An analysis of the B-adrenergic action of oxyfedrine

1-3-methoxy-ω-(1-hydroxy-1-phenylisopropylamino)-propiophenone hydrochloride (oxyfedrine) (10^?8–10^?6 g/ml) produces a positive inotropic effect on electrically driven guinea-pig left atria which is prevented by propranolol; higher concentrations depress contractile force. Oxyfedrine (10^?8–10^?6 g/ml) effectively antagonizes the action of isoprenaline but not that of theophylline ethylenediamine. Oxyfedrine (10^?5 g/ml)-induced relaxation of the guinea-pig tracheal chain is not reversed by repeated washing but is antagonized by propranolol (10^?7 g/ml). The relaxed tracheal chain contracts when an additional dose of oxyfedrine (10^?5 g/ml) or quinidine (10^?5 g/ml) was administered. The oxyfedrine-induced contraction is relaxed by papaverine (5 × 10^?6 g/ml), theophylline ethylene-diamine (10^?5 g/ml) or adenosine (5 × 10^?5 g/ml) but not by isoprenaline (2 × 10^?8 g/ml) or adrenaline (10^?7 g/ml) nor is it prevented by dibenamine (10^?5 g/ml), methysergide (10^?6 g/ml), atropine (10^?5 g/ml) or tripelennamine (10^?7 g/ml). These observations suggest that oxyfedrine interacts with the ß-adrenergic receptor, inducing at adequate concentrations, stimulation and blockade to catecholamines simultaneously; in this interaction, higher concentrations of oxyfedrine produces a direct depression (quinidine-like) of cardiac muscle and a contraction of tracheal muscle.     

An investigation of the long duration of action of oxyfedrine

The long-lasting sympathomimetic effects of oxyfedrine on the rat perfused heart, rat uterus and guinea-pig trachealis can be prevented or terminated by propranolol. Reserpine pretreatment did not affect the early peak cardiac responses or the responses of the other two tissues but abolished the late phase of its cardiac action. Oxyfedrine caused partial depletion of cardiac noradrenaline. A high concentration was needed to affect the uptake of ³H-noradrenaline by the rat uterus. ¹⁴C-oxyfedrine was taken up by tissues — this uptake was unaffected by cocaine, desipramine, metanephrine or phenoxybenzamine; it was reduced by cooling and increased by reserpine pretreatment. The chloroform-aqueous phase partition of oxyfedrine indicated high lipid solubility and its tissue uptake was attributed to this property. In the rat uterus the slow efflux of active drug molecules could account for its long duration of action.     

Studies of the action of nicotine in guinea-pig tracheal smooth muscle: interaction with beta-adrenoceptor antagonists

Nicotine produced cholinergic excitatory and adrenergic and non-adrenergic inhibitory responses in isolated guinea-pig trachea. Responses were blocked by hexamethonium (10 micro M), lidocaine (85 micro M) or tetrodotoxin (0.01 micro M) demonstrating that nicotinic receptors in nervous tissue were being activated. In the presence of atropine (0.1 micro M), inhibitory responses to nicotine were partially blocked by specific, experimentally determined, beta-blocking concentrations of pindolol or sotalol or by pretreatment with 6-hydroxydopamine or reserpine but were completely blocked by the less specific beta-blocking drugs 1- and dl-propranolol. Parallel experiments on guinea pig ileum revealed a marked attenuation by dl-propranolol of the atropine sensitive, cholinergic excitatory response to applied nicotine. The non-beta-adrenoceptor blocking agent d-propranolol, produced qualitatively similar attenuation of all excitatory and inhibitory responses to nicotine on both preparations. The remarkable susceptibility of nicotine-induced, neurally mediated responses to low, beta-blocking concentrations of dl-propranolol and to low concentrations of both of its racemates suggests that the non-specific actions of these compounds may have much more significance than is customarily believed. Such studies on the interaction between nicotine and some beta-adrenoceptor blocking drugs are consistent with the hypothesis that non-beta-blocking so-called 'non-specific membrane depressant actions' of dl-propranolol may in concentrations previously considered 'sub-local anaesthetic', significantly depress physiological transmission induced by activation of nicotinic receptors.     

