Biomedical subjects

S Manzini

Publications and source records attributed to S Manzini.

At least 73 records · Page 4Linked to original sources

PubMed1993

Isbufylline, a new xanthine derivative, inhibits airway hyperresponsiveness and airway inflammation in guinea pigs.

The pharmacological actions of the new xanthine, isbufylline, were evaluated in several models of airway hyperresponsiveness and airway inflammation in guinea pigs. At a dose (106 mumol kg-1 i.p.) providing complete protection against acetylcholine aerosol-induced dyspnea in the guinea pig, isbufylline inhibited platelet activating factor (PAF)- and antigen-induced eosinophil infiltration into bronchoalveolar lavage fluid 24 h after challenge of normal and actively immunized guinea pigs, respectively. In addition, this dose of isbufylline also inhibited capsaicin-induced extravasation of protein into bronchoalveolar lavage fluid. Isbufylline, 4.2 mumol kg-1 i.v., significantly inhibited PAF-induced bronchial hyper-responsiveness to i.v. histamine, without exerting evident bronchodilator activity. On the other hand the bronchodilator, salbutamol, at a dose (10.4 mumol kg-1 i.p.) shown to be equieffective to isbufylline (106 mumol kg-1 i.p.) for blocking acetylcholine aerosol-induced dyspnea, had no protective action against PAF- or antigen-induced eosinophil recruitment in bronchoalveolar lavage fluid, or against capsaicin-induced plasma protein extravasation. Furthermore, salbutamol (3.5 mumol kg-1) significantly potentiated allergen-induced cell infiltration and PAF-induced bronchial hyperresponsiveness. The results suggest that isbufylline can exert significant anti-inflammatory actions in guinea pig airways, in addition to its bronchodilator activity. These pharmacological activities are not shared by the beta 2-adrenoceptor agonist, salbutamol.

1-Methyl-3-isobutylxanthine↗

PubMed1993

Topical capsaicin administration protects against trinitrobenzene sulfonic acid-induced colitis in the rat.

We used the [3H]resiniferatoxin binding assay to demonstrate for the first time the existence of vanilloid receptors in the rat colon and to explore their expression during trinitrobenzene sulfonic acid-induced colitis. Membranes obtained from control colon bound [3H]resiniferatoxin with an affinity of 3 nM; the receptor density was 450 fmol/mg protein or 9 fmol/mg wet weight. Capsaicin and capsazepine, a competitive antagonist of capsaicin, inhibited specific resiniferatoxin binding with Ki values of 3 microM and 0.1 microM, respectively. Trinitrobenzene sulfonic acid induced a very rapid ulceration in the colon: 1 h after treatment 90% of the colon showed ulcerative damage. Coadministration of 640 microM capsaicin diminished the ulcerative effect of trinitrobenzene sulfonic acid to 64% when examined 1 h after trinitrobenzene sulfonic acid challenge; however, this protective action was lost 23 h later. Colon samples obtained 4 h, 24 h, and 1 week after trinitrobenzene sulfonic acid challenge bound resiniferatoxin, capsaicin, and capsazepine with affinities similar to those of control samples. The receptor density remained at an essentially constant level when expressed in fmol/mg protein but, in keeping with the increased wet weights, showed a reduction when expressed in fmol/mg wet weight. We conclude that acute capsaicin administration protects against the ulcerative action of trinitrobenzene sulfonic acid, most likely via the release of protective neuropeptides from capsaicin-sensitive nerve endings. The loss of this protective action is presumably due to a depletion of the protective neuropeptides rather than to a loss of vanilloid (capsaicin) receptors.

Administration, Topical↗

PubMed1993

The effect of neonatal capsaicin on the development of bronchial hyperresponsiveness in allergic rabbits.

