Sodium cromoglycate, verapamil and nicardipine antagonism to leukotriene D4 bronchoconstriction.

1--The effects of nicardipine, verapamil and sodium cromoglycate (SCG) on the increase in pulmonary airway resistance(RAw) and decrease in pulmonary dynamic compliance (CDyn) induced by leukotriene D4 (LTD4) 0.5 micrograms kg-1 and acetylcholine (ACh) 3 micrograms kg-1 were investigated in anaesthetized guinea-pigs. The effects of these three agents on the contractile effects of LTD4 and ACh were tested on isolated tracheal preparations of the guinea-pig. 2--Nicardipine and verapamil (0.3 and 1 mg kg-1), as well as SCG (3 and 10 mg kg-1), partially but significantly inhibited the effects of LTD4 on RAw. Partial inhibition of the effect of LTD4 on CDyn was only observed with verapamil (0.3 and 1 mg kg-1). Nicardipine and verapamil had no effect on ACh-induced bronchoconstriction in vivo. 3--In concentrations higher than 10(-5) M, nicardipine and verapamil inhibited the contractile effects of LTD4 and ACh on guinea-pig isolated trachea. SCG had no effect on this preparation. 4--These results suggest that nicardipine, verapamil and SCG partially reduce the component of bronchoconstriction associated with stimulation of irritant receptors by LTD4. However, the site and mechanism of action of Ca2+-entry antagonists remain uncertain.     

Histamine H3-receptors modulate nonadrenergic noncholinergic neural bronchoconstriction in guinea-pig in vivo

We have investigated whether the histamine H3-receptors influence nonadrenergic noncholinergic (NANC) bronchoconstriction in guinea-pig in vivo. Atropine, propranolol, mepyramine and cimetidine were administered to block the effects of beta-adrenoceptor-, acetylcholine, H1- and H2-receptor-mediated responses, respectively. Vagal stimulation evoked a NANC bronchoconstrictor response. The selective H3-agonist, alpha-methylhistamine (alpha-MeHA, 1-10 mg/kg i.v.) did not alter basal respiratory insufflation pressure, but reduced the NANC bronchoconstrictor response to vagal stimulation in dose-dependent manner (with a maximal inhibition of 46.0 +/- 10.3%; mean +/- S.E. at 10 mg/kg) (P less than 0.02). Histamine itself also had a significant inhibitory effect on NANC responses with H1- and H2-blockade. The alpha-adrenoceptor antagonist phentolamine had no effect on the inhibitory response produced by alpha-MeHA, but the H3-receptor antagonist thioperamide blocked the inhibitory effect of alpha-MeHA. alpha-MeHA had no inhibitory effect on bronchoconstriction induced by exogenous substance P (5-25 micrograms/kg i.v.). We conclude that H3-receptors inhibit the release of transmitter from NANC nerves and that H3-receptors might play a role in regulation of neurogenic inflammatory responses in the airways.     

雌二醇对离体和在体气管平滑肌收缩活动的抑制作用

目的:研究雌二醇对离体和在体气管平滑肌收缩的作用.方法:(1)将家兔离体气管平滑肌条置于装有Krebs液的肌槽中温育,并通入95％O_2和5％CO_2的混合气体.二导记录仪记录肌条的等长张力.(2)测量肌注雌二醇(1mg/kg)前后乙酰胆碱和组胺引发豚鼠哮喘的潜伏期.结果:(1)雌二醇(100μmol/L)对乙酰胆碱和氯化钾诱发的收缩有明显的舒张作用(舒张百分比分别为39％±5％和45％±19％).其作用可被蚓哚美辛和亚甲蓝部分阻断(26％±8％和28％±13％),但不能被L-NNA、心得安和去除上皮所影响(舒张百分比分别为38％±10％,40％±15％,37％±8％).雌二醇能使乙酰胆碱及氯化钙的量效曲线明显右移(pD_2~′值分别为3.98和4.75).另外,雌二醇可明显抑制乙酰胆碱引起的第Ⅰ时相性收缩,对氯化钙引起的第Ⅱ时相性的收缩无明显影响.(2)肌注雌二醇(1mg/kg)可使豚鼠的引喘潜伏期明显延长.结论:(1)雌二醇对兔离体气管平滑肌的作用是非上皮依赖性的,与抑制电压依赖性钙通道和细胞内钙从内质网的释放有关,还部分与cGMP介导的松弛途径及刺激气道平滑肌释放前列腺素类物质有关,但与β-肾上腺素能受体介导的舒张无关.(2)雌二醇可明显舒张豚鼠在体气管平滑肌.     