Effects of oxyfedrine and ouabain on the heart-lung preparation of the dog

Summary The actions of l-3-methoxy--(1-hydroxy-1-phenylisopropylamino) propiophenone hydrochloride (oxyfedrine) and ouabain in the canine heart-lung preparation (HLP) were studied taking particular notice of the changes of competence index and cardiac output. Both of these drugs caused potent cardiotonic effects in pentobarbital-induced heart failure but only slight effect on the normal heart. 280 g of oxyfedrine corresponded with 64 g of ouabain in this respect. Increasing doses of ouabain resulted in ventricular extrasystoles and fibrillation at 76 and 125 g respectively on the average, but no arrhythmia was observed even with 5 mg of oxyfedrine. Cardiotonic effect of oxyfedrine was prevented by pretreatment of the heart with propranolol but was intact in reserpinized HLP.     

Muscarinic inhibition of acetylcholine release from a novel in vitro preparation of the guinea-pig trachea

Summary An isolated preparation of the guinea-pig trachea is described which allows the simultaneous measurement of acetylcholine release and smooth muscle contraction. Incubation of the epithelium-free preparation with [³H]choline resulted in the formation of [³H]acetylcholine. Electrical stimulation caused the release of [³H]acetylcholine and a contractile response. Tetrodotoxin and omission of calcium from the medium abolished both the evoked release and contractions.The muscarinic agonists oxotremorine, carbachol and pilocarpine concentration-dependently inhibited the electrically evoked acetylcholine release and contracted the tracheal smooth muscle. Pre- and postsynaptic EC₅₀ values for a given agonist were not different. Atropine (100 nmol/l) significantly faciliated the evoked acetylcholine release. A concentration of 10 nmol/l atropine did not change the evoked release but antagonized the inhibitory effect of oxotremorine. It is concluded that presynaptic muscarine autoreceptors inhibit the release of acetylcholine from parasympathetic nerves of the guinea-pig trachea.Send offprint requests to G. D'Agostino at the above address     

Effects of low temperature and pharmacological interventions on the responses of the isolated guinea-pig trachea

Summary Cooling the guinea-pig isolated trachea from 37°C to 20°C virtually abolished the response to CaCl₂ (in K⁺-depolarized tissues) and depressed that to histamine (about 75% reduction), KCl and 5-hydroxytryptamine (around 50% inhibition) while the response to acetylcholine remained unaffected. A further cooling to 10°C was necessary to inhibit acetylcholine-induced contractions. Hyporesponsiveness to spasmogens by cooling was not associated with subsensitivity (increased EC₅₀) except for 5-hydroxytryptamine. Contractile responses to KCl (50 mmol/l), histamine (1 mmol/l) and 5-hydroxytryptamine (0.1 mmol/l) in a Ca²⁺-free EGTA (0.1 mmol/l)-containing solution were inhibited by cooling to 20°C but responses to acetylcholine (1 mmol/l) in the same experimental conditions were not affected. Cooling to 20°C after treatment with an antagonist (ouabain 10 µmol/l, amiloride 0.1 mmol/l or vanadate 0.1 mmol/l) or after incubation in K⁺-free medium or low Na⁺ (25 mmol/l) solution produced the same or greater inhibitions of tracheal responses to spasmogens than cooling alone. The guinea-pig trachea treated with phorbol 12,13-diacetate (PDA; 1 µmol/l) and cooled to 20°C responded to spasmogens similarly to a trachea untreated with PDA at 37°C. In contrast, PDA (1 µmol/l) did not counteract the depressed responsiveness to histamine of ouabain (10 µmol/l)- or amiloride (0.1 mmol/l)- treated tracheal strips at 37°C. PDA (1 mol/l) enhanced tracheal contractions caused by KCl (50 mmol/l) in Ca²⁺-free medium at 20°C but failed to augment those to histamine in the same conditions. PDA (0.1 or 1 µmol/l) did not change the concentration-response curve for Ca²⁺ in skinned trachea. In conclusion, low temperature inhibits the responses to spasmogens in the guinea-pig trachea. Probably, reduced temperature interferes with extracellular and intracellular sources of Ca²⁺ which are differently affected by various spasmogens. Alteration by cooling of the electrogenic Na⁺ pump, Na⁺/Ca²⁺ exchange system, and Ca²⁺-ATPase may participate in the decrease of tracheal responsiveness to agonists. Reversion by PDA of the inhibitory effect of low temperature suggests a role for protein kinase C in the cooling-induced changes of tracheal responses. Correspondence to J. Cortijo at the above address     