We have investigated the effects of neonatal capsaicin treatment of rabbits on the development of bronchial hyperresponsiveness following allergen exposure from birth. In vivo airways responsiveness was assessed as the concentrations of histamine to cause a 35% decrease in compliance (PC35) and a 50% increase in resistance (PC50). Rabbits treated with vehicle capsaicin (10% ethanol, 10% tween 80 and 80% saline) and then immunised with Altenaria tenius (40,000 protein nitrogen units (PNU)/ml + AL(OH)3 + saline in a ratio 2:1:1) were more responsive to aerosol histamine in vivo at three months of age when compared to sham-immunised (AL(OH)3 + saline 1:3) or saline-treated rabbits for compliance measurements (P < 0.05). However, immunised rabbits although not significantly different to sham-immunised (P > 0.05) were significantly more responsive than saline-treated rabbits for resistance measurements (P < 0.05). Neonatal capsaicin treatment significantly attenuated the increased responsiveness seen in immunised rabbits for both compliance and resistance measurements (P < 0.05). The bronchial hyperresponsiveness is unlikely to be due to cellular infiltration per se as cell numbers assessed by bronchoalveolar lavage were not significantly different between groups (P > 0.05). Exogenous in vitro functional bronchial responses to capsaicin were increased in vehicle-immunised rabbits, an effect attenuated by neonatal capsaicin treatment (P < 0.05) whereas responses to methacholine, histamine or electrical field stimulation remained similar between groups (P > 0.05). Bronchial levels of calcitonin gene-related peptide- and substance P-like immunoreactivity were unaffected by any treatment (P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Isbufylline, a xanthine derivative, inhibits bronchoconstrictor responses produced by stimulation of capsaicin-sensitive sensory nerves in guinea-pig: 'In vitro' and 'in vivo' evidence.

Isbufylline (1,3-dimethyl-7-isobutylxanthine) is a new xanthine derivative claimed to possess remarkable antibronchospastic properties coupled to reduced pro-convulsive side-effects. In guinea-pig bronchial preparations, isbufylline showed a differential and more pronounced, as compared to theophylline, relaxant activity on tonic bronchial contractions evoked by exogenous administration of equieffective concentrations of capsaicin (0.3 microM), neurokinin A (0.1 microM) and carbachol (0.3 microM) (in the presence of indomethacin 5 microM and thiorphan 10 microM). Isubfylline gave an IC50 of 21 (19-25, 95% confidence limits) microM on capsaicin-evoked contractile effects, and 36 (30-43) microM on carbachol-produced contractile effects, whilst it was almost ineffective in inhibiting neurokinin A-induced bronchospasm (IC50 not evaluable, > 100 microM). 'In vitro' studies were also performed using electrical field stimulation (EFS) to produce non-adrenergic non-cholinergic (NANC)- or cholinergic nerves-mediated contractions in guinea-pig isolated bronchi or trachea. Isbufylline (10-90 microM) produced a concentration-dependent inhibition of the NANC response (EFS: 20 Hz, supramaximal voltage, 0.5 ms pulse, width for 10 s) of bronchi (IC50 = 47 microM) without affecting the cholinergic contractile response in tracheal smooth muscle (EFS: 0.5 up to 32 Hz, supramaximal voltage, 0.5 ms pulse, for 15 s every min). The activity of isbufylline was also confirmed in anaesthetized guinea-pig showing a greater antibronchospastic activity towards capsaicin (8 nmol/kg i.v.) or vagal non-cholinergic (10 V, 1 ms, 20 Hz for 20 s) stimulation as compared to the inhibition exerted against acetylcholine (50 nmol/kg i.v.) or neurokinin A (1 nmol/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗

PubMed1993

Vanilloid receptors in the urinary bladder: regional distribution, localization on sensory nerves, and species-related differences.

