Heterogeneous effect of leucotriene CysLT1 receptor antagonists on antigen-induced motor and inflammatory responses in guinea-pig airways

1. The effect of montelukast or MEN91507, selective leucotriene CysLT1 receptor antagonists, on antigen-induced airway inflammation and bronchoconstriction were compared in anaesthetized guinea-pigs. 2. In sensitized animals, ovalbumin (0.3 mg kg(-1), i.v.)-induced microvascular leakage in trachea, intrapulmonary airways, total lung (parenchyma and intrapulmonary airways) and urinary bladder was reduced by MEN91507 (0.01-1 micromol kg(-1), i.v.), whereas montelukast (0.01-1 micromol kg(-1), i.v.) antagonized the effect of the antigen only in the lung and urinary bladder. 3. Ovalbumin (1 mg kg(-1), i.v.)-induced bronchoconstriction was dose dependently antagonized by MEN91507 (10-30 micromol kg(-1), i.v.), whereas the effect of montelukast (0.1-30 micromol kg(-1), i.v.) was marginal (15-30% inhibition). Neither MEN91507 nor montelukast (30 micromol kg(-1), i.v.) affected the bronchoconstrictor response induced by acetylcholine (0.3 micromol kg(-1), i.v.) in sensitized animals. 4. It is concluded that montelukast and MEN91507 display a differential activity against the effect of endogenous leucotrienes, despite the fact that both compounds show a similar antagonist profile against exogenous leucotrienes acting through CysLT1 receptors.     

Neurogenic plasma leakage in mouse airways

1. This study sought to determine whether neurogenic inflammation occurs in the airways by examining the effects of capsaicin or substance P on microvascular plasma leakage in the trachea and lungs of male pathogen-free C57BL/6 mice. 2. Single bolus intravenous injections of capsaicin (0.5 and 1 micromol kg(-1), i.v.) or substance P (1, 10 and 37 nmol kg(-10, i.v.) failed to induce significant leakage in the trachea, assessed as extravasation of Evans blue dye, but did induce leakage in the urinary bladder and skin. 3. Pretreatment with captopril (2.5 mg kg(-1), i.v.), a selective inhibitor of angiotensin converting enzyme (ACE), either alone or in combination with phosphoramidon (2.5 mg kg(-1), i.v.), a selective inhibitor of neutral endopeptidase (NEP), increased baseline leakage of Evans blue in the absence of any exogenous inflammatory mediator. The increase was reversed by the bradykinin B2 receptor antagonist Hoe 140 (0.1 mg kg(-1), i.v.). 4. After pretreatment with phosphoramidon and captopril, capsaicin increased the Evans blue leakage above the baseline in the trachea, but not in the lung. This increase was reversed by the tachykinin (NK1) receptor antagonist SR 140333 (0.7 mg kg(-1), i.v.), but not by the NK2 receptor antagonist SR 48968 (1 mg kg(-1), i.v.). 5. Experiments using Monastral blue pigment as a tracer localized the leakage to postcapillary venules in the trachea and intrapulmonary bronchi, although the labelled vessels were less numerous in mice than in comparably treated rats. Blood vessels of the pulmonary circulation were not labelled. 6. We conclude that neurogenic inflammation can occur in airways of pathogen-free mice, but only after the inhibition of enzymes that normally degrade inflammatory peptides. Neurogenic inflammation does not involve the pulmonary microvasculature.     

The effect of the selective PAF antagonist CIS-19 on PAF- and antigen-induced bronchoconstriction, microvascular leakage and bronchial hyperreactivity in guinea-pigs