The effects of arachidonic acid, indomethacin and SC-19220 on guinea-pig tracheal muscle tone

The effects on guinea-pig tracheal muscle of a prostaglandin synthesis inhibitor, indomethacin, antagonist, SC-19220, and precursor, arachidonic acid have been studied in order to investigate the possible role of prostaglandins in the maintenance of respiratory smooth muscle tone. Indomethacin reduced the resting tone of the muscle, and increasing concentrations reduced the response to arachidonic acid without affecting the response to acetylcholine. Prostaglandins E₂ and F₂ caused contractions of indomethacin-relaxed muscle, and tachyphylaxis was induced by repeated exposure of the muscle to these agonists, but not to arachidonic acid. The prostaglandin antagonist, SC-19920 relaxed the muscle, and abolished its response to a standard dose of prostaglandin E₂. Increasing concentrations of SC-19220 reduced the responses to both arachidonic acid and large doses of prostaglandins E₂. The responses of tracheal muscle to arachidonic acid are concluded to be partly due to prostaglandin synthesis, supporting the hypothesis that this process maintains tracheal muscle tone.     

Differences in the prejunctional effects of methacholine and pilocarpine on the release of endogenous acetylcholine from guinea-pig trachea

We investigated the effects of the full muscarinic acetylcholine receptor agonist methacholine and the partial and putatively M₂-selective agonist pilocarpine on endogenous acetylcholine release from guinea-pig trachea by use of high-performance liquid chromatography with electrochemical detection. Atropine-induced increases in acetylcholine release were used to monitor the system.Electrical field stimulation (8 V, 30 Hz, 0.5 ms for 5 min)-induced acetylcholine release in the presence of neostigmine, with or without preincubation with choline to maximally enhance acetylcholine output, was increased to about 225% by 0.3 M atropine, indicating functional autoinhibition. However, methacholine (10 M) did not affect the acetylcholine release, whereas it was enhanced to 166% by 30 M pilocarpine. When electrical field stimulation was applied at lower intensity (8 V, 16 Hz, 0.1 ms for 5 min) and in the absence of neostigmine, an increase by 0.3 M atropine (to 177%) but a decrease of the acetylcholine release by 10 M methacholine (to 65%) and 30 M pilocarpine (to 63%) were observed. These results clearly demonstrate (i) that inhibition of evoked endogenous acetylcholine release from prejunctional nerve terminals in guinea-pig trachea can only be demonstrated under conditions of low junctional concentrations of acetylcholine, and (ii) that pilocarpine, as a partial muscarinic agonist, behaves as an antagonist under high junctional concentrations of the neurotransmitter.     

Cooling-induced contraction of trachea isolated from normal and sensitized guinea-pigs