Using selective surgical ablations we have investigated the localization of vanilloid receptors (specific [3H] resiniferatoxin binding sites) on terminals of the pelvic, hypogastric, and pudendal nerves in the rat urinary bladder. Pelvic and hypogastric nerve resections resulted in 90% and 25% loss of specific [3H] resiniferatoxin (RTX) binding sites, respectively, whilst pudendic nerve resection had no measurable effect on the binding. In control animals, the density of vanilloid receptors was 1.7-fold higher in the neck than in the dome of the urinary bladder; the Bmax values were 57 +/- 8 and 34 +/- 7 fmol/mg protein, respectively. The binding characteristics of the vanilloid receptor were similar in the urinary bladder of the rat and mouse: Kd values were 87 +/- 15 and 61 +/- 11 pM, Bmax values were 37 +/- 2 and 60 +/- 10 fmol/mg protein, respectively. In contrast to the findings for the rat and mouse, in the urinary bladder of the guinea pig and the hamster the low level of specific [3H]RTX binding prevented the detailed characterization of vanilloid receptors. Nonetheless, at a fixed (60pM) concentration of [3H]RTX, specific binding both in the guinea pig and hamster urinary bladder was approximately 20% of that in the rat urinary bladder. In the urinary bladder of newborn rats, as in adults, a single class of specific [3H]RTX binding sites was found which bound RTX with an affinity of 110 +/- 20 pM and with a maximal binding capacity of 30 +/- 5 fmol/mg protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Characterization of a peripheral vanilloid (capsaicin) receptor in the urinary bladder of the rat.

Specific binding of [3H]resiniferatoxin (RTX) is thought to represent the vanilloid (capsaicin) receptor. In the present study, we have used this binding assay to identify for the first time a vanilloid receptor in the periphery and to compare it to central vanilloid receptors present in dorsal root ganglia (DRG) as well as in spinal cord of the rat. Rat urinary bladder membranes bound [3H]RTX with a Kd of 30 +/- 4 pM and a Bmax of 65 +/- 14 fmol/mg protein; the corresponding values were 19 +/- 3 pM and 104 +/- 14 fmol/mg protein in DRG, and 16 +/- 3 pM and 50 +/- 9 fmol/mg protein in spinal cord. Capsaicin inhibited [3H]RTX binding to membranes from urinary bladder, spinal cord, and DRG with similar potency (Ki values were 0.5 +/- 0.1 microM, 0.3 +/- 0.1, and 0.6 +/- 0.1 microM, respectively). Interestingly, [3H]RTX bound to urinary bladder in a non-cooperative fashion in contrast with the apparent positive cooperativity of [3H]RTX binding in both DRG and spinal cord (cooperativity index = 1.8 and 1.7, respectively). This finding suggests heterogeneity in the properties of the vanilloid receptors in the rat.

Animals↗

PubMed1993

A new method for assessing Ca2+ requirements for vasoconstriction in the rat isolated perfused kidney. Effect of norepinephrine and endothelin.

The consecutive perfusion with three different media containing 1) a high-K+, Ca(2+)-free solution with 1 mM of EDTA, 2) a high-K+, Ca(2+)-free solution with 1mM of EDTA and 0.3-10 microM of norepinephrine (NE) or 1-10 nM of endothelin (ET), and 3) a normal K+ solution without EDTA, NE, or ET, respectively, produced three rapid and transient vasoconstrictions of the isolated and perfused rat kidney. Results obtained from preincubation with prazosin (0.9 nM) and nifedipine (10 nM) or reperfusion at various Ca2+ concentrations showed that the responses involved are characterized by a different mobilization of cellular and extracellular Ca2+. The first phase greatly depends on the influx of extracellular Ca2+ and/or membrane Ca2+ through voltage-dependent channels, the second from mobilization of intracellular Ca2+, while the third is due mainly to the influx of extracellular Ca2+ through receptor-activated channels. NE elicited Ca2+ mobilization from both cellular and extracellular sources through activation of alpha-1 adrenoceptors. ET is particularly effective in producing extracellular Ca(2+)-dependent vasoconstriction in a prazosin-resistant manner. Present results show that this method could be suitable to distinguish different Ca2+ requirements for spasmogen-induced vasoconstriction in the isolated and perfused rat kidney.