We investigated the effects of a novel platelet-activating factor (PAF) receptor antagonist, CIS-19 [cis-2-(3, 4-dimethoxyphenyl)-6-isopropoxy-7-methoxy-1-(N-methylformamido)-1, 2, 3, 4-tetrahydronaphthalene], on PAF-, histamine-, substance P- and antigen-induced bronchoconstriction and microvascular leakage, as well as PAF- and antigen-induced bronchial hyperreactivity to methacholine in urethane-anesthetized guinea-pigs. Administration of CIS-19 (0.5–5 mg/kg, i.v.) inhibited the increase in lung resistance induced by PAF (30 ng/kg, i.v.) in a dose-dependent manner, but failed to inhibit the increase induced by histamine (30 μg/kg, i.v.) or substance P (6.5 μg/kg, i.v.). CIS-19 (5 mg/kg, i.v.) did not inhibit the increase in lung resistance induced by ovalbumin (2 mg/kg, i.v.) in actively sensitized guinea-pigs. PAF (30 ng/kg, i.v.)-induced microvascular leakage, measured by the extravasation of Evans blue dye, was dose-dependently inhibited by CIS-19 (0.5–5 mg/kg, i.v.) in the trachea, main bronchi and intrapulmonary airways, but it did not affect histamine (30 μg/kg, i.v.)- or substance P (6.5 μg/kg, i.v.)-induced microvascular leakage at all airway levels. CIS-19 (2.5 and 5 mg/kg) did not affect ovalbumin (2 mg/kg, i.v.)-induced microvascular leakage in all airway levels in actively sensitized guinea-pigs. CIS-19 (2.5 and 5 mg/kg, i.v.) significantly inhibited PAF-induced enhancement of the bronchial response to methacholine, but had no effect on ovalbumin (0.05 mg/kg, i.v.)-induced bronchial hyperreactivity in actively sensitized guinea-pigs. It is concluded that CIS-19 is a potent PAF receptor antagonist which inhibits PAF- but not antigen-induced bronchoconstriction, microvascular leakage and bronchial hyperreactivity. These results suggest that PAF plays little or no role in early airway responses following antigen challenge. Received: 29 April 1996 / Accepted: 10 October 1996     

Characterization of 5-hydroxytryptamine (5-HT) receptor subtypes influencing colonic motility in conscious dogs

We examined the effects of exogenous 5-hydroxytryptamine (5-HT) and selective 5-HT receptor agonists and antagonists on proximal, middle and distal colonic motility in conscious fasted dogs with extraluminal force transducers implanted chronically. 5-HT (0.003–0.1 mg/kg i.v.) dose-dependently enhanced motility along the entire length of the colon. The 5-HT (0.03 mg/kg i.v.)-induced response was inhibited by 0.1–1.0 mg/kg i.v. methysergide, a 5-HT_/12 antagonist, at all recording sites and by 0.1–1.0 mg/kg i.v. ketanserin, a 5-HT_2A antagonist, at the middle and distal sites only. At 1 mg/kg i.v., YM060, a 5-HT₃ antagonist, reduced the amplitude of the initial transient high-amplitude contractions induced by 5-HT, but did not affect the tonic contraction induced by 5-HT. At doses up to 3 mg/kg i.v.,2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino) ethyl ester (SDZ205-557), a 5-HT₄ antagonist, and hexamethonium (up to 10 mg/kg i.v.) did not affect 5-HT-induced responses at any recording site. Renzapride, a 5-HT₄ agonist, also stimulated motility along the entire length of the colon at 0.3 mg/kg i.v.. The renzapride-induced response was inhibited by 1 mg/kg i.v. SDZ205-557 or 3 mg/kg i.v. hexamethouium. m-Chlorophenylbiguanide (m-CPBG), a 5-HT₃ agonist, (1 mg/kg i.v.) produced a transient high-amplitude contraction at all recording sites and this contraction was eliminated by pretreatment with 0.03 mg/kg i.v. YM060. The contraction produced by m-CPBG declined rapidly, so the increase in the motility index by m-CPBG was not significant at any recording site. Of the antagonists tested, 0.1–1 mg/kg i.v. methysergide produced a delayed and prolonged contractile response at the middle and distal sites. The onset of the response was delayed about 20 min after application and the response was maintained over the subsequent 60-min observation period. The methysergide (1 mg/kg i.v.)-induced response was inhibited by 3 mg/kg i.v. hexamethonium. The other antagonists, ketanserin, YM060 and SDZ205-557, had no contractile effect at any recording site.These results indicate that exogenous 5-HT stimulates motility along the entire length of the fasted canine colon and that 5-HT-induced responses in the proximal colon are mediated mainly by 5-HT₁, whereas those in the middle and distal colon are mediated by both 5-HT₁ and 5-HT₂ receptors. Renzapride and methysergide also stimulate colonic motility via additional mechanisms. The activation of 5-HT₄ receptors and the blockade of endogenous 5-HT inhibitory regulation via 5-HT₁ receptors may be involved in the action of renzapride and methysergide respectively.     