Summary Fast (–7°C/min) cooling of guinea-pig isolated trachea produced a rapidly developing, transient contraction followed by relaxation. Cooling-induced contraction was dependent on temperature (30, 20 or 10°C) and responses in trachea obtained from actively sensitized guinea pigs were significantly greater (20 and 10°-C) than those observed in normal trachea. Cooling to 20°C was selected for subsequent experiments. Pre-treatment with sufficient concentrations of atropine, clemastine, cromoglycate, indomethacin, or nordihydroguaiaretic acid did not depress contraction to cooling in either normal or sensitized trachea. This indicates a direct effect of cooling. The contraction. produced by cooling was resistant to verapamil (1 mol/l) or dantrolene (0.3 mmol/l). Calmodulin antagonists (trifluoperazine, W-7 and calmidazolium; all of them at 10–100 mol/l) inhibited contraction in sensitized and normal trachea. Activators of protein kinase C (phorbol 12,13-diacetate, 1 mol/l) enhanced while inhibitors (H-7, 20 mol/l; staurosporine, 10 mol/l) depressed cooling-induced contraction in both normal and sensitized tissues. Incubation (20 min) in a Ca²⁺ -free solution inhibited cooling-induced contraction in normal but not in sensitized trachea. Exposure to a low Na⁺ (25 mmol/l) or a K⁺-free medium abolished contraction to cooling in normal and sensitized trachea. Ouabain (0.1–10 mol/l) and vanadate (0.01–5 mmol/l) inhibited cooling-induced-contraction to a greater extent in normal than in sensitized trachea. Polymyxin B (0.5 mmol/l) selectively depressed responses to cooling in sensitized trachea. In a separate series of experiments, it was shown that sensitized trachea was hyperresponsive to ouabain and vanadate. Previous cooling to 20°C abolished responses to ouabain but only attenuated those to vanadate. These results are compatible with an enhancement of Na⁺,K⁺-ATPase and Ca²⁺-ATPase activities in sensitized trachea and further support the notion that intracellularly stored Ca²⁺ plays a decisive role in the activation of sensitized tracheal muscle. Send offprint requests to J. L. Ortiz at the above address     

钾通道开放剂的抗过敏作用及其机制

用多种抗变态反应实验方法,研究钾通道开放剂米诺地尔(Min)与二氮嗪(Dia)的抗过敏作用,并探讨其作用机制。结果表明,Min能抑制大鼠同种被动皮肤过敏反应,拮抗5-HT引起的大鼠皮肤血管通透性增高。Dia和Min均能抑制豚鼠离体回肠平滑肌的过敏性收缩,Dia并能抑制A₂₃₁₈₇和化合物48/80诱发的肥大细胞释放组胺。因此钾通道开放剂Min与Dia具有抗过敏作用,作用的主要机理是抑制肥大细胞外Ca²⁺内流和细胞内贮存钙的释放,从而抑制组胺的释放,此可能与药物开放钾通道的作用有关。     

The effects of metoclopramide on acetylcholine release and on smooth muscle response in the isolated guinea-pig ileum

Summary The effects of metoclopramide on smooth muscle contraction and on release of acetylcholine were studied in the guinea-pig myenteric plexus longitudinal muscle preparation. Acetylcholine was determined either as endogenous acetylcholine, or as labelled transmitter from strips preloaded with ³H-choline.Metoclopramide caused an increase in resting tension of longitudinal muscle as well as an increase in resting output of either endogenous or labelled acetylcholine. Tetrodotoxin abolished the metoclopramide-evoked increase in transmitter release. The increase in smooth muscle tension was clearly related to the increase in resting output. The effects of metoclopramide on both longitudinal muscle contraction and resting release of labelled acetylcholine were prevented in the presence of a concentration of 5-hydroxytryptamine (5-HT) that desensitized 5-HT receptors. This suggests that metoclopramide stimulates neuronal 5-HT receptors and, thereby, facilitates acetylcholine release.Metoclopramide augmented the twitch-like contractions induced by field stimulation at 0.1 Hz. Contractions elicited at 1 Hz were only slightly enhanced. Similarly, metoclopramide facilitated only the release of labelled acetylcholine evoked by electrical stimulation at 0.1 Hz, but not that at 1 Hz. The facilitatory effetts of metoclopramide on twitch height and evoked release could not be attributed to a blockade of presynaptic inhibitory -adrenoceptors, dopamine or muscarine receptors.     