Dopaminergic activity of cis-trans isomers of benzhydro[f]quinoline analogs

A comparison of the biological activity of isomers with varying alkyl substitutions on the heterocyclic nitrogen of benzhydro[f]quinoline derivatives was made. The secondar amines did not inhibit adrenergic transmission. The trans-isomer of the secondary amine was 0.5 as active as norepinephrine when evaluated for positive chronotropic action in anesthetized cats. The trans-isomers of the N-alkyl derivatives produce inhibition of responses produced by stimulation of cardioaccelerator nerves with doses of 1–5 μmol/kg. Likewise potent emetic activity (dog) and rotational behavior (rat) was observed with the N-alkyl derivatives when administered subcutaneously. The cis-isomers were much less active. The neuronal inhibitions in cats were antagonized by haloperidol 100 μg/kg, except the cis-isomer of the N-ethyl derivate which required phentolamine, 2 mg/kg. In general, the trans-isomers were more potent in contracting the isolated rabbit aorta. This response appeared to be mediated through an α-adrenergic mechanism since phentolamine blocked these responses. The trans-isomer TL-305 was effective in relaxing methacholine contracted guinea-pig trachea through a β-adrenergic mechanism since propranolol blocked this response.     

Effects of arotinolol on hemodynamics and adrenergically induced renin release and renal vasoconstriction

Effects of 5-[2-[(3-tert-butylamino-2-hydroxypropylthio)-4-thiazolyl]-2- thiophenecarboxamide hydrochloride (arotinolol, S-596) on hemodynamic and adrenergically induced renin release and renal vasoconstriction were investigated in pentobarbital anesthetized dogs. Arotinolol (1 mg/kg i.v.) decreased systemic blood pressure (SBP), heart rate (HR) and renin secretion rate without change in renal blood flow. Degree of hypotension induced by arotinolol and basal plasma renin activity prior to the injection of the drug showed significant correlation. Arotinolol (20 micrograms/min) produced significant suppression of renal nerve stimulation (RNS)-induced renin release and attenuated an increase in renal vascular resistance during RNS at 3 Hz. The same extent of inhibition in the renin secretion response to RNS was also obtained during the infusion of dl-propranolol (100 micrograms/min). The renal vasoconstriction induced by RNS and norepinephrine (NE) was inhibited dose-dependently during the infusion of arotinolol (10, 30 and 100 micrograms/min), phentolamine (3, 10 and 30 micrograms/min) or prazosin (1, 3 and 10 micrograms/min). Arotinolol and prazosin exerted a greater inhibitory effect on RNS- than NE-induced vasoconstriction, and the opposite was true of phentolamine. Arotinolol dose-dependently decreased SBP and HR in a dose range of 0.01 to 3.0 mg/kg. The greater reduction in HR was observed with arotinolol at a lower dose range (0.01 to 0.1 mg/kg) than with propranolol. Arotinolol produced larger reduction of SBP, and less increase in carotid, vertebral, renal and external iliac vascular resistances than propranolol. These results suggest that arotinolol posesses a- and beta-adrenoceptor blocking properties, which effectively contribute to the suppression of the adrenergically induced renin release and renal vasoconstriction, and to the hypotensive effect.     

