白三烯拮抗剂ONO-1078对电刺激迷走神经、辣椒素和P物质引起的豚鼠心血管反应的作用(英文)

阐明ONO-1078(ONO,4-氧-8-[对-(4-苯丁氧基)苯甲酰氨基]-2-(5-四唑基)-4H-1-苯并毗喃)对神经原性刺激诱导心血管反应的作用.方法:观察豚鼠心房和心室伊文思蓝渗出以及平均主动脉压(MAP)变化.结果:在阿托品(1 mg·kg~(-1),iv)预先处理后,电刺激迷走神经(ESV,10 Hz,5 ms,2或10 V,90 s)显著增高伊文思蓝渗出;辣椒素和P物质也增加染料渗出并降低平均动脉压(MAP).ONO(0.03,0.1 mg·kg~(-1),iv)抑制ESV的反应,在刺激强度低(2 V)时更明显;ONO 0.03 mg·kg~(-1)减弱辣椒素引起的微血管渗漏和低血压,但对P物质无影响.结论:ONO-1078可能通过抑制感觉神经肽释放而调节神经原性炎症时的心血管反应.     

Capsaicin pretreatment reduces the gastric acid secretion elicited by histamine but does not affect the responses to carbachol and pentagastrin

Gastric acid secretion was studied following stimulation with a subcutaneous injection of histamine (0.1, 0.5 or 5 mg/kg), carbachol (4, 40 or 160 micrograms/kg) or pentagastrin (25 or 250 micrograms/kg) in conscious rats pretreated with either capsaicin or the vehicle. The secretory response to histamine (0.5 or 5 mg/kg) was greatly reduced in the capsaicin-treated rats, while the slight effect of 0.1 mg/kg histamine and the increase of secretion in response to carbachol and pentagastrin were not affected. The basal secretion was also normal in the capsaicin-treated rats. It is suggested that unlike the effects of carbachol and pentagastrin, the increase of acid secretion elicited by histamine involves a capsaicin-sensitive mechanism. Since capsaicin is a specific neurotoxin for the peptide-containing primary sensory neurons, the present results may indicate that the neurons contribute essentially to the effect of histamine on gastric acid secretion.     

Anomalous responses to histamine stimulation of guinea-pig oesophageal muscularis mucosae.

The incomplete tachyphylaxis of the contractile response to the H1-stimulants observed on guinea-pig oesophageal muscularis mucosae seems to be H2- and H3-antagonist as well as atropine- and tetrodotoxin-resistant. Lidocaine and eserine partially prevented this process probably by a mechanism independent of their main activity. The dualistic antagonism exerted by mepyramine and methysergide on reproducible histamine responses could be explained by a kinetic condition of "hemi-equilibrium state" together with changes of drug-receptor interaction and by non-specific properties of methysergide. On the whole, the present data indicate that the role of histamine in this tissue has still to be defined.     

Capsaicin in adult frogs: Effects on nociceptive responses to cutaneous stimuli and on nervous tissue concentrations of immunoreactive substance P,somatostatin and cholecystokinin

Summary Adult frogs (Rana esculenta) were given subcutaneous injections of 10, 20, 30, 50 and 100 mg/kg capsaicin in sequential order over 5 days, or the vehicle only. The nociceptive thresholds to electrical, thermal and chemical stimuli were measured before, and 1, 5 and 24 h after each injection. Capsaicin was followed by a dose-related reduction of nociceptive responses to all stimuli, but these effects lasted for only 1–5 h after the given injection. Water/acetic extracts of undivided brains and spinal cords were prepared at the corresponding time periods for the radioimmunoassay of peptides. Spinal cord concentrations of immunoreactive substance P were essentially unaffected by capsaicin, while those of immunoreactive somatostatin were significantly increased after the second for fourth injections (20, 30 and 50 mg/kg) of capsaicin. Brain extracts showed an increase of somatostatin and substance P concentrations after the dose of 50 mg/kg. In an additional experiment, immunoreactive substance P, somatostatin and cholecystokinin were measured in tissue samples taken at 2 and 10 min, and 1, 5 and 24 h after a single dose of either 50 mg/kg capsaicin or the vehicle. The only signficant effect of capsaicin was an increase of immunoreactive somatostatin concentration in brain homogenates at 5 h, while the vehicle in itself elicited major variations of all three peptides in spinal cord and/or brain. These results indicate that capsaicin reduces the nociceptive responses to cutaneous stimuli in adult frogs. This effect is transient, and bears no clear relationship to the variations of spinal cord nor of brain concentrations of immunoreactive substance P, somatostatin and cholecystokinin. In the present experimental conditions, the effects of the vehicle injection to neuropeptides far exceeded those of capsaicin itself.     