Studies on the release of histamine from isolated guinea pig mast cells stimulated by ionophore A23187 or by the anaphylactic reaction

Summary The divalent cation ionophore A23187 was found to produce a dose-dependent release of histamine from isolated mesenteric mast cells of the guinea pig. The process showed a specific requirement for calcium ions and was blocked by inhibitors of glycolysis.The effect of cAMP^**, theophylline, sympathomimetic amines and DSCG on the histamine release induced by the ionophore or by the antigen-antibody reaction was compared. In both cases, the release was inhibited by Bu₂cAMP and by theophylline but higher concentrations were required with the ionophore. Adrenaline, isoprenaline and DSCG were effective only in the anaphylactic system.These results are compared with those previously reported for human leucocytes and rat peritoneal mast cells in which the release produced by the ionophore was found not to be inhibited by cAMP and its analogues. On the basis of these findings, the possible role of cAMP in the modulation of histamine release is discussed.Parts of this work have been presented to the 18. Spring Meeting of the German Pharmacological Society, Mainz, March 1977     

腺苷受体激动剂在豚鼠离体气管螺旋条中的作用

腺苷在心血管已有广泛研究,其在气道中的作用已有报道[1]。腺苷受体激动剂Ｒ苯异丙基腺苷(Ｒｐｈｅｎｙｌｉｓｏｐｒｏｐｙｌａｄｅｎｏｓｉｎｅ,ＲＰＩＡ)在气道中作用如何呢?我们通过观察ＲＰＩＡ在豚鼠离体气管条中的作用,旨在了解ＲＰＩＡ对气道上皮及平滑肌的影响。1　材料与方法1.1　动物选择与处理　取Ｈａｒｔｌｅｙ豚鼠20只,♀♂不拘,体重(250±50)ｇ。用断头术击毙豚鼠,取整条气管,在Ｋｒｅｂｓ营养液内分离干净外面包绕的组织,分成长度相等的两段,随机取一段,用直径与之相似的毛玻璃棒去掉上皮,剪成螺旋条。另一段不去上皮,直接…     

Characterization of muscarinic receptors mediating release of epithelial derived relaxant factor (EpDRF) in guinea-pig isolated trachea

Summary Muscarinic receptors mediating the release of epithelial derived relaxant factor (EpDRF) have been studied by using both contractions of the guinea-pig tracheal strip (with epithelium intact or denuded) or a coaxial bioassay assembly (rat anococcygeus-recipient; guinea-pig trachea-donor tissue). Indomethacin (1 M/l) and physostigmine (0.1 M/l) were both present throughout the study.In the tracheal strip studies, the potencies and maximal effects of all agonists studied (acetylcholine, arecoline, bethanechol, carbachol, (+)cis-dioxolane, ethoxyethyltrimethylammonium, L-660,863, (±)methacholine and OXA-22) were not affected or were only slightly (but significantly) reduced by removal of the epithelium. The -log K_B for the muscarinic antagonists, atropine, pirenzepine, methoctramine and 4-DAMP (4-diphenyl-acetoxy-N-methylpiperidine) were also not affected and the -log K_B values were consistent with M₃ muscarinic receptor function. However, the -log K_B value of para-fluoro-hexahydro-siladifendol (p-F-HHSiD) was significantly (P < 0.05) increased upon epithelial denudation (epithelium intact, 7.1; epithelium removed, 7.6). The coaxial bioassay assembly provided more convincing evidence for release of EpDRF in that all muscarinic agonists studied caused relaxations of a precontracted anococcygeus tissue. These relaxations were observed only in the presence of a tracheal tube possessing an intact epithelium. The rank order of potencies for agonists at receptors mediating EpDRF dependent relaxation were similar to those estimated at receptors causing contraction. These data suggested that a substantial receptor reserve was associated with the receptors mediating both EpDRF release and contraction. The affinities of the muscarinic antagonists (atropine, pirenzepine, methoctramine, p-F-HHSiD, 4-DAMP and gallamine) indicated that M₃ receptors also mediated EpDRF release.It is concluded that EpDRF release in guinea-pig trachea is a general property of muscarinic agonists and that this process is mediated, like the contractile response, by M₃ receptors. Send offprint requests to R. M. Eglen at the above address     