Adrenergic Receptors in the Guinea Pig Trachea and Lung

The effect of adrenaline, noradrenaline, and isoprenaline was studied in vitro on the spirally-cut trachea and in anaesthetized animals in vivo. In the in vitro studies, all agents caused a relaxation of the tracheal muscles, and the relative potencies were in descending order, isoprenaline (142.2), adrenaline (21.9), and noradrenaline (1.0). After pretreatment for 20 minutes with propranolol (> 0.5 μg/ml) or INPEA (> 3 μg/ml) adrenaline and noradrenaline caused a contraction of the tracheal muscles. The effect of noradrenaline was 0.44 times that of adrenaline. The constrictor effect of adrenaline and noradrenaline was antagonized or completely inhibited by the α-receptor blocking agents phenoxy-benzamine and dibenamine in a concentration of 1–5 μg/ml. Isoprenaline did not produce any contraction of the tracheal muscles after pretreatment with propranolol or INPEA. In the in vivo studies, the animals were anaesthetized with pentobarbital sodium (50 mg/kg intraperitoneally). Intravenous injections were made into the right jugular vein. Changes in tidal volume were recorded according to the method of KONZETT & RÖSSLER. Adrenaline, in the doses 2–4 μg/kg, produced a weak bronchoconstriction that was enhanced after pretreatment of the animals with propranolol (2 mg/kg). The bronchoconstrictor effect of adrenaline and noradrenaline was not affected by atropine but was inhibited by phenoxybenzamine or dibenamine (1–2 mg/kg). Isoprenaline in doses up to 0.1 mg/kg did not produce any bronchoconstriction after pretreatment with propranolol. The results obtained suggest that the smooth muscles in the guinea-pig trachea and lung contain both α- and β-receptors, the β-receptor being dominant.     

Leukotriene D4 potentiates histamine-induced bronchoconstriction in guinea-pigs

Histamine concentration-response curves performed on isolated airways smooth muscle preparations were unaffected by threshold constrictor concentrations of LTD4 (194 +/- 34 pM for parenchymal strips and 1940 +/- 480 pM for isolated trachea, respectively). In contrast, LTD4, when administered between 2 and 60 s beforehand, potentiated bronchoconstrictor responses to histamine in anaesthetized, artificially ventilated guinea-pigs. Doses of LTD4, which did not produce direct effects on airways resistance, potentiated histamine-induced bronchoconstriction to a lesser degree than those having small direct effects. This potentiation was prevented by bilateral vagotomy. In addition, the antagonists atropine (100 micrograms/kg), FPL55712 (5 mg/kg) and indomethacin (1 mg/kg) effectively prevented the interaction. It is suggested that the interaction between LTD4 and histamine involves a specific leukotriene receptor, possibly linked to the generation of a cyclo-oxygenase metabolite and requires intact cholinergic innervation of airways smooth muscle. Furthermore, these results are consistent with the hypothesis that LTD4 may be a mediator of bronchial hyperreactivity.     

Dual effects of aspirin in guinea-pig lungs.

Dual effects of aspirin were demonstrated in guinea-pig lungs: (a) aspirin (3.3 mg/kg i.v.) antagonized bronchoconstriction induced by slow reacting substance of anaphylaxis (SRS-A); (b) aspirin produced bronchoconstriction when injected in the presence of propranolol into guinea-pigs in vivo at 330 mg/kg, or into guinea-pig isolated lungs in vitro as a 4% solution (40 mg/ml). 2 The severity of bronchoconstriction following administration of aspirin was directly related to the degree of beta-adrenoceptor blockade and to the age of the guinea-pigs. Aspirin-induced bronchoconstriction was prevented in vivo and in vitro by atropine and it could be reversed in vivo by atropine. Aspirin-induced bronchoconstriction was not inhibited by vagotomy or phenoxybenzamine. 3 These data suggest that the mechanism involved in aspirin-induced bronchoconstriction may be local cholinergic stimulation and that reduced beta-adrenergic drive may be a predisposing factor.     

Airways hyperreactivity and bronchoconstriction induced by vanadate in the guinea-pig.

1 The characteristics of vanadate-induced bronchoconstriction and airways hyperreactivity were observed in spontaneously breathing anaesthetized guinea-pigs by measurement of airways resistance (Raw) and dynamic lung compliance (Cdyn). Vanadate (0.3-3 mg kg-1 i.v. over 25 min) increased Raw and decreased Cdyn in a reversible, dose-related manner. This action (1 mg kg-1 vanadate) was not inhibited by atropine (1 mg kg-1 i.v.), propranolol (1 mg kg-1 i.v.) or bilateral vagotomy, suggesting a direct effect on the airways smooth muscle. 2 An aerosol of vanadate (10% w/v in H2O) for 3 min decreased Cdyn by 19.5% (P less than 0.05, n = 6) but caused no change in Raw. 3 Histamine (3 micrograms kg-1 i.v.) caused a bronchoconstriction which was enhanced by vanadate in a dose-related manner. This hyperreactivity (after 1 mg kg-1 i.v. vanadate) was unchanged after propranolol or bilateral vagotomy, but was partly blocked by atropine (enhancement by vanadate of the Cdyn change to histamine was diminished, P less than 0.02, n = 3). 4 Bronchoconstrictor responses to acetylcholine (6 micrograms kg-1 i.v.) and 5-hydroxytryptamine (6 micrograms kg-1 i.v.) were also enhanced by vanadate (1 mg kg-1 i.v.) Hyperreactivity after vanadate to the three bronchoconstrictors tested continued during vanadate infusion and was reversed 45 min after cessation of infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

