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D W Hay

Publications and source records attributed to D W Hay.

At least 109 records · Page 6Linked to original sources
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

Is the guinea pig trachea a good in vitro model of human large and central airways? Comparison on leukotriene-, methacholine-, histamine- and antigen-induced contractions.

To analyze comprehensively the relevance of the guinea pig trachea as a model of human large and central airways, the contractile effects of the peptidoleukotrienes (LTs), histamine, methacholine and antigen on guinea pig and human airways were compared in vitro. Although some differences were apparent, LTC4, LTD4, LTE4, histamine and methacholine had comparable EC50 values and elicited similar maximal responses in both guinea pig trachea and human bronchus (second-seventh generation). In the presence of l-serine borate (45 mM), LTC4 concentration-response curves were shifted significantly to the left in guinea pig trachea but not in human bronchus. Furthermore, the LT receptor antagonists (SK&F 102922 and FPL 55712) had similar potencies against LTC4- and LTD4-induced contractions of human bronchus, whereas, in the guinea pig trachea, they were much more effective antagonists of responses produced by LTD4 than those elicited by LTC4. These results provide further evidence that, unlike in human bronchus, LTC4- and LTD4-induced contractions in the guinea pig trachea are mediated via distinct leukotriene receptors. Ovalbumin-induced contractions of actively sensitized guinea pig tracheae exhibited the same profile as anti-immunoglobulin E-induced contractions of the passively sensitized human bronchus. Furthermore, antigen-induced contractions in both the guinea pig trachea and human bronchus possessed a similar sensitivity to inhibition by mepyramine (10 microM) and the LT antagonists (10 microM), added either alone or in combination. These results indicate that the isolated guinea pig trachea is a suitable model of human large and central airways.

Adult↗
PubMed1987

Pharmacologic profile of SK&F 104353: a novel, potent and selective peptidoleukotriene receptor antagonist in guinea pig and human airways.

In this report, we describe the in vitro and in vivo pharmacologic profile of 2(S)-hydroxy-3(R)-[(2-carboxyethyl)thio]-3-[2-(8-phenyloctyl)pheny l]- propanoic acid (SK&F 104353) in guinea pig and human airways. In the isolated guinea pig trachea, SK&F 104353 was a potent, competitive antagonist of leukotriene (LT) D4-induced contractions (pA2 = 8.6). In contrast, SK&F 104353 produced little effect on LTC4 concentration-response curves under conditions where the bioconversion of LTC4 to LTD4 was inhibited. LTE4-induced contractions in guinea pig trachea were sensitive to inhibition by SK&F 104353 (pKB greater than 8.9). SK&F 104353 (10 microM) had no intrinsic contractile activity and was without effect on contractions produced by KCl, histamine, prostaglandin D2, platelet-activating factor or U-44069 in guinea pig trachea. Furthermore, unlike other purported LT antagonists, LT 171883 and FPL 55712, SK&F 104353 (30 microM) did not inhibit cyclic nucleotide phosphodiesterase activity measured in homogenates from canine tracheal smooth muscle. In the isolated human bronchus, SK&F 104353 produced concentration-dependent rightward shifts in LTD4 concentration-response curves and, unlike in guinea pig trachea, was an effective antagonist of LTC4-induced contractions with a pKB of 8.0 to 8.4. This provides further evidence that, in contrast to guinea pig airways, responses produced by LTC4 and LTD4 in human bronchus appear to be mediated via the same LT receptor population. SK&F 104353 was also an effective antagonist of LTE4-induced responses in human bronchus (pKB greater than 8.2).(ABSTRACT TRUNCATED AT 250 WORDS)

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
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

Differences in the ability of salbutamol to prevent and reverse LTC4-induced contractions of the guinea-pig isolated trachea: influence of l-serine borate.

In the presence of l-serine borate, salbutamol was much more effective in reversing rather than preventing LTC4-induced contractions of guinea-pig trachea. This suggests that different mechanisms are involved in initiating versus maintaining LTC4-induced contractions. In addition, the ability of salbutamol pretreatment to prevent LTC4-induced contractions was reduced substantially in the presence of l-serine borate, suggesting that the metabolites of LTC4 (LTD4 and LTE4) are more sensitive to inhibition by beta-adrenoceptor agonists than is LTC4 itself.

Albuterol↗
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

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↗
PubMed1986

An overview of species differences in the effects of a water extract of cotton bract on isolated airway smooth muscle, and effects of E. coli lipopolysaccharide.

