosol)-induced bronchial hyperreactivity and on PAF (tracheal instillation)-induced microvascular leakage in the guinea-pig. Nebulized RP 58802B produced a rapid onset and long lasting inhibition of histamine-induced bronchospasm in the anaesthetized guinea-pig (EC50 = 3.2 +/- 0.9 micrograms/ml; duration greater than 90 min). Given orally, RP 58802B (5 mg/kg, 60 min before challenge) produced a greater than three-fold shift to the right of the dose-response curve and depressed the maximum response to histamine by 39 +/- 11%. Increasing the concentration to 25 mg/kg had no futher effect. Similar protection was still seen 4 h after oral dosing. In conscious guinea-pigs, RP 58802B (5 or 25 mg/kg, p.o. 60 min before challenge) significantly attenuated antigen-induced dyspnoea with the time to severe dyspnoea increasing from 170 +/- 32 to 325 +/- 32 s at the higher dose of drug. RP 58802B (10 or 25 mg/kg, p.o. 60 min before exposure to PAF) prevented the development of bronchial hyperreactivity. Although PAF-induced bronchial hyperreactivity was not accompanied by an increase in the number of pulmonary eosinophils, RP 58802B (25 mg/kg p.o.) reduced the numbers of eosinophils recovered by lavage. RP 58802B (10 mg/kg p.o.) significantly inhibited PAF-induced microvascular leakage into guinea-pig lung. These data suggest that RP 58802B, in addition to being a potent and long acting bronchodilator, may have a prophylactic role in preventing bronchial hyperreactivity and in reducing plasma exudation into the lungs.

Administration, Inhalation↗
PubMed1992

Techniques for drug delivery to the airways, and the assessment of lung function in animal models.

A common approach to understanding the mechanisms underlying clinical asthma and in new drug development is to mimic the disease in animal models. When developing animal models of pulmonary diseases, such as asthma, the experimentally induced disease may be characterized in terms of pathophysiological changes induced (e.g., inflammation, smooth muscle contraction) or by the indices of lung function that are effected by such changes. Similarly, the effects of drugs can be assessed in terms of the reversal of disease- or mediator-induced changes in lung function. Small animals, such as the guinea pig and rat, are commonly used for the assessment of lung function in models of pulmonary diseases, such as asthma, and to evaluate the effects of drugs. A variety of techniques, differing in their level of sophistication, has been developed to measure parameters of lung function in small laboratory animals. Simple techniques involve the visual assessment of the response of a conscious animal to bronchoconstriction induced by an inhaled spasmogen or antigen. This technique is rapid but gives results that are difficult to interpret in physiological terms. Bronchospasm can be better assessed in anesthetized, mechanically ventilated animals by recording bronchial tone as changes in either 1) ventilation circuit pressure or 2) air overflow as the lungs are inflated. These techniques are widely used but because they require surgical intervention they are not suited to long-term or repeat studies. In addition, they give only a limited indication of the physiological changes that affect airway caliber. To improve the models available, researchers have subsequently developed techniques that use the same physiological principles as some of the tests applied to the assessment of lung function in humans. These techniques allow the measurement of parameters of respiratory mechanics, such as lung compliance and airway resistance, that determine the relationship between pulmonary pressure changes and air flow into and out of the lungs. Continued development has resulted in models that use nonsurgical plethysmographic techniques. These allow the long-term or repeated measurement of lung function in conscious animals under minimal restraint. In the treatment of asthma, inhalation is the preferred route of administration of a drug as it allows rapid drug delivery to the site of action. Systemic effects are reduced, and the therapeutic dose is minimized. Drugs are generally inhaled as either nebulized liquids or dry-powder formulations. Because drug inhalation requires patient cooperation, techniques have been modified to allow drug delivery to the airways of experimental animals.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

A novel technique for the administration of bronchodilator drugs formulated as dry powders to the anaesthetized guinea pig.