DUAL MODES OF ACTION FOR DISODIUM CROMOGLYCATE IN INHIBITION OF ANTIGEN-INDUCED CONTRACTIONS OF GUINEA-PIG ISOLATED AIRWAYS SMOOTH MUSCLE

Disodium cromoglycate (DSCG; 10 mumol/l-1 mmol/l) relaxed the tone induced in the guinea-pig isolated trachea by histamine (5 mumol/l). Both isoprenaline and fenoterol were approximately 1000 times more potent than DSCG in relaxing tracheal smooth muscle. Ovalbumin (1 microgram/ml) contracted isolated tracheal and parenchymal strips from sensitized guinea-pigs. The sensitization procedure used was selective for eliciting IgG antibody production. In concentrations equieffective for relaxation of the isolated trachea, fenoterol (20 nmol/l), isoprenaline (60 nmol/l) and DSCG (100 mumol/l) inhibited ovalbumin-induced contractions of both tracheal and parenchymal strip preparations. DSCG produced a significantly greater (P less than 0.05) inhibition of ovalbumin-induced contractions of isolated trachea than did isoprenaline, suggesting that at 100 mumol/l DSCG produced a greater inhibition of mediator release than that produced by isoprenaline. Compound 48/80 (200 micrograms/ml) contracted the isolated trachea whereas this concentration had no contractile effect on the parenchymal strip. The failure of DSCG to inhibit compound 48/80 induced contractions of the isolated trachea together with the lack of contractile effect of compound 48/80 on the parenchymal strip suggest that compound 48/80 is inferior to antigenic stimulation as a reliable analogue of immunological activation of mast cells and consequent mediator release.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary anti-anaphylactic activity of clenbuterol tested on actively and passively sensitized guinea-pigs

Clenbuterol, an adrenergic beta-mimetic agent free of cardiostimulant effects, prevents the release of histamine from isolated rat mast cells. We studied its anti-anaphylactic activity in guinea-pigs and compared it with that of isoprenaline. At doses inactive against the bronchoconstriction caused by 5HT, clenbuterol (3 micrograms/kg) and isoprenaline (0.1-0.3 micrograms/kg) prevented the bronchoconstriction due to 1 mg/kg ovalbumin infused into passively sensitized animals. Clenbuterol and isoprenaline (0.5-1 microM) inhibited by 40% the contractions of superfused parenchyma lung strips from actively sensitized animals, stimulated with 0.3, 1 and 10 micrograms of ovalbumin. When strips from passively sensitized animals were challenged in the organ bath, clenbuterol and isoprenaline (0.01 microM) reduced by 50% the contraction triggered by 10 micrograms/ml of ovalbumin. These concentrations of clenbuterol were ineffective against contractions caused by acetylcholine. Clenbuterol and isoprenaline (0.001-0.01 microM) inhibited the release of histamine and of thromboxane A2 triggered by ovalbumin (0.1, 1 and 10 micrograms) injected into isolated lungs from actively sensitized guinea-pigs indicating that the anti-anaphylactic properties of clenbuterol are independent from its smooth muscle relaxing activity.     

Mechanism of vanadate-induced contraction of airways smooth muscle of the guinea-pig.