Our laboratory has been comparing the activity of a water extract of cotton bract (CBE) with the isolated trachealis smooth muscle of the dog, guinea pig, and cat. CBE induced contractions that were not mediated by 5-hydroxytryptamine (5-HT), histamine, or muscarinic receptors. The active agent(s) in CBE was dialyzable (less than 14,000 molecular weight), and substantial activity was retained after low-temperature ashing. CBE potentiated contractions of dog trachealis to histamine and 5-HT and relaxation responses to isoproterenol, whereas it had no effect on responses to methacholine and KCl. In the guinea pig trachealis, CBE reduced responsiveness to KCl, potentiated relaxations to adenosine and ATP, and did not alter the responses to the remaining agents. Responses of cat trachealis to KCl and isoproterenol were potentiated by CBE, while those to 5-HT were unaffected. Neurogenic cholinergic contractile responses were potentiated by CBE in the trachealis of the dog, but not of the guinea pig, while neurogenic relaxations were potentiated by CBE in guinea pig trachealis but not in the dog trachealis. There are thus marked species differences in the acute effects of CBE on airway smooth muscle. Due to recent interest in the possible involvement of bacterial endotoxins in the etiology of byssinosis, we examined the effects of E. coli lipopolysaccharide (LPS) in guinea pig trachealis. An initial examination revealed that LPS potentiated responses to histamine, but not those to methacholine and isoproterenol. This effect vanished upon a second appraisal with a different batch of LPS. The effect of LPS in airway smooth muscle is thus, at present, equivocal.

Airway Resistance↗
PubMed1985

Sensitivity changes in the smooth muscle of the guinea-pig isolated vas deferens after treatment of animals with 6-hydroxydopamine.

Postjunctional supersensitivity of the smooth muscle of the guinea-pig vas deferens induced by denervation, decentralization and treatment of animals with reserpine has been attributed, in part, to a partial membrane depolarization (8-10 mV) resulting from reduced electrogenic Na+,K+-pumping activity. This study was undertaken to characterize sensitivity changes which occur after treatment of animals with 6-hydroxydopamine (100 mg/kg + 250 mg/kg i.v., 1 day apart). Seven days after the second injection, concentration-response curves for isometric contractile responses to norepinephrine, methoxamine, acetylcholine and histamine were shifted 40.6-, 1.7-, 3.6- and 2.7-fold, respectively, to the left of control; however, the sensitivity to KCl was not increased, which contrasts with the results after denervation, decentralization and reserpine treatment. Ouabain (10(-5) M) produced 1.8- and 1.3-fold leftward shifts of the KCl concentration-response curves in tissues from control and 6-hydroxydopamine-treated animals, respectively. The pronounced effect of ouabain in tissues from treated animals may be an indication that 6-hydroxydopamine treatment does not result in as much inhibition of electrogenic Na+,K+-pumping, and resultant membrane depolarization, as other methods which induce supersensitivity of the guinea-pig vas deferens.

Acetylcholine↗
PubMed1984

Effects of KCl on 45Ca uptake and efflux in the rat vas deferens.

The effects of KCl 160 mM on 45Ca uptake and efflux in the rat isolated vas deferens were investigated using a modification of the lanthanum method and a superfusion system respectively. In the prostatic half, basal cellular 45Ca uptake was 679 +/- 21 nmol g-1 tissue wet weight and KCl 160 mM increased this by 155%. In the epididymal half, basal cellular 45Ca uptake was 730 +/- 28 nmol 45Ca g-1 and KCl 160 mM increased this by 46%. Verapamil 2.04 microM or nifedipine 0.29 microM had no or little effect on basal 45Ca efflux or on basal 45Ca uptake. The KCl-induced increase in 45Ca uptake in both halves was inhibited by verapamil 2.04 microM or nifedipine 0.29 microM, concentrations which markedly reduce the contractile response. It is concluded that high K+ contracts the rat vas deferens by stimulation of the entry of extracellular Ca2+ to the intracellular compartment. KCl 160 mM produced a large, rapid and reversible increase in the rate of 45Ca efflux into Ca2+-containing and Ca2+-free Krebs-Henseleit solutions, which was not inhibited by verapamil 2.04 microM, nifedipine 0.29 microM or nitroprusside 1,678 microM. The relative size of the slow component of 45Ca efflux was larger in the prostatic half compared to the epididymal half of bisected tissues, suggesting that the postulated high affinity binding sites are predominant in this region. However, the rates of the fast and slow components of 45Ca efflux from prostatic and epididymal halves were identical. KCl 160 mM produced a similar increase in 45Ca efflux in prostatic and epididymal halves.

Animals↗
PubMed1983

The effects of calcium channel inhibitors on twitches and noradrenaline contractions of the rat bisected vas deferens.

