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S Manzini

Publications and source records attributed to S Manzini.

At least 109 records · Page 6Linked to original sources
PubMed1990

Sensory neuropeptides in health and disease. Conference report on Florence '89.

A workshop (chaired by F. Lembeck, Graz) was held in Florence on 1 and 2 June 1989 with the aims to present and discuss the state of the art of research on sensory neuropeptides, i.e. those peptides demonstrated to be coded and synthetized in and released from sensory neurons. The meeting was therefore, particularly focused on tachykinins (substance P, neurokinin A and B) and calcitonin gene-related peptide (CGRP) and on the use of capsaicin as a pharmacological tool for studying the function of the related neurons. Particular relevance was paid to the biological effects and pathophysiological role(s) of sensory neuropeptides peripherally released ('efferent' function) from capsaicin-sensitive primary afferents.

Animals↗
PubMed1990

Sensory nerves, vascular endothelium and neurogenic relaxation of the guinea-pig isolated pulmonary artery.

1. In the presence of atropine and guanethidine (3 mumol/l each), electrical field stimulation (1-20 Hz) produced frequency-dependent relaxations of the histamine- (3 mumol/l) induced vascular tone in isolated rings from the guinea-pig pulmonary artery. The electrically-evoked relaxations were abolished by tetrodotoxin (1 mumol/l). The amplitude of these nerve-mediated, non-adrenergic non-cholinergic (NANC) relaxations was unaffected by removal of the vascular endothelium produced through rubbing of the internal surface. 2. Capsaicin (1 mumol/l) produced a prompt and sustained relaxation of the histamine-induced tone which was unaffected by removal of the endothelium. A second application of capsaicin 60-120 min later had no further relaxant effect, indicating desensitization. After in vitro capsaicin desensitization, the electrically-evoked NANC relaxations were abolished, both in the presence or absence of the vascular endothelium. 3. Substance P evoked a prompt and transient relaxation in precontracted arterial rings with intact endothelium and a transient small contraction in rings in which the endothelium had been mechanically removed. The selective NK-1 receptor agonist, [Pro9]-substance P sulfone closely mimicked the relaxation produced by substance P while the selective NK-2 or NK-3 receptor agonists had no relaxant effect. Tachyphylaxis to substance P did not modify the amplitude of the capsaicin-induced relaxation. 4. Human alpha calcitonin gene-related peptide (CGRP) produced a prompt and sustained relaxation both in the presence and absence of the vascular endothelium. 5. Ruthenium red (10 mumol/l) blocked the relaxation to capsaicin while leaving unaffected the relaxation to electrical field stimulation or CGRP (0.1 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

2-Chloroadenosine induction of vagally-mediated and atropine-resistant bronchomotor responses in anaesthetized guinea-pigs.

1. The bronchoconstrictor effects of intravenous administration of adenosine derivatives in anaesthetized non-curarized guinea-pigs have been studied. 2. 2-Chloroadenosine (2-Cl-Ade), 5'-N-ethylcarboxamideadenosine (NECA) and L-N6-phenylisopropyl-adenosine (L-PIA) all produced dose-dependent, transient increases in tracheal insufflation pressure, with an order of potency (NECA greater than or equal to 2-Cl-Ade much greater than L-PIA) typical of A2-receptor mediated biological responses. 3. 2-Chloradenosine-induced bronchoconstrictor responses disappeared after vagotomy or topical application of tetrodotoxin (TTX) on cervical vagal trunks. 4. 2-Chloradenosine-induced bronchospasm was unaffected by atropine (1 mg kg-1 i.v.), physostigmine (50 micrograms kg-1 i.v.) and hexamethonium (30 mg kg-1 i.v.) but was significantly reduced by theophylline (25 mg kg-1 i.v.). 5. The magnitude of 2-Cl-Ade-induced bronchospasm was significantly reduced by acute (10 micrograms kg-1 i.v.) or chronic (55 mgkg-1 s.c. four days before the experiment) pretreatment with capsaicin. 6. Guanethidine (20 mg kg-1 s.c on two consecutive days), prazosin (10 micrograms kg-1 i.v.), diphenhydramine (1 mg kg-1 i.v.) and indomethacin (1 mg kg-1 i.v.) failed to block the bronchomotor response to 2-Cl-Ade. In contrast, cyproheptadine (1-5 mgkg-1 i.v.) markedly reduced, but did not abolish the bronchospasm elicited by the purine derivative. 7. We conclude that in anaesthetized non-curarized guinea-pigs, a transient vagally-mediated bronchospasm can be induced by stimulation of A2-purinoceptors. This effect is complex and involves, at least in part, stimulation of capsaicin-sensitive sensory nerves and 5-hydroxytryptamine release. This experimental model might be useful for the further study of the potential role of adenosine in asthma, and for the evaluation of new antiasthma drugs.

