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D W Hay

Publications and source records attributed to D W Hay.

At least 91 records · Page 5Linked to original sources
PubMed1991

Pharmacologic and pharmacokinetic profile of SK&F S-106203, a potent, orally active peptidoleukotriene receptor antagonist, in guinea-pig.

In this report the pharmacologic and pharmacokinetic profile of the leukotriene receptor antagonist 3(S)-[(2-carboxyethyl)thio]-3-[2-(8-phenyloctyl)phenyl] propanoic acid (SK&F S-106203) in guinea-pigs is described. In isolated guinea-pig tracheae SK&F S-106203 was a potent, competitive antagonist of leukotriene (LT) D4-induced contractions (pA2 = 7.6). SK&F S-106203 was also a potent antagonist of LTE4-induced contractions (pKB = 7.3), but had little effect on those elicited by LTC4 (pKB = 5.5). SK&F S-106203 (10 microM) had no effect on contractions produced by histamine, carbachol, KCl, U-44069, PGF2 alpha or PGD2. In addition, SK&F S-106203 (10 microM) did not inhibit cyclic nucleotide phosphodiesterase (PDE) activity of several PDE isozymes. In guinea-pig lung membrane preparations, SK&F S-106203 was a potent antagonist of 3H-LTD4 binding with a Ki = 19.4 +/- 2.1 nM (n = 5). The pharmacokinetic profile of SK&F S-106203 was determined in unanesthetized guinea-pigs. Following an i.v. (bolus) dose (25 mg/kg), SK&F S-106203 disappeared from plasma in a biphasic fashion with half-lives of 0.1 h (50% of the area under the plasma concentration-time curve, AUC) and 11 h. The AUC obtained for SK&F S-106203 following i.v. administration was 87.3 +/- 7.5 micrograms-h/ml. Following an oral dose of SK&F S-106203 (100 mg/kg), the maximal plasma concentration (Cmax) and the time Cmax was achieved (Tmax) were 21.62 +/- 2.26 micrograms/ml and 4 +/- 1 h, respectively; the AUC was 279.9 +/- 41.8 micrograms-h/ml. Studies examining the effects of i.v. infusion of SK&F S-106203 revealed that marked inhibition of LTD4-induced bronchospasm was produced with steady-state plasma levels of SK&F S-106203 less than 1 microgram/ml (less than 2 microM). Oral (p.o.) pretreatment with 100 mumol/kg SK&F S-106203 for up to 24 h essentially abolished LTD4-induced bronchospasm; this correlated with sustained plasma concentrations of greater than 2 micrograms/ml. The results indicate that in guinea-pig airways, SK&F S-106203 is a potent and selective LT receptor antagonist that is active via aerosol, oral and i.v. routes of administration. When given orally, SK&F S-106203 is highly bioavailable and has a very long duration of action which correlates with the pharmacokinetic profile of the compound. SK&F S-106203 may be useful therapy in asthma and other disorders in which the LTs are thought to play a prominent pathophysiological role.

Animals↗
PubMed1990

Airway epithelium-derived inhibitory factor.

Various bronchoactive agents can induce the release from the airway epithelium of an inhibitory substance that is able to relax certain tissues including rat aorta and possibly also airway smooth muscle. This substance, whose existence has recently been confirmed using a new bioassay system, is distinct from nitric oxide (EDRF) and is also known to be non-prostanoid in nature. Roy Goldie and colleagues describe the properties of this factor, and its potential clinical significance.

Animals↗
PubMed1990

The effect of inhibitors of prostaglandin formation on contraction of the rat, rabbit and human vas deferens.

1. The rat vas deferens releases both PGE2 and PGF2 alpha under basal conditions in vitro but the human vas deferens synthesizes prostaglandins only when arachidonic acid is supplied exogenously. 2. The release of PGE2 and PGF2 alpha is augmented by alpha-adrenoceptor activation or by BaCl2, both of which cause contraction. 3. Release of PGE2 and PGF2 alpha is substantially inhibited by indomethacin 10 micrograms ml-1 which does not affect contraction. 4. Contraction is strongly inhibited by higher concentrations of indomethacin (50-80 micrograms ml-1). 5. It is concluded that the release of PGE2 and PGF2 alpha from the rat and human vas deferens is not correlated with contraction.