Mediators of adenosine- and ovalbumen-induced bronchoconstriction of sensitized guinea-pig isolated airways

The mediators of bronchoconstriction of isolated lungs and trachea from ovalbumen sensitized guinea-pigs to adenosine and ovalbumen were examined using relevant antagonists. Changes in perfusion pressure and tension of paired lung halves and tracheal spiral strips, respectively, were recorded in response to adenosine (1 mM lung, 300 microM trachea), histamine (10 microM), methacholine (10 microM) and ovalbumen (10 microg). One half was perfused with antagonist while the other received vehicle. Tracheal strips were superfused throughout with the P(1) receptor antagonist 8-phenyltheophylline, to examine 8-phenyltheophylline-resistant responses. The histamine H(1) receptor antagonist, mepyramine (1.5 mM), the cyclooxygenase inhibitors, indomethacin (5 mM) and diclofenac (5 mM), the leukotriene receptor antagonist, zafirlukast (1 mM), and the lipoxygenase inhibitor, zileuton (20 mM), alone failed to inhibit bronchoconstriction by adenosine and ovalbumen of the lung and trachea. When two antagonists were combined, only mepyramine and zafirlukast significantly reduced the lung responses to adenosine and ovalbumen. The tracheal adenosine response was substantially reduced, although not significantly, while ovalbumen was significantly reduced. When mepyramine, indomethacin and zafirlukast were combined, the lung constriction by adenosine and ovalbumen were virtually abolished. Similarly, the combination of mepyramine, diclofenac and zafirlukast significantly attenuated the lung responses to adenosine and ovalbumen. Thus, histamine, cyclooxygenase products and leukotrienes alone are not responsible for the bronchoconstriction of isolated sensitized lung tissues to adenosine or ovalbumen, which appears to be due to the release of all three mediators.     

普罗托品松弛气管平滑肌的作用机制研究

目的　为评价普罗托品 (Pro)作为平喘药侯选者的可能性提供资料。方法　①观察不同浓度Pro对组胺、乙酰胆碱收缩的豚鼠离体气管螺旋条的舒张作用及其量效反应。②放射免疫法测定Pro对家兔气管平滑肌中环腺苷酸 (cAMP)、环鸟苷酸(cGMP)水平的影响。③高效液相色谱法检测Pro对豚鼠气管平滑肌磷酸二酯酶 (PDE)活性的影响。结果　①Pro能明显抑制组胺和乙酰胆碱引起的豚鼠离体气管条收缩 ,使其量效曲线右移 ,最大反应压低 ,pD2 ′分别为 3.11和 3.4 5。②Pro能增加家兔气管平滑肌中cAMP水平 ,而cGMP水平的变化无统计学意义。③Pro能抑制水解cAMP的PDE活性 ,但水解cGMP的PDE活性无明显降低。结论　Pro可抑制豚鼠气管平滑肌的收缩 ,其作用机制之一可能为其抑制气管平滑肌PDE活性 ,主要通过提高细胞中cAMP水平 ,进而松弛气管平滑肌     

骆驼蓬总生物碱对豚鼠离体气管平滑肌收缩功能的影响

目的研究骆驼蓬总生物碱对刺激因素诱发的豚鼠气管平滑肌收缩的影响。方法制备豚鼠离体气管平滑肌螺旋条,于恒温浴槽装置中,用乙酰胆碱、组胺和KCl刺激气管平滑肌,观察药物的作用。结果骆驼蓬总碱和鸭嘴花碱均可使乙酰胆碱、组胺的刺激量-效曲线明显右移,并呈剂量依赖性地抑制乙酰胆碱、组胺和KCl诱发的豚鼠气管平滑肌收缩。结论骆驼蓬总碱、鸭嘴花碱能够明显地抑制刺激因素诱发的豚鼠气管平滑肌收缩。     

去上皮对离体气管平滑肌反应性的影响(英文)