A novel in vivo test for drugs affecting central serotonergic and adrenergic systems

In urethane-anaesthetized rats, myoclonic twitches of the anterior digastricus muscle were evoked by L-5-hydroxy-tryptophan (L-5-HTP, 50-100 mg/kg iv.), the serotonin (5-HT) receptor agonist, quipazine (1-8 mg/kg i.v.) and the 5-HT releaser, fenfluramine (4-8 mg/kg i.v.). The effect of L-5-HTP or quipazine on the frequency of twitches was inhibited by the 5-HT receptor antagonist cyproheptadine. Also L-DOPA (100 mg/kg i.p.) or the alpha 1-adrenoceptor agonist, cirazoline (0.3-3 mg/kg i.v.) evoked twitches of the muscle which were inhibited by the alpha 1-adrenoceptor antagonist, prazosin. In decerebrate, artificially respired rats, neither L-5-HTP nor L-DOPA evoked the twitches. The frequency of twitches evoked by fenfluramine but not by L-DOPA was increased by the alpha 2-adrenoceptor agonist, clonidine (0.2 and 0.4 mg/kg i.v.); clonidine's effect was abolished by the alpha 2-adrenoceptor antagonist, yohimbine. The beta 2-adrenoceptor agonist, salbutamol (0.01-1 mg/kg i.v.) had no effect on fenfluramine-induced twitches. It is concluded that (1) activation of 5-HT receptors or alpha 1-adrenoceptors in the brain of urethane-anaesthetized rats evokes twitches of the anterior digastricus muscle, and (2) this preparation can be utilized as a test to study the action of compounds on central 5-HT and adrenergic systems.     

Effects of traxanox sodium on experimental nasal allergy

The anti-allergic actions of traxanox sodium pentahydrate (traxanox) were examined using experimental allergic rhinitis models. Traxanox (10 and 30 mg/kg, p.o.), tranilast (30 and 100 mg/kg, p.o.) and disodium cromoglycate (DSCG, 3 and 10 mg/kg, i.v.) dose-dependently inhibited the increase of dye leakage in rats actively sensitized with dinitrophenol-coupled ascaris extract. Traxanox was about 4 times more potent than tranilast. In this test, the inhibitory activity of traxanox (30 mg/kg, p.o.) was not affected by predosing with the same dose for 7 days. In addition, traxanox (1-10 mg/kg, i.v.) inhibited the allergically induced increase in nasal resistance of guinea pigs actively sensitized with egg albumin, while tranilast (10 mg/kg, i.v.), DSCG (100 mg/kg, i.v.) and mepyramine (1 mg/kg, i.v.) had little effect. These results suggest that traxanox may be clinically effective in treating patients with nasal allergies.     

The 5-HT2B antagonist and 5-HT4 agonist activities of tegaserod in the anaesthetized rat.

The 5-HT4 receptor agonist and gastroprokinetic, tegaserod, possesses 5-HT2B receptor antagonist activity. However, the relevance of such activity is unclear. In this study, the 5-HT2B receptor antagonist and 5-HT4 agonist activities of tegaserod were investigated. Two piezoelectric crystals were implanted on the stomach fundus or oesophagus of anaesthetized Sprague-Dawley rats. Measurement of the transmission time of ultrasonic pulses between the implanted crystals provided a continuous record of inter-crystal distance, and thus of muscle length. In the stomach fundus, tegaserod (1 and 3 mg kg(-1)), administered subcutaneously (s.c.), inhibited the contractile response evoked by the 5-HT2B receptor agonist, BW 723C86 (0.01-1 mg kg(-1) intravenously (i.v.)). SB 206553 (1 mg kg(-1) s.c.), a selective 5-HT2B/2C receptor antagonist, also inhibited the BW 723C86-mediated responses. In the rat oesophagus, tegaserod (0.001-0.3 mg kg(-1) i.v. or 0.003-3 mg kg(-1) s.c.) increased inter-crystal distance, consistent with smooth muscle relaxation; the responses were inhibited by the 5-HT4 antagonist, piboserod (0.1 mg kg(-1) s.c.). Data from this in vivo rat study are consistent with tegaserod-induced 5-HT4 receptor-mediated oesophageal relaxation, and antagonism of 5-HT2B receptor-mediated stomach fundus contraction. The clinical relevance of the 5-HT2B receptor antagonism of tegaserod remains to be determined.     