2-Chloroadenosine↗
PubMed1990

Physico-chemical properties of the new antibronchospastic agent isbufylline.

Physico-chemical properties, i.e. elemental analysis, spectra (NMR, MS, IR, UV), X-ray crystal structure, solubilities, partition coefficient, melting point, HPLC, GC, and data about purity and stability of 1,3-dimethyl-7-isobutyl xanthine (isbufylline, TE/06, CAS 90162-60-0), a new drug with antibronchospastic properties, are reported.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Pharmacodynamic profile of isbufylline, a new antibronchospastic xanthine devoid of central excitatory actions.

1,3-Dimethyl-7-isobutylxanthine (isbufylline, TE/06; CAS 90162-60-0) is a newly synthetized xanthine derivative. This compound exhibits remarkable antibronchospastic properties both in in vitro and in vivo (after oral or intravenous administration) experimental models. Isbufylline is significantly more effective than theophylline in antagonizing bronchospasms elicited by spasmogens (capsaicin, arachidonic acid, PAF and antigen) which mainly act by a local release of biologically active substances proposed to be involved in the pathogenesis of asthma. Isbufylline, unlike theophylline, possesses little or no CNS excitatory properties. This reduced neuroexcitatory action is probably related to the poor affinity of isbufylline, as compared to theophylline, to A1 purinoceptor. Indeed, isbufylline is ineffective in antagonizing 2Cl-adenosine-induced EEG synchronization. In normotensive and hypertensive rats oral administration of isbufylline resulted in small and transient positive chronotropic and hypotensive response, markedly lower than those elicited by theophylline or enprofylline. Finally isbufylline exhibits phosphodiesterase inhibitory properties, although at concentration 50-100 times higher than those exerting spasmolytic effects in isolated bronchial tissues. As a whole the pharmacodynamic profile of isbufylline is promising and, in the clinical setting, this compound might exert enhanced antiasthma effects coupled to a low incidence of central and cardiovascular adverse effects.

1-Methyl-3-isobutylxanthine↗
PubMed1989

Contractile effect of endothelin on isolated iris sphincter muscle of the pig.

Porcine endothelin (1 nM-0.3 microM) produced a concentration-dependent contraction of the isolated sphincter muscle of the pig iris. Neither atropine (1 microM) nor tetrodotoxin (1 microM) nor pre-exposure of the preparation to 10 microM capsaicin for 15 min affected the endothelin-induced response. We propose that the endothelin-induced contraction of the iris sphincter muscle of the pig is largely due to a direct action on smooth muscle cells and is unrelated to neurogenic myotic mechanisms.

Animals↗
PubMed1989

Determination of the antihypertensive drug 1-[2-ethoxy-2-(3'-pyridyl)ethyl]-4-(2'-methoxyphenyl) piperazine (IP/66) in rat and human plasma by high-performance liquid chromatography and isotope dilution mass spectrometry.

In connection with pharmacokinetic studies on the antihypertensive drug 1-[2-ethoxy-2-(3'-pyridyl)ethyl]-4-(2'-methoxyphenyl)piperazine (IP/66) (I), appropriate high-performance liquid chromatographic (HPLC) and gas chromatographic-mass spectrometric isotope dilution (GC-MS-ID) methods for its determination in rat and human plasma, respectively, were developed. In both techniques, deproteinized and basified plasma samples were extracted and purified by adsorption on an Extrelut-1 column, then the drug was eluted with dichloromethane. Quantitative HPLC analysis was performed on a C8 reversed-phase column. The mobile phase was phosphate buffer (0.02 M, pH 2.8)-acetonitrile (65:35), with UV detection at 208 nm. The internal standard was 1-[2-butoxy-2-(3'-pyridyl)ethyl]-4-(2'-methoxyphenyl)piperazine, a homologue of I. The inter-assay coefficient of variation (C.V.) was 9.9% for a drug level of 2 micrograms/ml. Quantitative GC-MS-ID analysis was performed with a DB-17 fused-silica capillary column using the selected-ion monitoring technique. The deuterated form of I, 1-[2-ethoxy-2-(3'-pyridyl)ethyl]-4-2'-trideuteromethoxyphenyl)pipe razine, utilized as internal standard, was synthesized. The inter-assay C.V. was 7.36% for a drug level of 1 ng/ml.