Animals↗
PubMed1990

Mechanism of endothelin-induced contraction in guinea-pig trachea: comparison with rat aorta.

1. Endothelin (1 nM-0.3 microM) produced a concentration-dependent contraction of guinea-pig epithelium-containing (intact) trachea (EC50 = 30.9 nM). Endothelin was a less potent agonist than leukotriene D4 (LTD4; EC50 = 0.77 nM), but was more potent than carbachol (EC50 = 0.15 microM) or substance P (EC50 = 1.4 microM). Endothelin was a more potent contractile agent in rat endothelium-denuded aorta (EC50 = 2.1 nM) than in guinea-pig trachea. 2. Endothelin-induced contraction in guinea-pig trachea was unaffected by mepyramine (10 microM), atropine (1 microM), SK&F 104353 (10 microM), a leukotriene receptor antagonist, or SQ 29,548 (1 microM), a thromboxane receptor antagonist. The contraction produced by 0.3 microM endothelin was potentiated by cyclo-oxygenase inhibition with 5 microM indomethacin. 3. Nicardipine (0.01 or 0.1 microM) or incubation in calcium-free medium +0.1 mM EGTA for 30 min had a relatively minor or no effect on endothelin concentration-response curves in guinea-pig intact trachea, but markedly inhibited responses produced by endothelin in endothelium-denuded aorta of the rat. Increasing the EGTA concentration in calcium-free medium to 1 mM abolished endothelin-induced contraction in guinea-pig trachea. 4. In guinea-pig trachea, ryanodine (10 microM) produced a 2.1 fold shift to the right of endothelin concentration-response curves and reduced the maximum response elicited by 0.3 microM endothelin. 5. Staurosporine (0.01 microM and 0.1 microM), a protein kinase C inhibitor, was without effect on endothelin- or carbachol-induced contraction in guinea-pig trachea, but markedly inhibited the response produced by endothelin in rat aorta. 6. Endothelin (3 nM-0.3 microM) produced a concentration-dependent stimulation of phosphatidylinositol (PI) turnover in guinea-pig intact trachea, with an EC50 value of 45.9 nM. 7. Removal of the epithlium markedly potentiated endothelin-induced contraction in guinea-pig trachea, producing a 4.7 fold leftward shift in endothelin concentration-response curves and an increase in the contractile response elicited by 0.3 microM endothelin. 8. These data indicate that endothelin is a potent agonist in guinea-pig trachea whose response is markedly enhanced by removal of the airway epithelium. Endothelin-induced contraction is not mediated to a marked extent by calcium influx via dihydropyridine-sensitive calcium channels and does not involve the release of histamine, acetylcholine, leukotrienes or thromboxane. Rather, endothelin appears to produce contraction of guinea-pig trachea via a direct action which involves stimulation of PI turnover and utilization of calcium from intracellular stores and, also, calcium influx via a pathway that is not sensitive to dihydropyridine calcium channel inhibitors. Endothelin-induced contraction of rat aorta was more sensitive to the effects of incubation in Ca2 +-free medium, nicardipine or staurosporine, suggesting that differences exist in the relative mechanisms whereby endothelin produces contraction in different tissues.

Animals↗
PubMed1990

Chemical species of lipids in bile.

Bile salts, phospholipids and sterols are the major lipid species in bile. The common bile salts possess a steroid nucleus of four fused hydrocarbon rings with polar hydroxyl functions and an aliphatic side chain conjugated in amide linkage with glycine or taurine. Since the ionized carboxylate or sulfonate group on the side chain renders bile salts water soluble, they are formally classified as soluble amphiphiles. The common bile salts differ in the number and orientation of the hydroxyl groups on the steroid nucleus. Bile salts synthesized from cholesterol in the liver are called primary bile salts, which in humans are cholate, with three hydroxyl groups, and chenodeoxycholate, with two hydroxyl groups. Secondary bile salts are created by the action of intestinal bacteria on primary bile salts; deoxycholate, with two hydroxyl groups, and lithocholate, with a single hydroxyl group, are formed from cholate and chenodeoxycholate, respectively. "Tertiary" bile salts are the result of modification of secondary bile salts by intestinal flora or hepatocytes; in humans these are the sulfate ester of lithocholate and ursodeoxycholate, the 7 beta-epimer of chenodeoxycholate. Lecithin (diacylphosphatidylcholine), the major phospholipid in bile, is an insoluble, swelling amphiphile with a hydrophilic, zwitterionic phosphocholine head group and hydrophobic tails comprised of two long fatty acyl chains. Biliary lecithin is derived from the least hydrophobic hepatic lecithins and typically contains a saturated C-16 acyl chain in the sn-1 position and an unsaturated C-18 or C-20 acyl chain in the sn-2 position. Cholesterol, present solely as the nonesterified free alcohol, accounts for more than 90% to 95% of the sterols in bile.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Guinea-pig tracheal epithelium and endothelin.