Pharmacological evidence that 5-HT(1B/1D) receptors mediate hypotension in anesthetized rats

5-Carboxamidotryptamine (5-CT; 0.003-310 microg/kg, i.v.) produced dose-dependent hypotensive responses which were blocked in a complex manner by the 5-HT(7) receptor antagonist, (R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl) ethyl] pyrrolidine (SB-269970; 1 mg/kg, i.v.), in anesthetized vagosympathectomized rats. Interestingly, the 5-HT(1B/1D) receptor antagonist, N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1-biphenyl]-4-carboxamide hydrochloride monohydrate GR-127935 (1 mg/kg, i.v.), also inhibited 5-CT-induced hypotension but the effect was clearly noncompetitive. Finally, the combination of GR-127935+SB-269970 (1 mg/kg, i.v., each) produced a further decreased of 5-CT-induced responses as compared to the effect of individual treatments. These data suggest that, in addition to 5-HT(7) receptors, 5-HT(1B/1D) receptors may also mediate hypotension in rats.     

Effects of Y-20811, a specific thromboxane A2 synthetase inhibitor, on chemical mediator-induced bronchoconstriction in guinea pigs

We investigated the effects of Y-20811 on chemical mediator-induced bronchoconstriction and the release of chemical mediators into lung perfusion fluid during arachidonic acid (AA)-induced bronchoconstriction in guinea pigs. Y-20811 (0.01-1 mg/kg, i.v.), like acetylsalicylic acid or indomethacin, dose-dependently suppressed arachidonic acid- and LTD4-induced bronchoconstriction, and it (1 mg/kg, i.v.) also inhibited PAF-induced bronchoconstriction in guinea pigs. However, at a dose of 1 mg/kg, i.v., it was inactive against the bronchoconstriction induced by histamine, serotonin and acetylcholine in guinea pigs. Y-20811 (0.3-10 mg/kg) administered orally also prevented the LTD4-induced bronchoconstriction in a dose-dependent manner. This protective effect of Y-20811 (10 mg/kg, p.o.) persisted for at least 24 hr. Y-20811 (10 mg/kg, p.o.) also inhibited antigen-induced bronchoconstriction in guinea pigs passively sensitized with anti-ovalbumin guinea pig serum and pretreated with mepyramine. In the perfused and ventilated guinea pig lungs, Y-20811 inhibited AA-induced bronchoconstriction, decreased the release of TXA2 (estimated as TXB2) and increased the release of PGE2 into the perfused lung fluid, significantly (TXB2 and PGE2 were measured by HPLC). Therefore, Y-20811 suppressed various stimulant-induced bronchoconstrictions through the decrease of TXA2 production and the increase of PGE2 production. Thus, Y-20811 should prove useful as an anti-asthmatic drug.     

Interactive roles of superoxide and inducible nitric oxide synthase in rat intestinal injury provoked by non-steroidal anti-inflammatory drugs.