Animals↗

PubMed1993

Intraurethral capsaicin produces reflex activation of the striated urethral sphincter in urethane-anesthetized male rats.

The effect of intraurethral application of capsaicin on the urethral motility of urethane anesthetized rats has been investigated. The urinary bladder and the urethra were surgically disconnected, and both organs were cannulated to record variations in intraluminal pressure (cystourethrogram). Urinary bladder reflex contractions in response to intravesical infusion of saline were paralleled by activation of the external striated urethral sphincter, resulting in intraluminal pressure high frequency oscillations (IPHFO) which were recorded at the urethral level. Intraurethral capsaicin (0.2 microgram./30 microliters.), produced an immediate enhancement of the IPHFO, the amplitude of which (70 +/- 9 mm.Hg) was significantly (p < 0.01) higher as compared with that recorded before drug administration (15 +/- 3 mm.Hg). The potentiation was followed (11 of 15 rats) by a period (5 to 12 minutes) characterized by a continuous low-amplitude urethral phasic activity. Throughout this period urinary bladder motility was inhibited. A second administration of capsaicin in the same animal was ineffective, and the response was absent in rats desensitized to capsaicin (50 mg./kg., subcutaneously, 4 days before), after application of tetrodotoxin (10 micrograms.) on the pudendal nerves, or after acute (3 hours before) sectioning, as well as in rats pretreated with d-tubocurarine (d-Tc, 100 micrograms./kg. intravenously). Intraurethral injection of capsaicin (0.2 microgram./30 microliters.), performed when the urinary bladder was empty, triggered IPHFO (12 +/- 3 mm.Hg) in 5 of 6 rats. This response was unaffected by hexamethonium (20 mg./kg., intravenously) or after removal (6 hours before) of the major pelvic ganglia, while it was absent after destruction of the lumbosacral spinal cord (3 to 6 hours before), in rats acutely spinalized (T13-L1), or after sectioning of the pudendal nerves. In rats receiving intrathecal (L5-S1) capsaicin (60 micrograms., 24 hours before), the capsaicin-induced IPHFO activation was lacking. Electrical field stimulation (EFS, 0.1 Hz, 30 microseconds, 20 to 30 v) of the rat isolated external urethral sphincter (EUS), elicited d-tubocurarine and tetrodotoxin-sensitive twitch contractions, the amplitude of which was unaffected by capsaicin (1 microM.). Altogether these results suggest a physiological interaction between capsaicin-sensitive primary afferents innervating the urethra and the somatic efferent innervation to the urethral rabdosphincter. Present findings suggest the existence of a chemonociceptive urethro-urethral neural loop which, via pudendal nerves, leads to a supraspinally-mediated activation of the external urethral sphincter.

Afferent Pathways↗

PubMed1993

Capsaicin-induced relaxation in the rat isolated external urethral sphincter: characterization of the vanilloid receptor and mediation by CGRP.

