Effects of famotidine and cimetidine on plasma levels of epidurally administered lignocaine

The effects of two H2-receptor antagonists, famotidine and cimetidine, on the plasma levels of epidurally administered lignocaine were studied. Group A (n = 20) received famotidine 20 mg orally the night before surgery and 20 mg intramuscularly 60 minutes before induction of anaesthesia. Group B (n = 15) received cimetidine 200 mg orally the night before the surgery and 400 mg orally 60 minutes before the anaesthetic induction. Group C (n = 20) received neither famotidine nor cimetidine and served as controls. Twelve millilitres of 2.0% lignocaine with adrenaline 1:200,000 was injected into the epidural space in all patients, after the establishment of general anaesthesia with nitrous oxide, oxygen, and enflurane (0.3-0.5%). The patients who received cimetidine showed significantly higher plasma concentrations of lignocaine compared with either group A or group C at all investigation times (p less than 0.01). The mean peak plasma concentrations were 2.4 (SEM 0.1), 3.2 (SEM 0.2) and 2.3 (SEM 0.1) micrograms/ml in group A, B, and C, respectively. This study suggests that famotidine is preferable to cimetidine for control of gastric acidity before the use of lignocaine as the epidural anaesthetic.     

内毒素在支气管高反应性形成中的作用

观察了以内毒素作为致病原在支气管高反应性形成中的作用。结果：豚鼠腹腔注射内毒素后，其气道对组织胺引起哮喘潜伏期明显缩短，组织胺收缩离体气管平滑肌的ＰＤ２值明显增高，异丙肾上腺素松弛作用的ＰＤ２值显著降低，同时血浆及肺组织中组织胺含量显著增高。提示内毒素可能是呼吸道感染诱发支气管高反应性形成的重要因素，其机制与β受体功能改变及组织胺含量升高有关。     

Chronotropic and inotropic effects of histamine in developing chick heart: differential mechanisms before and after hatching

Chronotropic and inotropic effects of histamine were examined in isolated atrial and ventricular preparations from embryonic and hatched chicken hearts. Histamine produced positive chronotropic and inotropic responses both in embryonic and hatched hearts. The responses to histamine in middle embryonic myocardia, which were observed in the micromolar range, were antagonized by H₂ antagonists but not by H₁, H₃ antagonists and propranolol. Isobutylmethylxantine, an inhibitor of phosphodiesterase, produced a leftward shift of the concentration-response curve for the chronotropic effect of histamine in the embryo. The responses to histamine in myocardia from hatched chicks, which were observed in the milimolar range, appeared concurrently with the responses to tyramine during development and were antagonized by beta adrenoceptor antagonists but not by any of the histamine antagonists. The positive inotropic response to histamine in hatched ventricular preparations were greatly attenuated by reserpine pretreatment or in the presence of desipramine. Thus, we demonstrated that exogenously applied histamine produces positive chronotropic and inotropic responses in developing chicken hearts and that the mechanisms are different between embryonic and hatched chicks: direct action on H₂ receptors in the embryonic heart and release of norepinephrine from sympathetic nerve terminals in hatched hearts.     

Characteristics of β-endorphin-induced histamine release from rat serosal mast cells Comparison with neurotensin,dynorphin and compound 48/80

Summary Rat peritoneal mast cells were exposed to the neurohormone and basic opioid peptide -endorphin. -Endorphin induced a dose-dependent release of histamine from the mast cells. A significant histamine release was found at 5 mol/l of -endorphin and maximal release (35% of total) at 20 mol/l. The histamine release process was very rapid and terminated within 30 s at 37°C, and in this sense is very similar to the histamine release induced by compound 48/80 or neurotensin. The histamine release was temperature-dependent showing an optimum release around 30°C, and it was independent of available extracellular calcium, but was inhibited in the presence of high extracellular calcium concentrations. Naloxone, only in very high concentrations (10 mmol/l), inhibited the release, and the very same concentration also inhibited the neurotensin — as well as the compound 48/80-induced histamine release. Cromoglycate and benzalkoniumchloride, a 48/80 antagonist, both produced a progressive dose-dependent inhibition of -endorphin-, neurotensin- as well as compound 48/80-induced histamine release. Taken together, the findings indicate that the opioid peptide -endorphin induces a selective, energy-dependent release of histamine from peritoneal rat mast cells. The pattern of release has much in common with that of compound 48/80 and other basic peptides, such as neurotensin and substance P. In addition this pattern of release is similar to that induced by dynorphin. Send offprint requests to Anita Sydbom at the above address     