The characteristics of vanadate-induced contraction of airways smooth muscle are described in isolated preparations of guinea-pig central and peripheral airways. Vanadate (1-1000 microM) induced sustained contractions of trachea and lung parenchymal strips within 1 min of challenge. It was more potent (P less than 0.001) on the lung strip (EC50 = 63 microM) than on the trachea (EC50 = 123 microM). The lung strip also developed greater maximum isometric tension (P less than 0.001) than the trachea. The efficacy on the lung strip was 2 and the trachea 0.6, relative to the response to acetylcholine (efficacy = 1). Vanadate-induced contractions of the trachea were not inhibited by atropine, mepyramine, phentolamine or indomethacin, nor after mast cell depletion by compound 48/80, showing that contractions were not mediated via specific receptors or by release of endogenous mediators of tone. Inorganic phosphate specifically inhibited vanadate responses in a dose-dependent and reversible manner, suggesting a common site of action. Contractions could be elicited in depolarized muscle and after treatment with ouabain plus propranolol, showing that membrane depolarization and inhibition of the Na, K-ATPase system were not involved in the contractile action of vanadate. Pretreatment of tracheal smooth muscle with verapamil had no influence on contractions elicited by vanadate. After removal of extracellular calcium, vanadate-induced contractions declined slowly with time, indicating that influx of extracellular calcium was not giving rise to contractions elicited by vanadate. Vanadate markedly increased the rate of calcium efflux from trachealis muscle loaded with 45Ca into both Ca2+-free and normal Krebs solutions; this is compatible with vanadate mobilizing an intracellular store of Ca2+. Such a store involving sites with Ca-ATPase activity would be consistent with the action of vanadate in isolated membrane preparations. Membrane-skinned tracheal fibres contracted by micromolar Ca2+ were relaxed by vanadate in a reversible dose-related manner, indicating that the contractile action of vanadate was not related to its interaction with proteins at the cross-bridge level.     

Effects of REV 5901, a 5-lipoxygenase inhibitor and leukotriene antagonist, on pulmonary responses to platelet activating factor in the guinea-pig.

1. The effects of REV 5901 on the platelet activating factor (Paf)-induced (a) bronchoconstriction, (b) contraction of lung parenchymal strips and (c) increased airways responsiveness to histamine, were assessed in the guinea-pig. REV 5901 is a 5-lipoxygenase inhibitor and competitive peptidoleukotriene antagonist which does not inhibit multiple forms of phosphodiesterase. 2. In urethane/pentobarbitone anaesthetized animals, REV 5901 (10 or 30 mg kg-1, i.v.) substantially inhibited the bronchoconstriction, measured as changes in airways resistance (RL) and dynamic lung compliance (Cdyn), induced by leukotriene D4 (2.5 micrograms kg-1, i.v.) but did not attenuate that induced by Paf (50 ng kg-1, i.v.). 3. Paf contracted the lung parenchymal strip in a concentration-dependent manner. REV 5901 (25 microM) neither altered the magnitude of the contractions nor the tissue sensitivity to Paf. The sustained contraction induced by Paf was not affected when REV 5901 was added after the response had reached a plateau. 4. Contractions of parenchymal strips to Paf (50 nM) were prevented by pretreatment with the competitive Paf antagonists, SRI 63441 and WEB 2086. Also WEB 2086, but not SRI 63441, reversed established Paf-induced contractions and relaxed parenchymal strips from intrinsic tone in the absence of Paf. 5. Paf (20 ng kg-1, i.v.) caused an acute increase in airways responsiveness to histamine (4-12 micrograms kg-1, i.v.) which was attenuated by REV 5901 at 10 mg kg-1, i.v. and abolished by 30 mg kg-1, i.v.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interference of BN 52021 (ginkgolide B) with the bronchopulmonary effects of PAF-acether in the guinea-pig

The interaction between the ginkgolide BN 52021 and the effects of PAF-acether on the bronchopulmonary system of the guinea-pig was studied. In pentobarbitone or ethyl carbamate-anaesthetized animals, BN 52021 (1 mg/kg i.v. or 10 mg/kg p.o.) inhibited bronchoconstriction, the hematocrit increase and the accompanying thrombopenia and leukopenia induced by PAF-acether (33-100 ng/kg) and failed to block the bronchoconstriction produced by collagen, arachidonic acid and the tripeptide formyl-Met-Leu-Phe (FMLP). BN 52021, 3 mg/kg, reduced the bronchoconstriction induced by aerosolized PAF-acether. BN 52021, 300 microM, also inhibited the superoxide production by PAF-acether-stimulated alveolar macrophages and failed to reduce the same effects when triggered by FMLP (0.01-1 microM). BN 52021 blocked the formation of thromboxane-triggered by PAF-acether (100 ng) injected into perfused lung, under conditions where the effects of arachidonic acid where not modified. Finally, pretreatment of parenchyma lung strips with BN 52021 (100 microM) partially inhibited the contraction induced by PAF-acether (0.1 microM) and suppressed the accompanying release of thromboxane. BN 52021 is a selective antagonist of the effects of PAF-acether on the bronchopulmonary system and on circulating blood cells of the guinea-pig.     