Nocturnal asthma, histamine and vagal activity

In a study of two groups of nine allergic asthmatic children, consisting of one group with (group I) and one group without (group II) increased nocturnal airflow obstruction, we determined whether an increase in vagal activity, or inflammatory mediators like histamine are responsible for the nocturnal increase in airflow obstruction. The results of investigations in the two groups of asthmatics were compared to the results of an age matched control group. Forced expiratory volume in one second (FEV1) and electrocardiogram recordings of one minute were obtained every 4 hours during 24 hours. Heart rate and sinus arrhythmia gap were used to express vagal activity indirectly. N tau-methylhistamine was determined in urine samples collected in periods of 4 hours between the measurements. In group I, overall N tau-methylhistamine excretion was on a higher level than in both other groups, and was significantly higher overnight. Parasympathetic stimulation did not seem of importance to the increase of airflow obstruction at night.     

Effects of vagal perineural capsaicin treatment on vagal efferent and airway neurogenic responses in anesthetized rats

The acute effect of vagal perineural capsaicin treatment (VPCT) on parasympathetic bradycardia and tracheal neurogenic protein extravasation was examined. In nine anesthetized male Wistar rats the effect of VPCT on the bradycardia induced by electrical stimulation of the vagus was examined. In 24 anesthetized male Wistar rats the effect of VPCT on the tracheal protein extravasation induced by the inhalation of capsaicin aerosols was also studied. VPCT did not alter the bradycardia induced by vagal stimulation or the tracheal protein extravasation induced by the inhalation of capsaicin aerosol. The results of these studies further demonstrate the selectivity of perineural capsaicin treatment on vagal sensory nonmyelinated fibers in the rat and indicate that it is a useful tool for examining the role of sensory vagal C-fibers in pulmonary and cardiovascular reflexes and in isolating C-fiber-mediated reflex responses from those mediated by the release of neuropeptides.     

Modulation of bronchoconstrictor responses to histamine in pithed guinea-pigs by sympathetic nerve stimulation.

1 Electrical stimulation (40V, 0.5-8 Hz, pulse width 0.5 ms) of the thoracic spinal outflow for between 10 and 120 s inhibited histamine-induced bronchoconstriction in pithed guinea-pigs. 2 The degree of this bronchodilatation varied with the position of the stimulating electrode within the spinal canal. Two maxima were identified. The first, at the level of the 9th and 10th thoracic vertebrae, was abolished by adrenalectomy. The second, at the level of the 3rd and 4th thoracic vertebrae, was associated with tachycardia and was unchanged by adrenalectomy. 3 The magnitude of this second bronchodilator effect varied with the frequency of stimulation. It was abolished by pretreatment with reserpine (5 mg/kg i.p. 48 and 24 h beforehand) and was competitively blocked by propranolol (0.01-1.0 mg/kg). 4 These observations are consistent with the view that bronchodilator tone is derived from neuronally-released noradrenaline within the lung. The noradrenaline probably overflows from well-innervated vasculature adjacent to sparsely innervated airways.     

Pharmacological properties of mechanical responses of the rat oesophageal muscularis mucosae to vagal and field stimulation.

Electrical stimulation applied to vagal oesophageal branches of the isolated curarized oesophagus, or via field electrodes to the isolated tunica muscularis mucosae (TMM), increased longitudinal tension and intraluminal pressure in a frequency-dependent manner. Differences between cervical and distal TMM segments were noted in frequency-response relationships, as well as in the pulse-width dependence of contractions to field stimulation. Vagally- and field-stimulated contractions were eliminated by tetrodotoxin or hyoscine, indicating their mediation by cholinergic neurones. The field-stimulated postganglionic responses were resistant to hexamethonium or (+)-tubocurarine and weakly inhibited by morphine. Vagally- and field-stimulated TMM contractions were mimicked by muscarinic agonists, augmented by acetylcholinesterase inhibitors, and inhibited more effectively by beta-than by alpha 1-or alpha 2-adrenoceptor agonists. 5-Hydroxytryptamine (5-HT) exerted excitatory and/or inhibitory effects: TMM in situ responded with a hexamethonium-resistant, ketanserin-sensitive transient increase in tension comparable to that produced by field stimulation. In the isolated TMM, moderate excitatory responses were limited to the distal portion with inhibition predominating in the remaining proximal portion. 5-HT-induced inhibitory effects on field-stimulated tension responses were paralleled by relaxant effects on muscarinic agonist-induced tonic contractile responses, both of which were resistant to 5-HT-receptor antagonists including ketanserin, lysergic acid diethylamide (LSD), methysergide or methergoline. Field stimulation at a low frequency and pulse durations greater than 1.0 ms produced a relaxation response in preparations exposed to tetrodotoxin or hyoscine, provided that active muscle tonus was present. The relaxation in response to field stimulation was insensitive to antagonists of 5-HT, catecholamines, histamine, or indomethacin, suggesting a non-neurogenic origin. Histochemical examination of the isolated TMM preparation for cholinesterases revealed the presence of an extensive submucosal ganglionic plexus. It is concluded that: (i) intrinsic cholinergic neurones of the submucosal plexus form the final common pathway for extrinsic vagal and local (myenteric) projections to the TMM; (ii) the neural basis, if any, of non-cholinergic non-adrenergic inhibitory mechanisms remains to be established; (iii) the TMM may assist in generating propulsive oesophageal motility.     

