The effects of intra-arterial bradykinin, histamine, acetylcholine and prostaglandin E1 on nociceptive and non-nociceptive dorsal horn neurones of the cat.

The effects of peripherally administered algesic agents were investigated on the firing of cat dorsal horn interneurones classified as nociceptive or non-nociceptive according to the peripheral stimuli that excited them. A small amount of bradykinin injected into the blood supplying the receptive fields of cells was a potent specific stimulus causing activation of nociceptive cells and slowly conducting nerve fibres. Larger amounts of bradykinin and large amounts of histamine, 5-hydroxytryptamine and acetylcholine activated both nociceptive and non-nociceptive cells. Prostaglandin E1 enhanced the effects of bradykinin and histamine on nociceptive cells. Prostaglandin E1 also increased the response of these cells to the application of noxious heat whilst aspirin reduced this response. These results support a chemosensitive theory of nociceptor activation and show bradykinin to be the most potent and specific of the suggested endogenous algesic agents in causing activation of CNS nociceptive pathways.     

Inhibition by 5-hydroxytryptamine of anaphylactic histamine release from bovine granulocytes.

A suspension of granulocytes from calves sensitised to horse plasma released histamine when exposed to the antigen. Histamine release was strongly inhibited by 5-hydroxytryptamine in a dose-related fashion. 5-HT is known to be released from bovine lungs in vitro, and may regulate the release of histamine in vivo during anaphylaxis.     

Age-dependent effect of secretagogues during colonic maturation

Intestinal secretory response is altered during colonic development. The aim of this report was to study the developmental changes of the Ca(2+)- and cAMP-induced regulatory pathways with special attention to the direct and indirect effect of secretagogues on the colonic epithelium. We investigated the effect of bethanechol, 5-hydroxytryptamine (5-HT), and histamine on Cl(-) secretion and stimulation of intracellular Ca(2+) ([Ca(2+)](i)) and cAMP in the distal colon of suckling, weanling and adult rats. In the presence of tetrodotoxin, immature colon of suckling and weanling rats displayed higher potency (EC(50)) of 5-HT to stimulate Cl(-) secretion, whereas the potency of histamine was not changed during development. The potency of bethanechol was reduced during weaning and partially restored in adulthood. 5-HT increased cAMP level similarly in both neonatal and adult colonic crypts, but the adults had higher basal level of cAMP than suckling rats. Also the effect of bethanechol on [Ca(2+)](i) was independent of colonic maturation. The results suggest that colonic Cl(-) secretion displays developmental changes of regulation depending on the non-neural secretagogue-signalling pathway and that these developmental changes seem to be localized somewhere outside colonocytes.     

A comparison of the bronchodilator action of pseudoephedrine and ephedrine in patients with reversible airway obstruction

Summary A double-blind randomised cross-over study was performed on 12 subjects suffering from reversible airway obstruction (asthma) to determine the relative bronchodilator effects of oral pseudoephedrine 60 mg, pseudoephedrine 180 mg, ephedrine 25 mg and matched placebo. Spirometry was used to measure vital capacity and forced expired volume in 1 s, and whole body plethysmography was used to measure specific airway conductance. Measurements were recorded before each drug was given, and 1 h and 2 h after each drug. Reversibility of the airway obstruction on each day of the study was demonstrated by significant improvements in all parameters of lung function in response to 400 µg of isoprenaline inhaled after the 2-h measurement. No significant bronchodilator effect could be shown following the ingestion of pseudoephedrine 60 mg or 180 mg. Only a week bronchodilator effect was demonstrated after ephedrine 25 mg in that the percentage change in vital capacity at 2 h after ephedrine was greater than that following either dose of pseudoephedrine or the placebo. It is concluded that oral pseudoephedrine in single doses of 60 mg or 180 mg has no significant bronchodilator action in man, and that a single dose of up to 180 mg pseudoephedrine does not cause tachycardia or hypertension.     