Effect of crude extracts from Leonotis nepetaefolia (Labiatae) on rat and guinea-pig smooth muscle and rat cardiac muscle.

The actions of hydroalcoholic and tea extracts of stems of Leonotis nepetaefolia on agonist-induced and electrically-evoked contractions have been analysed in-vitro in rat uterus and left atrium and in guinea-pig ileum and trachea. The tea extract (500-2000 micrograms mL-1) caused parallel and graded rightward shifts of concentration-response curves to bradykinin and BaCl2 in the rat isolated uterus, but antagonized responses to prostaglandin F2 alpha in a typically non-competitive manner. The hydroalcoholic extract also caused rightward displacements of the curves to bradykinin, acetylcholine (ACh), angiotensin II, oxytocin and BaCl2 and reduced their maximal contractile effects. Both extracts (30-3000 micrograms mL-1) relaxed uterine preparations precontracted with KCl (80 mM), the hydroalcoholic extract being about 2-fold more potent than the tea extract. The relaxant response to the former was unaffected by propranolol (1 microM) or forskolin (10 nM), but was potentiated 2-fold by 3-isobutyl-1-methylxanthine (10 microM). In the guinea-pig ileum the hydroalcoholic extract shifted the ACh- and bradykinin-induced contractile curves to the right and markedly inhibited their maximal effects, whereas the tea extract caused a typical non-competitive antagonism of ACh-induced contractile responses. In field-stimulated ileal strips, both extracts (3-3000 micrograms mL-1) caused contractions and inhibited twitch responses. Guinea-pig tracheal rings precontracted with carbachol (0.3 microM) were relaxed only by concentrations of either extract in excess of 1000 micrograms mL-1, an action that was unaffected by propranolol (0.1 microM) or by offomethacin (1 microM).(ABSTRACT TRUNCATED AT 250 WORDS)     

Morphine and supraspinal inhibition of spinal neurones: evidence that morphine decreases tonic descending inhibition in the anaesthetized cat.

1 The effects of adrenoceptor blocking drugs on the metabolic responses to adrenaline infusion (1 microgram kg-1 min-1) have been studied in the anaesthetized, fasted cat. 2 Propranolol, in doses (0.25 or 1 mg/kg) which prevented completely adrenaline-induced tachycardia, reduced but did not abolish adrenaline-induced hyperglycaemia. 3 Phentolamine infusion, at a rate (15 micrograms kg-1 min-1 after a priming dose of 2.5 mg/kg) which reversed the pressor effect of adrenaline, reduced but did not abolish adrenaline-induced hyperglycaemia. 4 The continuous infusion of a combination of phentolamine (15 micrograms kg-1 min-1 after a priming dose of 2.5 mg/kg) and propranolol (5 micrograms kg-1 min-1 after a priming dose of 0.25 mg/kg) prevented completely the hyperglycaemia response to adrenaline infusion over a 6 h period. 5 The increase in blood lactate concentration produced by adrenaline was prevented completely by the combined infusion of propranolol and phentolamine but was not modified by phentolamine alone.     

Effects of labetalol on in vitro preparations of the trachea and lung strips and on ventilation overflow in vivo in guinea pigs

The responses of guinea pig central and peripheral airways to labetalol (both alpha- and beta-adrenoceptor blocker with intrinsic sympathomimetic activity) were studied using in vivo and in vitro preparations of the trachea and lung strips. The ventilation overflow enhanced by infusion of histamine in anesthetized guinea pigs was much more aggravated by labetalol and propranolol. The beta-adrenoceptor blocking potency of labetalol and propranolol was not significantly different between the in vitro tracheal preparations and the lung strips. Isoproterenol and salbutamol relaxed the tracheal preparations more markedly than they did the lung strips. Histamine and acetylcholine contracted the lung strips more remarkably than they did the trachea. Labetalol relaxed the trachea more markedly than it did the lung strips by its intrinsic sympathomimetic activity. These results suggest that the peripheral airways are more sensitive to constrictors and the central airways are more sensitive to relaxants such as beta-stimulants, and that the different responsiveness between the two airways to labetalol and histamine might have produced the different in vivo observations.     