The role of nitric oxide (NO) formed by inducible NO synthase (iNOS), superoxide and the lipopolysaccharide from luminal bacteria in non-steroidal anti-inflammatory drug-induced intestinal injury was investigated in the rat. Administration (s.c. or p.o.) of indomethacin (10 mg kg(-1)), flurbiprofen (40 mg kg(-1)) or diclofenac (40 mg kg(-1)) increased the vascular leakage of radiolabelled albumin in the jejunum, determined after 24 h, associated with the induction of iNOS, assessed by the conversion of radiolabelled L-arginine. Pre-treatment with ampicillin (200 mg kg(-1) day(-1), p.o.), metronidazole (200 mg kg(-1) day(-1), p.o.), or polymixin B (15 mg kg(-1) day(-1), s.c.), inhibited indomethacin-induced lesion formation, reduced microvascular leakage and prevented the expression of iNOS activity. Administration of the highly selective iNOS inhibitor, GW273629 ((R)-2-amino-4,4-dioxo-6(1-iminioethylamino)-4-thiahexanoic acid; 5 mg kg(-1), s.c.), 18 h after indomethacin, likewise prevented the intestinal lesions and attenuated the microvascular leakage. Superoxide dismutase conjugated with polyethylene glycol (3000 U kg(-1), i.v.), inhibited the indomethacin-induced lesions and microvascular leakage, but not the expression of iNOS activity. These findings suggest that non-steroidal anti-inflammatory drugs compromise mucosal integrity, leading to luminal bacterial translocation. This provokes iNOS induction, leading to microvascular injury involving both NO and superoxide.     

The effect of a tachykinin NK1 receptor antagonist, SR140333, on oedema formation induced in rat skin by venom from the Phoneutria nigriventer spider.

1. The possibility that tachykinin NK1 receptors are involved in the plasma extravasation evoked by intradermal (i.d.) injection of Phoneutria nigriventer venom (PNV) in rat dorsal skin in vivo has been investigated. 2. Local oedema formation induced by the i.d. injection of test agents was measured by the extravascular accumulation of intravenously (i.v.) injected 125I-labelled human serum albumin over a 30 min period. 3. The tachykinin NK1 agonist, GR73632 (30 pmol per site), induced local oedema formation which was potentiated by co-injection with the neuropeptide vasodilator, calcitonin gene-related peptide (CGRP, 10 pmol per site). The non-peptide tachykinin NK1 receptor antagonist, SR140333 (0.03-1 nmol per site co-injected, i.d.) significantly inhibited (0.3 nmol per site, P < 0.05; 1 nmol per site, P < 0.001) local oedema formation induced by GR73632 with CGRP but not that induced by histamine (10 nmol per site) with CGRP. 4. PNV (0.03-0.3 microgram per site) injected i.d. induced dose-dependent local oedema formation. SR140333 (1 nmol per site, co-injected i.d.) inhibited oedema formation; with complete inhibition observed at doses of 0.03 microgram (P < 0.05) and 0.1 microgram (P < 0.001); and partial inhibition (50%) observed with the highest dose of PNV, 0.3 microgram (P < 0.05). 5. Local oedema formation induced by PNV was not affected by systemic pretreatment with the bradykinin B2 receptor antagonist, Hoe 140 (80 nmol kg-1, i.v.), which was used at a dose which significantly inhibited oedema formation by bradykinin (1 nmol per site). 6. Local oedema formation induced by PNV was significantly inhibited (P < 0.01) by co-injection of the histamine H1 receptor antagonist, mepyramine (2.5 nmol per site), together with the 5-hydroxytryptamine (5-HT) antagonist, methysergide (2.8 nmol per site). 7. In the presence of all three antagonists (mepyramine 2.5 nmol per site; methysergide, 2.8 nmol per site and SR140333 1 nmol per site), the plasma extravasation induced by PNV was further significantly inhibited (P < 0.001, when compared with PNV injected i.d. alone; P < 0.05 when compared with PNV co-injected with mepyramine and methysergide and P < 0.01, when compared with PNV co-injected with SR140333). 8. These results suggest that oedema formation evoked by i.d. PNV in rat skin may be partially mediated via a mechanism involving tachykinin NK1 receptors and that this effect is independent of histamine and 5-HT.     