Interaction between 5-hydroxytryptamine and other vasoconstrictor substances in the isolated femoral artery of the rabbit; effect of ketanserin (R 41 468)

Experiments were designed to determine whether or not ketanserin (R 41 468) antagonizes the augmentation by 5-hydroxytryptamine of contractions evoked in isolated arteries by non-adregergic vasoconstrictor substances. Rings of rabbit femoral arteries were studied under isometric conditions in organ chambers filled with Krebs-Henseleit solution (37°C). Ketanserin, unlike methysergide and LSD, was devoid of agonistic properties. It competitively antagonized contractile responses to 5-hydroxytryptamine and, at higher concentrations, to histamine. 5-Hydroxytryptamine amplified the contractions evoked by threshold concentrations of histamine, angiotensin II and prostaglandin F_2α; in all three cases, the amplification was antagonized by comparable concentrations of ketanserin. These experiments indicate that the interaction of 5-hydroxytrptamine with S₂-receptors of the vascular smooth muscle cells is essential to allow the expression of the monoamine-induced amplification of the response to other vasoconstrictor substances. The inhibition by ketanserin of the amplifying effect of 5-hydroxytryptamine on vascular responses may help explain the antihypertensive properties of the compound.     

Is intra-arterial 5-hydroxytryptamine a potent algogenic substance in the dog?

Acetylcholine injected into the femoral artery produced dose-graded vocalization responses in all 10 conscious dogs investigated and the mean threshold dose was about 1.7 μmol. In 9 of these 10 dogs, however, 5-hydroxytryptamine given into the same artery failed to cause vocalization or any other signs of niciception even with doses up to 10 μmol. Only one dog vocalized in response to 5-hydroxytryptamine, but the threshold dose was as high as 6 μmol.     

Local modulation of the 5-HT release in the dorsal striatum of the rat: an in vivo microdialysis study

Using in vivo microdialysis in freely moving rats, we examined the involvement of major striatal transmitters on the local modulation of the 5-HT release. Tetrodotoxin reduced the striatal 5-HT output to 15–20% of baseline. The selective 5-HT_1B receptor agonist CP 93129 (50 μM) reduced (50%) and the 5-HT_2A/2C receptor agonist DOI (1–100 μM) increased (220%) the 5-HT output. Neither GABA nor baclofen (100 nM–100 μM) altered the 5-HT output. The glutamate reuptake inhibitor -trans-PDC (1–4 mM) raised 5-HT to 280% of baseline. This effect was not antagonized by the NMDA receptor antagonist MK-801 (0.5 mg/kg i.p.). Local MK-801 (10–100 μM) did not significantly alter the 5-HT output. Finally, neither carbachol (10–100 μM) nor quipirole (10 μM–1 mM) affected 5-HT. These data suggest that the striatal 5-HT release is influenced by local serotonergic and glutamatergic (but not GABAergic) inputs.     

The effect of drugs influencing amine synthesis on the analgesic action of tremorine

The effect of reserpine, -methyl-dl-m-tyrosine (-MT), diethyl-dithiocarbamate (DDC) and p-chlorophenylalanine (p-Clphe) pretreatment on tremorine induced analgesia has been studied in mice by various methods. The ED 50 of tremorine was significantly increased by all the methods when the animals were pretreated with reserpine, DDC and p-Clphe. -MT had no significant effect on tremorine induced analgesia. The results are discussed with respect to the role of brain amines in the analgesic action of tremorine.     

Role of extra- and intracellular calcium in the contractile action of agonists in the guinea-pig ileum