去上皮致敏豚鼠气管标本对乙酰胆碱。组胺,P物质和氯化钡的敏感性比未去上皮标本为高。上述药物在去上皮标本上得到的EC_(50)仅为未去上皮的1/6—1/30。由抗原抗体反应或电场刺激所引起的去上皮标本的收缩幅度和对照组相比升高了50％—100％。这些实验结果提示,气管上皮对呼吸道,尤其是对其过敏性收缩具有重要调节作用。     

Cardiostimulatory effects of oxyfedrine,DMPP and sympathomimetics in relation to their3H-noradrenaline-releasing properties

Summary The effect of noradrenaline, norephedrine, oxyfedrine and DMPP on isotonic contractions and release of³H-noradrenaline was studied using isolated perfused guinea-pig hearts.The spontaneous rate of³H-release was linear from 30–70 min after infusion of a tracer dose of 20 Ci noradrenaline. The calculated size of the labeled noradrenaline-pool of the heart was 5–10% of the total noradrenaline-content.Oxyfedrine (10 g) caused strong and long lasting positive inotropic effects but only a weak and transient increase of³H-release. Equimolar doses of 5g 1-norephedrine which is a component of the oxyfedrine molecule had no significant inotropic effect but caused similar increases in³H-release.Noradrenaline (0.5 g, a dose with maximum positive inotropic action) released more³H-activity from the heart than oxyfedrine.DMPP, a ganglion stimulating agent, in doses of 250 g, increased contractions significantly but had very little effect on³H-noradrenaline-release. An additional release of non-labeled noradrenaline is discussed as explanation of the positive inotropic action of DMPP.After repeated administration of DMPP in large doses, the increase in contraction and³H-release was abolished. In this state of tachyphylaxis oxyfedrine also failed to release³H-noradrenaline but retained its full inotropic effect.The results do not provide evidence that a releasing effect on labeled and/or non-labeled endogenous noradrenaline significantly contributes to the positive inotropic action of oxyfedrine. This finding supports the view that oxyfedrine stimulates the heart by adirect action on sympathetic-receptors.     

Effect of Montelukast on bradykinin-induced contraction of isolated tracheal smooth muscle of guinea pig

Aim:

To explore the effect of montelukast on bradykinin-induced tracheal smooth muscle contraction of isolated guinea pig trachea.

Study Design:

To study the effect of bradykinin in the absence and in the presence of montelukast on the isolated tracheal smooth muscle of a guinea pig pretreated with indomethacin (10^-6M), phentolamine (10^-5M), and propranalol (10^-6M), to eliminate the effect of endogenous prostaglandins and catecholamines. The trachealis smooth muscle activity was recorded through the Isometric Force Displacement Transducer on a Four Channel Oscillograph. A cumulative dose-response relationship was demonstrated by adding successive doses of bradykinin on the tracheal strips, starting with 11 μg to 77 μg of 10^-4 concentration. A similar procedure was repeated in the presence of montelukast 0.5 μg/ml, which, was equal to approximate C_max achieved in vivo with a 10 mg oral dose of montelukast, and in the presence of 1 μg/ml of montelukast.

Statistical Analysis:

Data was expressed as mean ± standard error (SEM), and was analyzed using the SPSS version 15. A P value of less than 0.05 was considered significant.

Results:

Bradykinin produced a dose-dependent, reversible contraction of isolated tracheal smooth muscle. Montelukast significantly reduced the bradykinin-induced tracheal smooth muscle reactivity and shifted the bradykinin curve to the right and downwards, in the presence of both concentrations of montelukast. The mean magnitude of response achieved with 77 μg of bradykinin in the absence of montelukast was 39 mm ± 6.26, in the presence of 0.5 μg/ml of montelukast it was 24.17 mm ± 4.11, and in the presence of 1 μg/ml of montelukast it was 13 mm ± 2.6.

Conclusion:

It is concluded that montelukast significantly inhibits, in a dose-dependent manner, the bradykinin-induced contraction of the guinea pig tracheal smooth muscle, and alludes to an interaction between the bradykinin and leukotriene mediators.