In the prostatic half of the rat vas deferens, responses to noradrenaline 30 microM were biphasic. Ca-deprivation reduced both phases. The initial part of the noradrenaline contraction was resistant to verapamil (IC50 74.2 microM), methoxyverapamil (IC50 approximately 100 microM) and especially nifedipine (no effect up to 14.4 microM). The late part of this response and the entire response to noradrenaline in the epididymal half were abolished by verapamil (10.2 microM), methoxyverapamil (9.6 microM) or nifedipine (1.44 microM). The first phase of the twitch to single pulse transmural stimulation was abolished by nifedipine (14.4 microM) and inhibited by methoxyverapamil (57.6-96 microM); verapamil was less potent. The second phase of the twitch was totally resistant to nifedipine (14.4 microM), but more sensitive to inhibition by verapamil or methoxyverapamil than was the first. It was concluded that the calcium channel inhibitors can distinguish between three distinct types of calcium ion channel in the rat vas deferens: (1) sensitive calcium channels mediating the noradrenaline response in the epididymal half, and the late part of the noradrenaline response in the prostatic half (2) calcium channels responsible for the first phase of the twitch, blocked by high concentrations of nifedipine (3) calcium channels mediating the second phase of the twitch and the initial response to noradrenaline in the prostatic half, unaffected by nifedipine.

Animals↗
PubMed1983

The effects of calcium channel inhibitors and other procedures affecting calcium translocation on drug-induced rhythmic contractions in the rat vas deferens.

In the rat isolated vas deferens, methoxamine 8.1 microM produced an initial phasic response that declined towards baseline and was followed by rhythmic contractions that continued until wash-out. These responses were predominant in the epididymal half. BaCl2 1 mM produced a similar type of response which was not mediated by noradrenaline release or activation of alpha-adrenoceptors. The barium responses were similar in the epididymal and prostatic halves. Incubation in nominally Ca2+-free solution caused abolition or near abolition of rhythmic contractions produced by barium or methoxamine. The initial phasic response to methoxamine was abolished in Ca2+-free solution, whereas that produced by barium persisted. Rhythmic contractions produced by methoxamine or barium were inhibited by Mg2+ (2.4-20 mM) and by La3+ (1-5 mM). Mg2+ had selectivity for inhibition of the frequency of methoxamine- but not barium-induced rhythmic contractions. Despite their dependence on [Ca2+]o, barium- and methoxamine-induced rhythmic contractions were resistant to inhibition by calcium channel inhibitors. Verapamil, nifedipine and flunarazine inhibited the amplitude of rhythmic contractions more readily than the frequency (methoxamine IC50 for verapamil: amplitude = 29.8 +/- 5.40 microM, n = 6, frequency = 96.7 +/- 31.0 microM, n = 5, for nifedipine: amplitude = 2.42 +/- 0.34 microM, n = 7, frequency = 3.24 +/- 0.75 microM, n = 7, and for flunarizine: amplitude = 15.9 +/- 5.95 microM, n = 7, frequency = 153 +/- 28.6 microM, n = 7). There was no differentiation between inhibition of methoxamine and barium-induced responses. Like Mg2+, methoxyverapamil selectively inhibited the frequency of methoxamine-induced contractions (IC50: amplitude = 16.8 +/- 2.86 microM, n = 5, frequency = 2.07 +/- 0.81 microM, n = 5) but not barium-induced contractions (IC50: amplitude = 13.9 +/- 1.95 microM, n = 5, frequency = 48.5 +/- 8.98 microM, n = 5). Diazoxide (43.3-2167 microM) and nitroprusside (3.36-6712 microM) had only a small effect on barium contractions, but produced a dose-related reduction in the amplitude of methoxamine-induced responses. Diazoxide and nitroprusside caused methoxamine contractions to occur in groups, although they had no effect on their overall frequency. It is concluded that barium- and methoxamine-induced rhythmic contractions in the rat vas deferens are mediated by the entry of [Ca2+]o via membrane calcium channels that have a lower affinity (10-100 X) for calcium channel inhibitors than those mediating the KCl response. Channels activated by methoxamine are concentrated in the epididymal half, whereas those opened by barium are evenly distributed. However, although responses to methoxamine and barium are similar in form, differences in the effects of some of the drugs tested, together with the results of previous studies, indicate that they produce contractions by different mechanisms.

Animals↗
PubMed1982

Local anaesthetic activity of organic calcium antagonists: relevance to their actions on smooth muscle.

Local anaesthetic activity was measured on the rat phrenic nerve at 37 degrees C: Verapamil HCl had 5.1X and methoxyverapamil HCl had 3.0X the potency of lidocaine. Flunarizine was about equipotent with lidocaine, while nifedipine, diazoxide and sodium nitroprusside were without effect. It is concluded tht the smooth muscle inhibitory actions of the calcium antagonists, even when used in concentrations possessing local anaesthetic activity, are due to a reduction in Ca2+ permeability. In rat isolated vasa deferentia, lidocaine had both stimulant and inhibitory actions. On its own it induced rhythmic contractions (not blocked by phentolamine) and it also augmented the frequency of rhythmic contractions produced by methoxamine or barium. These actions may be due to block of K+ channels. Lidocaine also reduced the amplitude of methoxamine and barium induced contractions and both phases of the KCl contraction. The KCl response was restored by increasing "Ca2+]0, and it is therefore concluded that lidocaine was acting by blockade of Ca2+ channels.

Anesthetics, Local↗