Summary The effects of Ca²⁺-channel blockers (nifedipine and verapamil), EGTA, caffeine or the removal of external Ca²⁺ on the contractile action of different agonists and transmural electrical stimulation were examined in isolated segments of the proximal and terminal part of the guinea-pig ileum. The effects of agonists and nerve stimulation on membrane potential were also studied by means of the sucrose gap method. Acetylcholine-elicited contractions in both parts and noradrenaline-as well as histamine-induced contractions in the terminal part of the ileum were composed of an initial phasic and a sustained tonic component. Single pulse transmural nerve stimulation elicited smooth muscle twitches, whereas addition of CaCl₂ to the tissue bath containing Ca²⁺-free and high-K⁺ medium elicited a sustained contraction. Both verapamil and nifedipine were more potent in inhibiting the tonic phase of the responses to the agonists or CaCl₂ than inhibiting the phasic contractions elicited by transmural nerve stimulation, acetylcholine or noradrenaline. The excitatory junction potentials (e j.p.s.) as well as smooth muscle twitches were reduced only by high nifedipine concentrations. The effects of acetylcholine on membrane potential and input membrane resistance were affected minimally by the omission of extracellular Ca²⁺, while the contractions gradually disappeared on repetitive agonist application in the absence of external Ca²⁺ and were blocked by caffeine preexposure. In Ca²⁺-free solution noradrenaline and histamine partially reduced each other's motor effect, while neither of them changed the contractile action of acetylcholine, yet the contraction induced by noradrenaline was prevented and that of histamine significantly reduced by preexposure to acetylcholine. These results suggest that the potency of acetylcholine to release Ca²⁺ from its caffeine-sensitive intracellular stores is much higher than that of histamine and noradrenaline. Send offprint requests to V. Bauer at the above address     

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.     

麻黄碱联合丙泊酚抑制芬太尼咳嗽反射的临床研究

目的:研究麻黄碱联合丙泊酚对芬太尼咳嗽反射(fentanyl-induced cough,FIC)的抑制作用.方法:选择320例择期手术接受全麻的患者,根据计算机随机数字表随机进入4组:Ⅰ组(对照组)静脉注射2 mL生理盐水;Ⅱ组(麻黄碱组)静脉注射6 mg麻黄碱;Ⅲ组(丙泊酚组)静脉注射0.8 mg/kg丙泊酚;Ⅳ组(丙泊酚联合麻黄碱组)静脉注射0.8 mg/kg丙泊酚加6 mg麻黄碱.给予治疗药物2 min后,经外周静脉快速注射2 μg/kg芬太尼.观察并记录患者的血压、心率、脉博血氧饱和度等生命体征,并由一位医师按照盲法观察注射芬太尼后1 min内是否出现咳嗽,记录咳嗽发生的次数,并且根据咳嗽发生次数进行严重程度分级.结果:Ⅱ组、Ⅲ组和Ⅳ组患者的FIC发生率和严重程度均较Ⅰ组明显降低,而且Ⅳ组患者的血流动力学更加平稳.结论:麻醉诱导时联合应用麻黄碱和丙泊酚对FIC的抑制效果更好,患者血流动力学更加稳定,是临床上一个简单、有效的防治FIC的办法.     

Effects of ruthenium red and KCL on responses of guinea pig umbilical veins.

5-Hydroxytryptamine (10(-5) M), norepinephrine (10(-5) M) and acetylcholine (10(-5) M) induced maximal contractions in isolated guinea pig umbilical vein strips. Pretreatment with ruthenium red (2.7--90 mug/ml) for ten minutes reduced 5-hydroxytryptamine and norepinephrine responses in a dose-related manner but did not affect acetylcholine-induced responses. Ruthenium red alone did not produce contractions. In the presence of KC1 (125 MM) the responses to norepinephrine and acetylcholine were enhanced significantly. The sensitivity of umbilical veins to ruthenium red may be useful in determining to what extent various vasoactive agents utilize extracellular calcium to induce contractions.     