Lipoxygenase metabolites mediate increased airways responsiveness to histamine after acute platelet activating factor exposure in the guinea-pig

Platelet activating factor (Paf, 0.02 micrograms/kg, i.v. bolus) caused an acute increase in airways responsiveness to histamine in anaesthetized guinea-pigs prepared for recording airways resistance (RL) and dynamic compliance (Cdyn). Aspirin pretreatment (10 mg/kg, i.v.) attenuated the return of airways responsiveness to prechallenge levels. Pretreatment with the combined cyclooxygenase/lipoxygenase inhibitors BW 755C (20 mg/kg, i.v.) and ETYA (20 mg/kg, i.v.), or with the putative cysteinyl-containing leukotriene antagonist FPL 55712 (0.25 mg/kg/min, i.v.), or a Paf antagonist SRI 63441 (2.5 mg/kg, i.v.), prevented Paf-induced increased airways responsiveness. Inhibitors of leukotriene synthesis, BW 755C and ETYA, or action, FPL 55712, had variable effects on Paf-induced bronchoconstriction. These data suggest that lipoxygenase metabolites, possibly leukotrienes, may mediate an acute increase in airways responsiveness to histamine after Paf exposure.     

Effect of a Paf antagonist, WEB 2086, on airway microvascular leakage in the guinea-pig and platelet aggregation in man.

1. The triazolodiazepine WEB 2086 has been evaluated as an antagonist of platelet-activating factor (Paf) by studying its effects on Paf-induced human platelet aggregation and microvascular leakage in guinea-pigs. 2. WEB 2086 inhibited Paf-induced platelet aggregation in platelet-rich plasma in vitro (IC50 = 117 +/- 35 nM, mean +/- s.d.) but had no effect on adenosine 3',5'-diphosphate-induced aggregation. 3. Paf-induced microvascular leakage, measured by the extravasation of intravenously-injected Evans blue dye, was inhibited in a dose-related fashion in the airways and other tissues by WEB 2086, achieving a maximal inhibitory effect at 10 micrograms kg-1, i.v. 4. However, WEB 2086 (10 micrograms kg-1, i.v.) did not inhibit a comparable increase in vascular permeability induced by ovalbumin in sensitized guinea-pigs. 5. We conclude that WEB 2086 is a potent antagonist of Paf and that Paf does not appear to be responsible for antigen-induced microvascular leakage.     

Contraction of guinea-pig trachea and bronchus by honey bee venom

Isolated guinea-pig tracheal and bronchial spiral strips were relaxed by indomethacin and constricted by carbachol, histamine and honey bee venom. Constriction of the tracheobronchial smooth muscle by bee venom was not affected by indomethacin (a prostaglandin-synthetase inhibitor); methysergide (d-tryptamine receptor antagonist); compound FPL 55712 (a selective antagonist of slow-reacting-substance of anaphylasix: SRS-A) and trasylol (a potent kallikrein inhibitor). These observations appear to exclude the involvement of acetylholine, 5-HT, prostaglandins and slow-reacting substance in mediation of airway constriction by bee venom. Mepyramine (a selective histamine H₁-receptor the mediation of airway constriction by bee venom. Mepyramine (a selective histamine H₁-receptor antagonist), isoproterenol, terbutaline and salbutamol (β₂-agonists) reversed airway constriction to both histamine and bee venom. In the presence of mepyramine, bee venom relaxed guinea-pig trachea. This relaxation was inhibited by indomethacin but not by metiamide suggesting the release from the airways of inhibitory prostaglandins by bee venom. This study suggests that bee venom constricts guinea-pig airways by releasing histamine from the tissue mast cells.     

Nicotine inhibits firing activity of dorsal raphe 5-HT neurones in vivo

It is established that the brain monoaminergic systems are among the main targets of several dependence-inducing drugs, including nicotine. In the present study extracellular electrophysiological recordings were performed to investigate the effects of nicotine on dorsal raphe 5-HT neurones. Nicotine, administered systemically (50-400 microg/kg, i.v.) in chloral hydrate-anaesthetised rats, induced a transient inhibition of the majority of 5-HT neurones recorded (38 of 45). The inhibition was rapid in onset (about 30 s) and the firing rate returned to baseline within 1-3 min. No apparent tachyphylaxis was observed to this inhibitory effect. The centrally acting nicotine antagonist mecamylamine (4 mg/kg, i.v.), but not the peripherally acting nicotine antagonist chlorisondamine (0.3 mg/kg, i.v.) antagonised the nicotine-induced inhibition of 5-HT neurones. The inhibition of 5-HT neurones was also blocked with a selective 5-HT1A receptor antagonist (WAY 100635; 0.1 mg/kg, i.v.), indicating a possible involvement of somato-dendritic 5-HT1A receptors in the effect of nicotine. Interestingly, microiontophoretic application of nicotine into the dorsal raphe failed to inhibit 5-HT neurones, suggesting an indirect effect of nicotine on 5-HT neurones, possibly involving afferent pathways.     