1. The potential role of capsaicin-sensitive nerves in the relaxation of the rat external urethral sphincter (REUS) was evaluated by demonstrating the existence of specific vanilloid (capsaicin) receptors and by investigating the sensory neurotransmitter(s) putatively involved in this relaxation. 2. Capsaicin (1 microM) relaxed REUS strips precontracted with noradrenaline (NA) (0.1 mM). This effect underwent desensitization and it was absent in preparations taken from adult capsaicin-pretreated rats. 3. Capsaicin-induced relaxation of NA-precontracted REUS was mimicked by calcitonin gene-related peptide (CGRP, 0.3-10 microM), but not by substance P (1 microM), vasoactive intestinal polypeptide (VIP, 1 microM), alpha-beta methylene ATP (10 microM), gamma-aminobutyric acid (GABA, 3 mM) or galanin (1 microM). A cross-tachyphylaxis between capsaicin (1 microM) and CGRP (1 microM) was observed. Both capsaicin and CGRP-induced relaxation were partially antagonized by the proposed CGRP antagonist, CGRP (8-37) (10 microM). 4. Electrical field stimulation (EFS, 2.5 Hz, 60 V, 1 ms, trains of 5 s every 5 min) of REUS evoked a contraction characterized by a largely adrenergic slowly developing tonic contraction with superimposed fast twitches due to the striated component of the strips. Both capsaicin (1 microM) and CGRP (0.01-1 microM) produced an almost complete inhibition of EFS-induced tonic contraction. A cross-tachyphylaxis between capsaicin and CGRP was observed. Furthermore, these inhibitory actions were unaffected by CGRP (8-37) (10 microM). 5. [3H]-resiniferatoxin displayed specific, saturable binding to rat urethral membranes. Data were consistent with a single site with a Kd of 105 pM and a Bmax of 40 fmol mg-1 protein. This binding was inhibited by capsaicin with a Ki of 0.6 microM and it was reduced by approximately 80% in preparations taken from rats that had undergone surgical ablation of the major pelvic ganglion 4 days earlier.6. In conclusion we have demonstrated the existence of vanilloid receptors on capsaicin-sensitive nerves innervating the rat urethra mainly through the major pelvic ganglion. The activation of this set of nerves could lead to a local release of CGRP that in turn elicits a remarkable urethral relaxation. Such a mechanism could be of relevance in physiological conditions to facilitate urine expulsion during micturition and in pathological conditions to help removal of noxious stimuli following mechanical/chemical irritation of the lower urinary tract.

Animals↗

PubMed1993

Activation of capsaicin-sensitive sensory fibers modulates PAF-induced bronchial hyperresponsiveness in anesthetized guinea pigs.

In anesthetized guinea pigs, a slow intravenous infusion of platelet activating factor (PAF) (600 ng/kg over 1 h) but not of the carrier molecule bovine serum albumin (0.25%) induced immediate and transient bronchoconstriction and a fall in arterial blood pressure followed by an increase in bronchial responsiveness to histamine (0.56 to 1.8 microgram/kg intravenously). Pretreatment of guinea pigs with capsaicin (55 mg/kg subcutaneously over 2 days) 1 wk before the experiments, or with ruthenium red (5 mg/kg subcutaneously) 1 h before, completely inhibited capsaicin (2.5 micrograms/kg intravenously)-induced bronchoconstriction, and completely inhibited PAF-induced bronchial hyperresponsiveness. On the other hand, PAF-induced immediate bronchoconstriction and decreases in mean arterial blood pressure were not affected by capsaicin and/or ruthenium red pretreatment. However, pretreatment of guinea pigs with the PAF antagonist WEB 2086 resulted in a complete inhibition of PAF-induced direct bronchoconstriction, fall in arterial blood pressure, and bronchial hyperresponsiveness to histamine. It is suggested that in the guinea pig, PAF-induced bronchial hyperresponsiveness to histamine may be secondary to the activation of capsaicin-sensitive sensory fibers.

Anesthesia↗

PubMed1993

Endogenous tachykinins play a role in IL-1-induced neutrophil accumulation: involvement of NK-1 receptors.

Pretreatment of mice with capsaicin resulted in approximately 40% inhibition of the polymorphonuclear leucocyte (PMN) influx elicited by interleukin-1 (IL-1) injected into a murine air-pouch. This inhibition was mimicked by two selective antagonists of neurokinin-1 (NK-1) tachykinin (TK) receptors, i.e. CP-96,345 and RP-67,580, but not by the inactive enantiomer RP-68,651. A selective NK-2 antagonist, SR-48,968, was inactive. The natural peptide, substance P (SP), and a selective NK-1 agonist, (Sar9)SP, induced PMN infiltration into the murine air-pouch, whereas a selective NK-2 agonist, (beta Ala8)NK-A(4-10), was ineffective. Moreover, SP-induced PMN accumulation was prevented by co-administration of RP-67,580 and CP-96,345, but not by RP-68,651. These findings suggest that the release of an endogenous TK, possibly SP, may occur following IL-1 injection in vivo, indicating a contributory role for neuropeptides in the PMN migration elicited by this cytokine. The action of selective agonists and antagonists suggests the involvement of NK-1 receptors.