Sympathoadrenal mechanisms underlying cardiovascular responses to intrathecal substance P in conscious rats.

The sympathoadrenal mechanisms underlying cardiovascular responses to intrathecal (i.th.) injection of substance P (SP), at the T-9 spinal level, were investigated in conscious rats. Release of norepinephrine (NE), and epinephrine (EPI) could be induced by 6.5, 16.25, and 32.5 nmol SP correlated with a pressor and a positive chronotropic response. Release of neuropeptide Y (NPY) was evoked also by 32.5 nmol SP, and released NPY appears to derive from the adrenal medulla. The initial pressor response in intact rats is mediated by NE from sympathetic fibers, whereas the latent pressor response, observed in sympathectomized rats, is possibly due to NPY from the adrenal medulla. Although a functional balance between the sympathetic fibers and the adrenal glands is supported by the results, it appears that only the tachycardia can be efficiently produced by the adrenals in the absence of the sympathetic fibers. This study supports a functional role for SP in regulation of the sympathoadrenal system at the spinal level.     

Attenuation of human nasal airway responses to bradykinin and histamine by inhibitors of nitric oxide synthase.

1. The effects of inhibitors of nitric oxide synthase and local anaesthetics were studied on changes in human nasal airway patency and albumin extravasation in response to bradykinin and histamine, in vivo. 2. Compared with the action of the vasoconstrictor, ephedrine, 2.5 mumol, NG-nitro-L-arginine methyl ester (L-NAME), 1 mumol alone, did not change the resting value of the minimal cross-sectional area (A min) of the human nasal airway. L-NAME, 0.1 to 10 mumol, produced a dose-related inhibition of the reduction in A min caused by bradykinin, 300 micrograms. NG-monomethyl-L-arginine (L-NMMA), 1 mumol, similarly reduced the effect of bradykinin, 300 micrograms, on A min, but NG-nitro-D-arginine methyl ester (D-NAME), had no effect. L-NAME, 0.1 to 10 mumol, or L-NMMA, 10 mumol, failed to inhibit the effect of histamine, 300 micrograms on A min. 3. The inhibition by L-NAME, 1 mumol of the action of bradykinin, 300 micrograms on A min was maximal between 15 and 30 min after pretreatment with L-NAME. 4. L-NAME, 1 and 10 mumol, inhibited the extravasation of albumin into the nasal cavity induced by bradykinin, 300 micrograms, and also by histamine, 300 micrograms. D-NAME, 1 and 10 mumol had no effect on the extravasation of albumin in response to bradykinin or histamine. 5. L-Arginine, 30 mumol, reversed the effect of L-NAME, 1 mumol, on the bradykinin- and histamine-induced albumin extravasation into the nasal airway. 6. Local anaesthesia of the nasal airway with lignocaine, 10 mg, or benzocaine, 10 mg, failed to inhibit the reduction in A min or the albumin extravasation induced by either bradykinin, 300 micrograms, and histamine, 300 micrograms. 7. We conclude that the extravasation of plasma albumin caused by bradykinin and by histamine involves the generation of nitric oxide. The nasal blockage induced by bradykinin involves nitric oxide generation but the nasal blockage induced by histamine does not.     

Sensory responses of human skin to synthetic histamine analogues and histamine.

The potential for itch production in human skin of the synthetic analogues of histamine, 2-methyl histamine (an H1-receptor agonist) and 4-methyl histamine and dimaprit (H2-receptor agonists) has been studied in vivo and compared with histamine. Itch thresholds for 2-methyl histamine were consistently much higher than for histamine (P < 0.001). The H1-receptor antagonist chlorpheniramine raised the itch thresholds to 2-methyl histamine and histamine significantly (P < 0.001). Pruritus was not obtained with either 4-methyl histamine or dimaprit. No evidence of synergism between 2-methyl histamine and either 4-methyl histamine or dimaprit was found. The results suggest that histamine-induced pruritus is mediated in part through the H1-receptor and in part via an additional (but probably non-H2) mechanism.     

Clonidine reduces substance P binding in rat spinal cord membrane preparation.

The effects of clonidine on substance P (SP) binding was investigated using rat brain and spinal cord membrane preparations preincubated with various concentrations of clonidine. [3H]SP specific binding in the spinal cord was significantly decreased with 10(-4) M clonidine, but no effect on binding was seen in the brain. Scatchard analysis of SP binding indicated that Bmax was significantly depressed without changing the affinity. The mechanism of clonidine-induced analgesia includes a spinal neural component and action on the SP receptors.     