The effect of the 5-HT1A receptor agonist, 8-OH-DPAT, on motion-induced emesis in Suncus murinus

In the present study we evaluated the role of 5-HT(1A) receptors in mediating the inhibitory action of 8-OH-DPAT, a 5-HT(1A) receptor agonist, in motion sickness in Suncus murinus. 8-OH-DPAT (0.1 mg/kg, i. p) attenuated motion-induced emesis which was associated with an increase in the latency of the onset to the first emetic episode. Pre-treatment with methysergide (a 5-HT(1/2/7) receptor antagonist, 1.0 mg/kg, i. p.), WAY-100635 (a 5-HT(1A) receptor antagonist, 1.0 mg/kg, i. p.), SB269970A (a 5-HT(7) receptor antagonist, 1.0 and 5.0 mg/kg, i. p.), ondansetron (a 5-HT(3) receptor antagonist, 1.0 mg/kg, i. p) or GR13808 (a 5-HT(4) receptor antagonist, 0.5 mg/kg, i. p) failed to modify the inhibitory action of 8-OH-DPAT on motion sickness. Furthermore, the application of either methysergide, WAY-100635, SB269970A, ondansetron or GR13808 alone had no effect on motion sickness in its own right. These data indicate that neither 5-HT(1A) nor any 5-HT(2) receptor subtypes, 5-HT(3), 5-HT(4) and 5-HT(7) receptors are likely to be involved in the inhibition of motion-induced emesis mediated by 8-OH-DPAT.     

Are 5-HT receptors or beta-adrenoceptors involved in idazoxan-induced food and water intake?

Idazoxan (10 mg/kg, i.p.) produces an unexpected increase in food intake in freely-feeding rats which has been linked to its high affinity for non-adrenoceptor idazoxan binding sites. In this study, a dose-related antagonism of idazoxan-induced food intake by the beta-adrenoceptor antagonist (-)-propranolol (5-20 mg/kg, i.p.), which also blocks 5-HT1 (5-hydroxytryptamine1) receptors has been demonstrated. (+)-Propranolol (10, 20 mg/kg, i.p.) did not attenuate idazoxan-induced feeding. (-)-Propranolol (10 mg/kg, i.p.) but not the (+)-enantiomer (10 mg/kg, i.p.) also significantly inhibited the food intake, induced by the 5-HT1A agonist 8-OH-DPAT (0.25 mg/kg, i.p.). Idazoxan-induced feeding was not altered by the selective beta-adrenoceptor antagonists betaxolol (beta 1; 5 mg/kg, i.p.) and ICI 118,551 (beta 2; 5 mg/kg, i.p.) but was potentiated by the 5-HT receptor antagonist metergoline (5 mg/kg, i.p.). The anomalous findings with metergoline may reflect its action at different sub-types of 5-HT receptor. The water intake induced by idazoxan and the peripherally-active alpha 2-adrenoceptor antagonist L-659,066 was also blocked in a stereoselective manner by propranolol (10 mg/kg) but not significantly by either metergoline (5 mg/kg, i.p.), the beta 1-adrenoceptor antagonist betaxolol (5 mg/kg, i.p.) nor by the beta 2-adrenoceptor antagonist ICI 118,551 (5 mg/kg, i.p.). These results suggest that the food intake induced by idazoxan (and perhaps mediated by non-adrenoceptor idazoxan binding sites) may involve the 5-HT system, although further studies, using antagonists acting selectively at the different sub-types of 5-HT receptor, are required to confirm this.(ABSTRACT TRUNCATED AT 250 WORDS)     

