Inhibitory histamine H3-receptors on cholinergic nerves in human airways

The histamine H3-agonist, (R)-alpha-methylhistamine (alpha-MeHA) caused a dose-dependent inhibition of cholinergic contractile responses to electrical field stimulation in human bronchi without affecting the basal tone. alpha-MeHA, but, did not alter the response to acetylcholine. Blockade of H1- and H2-receptors, or alpha- and beta-adrenoceptors failed to prevent the inhibitory effect of alpha-MeHA, whereas the specific H3-antagonist, thioperamide, was effective. Our results indicate that H3-receptors modulate cholinergic neurotransmission in human airways.     

Inhibitory effect of streptozotocin-induced diabetes on non-cholinergic motor transmission in rat detrusor and its prevention by sorbinil.

1. Non-cholinergic motor transmission in the urinary bladder of streptozotocin (STZ)-diabetic rats was studied by recording contractile activity of strips of detrusor in vitro. 2. The neurogenic contractile responses to electrical field stimulation (EFS) of atropine-treated detrusor strips were decreased in 4, 8 and 12 week STZ-diabetic rats. The decrease was most marked in 12 week diabetic rats and least in 4 week ones. 3. Concentration-response curves showed no change in sensitivity of the detrusor to acetylcholine (ACh) in diabetic rats. The maximum tension generated by ACh was similar in diabetic and non-diabetic animals. 4. The contractile responses to EFS at frequencies greater than or equal to 1 Hz were not maintained during stimulation. The 'fade' was significantly greater in detrusor strips of diabetic rats. 5. The contractile response of detrusor to EFS was significantly greater in 12 week diabetic rats treated with the aldose reductase inhibitor sorbinil, than in untreated 12 week diabetic rats. The sensitivity to ACh was similar in the two groups. 6. It is concluded that the reduction of the neurogenic non-cholinergic responses of detrusor to EFS in STZ-diabetic rats is probably caused by a reduction in the release of the non-cholinergic motor transmitter. The results are discussed in relation to bladder dysfunction in human diabetes mellitus.     

Inhibitory effect of capsaicin on mouse lung tumor development

The modification potentials of capsaicin on the development of pulmonary adenoma in newborn NIH (GP) mice were examined. Mice were given a single subcutaneous injection of 1 mg of benzo(a)pyrene (BP) or 40 micrograms of 9,10-demethyl-1,2-benzanthracene (DMBA) within 24 hours after birth and then 0.01% capsaicin (CAP) in the diet (Groups 1 and 2) for 6 weeks after weaning. Mice of groups 3, 4, 5 and 6 were given capsaicin, BP, DMBA and vehicle alone. All mice were sacrificed at week 9. Capsaicin caused a significant inhibitory effect on the frequency of tumor-bearing mice (BP-treated group) and the mean number of tumor (DMBA-treated group). The inhibitory activity is most profound in the group of female mice given DMBA combined with capsaicin. These results showed that capsaicin has inhibitory potential in the mouse lung tumor development induced by polycyclic aromatic hydrocarbons (BP and DMBA).     

Inhibitory action of capsaicin on cholinergic responses induced by GABAA agonists in the guinea-pig ileum

Pretreatment of the guinea-pig ileum with capsaicin resulted consistently in depression of the neurogenic cholinergic contractions induced by the GABAA receptor agonists 3-aminopropane sulphonic acid (3-APS) and muscimol. Since capsaicin acts mainly by releasing and depleting substance P from its stores in intestinal nerves, it is likely that substance P plays a role in the response caused by GABAA-mimetic compounds, On the whole, our results suggest that excitatory responses to 3-APS and muscimol result from both direct and indirect activation of intrinsic intestinal cholinergic neurons innervating smooth muscle cells.     

山莨菪碱抑制离体交感神经节的胆碱能突触传递

了解山莨菪碱（Ａｍ）对交感神经节细胞烟碱型乙酰胆碱（Ａｃｈ）受体的作用。用离体蟾蜍椎旁神经节细胞内记录技术观察Ａｎｉ对胆碱能突触传递的影响。Ａｎｉ０．１～１．０ｍｍｏｌ·Ｌ－１灌流１５～２０ｍｉｎ（ｎ＝２８），对电刺激交感节前纤维诱发的顺行动作电位，可有起始段上升速率减慢、超极化后电位增大、去极化后电位减小以及在１．０ｍｍｏｌ·Ｌ－１使５７％的细胞（４／７）顺行动作电位发放率下降或完全取消等作用，其综合抑制有效率在０．１，０．３，１．０ｍｍｏｌ·Ｌ－１分别为２０％，５０％和１００％。另外，Ａｎｉ还可逆地降低外源性Ａｃｈ电位的幅度并缩短时程（ｎ＝３）。结论：高浓度Ａｎｉ对交感神经节细胞的烟碱型Ａｃｈ受体有一定的阻断作用。     