A technique is described for the administration of dry powder formulations of bronchodilator drugs to the anaesthetized guinea pig. The technique has been evaluated by comparing the efficacy of several bronchodilator drugs administered either as dry powders coformulated with a lactose carrier or as nebulized solutions. In each case, the dry powder formulation had comparable bronchodilator activity and duration of action to an equivalent dose administered as a nebulized solution. This technique offers a simple and inexpensive method for the rapid screening of bronchodilator drugs without the problems associated with aerosol administration.

Administration, Intranasal↗
PubMed1991

RP 49356 and cromakalim relax airway smooth muscle in vitro by opening a sulphonylurea-sensitive K+ channel: a comparison with nifedipine.

RP 49356 is a novel compound which relaxes airway smooth muscle in vitro. Like cromakalim, RP 49356 reduced contractility in guinea pig isolated trachealis under basal conditions or when challenged with low (less than 20 mM) but not high K+. These effects were antagonized by the sulphonylureas glibenclamide and glipizide. This spectrum of action is typical of the class of compounds known as potassium channel openers (KCOs). Unlike RP 49356 and cromakalim, nifedipine had no effect on basal tone, relaxed tissues contracted with low or high K+ and was not antagonized by the sulphonylureas. These data suggest that the KCOs are not acting directly at the voltage-gated Ca++ channel in this tissue. RP 49356 and cromakalim were similar to nifedipine by being more potent at relaxing tissues precontracted with carbachol or histamine (spasmolytic effects) than they were at preventing initiation of the response to these spasmogens (antispasmogenic effects). Because the maintained phase of contraction in airway smooth muscle may be associated with some Ca++ influx, the data presented here suggests that, like nifedipine, the KCOs are more active smooth muscle relaxants under conditions of Ca++ influx. In summary, RP 49356, like cromakalim, is a compound which relaxes airway smooth muscle in vitro by opening a sulphonylurea-sensitive K+ channel which may be similar to the ATP-sensitive K+ channel found in other tissues.

Animals↗
PubMed1990

Putative role of epithelial derived factors in airway smooth muscle reactivity.

Until recently the contractile actions of asthma mediators have been examined in vitro without consideration of the modulatory role of the associated epithelial cells. Removal of the epithelium in vitro augments contraction and reduces relaxation to several bronchoactive agents and bioassay experiments have shown that the protective effects of the epithelium can be transferred to denuded preparations. It now seems likely that one or more epithelial-associated factors eg EpDRF and PGE2 have a protective role in controlling airway contractility. These findings may be important in asthmatics in vivo since there may be some correlation between epithelial damage/loss and airway hyperreactivity. The identity of EpDRF remains unknown but it does not appear to be a prostanoid and is distinct pharmacologically from EDRF found in blood vessels.

Animals↗
PubMed1990

Effects of altered availability of Na+ on guinea-pig airway smooth muscle contractility.

The effects of altering the availability of sodium ions (Na+) on contractility of the guinea-pig isolated trachealis was examined using regimens which are reported to inhibit Na+/K+ ATPase activity (ouabain), Na+/H+ exchange (amiloride, ammonium ion (NH4+)) or Na+/Ca2+ exchange (reduced extracellular Na+). Inhibition of Na+/K+ ATPase and reversal of Na+/Ca2+ exchange resulted in increased 45Ca uptake and contraction of the trachealis by voltage-sensitive and voltage-insensitive mechanisms respectively. When Na+/H+ exchange was inhibited by amiloride the tissues relaxed to below their baseline tension. The relaxation was not due to reduced Ca2+ influx. Treatment with NH4+ produced a contractile response. Reduced extracellular Na+ caused a transient contraction as a result of reversal of the normal Na+/Ca2+ exchange process leading to accumulation of Ca2+ within the cell. Since the effects of amiloride and reduced extracellular sodium were different, it is unlikely that amiloride is acting primarily by inhibiting Na+/Ca2+ exchange. Amiloride reduced tissue sensitivity to methacholine and KCl without affecting Ca2+ influx. This may involve a secondary stimulation of Na+/Ca2+ exchange following changes in [Na+]i. Ouabain also reduced tissue sensitivity to methacholine and KCl. These findings suggest that Na+ are important in determining smooth muscle contractility. If NH4+ is altering pH then, at the concentrations used, the changes in [H+] were not sufficient to alter responses to the spasmogens.