Role of histamine receptor in mesencephalic nucleus dorsalis raphe in cardiovascular regulation

Summary The effects of microinjection of histamine and its antagonists into mesencephalic nucleus dorsalis raphe, were investigated on mean arterial pressure and heart rate in cats to elucidate the nature and role of histaminergic receptors in cardiovascular regulation. Microinjection of histamine (5 and 10 g) into nucleus dorsalis raphe elicited both inhibitory and excitatory cardiovascular responses respectively. On the other hand, microinjection of H₂-receptor blocker, cimetidine (10 g) resulted in hypertension and tachycardia while H₁-receptor antagonist, mepyramine (10 g) microinjection evoked hypotension and bradycardia. Furthermore, local pretreatment with cimetidine and mepyramine blocked the inhibitory and excitatory cardiovascular responses of graded doses of histamine microinjection. These H₁ and H₂ receptors are localized in nucleus dorsalis raphe since microinjection of histamine into adjoining neural structures did not evoke any cardiovascular change. Furthermore, both the inhibitory and excitatory cardiovascular responses to histamine microinjection could not be observed in animals with spinal cord transection and in animals pretreated with p-chlorophenylalanine while they could be observed in bilateral cervical vagotomized animals. Thus, it appears that these cardiovascular responses to microinjection of histamine into nucleus dorsalis raphe, are due to modulation of serotonergic bulbospinal influence on sympathetic preganglionic neurones in the spinal cord. Moreover, the excitatory cardiovascular responses of high dose of histamine (10 g) seem to result from a local release of noradrenaline since they were blocked by prior microinjection of guanethidine and piperoxan into nucleus dorsalis raphe. A release of noradrenaline in turn, modulates the activity of the neurones of the nucleus by acting on adrenoceptors and thereby alters the activity of sympathetic preganglionic neurones. These adrenoceptors appear to be of ₁ type (Saxena et al. 1985, 1987) since phenylephrine microinjection evoked excitatory cardiovascular responses could be blocked by piperoxan. Send offprint requests to K. K. Tangri at the above address     

Mechanism of histamine release from rat peritoneal mast cells

Summary The present communication endeavours to elucidate the mechanism of histamine release from rat peritoneal mast cells induced by selective histamine liberators.Of the different enzymatic processes involved in secretion the following are considered: ecto-ATPase activity in the mast cell, pro-esterase-esterase conversion during histamine secretion, cyclic AMP and microtubule association/dissociation, phospholipase A₂ and the effect of phospholipid metabolites on secretion, N-methyl transferase and the methylation of phospholipids and the phosphorylation and desphosphorylation of proteins.     

组胺H_2受体阻断剂对大鼠失血性应激反应时胃功能和溃疡指数的影响

用反射光谱法,研究了组胺H_2受体阻断剂Famotidine对急性失血大鼠胃粘膜血液量及血氧饱和度的影响。同时观察了胃液量和酸排出量的变化,并计量了溃疡指数。Famotidine(3mg/kg及8mg/kg,iv)对失血前大鼠胃粘膜血液量和血氧饱和度均未见有影响;对失血后胃粘膜血液量和血氧饱和度的降低有明显保护作用,对胃液量和酸排出量均有显著抑制作用,溃疡指数减小。     

Effect of terbutaline and bambuterol on immediate-type allergic skin responses and mediator release in human skin