Inhibitory effect of adenosine on transmission in sympathetic ganglia

Summary The effect of bath-applied adenosine on transmission in the isolated superior cervical ganglion of the rat was investigated. The compound post ganglionic action potential was recorded as an index of ganglionic transmission. Adenosine and 2-chloroadenosine were equipotent in producing a dose-dependent inhibition of the amplitude of the compound action potential. At the highest concentration tested (1 mM) adenosine and 2-chloroadenosine produced about 30% decrease in the amplitude of the compound action potential. This inhibitory effect was antagonized by theophylline (1 and 100 M) which by itself had no significant effect on ganglionic transmission. The adenosine uptake blocker dipyridamole (1 and 100 M) failed to potentiate the inhibitory action of adenosine. Both 4-aminopyridine (20 M) and high frequencies of stimulation (3, 10 and 20 Hz) were effective in nearly completely abolishing the inhibitory effect of adenosine on ganglionic transmission.The results suggest that the inhibitory effect of adenosine on ganglionic transmission may be the result of activation of presynaptic adenosine receptors in the ganglion.     

Non-adrenergic non-cholinergic excitatory innervation in the airways: role of neurokinin-2 receptors

1 The hypothesis that the non-adrenergic, non-cholinergic excitatory (NANC-e) innervation is involved in the induction of asthma and that antagonists of NANC-e neurotransmitter could reduce bronchoconstriction during asthma was tested. 2 The first objective was to identify the neurotransmitter(s) of NANC-e innervation from a group of selected putative neurotransmitters. The second objective was to use the antagonist of the identified neurotransmitter(s) to determine its effectiveness against bronchoconstriction to ovalbumin (OVA) in sensitized guinea-pigs. 3 Neurotransmitter identification was performed using the "tracheal pouch"', a surgical preparation established for demonstrating NANC innervation, in anaesthetized guinea-pig airways. A segment of trachea was cannulated and clamped at one end and the other end was connected to a pressure transducer. The stump of the trachea was connected to a ventilator to keep the blood gas values within the normal range. The vagus nerve and the sympathetic nerves were isolated bilaterally and cut. The left carotid artery was cannulated to monitor blood pressure and for sampling blood for blood gas analysis. The jugular vein was cannulated for administration of test agents. 4 Both NANC-e and NANC-i (inhibitory) control responses of airways were obtained by bilateral vagal stimulation after complete autonomic blockade with atropine, propranolol and prazosin. The relaxation of the tracheal pouch was indicative of the NANC-i response and the increase in insufflation pressure of the ventilated peripheral airways was due to NANC-e stimulation. 5 The involvement of the putative neurotransmitters such as neurokinin-A (NK-A), histamine, serotonin and endothelin (ET) was investigated by using the respective antagonists, MEN-10376, pyrilamine maleate, cyproheptadine hydrochloride, and two ET receptor antagonists (BQ-123 and IRL-1038), respectively. The antagonists were administered at the dose rate of 4 mg kg-1 i.v. which was determined from preliminary studies by testing against the respective agonists. 6 MEN-10376 (neurokinin-2 receptor antagonist) significantly inhibited the insufflation pressure (peripheral airway pressure) increase caused by NANC-e stimulation. MEN-10376 also inhibited the fall in blood pressure caused by bilateral vagal stimulation. The 5-HT antagonist, cyproheptadine, significantly enhanced the NANC-e response. 7 After identifying the NANC-e neurotransmitter as NK-A, the effectiveness of its antagonist, MEN-10376, was evaluated for its ability to attenuate the increase in insufflation pressure (bronchoconstriction) induced in guinea-pigs sensitized by OVA. Guinea-pigs were sensitized to OVA (200 mg i.p.) and 10 days later prepared for the determination of tracheal pouch and insufflation responses to 100 microg of OVA administered i.v. (challenge dose). This caused an increase in insufflation pressure in the presence of adrenergic and cholinergic blockade, which was significantly attenuated by MEN-10376. 8 These studies indicated that neurokinin-2 receptors were involved in the vagally mediated efferent neurotransmission of NANC-e and that NANC-e plays a role in allergen-induced bronchoconstriction.     