Contribution of prostaglandins and thromboxanes to the adenosine and ATP-induced contraction of guinea-pig isolated trachea.

1 In in vitro experiments adenosine 5'-triphosphate (ATP) and adenosine were found to exert different effects on the guinea-pig isolated trachea depending on whether the trachea had previously been contracted with acetylcholine (ACh) (6.6 x 10(-6) M) or was at resting tone. 2 ATP and adenosine (10(-5) and 10(-3) M) were equipotent in relaxing the precontracted guinea-pig trachea, since concentrations of 1.09 +/- 0.35 and 0.39 +/- 0.16 mM respectively reduced by 25% the ACh-induced contraction. 3 ATP and adenosine (10(-5) and 10(-4) M) caused a moderate contraction of the guinea-pi trachea under resting tone. This effect was antagonized by inhibitors of cyclo-oxygenase (indomethacin 10(-6) M, aspirin 0.3 x 10(-3) M and 3 x 10(-3) M) and of thromboxane synthetase (nictindole 10(-7) M, imidazole 5 x 10(-5) M), which suggests an indirect mechanism of action with release of arachidonic acid derivatives.     

A novel leukotriene D4/E4 antagonist, SR2640 (2-[3-(2-quinolylmethoxy)phenylamino]benzoic acid)

We have studied the leukotriene antagonistic activity of a novel compound, SR2640 (2-[3-(2-quinolylmethoxy)phenylamino]benzoic acid), in vitro and in vivo. SR2640 inhibited LTD4- but not histamine-induced contractions of guinea-pig ileum and trachea in a concentration-dependent manner. Schild plot analysis of tracheal LTD4 antagonism yielded a pA2 value of 8.7 and a slope not different from unity. SR2640 concentration dependently inhibited the binding of 0.4 nM [3H]LTD4 to guinea-pig lung membranes with an IC50 value of 23 nM. The curve was parallel to that of unlabelled LTD4 (IC50 = 2.2 nM). SR2640 was equally effective in antagonizing LTD4 and LTE4, but was much less potent in reducing LTC4-induced ileum contractions. In vivo, SR2640 in the dose range 0.03-1.00 mg/kg shifted the dose-response curve for guinea-pig bronchoconstriction induced by intravenous LTD4 administration to the right at a rate proportional to the dose of SR2640, without reducing the maximum attainable obstruction: the slope of the Schild plot was 0.99. SR2640 (1 mg/kg) also caused a significant inhibition of antigen-induced bronchoconstriction in anaesthetized guinea-pigs pretreated with pyrilamine, indomethacin, propranolol and suxamethonium. In conclusion, SR2640 appears to be a potent and selective competitive LTD4/LTE4 antagonist, and may be useful in elucidating the role of leukotrienes in human asthma.     

Reduction by phentolamine of the hypotensive effect of methionine enkephalin in anaesthetized rabbits.

In intact rabbits anaesthetized with pentobarbitone, methionine enkephalin (Met enkephalin, 1-1,000 micrograms kg-1 i.v.) produced a dose-dependent bradycardia and hypotension. The bradycardia and hypotension were antagonized by naloxone hydrochloride (1 mg kg-1), but not by naloxone methobromide (1.3 mg kg-1). Phentolamine (1 and 4 mg kg-1 i.v.) blocked both the hypotension and bradycardia produced by Met enkephalin. The inhibitory effect of phentolamine was not due to a simple hypotensive action of this drug per se because a similar degree of hypotension induced by nitroprusside (15 micrograms kg-1, i.v.) caused a further reduction of pressure when Met enkephalin was added. Atropine (2 mg kg-1) reduced the bradycardia but not the hypotensive response to Met enkephalin. Met enkephalin did not antagonize the vasopressor effect of exogenous noradrenaline (2-8 micrograms kg-1, i.v.). Met enkephalin had no significant effects in superfused thoracic aortic strips and in isolated perfused hearts of rabbits. It is concluded that the cardiovascular effects of Met enkephalin are more probably due to an action on the central nervous system, although a peripheral site of action cannot be completely excluded.