Removal of the epithelium increased the responsiveness of isolated guinea-pig trachea to the contractile effects of endothelin. This phenomenon was observed in the presence of indomethacin (5 microM), captopril (10 microM), bacitracin (20 micrograms/ml) or leupeptin (50 microM), but was inhibited by phosphoramidon (10 microM). Bacitrain enhanced contraction produced by endothelin. The increased responsiveness of denuded guinea-pig trachea to endothelin may be due to removal of an epithelium-derived phosphoramidon-sensitive peptidase.

Animals↗
PubMed1989

The bronchopulmonary pharmacology of SK&F 104353 in anesthetized guinea pigs: demonstration of potent and selective antagonism of responses to peptidoleukotrienes.

The bronchopulmonary pharmacology of SK&F 104353 [2(S)-hydroxy-3(R)-[2(2-carboxyethyl)thio]-3[2-(8- phenyloctyl)phenyl]-propanoic acid], a potent and selective leukotriene (LT) receptor antagonist in vitro, was assessed in anesthetized, spontaneously breathing guinea pigs. Aerosol administration of SK&F 104353 (5-2000 micrograms/ml x 100 breaths) reduced in a concentration-dependent manner the response to a standard LTD4 challenge (4.33 micrograms/ml x 5 breaths) given 30 min later. Inhalation of a 2000 micrograms/ml solution abolished LTD4-induced bronchoconstriction for at least 2 hr. The i.v. administration of SK&F 104353 10 min before challenge antagonized LTD4-induced bronchoconstriction with an ID50 of 0.55 mumol/kg (0.25 mg/kg). Substantial antagonism of LTD4-induced bronchospasm was observed for at least 60 min after i.v. administration of 5 mumol/kg of SK&F 104353. Infusion of SK&F 104353 at various rates revealed that a steady-state plasma concentration of 0.125 microM (0.06 micrograms/ml) reduced LTD4-induced bronchoconstriction by 60%. In addition to preventing the response to LTD4, i.v. administered SK&F 104353 (10 mumol/kg) rapidly and completely reversed ongoing LTD4-induced bronchoconstriction. SK&F 104353 also was effective when given intraduodenally 1 hr before LTD4 challenge, although the ID50 (32 mumol/kg) was 60-fold greater than the i.v. ID50. Given intragastrically, 100 mumol/kg of SK&F 104353 abolished the response to LTD4 for 1 hr, and reduced the response for 6 hr. SK&F 104353 (20 mumol/kg i.v.) had no effect on the bronchoconstriction induced by aerosolized acetylcholine, histamine or U-44069, but did antagonize the response to LTC4. SK&F 104353 alone did not produce bronchoconstriction when administered by any route or dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Aerosols↗
PubMed1989

Cellular mechanisms of endothelin in rabbit aorta.

The present studies were designed to investigate the cellular actions of endothelin in rabbit aorta. Endothelin produced concentration-dependent contraction of rabbit isolated aortic rings which was independent of the endothelium; the EC50 values were 6.1 and 5.6 nM for endothelium-intact and endothelium-denuded vascular rings, respectively. Endothelin (1 nM) did not induce the release or inhibit the effect of endothelium-derived relaxing factor in precontracted aortic rings. Removal of calcium from the external bathing medium reduced the maximal contractile response induced by endothelin (0.1 microM) by only 12%; however, addition of ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid (0.1 mM) to the calcium-free medium produced a marked inhibition (approximately 75%) of endothelin-induced contraction. The dihydropyridine calcium channel antagonists nicardipine (1 microM) or nifedipine (1 microM), and also diltiazem (1 microM), had little or no effect on endothelin concentration-response curves. Contraction produced by endothelin (30 nM) was not associated with an alteration in the levels of cyclic 3',5'-adenosine monophosphate or cyclic 3',5-guanosine monophosphate in either endothelium-intact or endothelium-denuded aortic rings. Endothelin (1 nM-0.1 microM) produced concentration-dependent stimulation of phosphatidylinositol (Pl) turnover in aortic rings when exposed to tissues for periods greater than or equal to 15 min. Endothelin-induced stimulation of Pl turnover was unaffected by nicardipine (0.1 microM). In calcium-free medium (+0.1 mM ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid) basal Pl turnover was reduced; however, endothelin (1 nM-0.1 microM) produced similar percentage increases over basal levels to those observed in the presence of calcium.(ABSTRACT TRUNCATED AT 250 WORDS)