痛啡肽抑制豚鼠气道兴奋性非肾上腺素能非胆碱能反应

目的:研究痛啡肽(Nociceptin,NC)及U-50488H对豚鼠离体支气管环的非肾上腺素能非胆碱能兴奋(eNANC)所致收缩的抑制作用。方法:记录电场刺激及辣椒素引起标本eNANC反应的收缩张力,了解NC及U-50488H的作用。结果:NC 0.001-0.1μmol·L~(-1)可抑制标本的eNANC收缩。与对照组相比,NC 0.01μmol·L~(-1)抑制收缩达(43±31)％;预用纳洛酮0.1μmol·L~(-1)后,NC仍抑制收缩达(46±28)％。IC_(50)(95％可信限)是6.12(3.8-9.9)nmol·L~(-1)。U-50488H 0.01 -1μmol·L~(-1)可抑制eNANC收缩,其IC_(50)(95％可信限)为1.08(0.5-2.2)μmol·L~(-1),但是U-50488H 0.1μmol·L~(-1)的抑制作用可被纳洛酮0.1μmol·L~(-1)完全取消。辣椒素0.01-1μmol·L~(-1)可引起eNANC收缩,NC 0.01μmol·L~(-1)和U-50488H 0.1μmol·L~(-1)均不能明显影响辣椒素的作用。外源性神经激肽A 0.01μmol·L~(-1)引起的收缩不受NC和U-50488H 0.1μmol·L~(-1)的影响。结论:NC非纳洛酮敏感地抑制电场刺激引起的豚鼠气道eNANC反应;U-50488H通过激动阿片受体而抑制电场刺激引起的豚鼠气道eNANC反应。     

Presence of non-cholinergic motor transmission in human isolated bladder

Atropine-sensitivity of the motor transmission in the isolated detrusor preparation from human bladder has been examined. The preparations were contracted by electrical field stimulation consisting either of short trains of pulses or of long trains of pulses. Part of the stable response to short-train stimuli (28%) was resistant to atropine, was not potentiated by physostigmine and was blocked by tetrodotoxin. The stable responses to long-train stimuli were fully blocked by atropine. It is concluded that the detrusor of the bladder in man, in common with other mammalian species, contains a noncholinergic component in its motor transmission, and that prolonged stimulation with long-train stimuli causes an extinction of the non-cholinergic motor transmission, probably through depletion of transmitter stores in the nerve-terminals.     

Inhibitory effect of lead on 5-hydroxytryptamine induced contractions of isolated ileum of rat

The present study examined the effects of lead (Pb) on the 5-hydroxytryptamine (5-HT) contracture and calcium (Ca++) kinetics of ileum of rat. Isolated ileum preparations incubated in excess Ca++ (2.8 mM) or in Ca++ free Tyrode solution showed decrease in sensitivity to 5-HT. The inhibitory action of Pb reduced the sensitivity and decrease maximum responses to 5-HT in any Mg++ concentration of the medium. In the normal Ca++ and its deficient medium deterioration in sensitivity to Pb and the relevant maximum response to 5-HT were observed. In excess Ca++, the Pb effect depressed corresponding to its maximal response to 5-HT. The presence of EDTA depressed the Pb effect irrespective of the Ca++ influence on the receptors. Thus Pb may be inhibiting responses to 5-HT by interfering Ca++ utilization.     

Inhibitory effect of noradrenaline uptake inhibitors on contractions of rat aortic smooth muscle.

1 The effects of noradrenaline (NA) uptake inhibitors on contractions induced by NA, high K+, and 12-O-tetradecanoylphorbol-13-acetate (TPA) in rat isolated aorta were investigated. 2 Protriptyline (0.3 microM) and amitriptyline (0.3 microM) produced an approximately parallel shift to the right in the dose-response curve to NA. Protriptyline (> 0.3 microM), amitriptyline (> 0.3 microM) and xylamine (0.01-1 microM) significantly reduced the maximal contractile response to NA. The IC50 values for inhibition of the contractile response to 3 microM NA were 1.58 microM for xylamine, 1.70 microM for amitriptyline and 2.57 microM for protriptyline. 3 Protriptyline and amitriptyline dose-dependently inhibited the high K+ (60 mM)-induced contraction (IC50 = 0.69 microM for protriptyline and IC50 = 3.15 microM for amitriptyline). In contrast, xylamine did not affect the high K(+)-induced contraction. 4 Protriptyline and amitriptyline dose-dependently inhibited TPA (1 microM)-induced contraction in calcium-free solution; xylamine (up to 30 microM) was without effect. Staurosporine (10 nM) completely inhibited the TPA- and NA-induced contraction. 5. Protriptyline (3 microM) and amitriptyline (3 microM) caused about 54% and 60% inhibition, respectively, of aortic contractions caused by endothelin-1 (10 nM) in the absence of endothelium. Xylamine (10 microM) was without effect. 6 Inhibitory effects of NA uptake inhibitors on contractions were independent of the presence of endothelium and were unaffected by the K+ channel blockers, tetraethylammonium ions (up to 3 mM) and glibenclamide (up to 30 microM). 7 These results indicate that tricyclic antidepressant drugs such as protriptyline and amitriptyline could act as both postsynaptic adrenoceptor antagonists and direct inhibitors of muscle contraction; whereas, xylamine, a structurally distinct NA uptake blocker might principally exert its action only at alpha-adrenoceptors on rat aortic smooth muscle.     