Animals↗

PubMed1993

Nonadrenergic, noncholinergic inhibitory control of the rat external urethral sphincter: involvement of nitric oxide.

Administration of norepinephrine (0.1 mM) to the isolated rat external urethral sphincter (EUS) produced a tonic contraction which was inhibited by phentolamine (3 microM), but not by tetrodotoxin (0.6 microM). Electrical field stimulation (EFS; 60 V, 1 msec, trains of 5 sec every 5 min) of the EUS, performed after norepinephrine-induced urethral contractions had reached steady state, resulted in a frequency-dependent (1.5-5 Hz) relaxation. EFS-induced relaxation was abolished by tetrodotoxin (0.6 microM); and it was diminished or abolished in samples taken from rats in which the pudendal nerves and/or the major pelvic ganglia or the lumbosacral spinal cord had been cut or removed 10 days before. Propranolol (3 microM), atropine (3 microM), indomethacin (5 microM) or hexamethonium (10 microM) did not affect EFS-induced relaxation. Preincubation with L-NG-nitro-arginine (L-NOARG), however, inhibited the EFS-induced relaxation in a concentration-dependent manner (10-100 microM). The effect of L-NOARG (50 microM) was reversed by L-arginine (300 microM), but not by D-arginine (300 microM). EFS (2.5 Hz, 60 V, 1 msec, trains of 5 sec every 5 min) of the resting EUS, produced a tetrodotoxin-sensitive response with a tonic contraction component, which was inhibited by phentolamine but, in contrast, was enhanced by L-NOARG (100 microM). Altogether, these findings indicate that the inhibitory nonadrenergic, noncholinergic pathways that innervate the EUS in rats travel mostly with the pudendal nerves. This neural inhibitory system may act via the synthesis and release of nitric oxide or a nitric acid-containing compound.

Animals↗

PubMed1993

Competitive inhibition by capsazepine of [3H]resiniferatoxin binding to central (spinal cord and dorsal root ganglia) and peripheral (urinary bladder and airways) vanilloid (capsaicin) receptors in the rat.

Capsazepine was reported to block capsaicin- and resiniferatoxin (RTX)-induced responses both in vivo and in vitro with Schild plots suggesting a competitive mechanism of action. We have used the [3H]RTX binding assay, thought to represent the vanilloid (capsaicin) receptor, to explore the inhibitory mechanism of capsazepine at the receptor level in the rat. In competition assays, capsazepine inhibited [3H]RTX binding by spinal cord, dorsal root ganglion (DRG) and urinary bladder membranes with similar Ki values of 4.0 +/- 0.3, 3.5 +/- 0.5 and 5.0 +/- 1.0 microM (mean +/- S.E.M.; three determinations), respectively. By contrast, capsazepine was 35- to 50-fold more potent for inhibiting specific [3H]RTX binding in the airways (Ki = 0.12 +/- 0.02 microM; mean +/- S.E.M.; four determinations). In experiments in which the concentration of [3H]RTX was varied, 10 microM capsazepine reduced the affinity of the vanilloid receptor expressed by DRG and spinal cord membranes for [3H]RTX from 15 +/- 3 to 43 +/- 5 pM, and from 20 +/- 3 to 80 +/- 5 pM (mean +/- S.E.M.; three determinations), respectively, without a measurable change in Bmax or in cooperativity index; these shifts in affinity yield Ki values of 5.2 and 3.3 microM for DRG and spinal cord membranes, respectively. Capsaicin inhibited [3H]RTX binding by spinal cord, DRG and urinary bladder membranes with a 6- to 13-fold higher potency than did capsazepine; the Ki values were 0.3 +/- 0.1, 0.6 +/- 0.4 and 0.5 +/- 0.2 microM (mean +/- S.E.M.; three determinations), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Interactions between sensory neuropeptides and lipid mediators in the airways.