Amiloride↗
PubMed1989

The effects of alterations in electrogenic Na+/K+ -pumping in guinea-pig isolated trachealis: their modulation by the epithelium.

1 An examination was made of the effect of epithelium removal on mechanical responses of guinea-pig isolated tracheal strips after inhibition or activation of electrogenic Na+/K+ -pumping. 2 The Na+/K+ -pump inhibitor ouabain (0.1-10 microM) evoked concentration-dependent contractions which were potentiated by epithelium removal. 3 K+-free solution, which inhibits Na+/K+-pumping, produced a slow, sustained relaxation in intact preparations. In epithelium-free preparations the relaxation was transient and of lesser magnitude. 4 The addition of K+ (10 or 30 mM), which activates Na+/K+-pumping, to preparations bathed in K+-free solution caused a relaxation of preparations under spontaneous tone or contracted with methacholine; the magnitude and duration of relaxation was greater in the epithelium-free preparations. Ouabain (0.1 microM) attenuated the relaxation to K+ in intact preparations and converted the response of epithelium-free preparations to a contraction. In the presence of a higher concentration of ouabain (1 microM), intact preparations contracted in response to K+. 5 In normal K+ solution, ouabain (0.1 microM) increased the sensitivity of intact preparations to methacholine but reduced their sensitivity to K+. Ouabain was without these effects in epithelium-free preparations. 6 Thus, responses of intact preparations to perturbations which affect electrogenic Na+/K+-pumping in trachealis are influenced by an epithelium-derived factor. The production of the factor may be linked to an epithelial Na+/K+-pump, or the factor may modulate the activity of an electrogenic Na+/K+-pump in the muscle.

Animals↗
PubMed1988

Is the epithelium-derived inhibitory factor in guinea-pig trachea a prostanoid?

To examine further the possible prostanoid involvement in the influence of the epithelium on guinea-pig tracheal smooth muscle responsiveness, we have analyzed the effects of LTD4, methacholine and histamine on the level of airway smooth muscle tone and on the amounts of PGE2, PGF2 alpha and PGI2 (determined by radioimmunoassay) in the presence and absence of the epithelium. Removal of the epithelium increased the sensitivity of guinea-pig trachea to the contractile effects of LTD4, methacholine and histamine. LTD4 (3-100 nM), methacholine (0.1-10 microM) or histamine (0.3-30 microM) did not increase prostanoid release above control values in either the presence or absence of the epithelium. The unstimulated release of PGE2 and PGF2 alpha, but not PGI2, was decreased in tissues lacking epithelium. Indomethacin (1 microM) reduced the baseline tone to a smaller extent in the absence of epithelium. In the presence but not the absence of the epithelium, indomethacin increased the sensitivity of preparations to the contractile effect of methacholine. The results support the postulate of an epithelium-derived inhibitory factor modulating guinea-pig tracheal smooth muscle responsiveness. The identity of this factor is not known but is not PGI2 and is unlikely to be PGF2 alpha or PGE2. However, the possibility remains that the basal release of PGE2 and/or PGF2 alpha derived from the epithelium may markedly affect the responsiveness of guinea-pig tracheal smooth muscle. Furthermore, the epithelium is a significant source of PGE2 and PGF2 alpha which may be involved in the maintenance of baseline tone.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Concentration-related differences in the effects of the Ca2+ agonist Bay K 8644 in human bronchus in vitro.

1. In human isolated bronchial muscle Bay K 8644 (1 nM-1 microM) increased the force of contraction. In concentrations greater than 1 microM (in sensitized tissues), and 10 microM (in control), Bay K 8644 relaxed tissues to below their pretreatment baseline tension. 2. In control tissues contracted with methacholine or LTD4, Bay K 8644 (10 microM) produced a further small contraction; Bay K 8644 (100 microM) relaxed the tissues below baseline. 3. In tissues contracted with histamine, Bay K 8644 (10-100 microM) produced only relaxation. 4. Bay K 8644 therefore has both Ca2+ agonist and Ca2+ antagonist properties, the calcium agonist activity is more pronounced in sensitized tissues.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