Inhibitory effect of enkephalins on contractions of the guinea-pig ileum elicited by PGE1

Methionine-enkephalin and leucine-enkephalin (m-enk and 1-enk) as well as D-Ala2-methionine-enkephalin amide have been shown to antagonize contractions of the isolated guinea-pig intestine elicited by PGE1, the last mentioned being the most potent of the three. The inhibitory effect of these pentapeptides is abolished by naloxone.     

Modulation of non-adrenergic, non-cholinergic neural bronchoconstriction in guinea-pig airways via GABAB-receptors.

1. Evidence suggests that gamma-aminobutyric acid (GABA) and its receptors are present in the peripheral nervous system. We have now investigated the effect of GABA and related substances on non-adrenergic, non-cholinergic (NANC) neurally-evoked bronchoconstriction in the anaesthetised guinea-pig. 2. Bilateral vagal stimulation (5 V, 5 ms, 3 or 5 Hz) for 30 s, after propranolol (1 mg kg-1 i.v.) and atropine (1 mg kg-1 i.v.) evoked a NANC bronchoconstrictor response manifest as a mean tracheal pressure rise of 21.9 +/- 1.04 cmH2O (n = 70). The bronchoconstrictor response was reproducible for any given animal. 3. GABA (10 micrograms-10 mg kg-1 i.v.) did not alter basal tracheal pressure but reduced the NANC bronchoconstrictor response to vagal stimulation in a dose-dependent manner (ED50 = 186 micrograms kg-1 with a maximal inhibition of 74 +/- 3.4% at 10 mg kg-1). Neither the opioid antagonist naloxone (1 mg kg-1 i.v.) nor the alpha-adrenoceptor antagonist phentolamine (2.5 mg kg-1 i.v.) had any significant effect on the inhibitory response produced by GABA (500 micrograms kg-1). 4. GABA-induced inhibition was not antagonised by the GABAA-antagonist bicuculline (2 mg kg-1 i.v.). 5. The GABAB-agonist baclofen (10 micrograms-3 mg kg-1 i.v.) caused a dose-dependent inhibition of the NANC response (ED50 = 100 micrograms kg-1 with a maximal inhibition of 35.5 +/- 2.8% at 3 mg kg-1). The GABAA-agonist, 4,5,6,7-tetrahydroisoxazolo[5,4-C] pyridin-3-ol (THIP), also inhibited the NANC bronchoconstrictor response.(ABSTRACT TRUNCATED AT 250 WORDS)     

不同部位气道对电场刺激和辣椒素反应的差异

目的:探讨豚鼠不同部位气道神经支配的差异．方法：采用便于定位的离体豚鼠3个不同部位气道环（气管、左主支气管和肺门支气管）标本，比较对电场刺激（EFS）和辣椒素（Capsaicin，Cap）反应的生理性差异。结果：EFS显示，气管抑制性NANC反应（iNANC）占63．4％±9．5％；肺门支气管兴奋性NANC（eNANC）却占64％±7．1％;而主支气管NANC却不明显．Cap量-效反应显示：肺门支气管对Cap反应明显高于气管和主支气管．结论：表明豚鼠气管神经支配，其iNANC明显地高于主支气管和肺门支气管；主支气管主要为肾上腺素能和胆碱能种经支配；而肺门支气管却明显存在与感觉神经C-纤维相关的eNANC。     

Inhibitory effects of prostaglandin E1 and E2 on cholinergic transmission in isolated canine tracheal muscle.

The contractile response of the isolated canine tracheal muscle to the transmural nerve stimulation was depressed by atropine and augmented by physostigmine, indicating that the response was predominantly mediated via the parasympathetic nerve. The contractile response to the transmural nerve stimulation was inhibited by prostaglandin E1 (PGE1) and E2 (PGE2) (10(-7) to 10(-5) g/ml) and the inhibitory action of PGE1 was more potent than that of PGE2. On the other hand, the contractile response of the tracheal muscle to exogenously administered ACh was unaffected by 10(-6) g/ml of PGE1 and PGE2. These findings lend support to the hypothesis that the PGE series, in a manner similar to adrenergic transmission, are involved in a negative feed-back control mechanism for the transmitter release in cholinergic transmission.     