Role of cholinergic, vagal reflexes on the bronchoconstrictor responses to histamine during carbon dioxide inhalation in conscious guinea-pigs

Histamine-induced bronchoconstriction in conscious guinea-pigs involves a cholinergic, bronchoconstrictor reflex, but the role of this reflex during elevated levels of inspired carbon dioxide is unknown. In this study we examined the role of cholinergic, vagal reflexes on the bronchoconstrictor responses to histamine during CO2 inhalation. Guinea-pigs were placed inside a whole body plethysmograph for measurement of tidal volume (VT), respiratory rate (f) and minute volume (V) and a head chamber was used to deliver a hypercapnic gas mixture (10% CO2, 21% O2, 69% N2) and for inhalation of aerosolized drugs. Inhalation of CO2 caused an increase in VT, f and V and these effects were reduced by exposure to aerosolized histamine (0.01-0.05% for 30 s). The histamine-induced reduction of VT was significantly (P less than 0.05) attenuated following a 60 s exposure to inhaled atropine (0.03 and 0.1%) as was the reduction of VT due to inhaled methacholine. Intravenous atropine (1 mg/kg) also blocked the VT reduction due to aerosolized histamine. Intravenous administration of the ganglionic blockers hexamethonium (1 mg/kg) and mecamylamine (10 mg/kg) did not inhibit the histamine-induced reduction of VT at doses of these drugs that revealed systemic evidence of ganglionic blockade, i.e. inhibition of vagally stimulated bronchoconstriction and bradycardia. The results demonstrate that the bronchoconstrictor responses to histamine during CO2 inhalation in guinea-pigs involves stimulation of airway cholinergic receptors, but this response does not involve ganglionic neurotransmission. It is speculated that histamine's bronchoconstrictor effects during CO2 breathing involves stimulation of postganglionic, parasympathetic nerves innervating airway smooth muscle.     

Gastric motor responses elicited by vagal stimulation and purine compounds in the atropine-treated rabbit.

1. The effects of vagal inhibitory stimulation and of purine compounds were studied in the rabbit stomach. 2. Gastric motility was assessed by the balloon method. Vagal nerves were electrically stimulated at the neck. Purine compounds were injected intra-arterially. 3. In the atropine-treated rabbit, vagal stimulation caused relaxant motor responses followed by a rebound contraction. 4. Among the purine compounds, only ADP and ATP caused relaxant motor responses similar to the effects of vagal inhibitory stimulation. However, the relaxation produced by ATP was more powerful than that due to ADP, especially at lower infusion rates. 5. Vagal inhibitory responses were recorded during and after infusion of ATP. When relaxation by ATP was fully developed, vagal inhibitory stimulation was ineffective. At the highest infusion rates of ATP, a depression of the vagal inhibitory motility was also observed after cessation of the infusion. 6. Relaxant responses to ATP and vagal inhibitory stimulation were not influenced by theophylline, scarcely affected by alpha,beta-methylene ATP, but were reduced or blocked by reactive blue 2. 7. The results are consistent with ATP being an inhibitory neurotransmitter in the stomach of the rabbit.     

迷走神经刺激预处理对急性心肌缺血大鼠心肌P物质和降钙素基因相关肽的影响

目的观察迷走神经刺激预处理对急性心肌缺血大鼠心肌组织缺血区和非缺血区P物质(SP)和降钙素基因相关肽(CGRP)表达的影响。方法健康成年雄性SD大鼠24只,体质量270~300g,随机分为3组,每组8只,假手术组(S组)、单纯冠状动脉结扎组(I组)和迷走神经刺激预处理冠状动脉结扎组(VS组)。S组大鼠开胸后在冠状动脉左前降支下穿线不结扎;Ⅰ组大鼠开胸后结扎冠状动脉左前降支;VS组大鼠实施迷走神经刺激30min后结扎冠状动脉左前降支。各组在手术后计时3h。采用免疫组织化学、酶免疫法和反转录-聚合酶链反应法从蛋白和基因水平观察各组大鼠缺血区和非缺血区心肌SP和CGRP的表达。结果Ⅰ组大鼠缺血区心肌SP/SP mRNA和CGRP/β-CGRP mRNA的水平较S组升高(P<0.05),VS组低于Ⅰ组(P<0.05),但仍高于S组(P<0.05)。非缺血区各组的变化趋势类同缺血区,但各扎闭冠状动脉组SP/SP mRNA和CGRP/β-CGRP mRNA的水平均低于相应组缺血区的水平(P<0.05)。结论迷走神经刺激预处理可降低急性心肌缺血大鼠心肌组织SP和CGRP的表达,提示迷走神经刺激预处理可能参与缺血心肌的保护。