The local release of sensory neuropeptides from capsaicin-sensitive primary afferents elicits prominent motor and inflammatory actions in mammalian airways. This neurogenic inflammation can contribute to the pathophysiology of asthma and airway hyperreactivity. In this review evidence will be presented regarding the involvement of this peptidergic neural pathway in the mediation of some pulmonary actions of lipid mediators such as eicosanoids and PAF.

Animals↗

PubMed1993

Effect of active sensitization on the bronchopulmonary responses to tachykinins in the guinea pig. Modulation by peptidase inhibitors.

The i.v. administration of substance P (SP, 0.25-16 micrograms/kg) or of the selective metabolic stable NK-1 agonist, [Glp6,Pro9]SP-(6-11) (septide, 0.03-0.25 microgram) to atropine-treated guinea pigs or to isolated perfused lungs triggered a dose-dependent bronchoconstriction, which was enhanced in animals actively sensitized to ovalbumin. In vivo, bronchial hyper-responsiveness was restricted to SP and to septide, inasmuch as neurokinin A (0.06-1 microgram/kg)- or capsaicin (0.5-32 micrograms/kg)-induced bronchoconstriction were not modified. In contrast, isolated lungs from sensitized guinea pigs exhibited an increased bronchoconstriction also in response to capsaicin (0.01-10 micrograms), which was inhibited by atropine in the medium. Pretreatment of actively sensitized guinea pigs either with indomethacin plus mepyramine, the lipoxygenase inhibitor BW A4C or with the platelet-activating factor antagonist SR 27417, did not modify bronchial hyper-reactivity to SP. Captopril (5 mg/kg i.v.), but not thiorphan (0.8 mg/kg i.v.), increased the SP-induced bronchoconstriction in actively sensitized animals, whereas both inhibitors were equally effective in nonsensitized guinea pigs. Thiorphan, however, did not modify the in vivo response to septide. Our results demonstrate that guinea pigs sensitized to ovalbumin exhibit bronchial hyperreactivity to SP, but not to neurokinin A, as compared to nonsensitized animals, suggesting a decrease in the neutral endopeptidase activity in the airways brought by the immunization. However, the results obtained by using septide indicate that other mechanisms may be involved in the bronchial hyper-reactivity to SP.

6-Ketoprostaglandin F1 alpha↗

PubMed1992

Differential effects of various xanthines on pentylenetetrazole-induced seizures in rats: an EEG and behavioural study.

The present study deals with the EEG (electroencephalogram) and behavioural effects of a subconvulsant dose (30 mg/kg i.p.) of pentylenetetrazole in freely moving rats pretreated (100 mg/kg p.o., 1 h before pentylenetetrazole) with two classic (theophylline and caffeine) and two new (enprofylline and isbufylline) xanthines. In rats treated with vehicle, pentylenetetrazole caused a slight desynchronization of the EEG, characterized by periods of 'wave discharges', and 'spike-and-wave discharge complexes'. In rats pretreated with xanthines (theophylline or caffeine) pentylenetetrazole produced a dramatic increase in ictal seizures with the appearance of continuous spikes; concomitantly animals experienced myoclonic jerks (100%) and in some cases (ca. 20%) the animals died. In contrast, in enprofylline-pretreated rats, pentylenetetrazole induced only brief periods of wave discharges and spike-and-wave discharge complexes whose duration was significantly reduced compared to that of controls, although these discharges were associated with mild epileptic behaviour. When isbufylline-pretreated rats were challenged with pentylenetetrazole, the EEG was characterized by a short run of wave discharges (whose duration was shorter than that of other groups). No enprofylline- or isbufylline-treated rats developed seizures or died. In conclusion, only xanthines with strong adenosine A1 receptor antagonism (theophylline and caffeine) markedly enhance the EEG and behavioural effects of a subconvulsive dose of pentylenetetrazole. The present experimental approach could be used to evaluate the pro-convulsive potential of new xanthine derivatives.