Effects of unilateral bronchoconstriction on distribution of aerosols in ovine airways.

The purpose of the study was to assess the effect of unilateral bronchoconstriction on the deposition patterns of aerosolized particles in a sheep model. Unilateral bronchoconstriction was induced in intubated conscious sheep by placing a protective, obstructing balloon catheter in either main bronchus, prior to administration of aerosolized carbachol at a dose that increased pulmonary resistance by 200-400% above baseline. The catheter was then removed and the animals were positioned under a gamma camera. An equilibrium image was obtained with xenon (133Xe), to determine a lung outline that was used to calculate the proportion of counts in each lung. Aerosols, labeled with technetium (99mTc) and generated by two jet nebulizers, were inhaled tidally by the sheep in serial experiments. (For nebulizer A, mass median aerodynamic diameter [MMAD] = 0.39 microm; for nebulizer B, MMAD = 1.1 microm.) For nebulizer A, percentage deposition in the treated and untreated lungs was not significantly different (50.8% versus 49.2%, respectively), while for nebulizer B, the median deposition in the carbachol treated lung was significantly greater than in the untreated lung (55.8% versus 44.2% respectively; p = 0.005). There was a more central pattern of deposition in the treated lung than in the untreated lung for both nebulizers, but the degree of central deposition was significantly greater with nebulizer B. The findings of the present study suggest that regional obstruction does not preclude the delivery of therapeutic aerosols to the airways in such a region, and may, depending on the size of the aerosol, result in enhanced airway deposition relative to less obstructed regions.     

粉防己碱抑制豚鼠离体气道C神经纤维兴奋引起的收缩(英文)

目的:研究粉防己碱(Tet)对豚鼠离体气管/支气管的感觉神经C纤维兴奋的抑制作用.方法:记录电场刺激所致的C纤维兴奋所产生的标本收缩(phase Ⅱ)张力,了解Tet的作用.结果:Tet 0.3—30 μmol·L~(-1)抑制phase Ⅱ收缩,在气管/支气管上,Tet 1 μmol·L~(-1)的抑制率分别是:40±38％和75±22％;用氯苯那敏或阿托品作用后,Tet 1 μmol·L~(-1)的抑制率分别是70±16％和64±16％;Tet不抑制外源性P物质引起的标本收缩.结论:Tet 1μmol·L~(-1)抑制豚鼠离体气道收缩的机理与其抑制感觉神经C纤维兴奋释放神经肽的作用有关.     

Inhibitory effect of mibefradil on contractions induced by sympathetic neurotransmitter release in the rat tail artery

This study tested whether mibefradil exerts a stronger inhibitory effect than verapamil on sympathetic neurotransmitter release provoked by electrical field stimulation. Tail arteries (diameter 620+/-9 microm) were obtained from male Wistar rats. Ring segments of 2 mm length were mounted in an isometric wire myograph. After an appropriate period of equilibration and a priming procedure the vessels were either subjected to electrical field stimulation (EFS; frequency 0.25-4 Hz for 30 s) or a concentration-response curve was generated with either noradrenaline (concentration range 0.03-3 microM) or ATP (concentration 0.3 mM) which served as baseline parameters. EFS-induced contractions were stable and reproducible and were blocked by tetrodotoxin (1 microM), guanethidine (3 microM), and the combination of suramin (0.5 mM) and prazosin (3 microM). EFS-induced contractions (1 Hz) were almost completely inhibited by 10 microM mibefradil (97%) but only partly by 10 microM verapamil (73%). Log IC50 values were -5.6 for mibefradil and -6.6 for verapamil. Calcium antagonists were equipotent in inhibiting noradrenaline (maximum inhibition by mibefradil and verapamil by 70% and 75%, respectively; log IC50: -6.5 and -6.7, respectively) and ATP-mediated contractions (maximum inhibition by mibefradil and verapamil by 92% and 97%, respectively; log IC50: -6.5 and -7.0, respectively). Consequently mibefradil displays an additional effect on contractions provoked by EFS-induced sympathetic noradrenaline release which cannot be explained by L-type calcium channel blockade. Probably this effect of mibefradil is mediated by the blockade of prejunctional N-type calcium channels, thereby inhibiting sympathetic noradrenaline release. Since activation of the sympathetic nervous system in hypertension is both common and undesirable, a calcium antagonist displaying both L- and N-type calcium channel blocking activities, would have major advantages over calcium antagonists lacking N-type calcium channel blocking activities.