Background: Beta-2 agonists are potent inhibitors of mast cell degranulation in vitro. Intradermally injected they also inhibit mast cell activation in human skin in vivo. To what extent orally administered ₂-agonists inhibit mast cell degranulation and allergic skin responses in vivo in daily recommended doses remains unclear.Purpose: The main purpose was to study the effects of oral administered terbutaline and bambuterol on allergen- and codeine-induced histamine release and skin responses in intact human skin in vivo. In addition, control studies were carried out with intradermally injected terbutaline.Methods: Ten allergic subjects were randomized to receive bambuterol (10 mg tablets twice daily), terbutaline (7.5 mg controlled release tablets twice daily) and corresponding placebo for 5 days with a washout phase of 3 days between treatments in a double-blind, double-dummy, cross-over trial. The patients were studied at the fifth day of each regimen, i.e. at day 5, 13, and 21. Allergen- and codeine-induced histamine release was measured by microdialysis technique. Wheal and flare reactions to allergen, codeine, and histamine were measured planimetrically. Measurements were performed in the morning on day 5 on each regimen before medication and for additional 5 h after administration of the morning dose. In a separate series of experiments in another 10 allergic patients, 1–1,000 nM (0.05–50 pmoles) of terbutaline was injected intradermally for measurement of histamine release, prostaglandin D2 (PGD2) synthesis and skin responses.Results: Neither orally administered terbutaline nor bambuterol significantly reduced allergen- or codeine-induced histamine release. Flare reactions to allergen, codeine and histamine remained unaffected which was also the case for the majority of the wheal reactions. In comparison, intradermally injected terbutaline significantly reduced allergen-induced histamine release, PGD₂ synthesis, and skin reactions. Codeine-induced histamine release remained unaffected. Terbutaline significantly reduced flare reactions to codeine and histamine with no effect on wheal reactions.Conclusions: Terbutaline, in micromolar concentrations, was a potent inhibitor of immediate allergic skin reactions primarily due to inhibition of mast cell degranulation. However orally administered terbutaline, as the active drug itself or released from its pro-drug bambuterol, did not inhibit mast cell activation or allergic skin responses. Received 28 January 2003; returned for revision 7 March 2003; accepted by M. Parnham 29 April 2003     

Different patterns of the L-histidine decarboxylase (HDC) gene expression in mice resistant and susceptible to experimental cutaneous leishmaniasis

Objective and design: In the present study the experimental murine Leishmania major (L. major) infection model was used to investigate the role of histamine biosynthesis in cutaneous leishmaniasis.Subjects, treatment and methods: A novel RNase Protection Assay (RPA) was developed and applied for the assessment of L-histidine decarboxylase (HDC) gene expression in organs of resistant C57BL/6 and susceptible BALB/c mice after infection with L. major.Results: In the acute phase of infection a rapid but transient induction of HDC expression was observed in the infected lymph nodes of both strains correlating both temporally and spatially with parasite spread. The signal was present in the draining popliteal lymph nodes of both hosts, however, only susceptible mice known to be unable to control parasite dissemination showed induction of HDC in their distant periaortic lymph nodes as well. During the chronic phase of infection only the heavily parasitized organs of BALB/c mice showed high HDC gene expression.Conclusions: These data suggest that expression of the histamine-producing enzyme HDC in the decisive acute phase of leishmaniasis is not coupled with development of either appropriate Th1 or inadequate Th2 responses to L. major. We hypothesize however, that during the chronic phase of infection elevated HDC levels, possibly of mast cell origin, are associated with Th2-dominated responses and serious disease development.Received 12 May 2003; returned for revision 3 July 2003; returned for final revision 11 September 2003; accepted by M. Parnham 24 September 2003     

蛋白酶激活受体2激动剂对肥大细胞释放组胺的影响

目的 研究PAR-2激动剂(tc-LIGRLO-NH2与SLIGKV-NH2)和胰蛋白酶对结肠肥大细胞释放组胺的影响。方法 结肠组织经酶消化后,细胞成份用全HBSS重新悬浮。激发过程在LP4试管中、37℃条件下完成。组胺水平用以玻璃纤维为基础的荧光方法测定。结果PAR-2激动剂tc-LIGRLO-NH2和SLIGKV-NH2均可诱导人结肠肥大细胞剂量依赖性组胺释放。浓度为100μmol／mL时,tc-LIGRLO-NH2和SLIGKV-NH2可分别引起比基础分泌量多出2．5倍和2倍的组胺释放,而反PAR-2激动剂tc-OLRGIL-NH2和VKGILS-NH2在实验浓度高至300μmol／mL时仍对组胺释放无影响。胰蛋白酶在1．0～100μg/mL间可引起剂量相关性组胺释放,胰蛋白酶抑制剂可抑制之。PAR-2激动剂tc-LIGRLO-NH2的作用从加样后1min开始,3min后完成。细胞经过百日咳毒素和代谢抑制剂预先处理后,几乎失去了对tc-LIGRLO-NH2、SLIGKV-NH2和胰蛋白酶刺激的反应性。结论 PAR-2激动剂和胰蛋白酶是高效的组胺释放刺激剂,其在人结肠炎症性疾病中起一定的作用。