1-Methyl-3-isobutylxanthine↗

PubMed1992

Effects of selective tachykinin receptor antagonists on capsaicin- and tachykinin-induced bronchospasm in anaesthetized guinea-pigs.

Bronchospasm induced by i.v. injection of equieffective doses of acetylcholine, capsaicin or selective tachykinin receptor agonists ([Sar9]SP sulfone or [beta-Ala8]neurokinin A (NKA-4-10)) (for NK1 and NK2 receptors, respectively) was studied in anaesthetized guinea-pigs. The NK1 and NK2 receptor antagonists, (+/-)-CP96,345 (3 mumol/kg i.v.) and MEN 10,376 (3 mumol/kg i.v.), selectively abolished the bronchoconstriction induced by the respective agonist, showing that both NK1 and NK2 receptors mediate bronchoconstriction in guinea-pig airways and that they are activated independently. Capsaicin-induced bronchospasm was inhibited by atropine (1.5 mumol/kg i.v.) and MEN 10,376 (3 mumol/kg i.v.), but unaffected by (+/-)-CP96,345 (3 mumol/kg i.v.). Hexamethonium (79 mumol/kg i.v.), propranolol (17 mumol/kg i.v.) and physostigmine (0.9 mumol/kg i.v.) enhanced the airway constriction induced by acetylcholine, capsaicin, [Sar9]SP sulfone or [beta-Ala8]NKA-(4-10) while guanethidine (67 mumol/kg s.c. for two days) increased only bronchoconstriction induced by capsaicin or the selective NK2 receptor agonist. In hexamethonium-treated animals, MEN 10,376 still abolished the increase in insufflation pressure induced by [beta-Ala8]NKA-(4-10) and reduced the increase elicited by capsaicin. In summary, in anaesthetized guinea pig i.v. capsaicin-induced bronchospasm through activation of postjunctional NK2 (but not NK1) receptors along with activation of cholinergic pathways. This motor response is moderated by the simultaneous stimulation of a sympathetic bronchodilating mechanism(s), possibly through activation of NK2 receptors localized in sympathetic ganglia.

Anesthesia↗

PubMed1992

Determination of the tricyclic compound adosupine and its three metabolites in plasma and brain of rat using high-performance liquid chromatography.

An analytical method for the detection in biological samples of the novel tricyclic compound adosupine (10-acetoamido-5-methyl-5,6-dihydro-11H-dibenzo[b,e]azepin-6 ,11-dione), which is capable of influencing various forms of urinary bladder hyperreflexia has been developed using high-performance liquid chromatography with UV detection. Liquid-liquid extraction was used to isolate the parent compound, three metabolites and an analogue (added as internal standard) from plasma and brain of rat. Adosupine was well separated from its three metabolites with 0.01 M disodium hydrogenphosphate-acetonitrile-methanol-nonylamine (59.986:38:2:0.014) at pH 4.5 as mobile phase using a C18 reversed-phase column. The standard curves were linear in the range 50-5000 ng/ml (or ng/g) for adosupine and metabolites in both plasma and brain. The between- and within-assay variations for high and low concentrations of the parent compound and the three metabolites were 8.2-14%. In the range 50-5000 ng/ml (or ng/g) the accuracy of the method was satisfactory, with the relative error always lower than 10%. Analytical recoveries of added adosupine and the three metabolites were higher than 82%. The method has been applied successfully, to investigate the pharmacokinetics of the drug and its distribution in the central nervous system of rats.

Animals↗