MEN16132, a kinin B2 receptor antagonist, prevents the endogenous bradykinin effects in guinea-pig airways

Kinins have been suggested to be involved in human airway diseases such as asthma and rhinitis. MEN16132 is a non-peptide kinin B(2) receptor antagonist able to inhibit the responses produced by intravenous bradykinin into the airways, as bronchoconstriction and microvascular leakage; we tested the effect of MEN16132 on endogenously generated bradykinin through the dextran sulfate-induced contact activation of kinin-kallikrein cascade in guinea-pigs. After dextran sulfate administration (1.5 mg/kg i.v.), the pulmonary insufflation pressure was monitored and the microvascular leakage of upper and lower airways was assessed using Evans blue as tracer of plasma protein extravasation. Our results demonstrated that topical MEN16132 strongly inhibited the dextran sulfate-induced bronchoconstriction (0.3 mM solution aerosol for 5 min) and plasma protein extravasation in both lower airways (3-10 microM solution aerosol for 5 min) and nasal mucosa (0.3 nmol/nostril); Icatibant, the peptide antagonist of kinin B(2) receptor, exerted a 3-30-fold less potent inhibitory effect than MEN16132. We conclude that local application of MEN16132 into the airways abolishes the responses produced by the endogenous generation of bradykinin and it can be useful as new pharmacological tool to check the role of kinins in human diseases.     

Possible involvement of opioid receptors in moclobemide-induced hypothermia in mice.

Effect of moclobemide, a selective monoamine oxidase-type A enzyme inhibitor, was investigated on the body temperature of male mice. Moclobemide (15-30 mg kg(-1), i.p.) produced significant reductions of body temperature in both normal and yeast-induced hyperthermic male mice. The hypothermic effect of moclobemide was moderate and short-lasting. Moclobemide-induced hypothermia was not antagonized by previous administration of prazosin (10 and 20 mg kg(-1), s.c.), propranolol (5, 10, and 20 mg kg(-1), s.c.), haloperidol (2 and 10 mg kg(-1), s.c.), atropine (10 and 20 mg kg(-1), s.c.), mepyramine (25 and 50 mg kg(-1), s.c.), or methysergide (0.5, 1, and 2 mg kg(-1), s.c.). Pretreatment with the opioid antagonist naloxone (10 mg kg(-1), s.c.), however, was able to reverse the hypothermic effect of moclobemide (30 mg kg(-1), i.p.) in both normal and yeast-induced hyperthermic mice. The present results indicate a possible role for central opioid receptors in the hypothermic effect of moclobemide. Also, a peripheral component for this effect of moclobemide at the mitochondria of peripheral tissues is suspected. The peripheral tissue mitochondria could be considered a common target for moclobemide and opioids actions on body temperature.     

5-HT7 receptor-mediated dilatation in the middle meningeal artery of anesthetized rats

Topical administration of 5-carboxamidotryptamine (5-CT; 0.01-1000 microM) to the exposed dura mater encephali of anesthetized rats produced decreases in blood pressure and dilatation in the middle meningeal artery. Pretreatment with the 5-HT(1B/1D) receptor antagonist, N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1-biphenyl]-4-carboxamide hydrochloride monohydrate (GR-127935; 1 mg/kg, i.v.), unmasked meningeal dilator responses to lower concentrations of 5-CT, and attenuated those to higher concentrations; GR-127935 also inhibited 5-CT-induced hypotension. The 5-HT7 receptor antagonist, (R)-1-{(3-hydroxyphenyl)sulfonyl}-2-{2-(2-(4-methyl-1-piperidinyl) ethyl} pyrrolidine (SB-269970; 1 mg/kg, i.v.), strongly inhibited dilator and hypotensive responses to 5-CT; the combination of GR-127935+SB-269970 (1 mg/kg, i.v., each) further inhibited meningeal and hypotensive responses. Thus, 5-CT may produce dilatation in the middle meningeal artery via 5-HT7 receptors; complex effects appear to involve 5-HT(1B/1D) receptors.