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

Functional antagonism by salbutamol suggests differences in the relative efficacies and dissociation constants of the peptidoleukotrienes in guinea pig trachea.

To assimilate information about the relative efficacies and affinities of the peptidoleukotrienes, the ability of the beta adrenoceptor agonist salbutamol to antagonize functionally contractions produced by leukotrienes (LT)C4, LTD4 and LTE4 was examined in the guinea pig trachea. There was a marked gradation in the sensitivity of LT-induced responses to antagonism by pretreatment with salbutamol (0.01-1.0 microM): LTC4 less than LTD4 less than LTE4. These data suggest marked differences in the receptor reserve for the LTs. However, this postulate is not supported by the finding that the magnitude of the ratio for the estimated dissociation constant, KA, and EC50 values, which provides an indirect measure of the relative receptor reserve, were similar: LTC4 = 4.50, LTD4 = 10.54 and LTE4 = 3.18. Substantial differences were apparent in the estimated KA values: LTC4 = 2.88 nM, LTD4 = 11.8 and LTE4 = 46.4 nM. In the presence of a maximally effective concentration of LTE4 (1 or 10 microM), addition of LTD4 (1 or 10 microM) produced further contraction of the tissue whereas the reverse was not the case. Furthermore, in the presence of salbutamol (70 nM), LTE4 (0.1 microM) produced a 3.6-fold rightward shift in LTD4 concentration-response curves with no effect on the maximum contractile response; a pKB of 7.42 was calculated for LTE4. The results suggest that the large differences in the ability of pretreatment with salbutamol to inhibit contractions produced by LTC4, LTD4 or LTE4 are not attributable solely to corresponding differences in receptor reserve for the individual LTs.(ABSTRACT TRUNCATED AT 250 WORDS)

Albuterol↗
PubMed1988

Subcellular localization of leukotriene D4 receptors in sheep tracheal smooth muscle.

The distribution of [3H]leukotriene D4 [( 3H]LTD4) receptors in subcellular membrane fractions obtained from sheep tracheal smooth muscle was studied. Using differential centrifugation and discontinuous sucrose density gradient centrifugation, the subcellular membranes were separated into six fractions. The [3H]LTD4 receptor distribution profile in these fractions correlated with markers for the plasma membrane (5'-nucleotidase and alkaline phosphodiesterase) and did not correlate with markers for the mitochondria (cytochrome c oxidase and succinate-dependent cytochrome c reductase). The dissociation constant (Kd) and maximum number of binding sites (Bmax) for [3H]LTD4 binding to the receptors in the crude mixture of membranes (PII) were 0.38 +/- 0.2 nM and 77 +/- 14 fmol/mg of protein, respectively. The Kd and Bmax of [3H]LTD4 binding to the receptors in the plasma membrane-enriched fraction (FII) were 0.40 +/- 0.2 nM and 268 +/- 46 fmol/mg of protein, respectively. The specificity profile of the [3H]LTD4 receptors in the plasma membrane-enriched fraction was equivalent to that observed in the crude membrane and correlated with the agonist myotonic activities in the smooth muscle contraction assay system. Furthermore, the binding of [3H]LTD4 to the plasma membrane receptors was modulated by guanine nucleotides in a manner analogous to that observed in crude membranes, suggesting that agonist interaction with the receptors was regulated by guanine nucleotide binding protein. These results suggest that, in sheep tracheal smooth muscle, the plasma membrane is the primary location of specific LTD4 receptors.

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

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↗