RP—HPLC法测定麻黄附子细辛汤水煎液中麻黄碱的含量

目的建立测定麻黄附子细辛汤水煎液中麻黄碱含量（以盐酸麻黄碱计）的反相高效液相色谱法。方法色谱柱：Diamonsil-C18柱（200mm×4．6mm）;流动相：乙腈：水（含0．02mol·μL^-1磷酸二氢钾和0．2％三乙胺）（10：90）;流速：1．0mL·min^-1;检测波长：210nm;柱温：27℃。结果样品中盐酸麻黄碱的色谱峰与其他组分完全达到基线分离,回归方程为：y=2229．4854x-22．2885,r=0．9998（n=6）,线性范围0．1776—1．3320μg,平均加样回收率为101．45％（RSD=I．9％,n=6）。结论所建立的测定方法快速简便,重现性良好,可用于麻黄附子细辛汤水提物中麻黄碱的含量测定。     

Pharmacological characterization of mediators and vagal influence in the acute allergic bronchoconstriction in guinea pigs

Summary The allergic bronchoconstriction in guinea pigs has been attributed mainly to the release of mast cell mediators. Histamine has been involved in the first minutes of the anaphylactic reaction and new-formed compounds in the subsequent response. In this asthma model the vagal influence has been sparsely investigated. In the present work we evaluated the pharmacological modification of the acute allergic bronchoconstrictor response in guinea pigs sensitized to ovalbumin through aerosol exposure. Pyrilamine (20 g/kg), diethylcarbamazine (a lipoxygenase inhibitor, 10 mg/kg) and dexamethasone (4 mg/kg) each reduced the antigen-induced bronchoconstriction throughout the 30 min studied. Indomethacin (3.1 mg/kg) did not modify the response to the antigen. Atropine (2 mg/kg) plus bilateral vagotomy also diminished this response from 5 min onward. On the other hand, from 5 min ahead pyrilamine-resistant bronchoconstriction was partially inhibited by dexamethasone, and it was almost completely blocked during all of the response when atropine plus bilateral vagotomy were added to dexamethasone. Dipyridamole (an inhibitor of the adenosine uptake, 0.4 mg/kg) enhanced the bronchoconstriction, though this was significant only in the 2–5 min time-interval of the response. These results suggest that histamine and vagal influence play an important role in the whole response to antigen, that other mediators, probably leukotrienes, participate in this response from 5 min onward, and that adenosine could exert a potentiation effect on this response. Send offprint requests to L. M. Montaño at the Instituto Nacional de Enfermedades Respiratorias     

Electrical stimulation and drug responses of isolated human umbilical blood vessels

Histochemical studies and electrical stimulation of isolated human umbilical arteries and veins confirm the absence of noradrenergic and cholinergic innervations. The order of potency in producing contractions of the two isolated tissues was 5-hydroxytryptamine (5-HT) > noradrenaline (NA) > acetylcholine (ACH).The maximal contractions to NA and ACH were less than those to 5-HT. These findings were related to the closure of the umbilical blood vessels at birth.     

Potentiating effects of caffeine on the cardiovascular teratogenicity of ephedrine in chick embryos

Ephedrine was administered to 3-day chick embryos (Hamburger-Hamilton developmental stage 19) together with caffeine at doses where each agent alone caused minimal embryotoxicity. Embryos were examined for malformations on day 14 of incubation. The teratogenicity of ephedrine in the chick cardiovascular system was significantly potentiated by caffeine at a dose as low as 0.5 mumol (0.1 mg/egg; 2 mg/kg egg).     

Supersensitivity to opioids following the chronic blockade of endorphin action by naloxone

Summary Rat brain cortex slices preincubated with ³H-5-hydroxytryptamine were superfused with physiological salt solution and stimulated electrically, or they were superfused with Ca²⁺-free solution containing 25 mM K⁺ and stimulated by introduction of 1.3 mM CaCl₂ for 2 min.After blockade of neuronal 5-hydroxytryptamine (5-HT) uptake with clomipramine or paroxetine, the ³H overflow evoked by both methods of stimulation was decreased by unlabelled 5-HT and increased by methiothepin. The inhibition caused by 5-HT was antagonized by simultaneous administration of methiothepin. The inhibition by 5-HT of Ca²⁺-induced overflow was also observed in the presence of tetrodotoxin.These results suggest than 5-HT regulates its own release from central serotoninergic neurones by activating presynaptic 5-HT autoreceptors, thus decreasing the availability of Ca²⁺ for stimulus-release coupling.     

全身麻醉诱导药伍用麻黄素防治诱导期低血压的临床观察

目的：在全身麻醉诱导药的基础上配伍麻黄素,以探讨全身麻醉诱导期用药合理性,防治全身麻醉诱导期低血压的发生。方法：选取择期手术患者60例,将其随机分为常规全身麻醉诱导组（对照组）30例,全身麻醉（全麻）药配伍麻黄素诱导组（配伍组）30例。两组均在全麻诱导前及诱导后3min监测HR、BP和SpO2的变化。结果：对照组诱导后3min较诱导前BP显著降低（P〈0.001）;配伍组诱导后3min较诱导前BP无显著减低（P〉0.05）;相对于对照组,配伍组诱导后3minBP显著提高（P〈0.001）。结论：在全麻诱导中配伍麻黄素能有效预防全麻诱导期低血压发生,是较好的全麻诱导药的伍用方法。     

舒郁胶囊中麻黄碱的鉴别与含量测定研究

目的:建立舒郁胶囊中麻黄碱的鉴别和含量测定方法.方法:采用TLC法和HPLC法对舒郁胶囊中的麻黄碱进行定性鉴别和含量测定.色谱条件:色谱柱为Diamonsil C<,18>柱(250 mm×4.6 mm,5 μm),流动相为乙腈-0.02 mol·L<'-1>磷酸二氢钾-磷酸(50:950:1),流速1.0 mL·mi...     

Further studies on the action of 5-hydroxytryptamine on lumbar motoneurones in the rat isolated spinal cord

Summary Using the hemisected spinal cord of the neonate rat, the effects of altered external Ca, thyrotrophin-releasing hormone (TRH) and a number of antagonists were tested on depolarizations evoked by 5-hydroxytryptamine (5-HT). Responses of populations of motoneurones were recorded via a ventral root. 5-Hydroxytryptamine depolarizations were not Ca-dependent but were enhanced in amplitude in Ca-free solutions. Raised Mg reversed this enhancement. 5-Hydroxytryptamine depolarizations persisted in the presence of Mn (1.53 mmol/l). TRH depolarized motoneurones; there was no evidence of modulation of 5-HT responses on concurrent application of TRH. Ritanserin (0.1 mol/l) had a modest blocking action on 5-hydroxytryptamine depolarizations reducing the maximum; 1mol/l ritanserin caused a greater antagonism which was unsurmountable (pIC₅₀ 5.2). Ritanserin (0.1 or 1 mol/l) did not depress responses to noradrenaline (NA). Ketanserin (0.1 mol/l) caused a blockade of slow onset, equilibrium with the receptors requiring 1 h. Blockade by 0.01, 0.1 and 1 mol/l ketanserin was concentration-dependent (pIC₅₀ 6.2). Ketanserin 1 mol/l, but not at lower concentrations, depressed noradrenaline responses. Mianserin (0.1 mol/l) also caused a blockade of slow onset; 0.1 or 1 mol/l produced a flattening of the 5-hydroxytryptamine concentration-response curve but did not depress noradrenaline responses (pIC₅₀ 4.7). The pIC₅₀ for spiperone was 8.0. DOI (10–100 mol/l) had no detectable agonist action but at concentrations of 0.01 and 0.1 mol/l it acted as an antagonist. Equilibration with the receptors occurred over 2 h. DOI (0.01 mol/l) depressed 5-hydroxytryptamine but not noradrenaline responses; higher concentrations of DOI also depressed noradrenaline responses. The pharmacological profile of the 5-hydroxytryptamine receptor mediating depolarization of spinal and facial motoneurones suggests that it belongs to the 5-HT_1C-5-HT₂, group of 5-hydroxytryptamine receptors but is not identical to 5-HT_1C or the 5-HT₂ CNS binding sites. Alternatively, the response might arise from a mixed population of 5-HT₁-like and 5-HT₂ receptors. Send offprint requests to D. I. Wallis at the above address