Animals↗
PubMed1989

Infravesical outflow obstruction in rats: a comparison of two models.

1. A new model of infravesical outflow obstruction was developed in male rats by the repeated s.c. administration of testosterone for 5-15 days (3 mg/kg die). The effects of this treatment which produced a 65% increase of prostate weight (10 days) on bladder voiding was evaluated in urethane anesthetized rats by the transvesical infusion of saline and compared to the cystometric alterations produced by application of a silk ligature at urethral level in female rats (4-8 weeks before) as described by Malmgren et al. (1987a, b). 2. Testosterone-pretreatment for 10 days produced little changes in bladder weight, bladder capacity or amplitude of micturition contraction but determined a marked increase in residual volume, indicating that infravesical outflow obstruction impaired significantly bladder voiding. Furthermore, detrusor instability was observed in the majority of testosterone-treated rats. 3. The participation of an active component to voiding impairment in testosterone-treated rats was suggested by the effect of intravenous prazosin which improved voiding efficiency. 4. In urethra-ligated female rats there was a marked increase in bladder weight which was paralleled by a dramatic alteration in micturition reflex that is marked increase in bladder capacity and residual volume. 5. It is concluded that these two models of infravesical outflow obstruction produce cystometric patterns simulating the urodynamic alterations observed in patients with benign prostatic hyperplasia and are potentially suitable for development of drugs in this field.

Animals↗
PubMed1989

Functional studies on the cholinergic and sympathetic innervation of the rat proximal urethra: effect of pelvic ganglionectomy or experimental diabetes.

1. Isolated rings of rat proximal urethra contracted in response to acetylcholine, noradrenaline, phenylephrine, tachykinins or field stimulation. In the presence of field stimulation-induced contractions, isoprenaline or CGRP produced an inhibitory effect on evoked contractions. 2. Electrical field stimulation produced frequency-related contractions which, when using trains of stimuli, consisted of a phasic and a tonic response. These contractions were abolished by tetrodotoxin (1 microM) but unaffected by hexamethonium (10 microM). 3. Atropine (3 microM) produced a partial inhibition of these nerve-mediated contractions, slightly more evident on the tonic than the phasic response. In the presence of atropine (3 microM), phentolamine (3 microM) or prazosin (1-10 nM) produced an almost complete inhibition of the response to field stimulation. 4. After bilateral removal of the pelvic ganglia, electrical field stimulation was still able to induce tetrodotoxin-sensitive contractions of the rat proximal urethra. However, the inhibitory effect of atropine was much reduced as compared to controls, while the phentolamine-sensitive portion of the response was increased. 5. DMPP (0.1 mM) a nicotinic receptor agonist, produced a contraction (phasic and tonic components) which was strongly inhibited by hexamethonium (10 microM), abolished by prazosin (1 microM) and reduced by tetrodotoxin (3 microM). 6. In urethral rings from diabetic rats (i.v. streptozotocin 7-9 weeks before) the contractile response to acetylcholine or noradrenaline as well as the response to field stimulation were unchanged as compared to controls. 7. Capsaicin (1 microM) produced an inhibitory effect on the nerve-mediated contractions of the rat proximal urethra. This response was abolished by pelvic ganglionectomy but was unaffected in streptozotocin-treated rats. 8. These findings provide functional evidence that both cholinergic and noradrenergic nerves mediate the contractions of the rat proximal urethra. In addition, capsaicin-sensitive sensory nerves can produce certain local motor responses through release of endogenous neuropeptides. In vivo studies are needed to examine the interplay between these differents sets of motor nerves in the regulation of proximal urethra motility.

Acetylcholine↗
PubMed1989

GABAA receptor-mediated positive inotropism in guinea-pig isolated left atria: evidence for the involvement of capsaicin-sensitive nerves.

1. Isolated left atria from reserpine-pretreated guinea-pigs, electrically driven (3 Hz) in the presence of atropine (1 microM), phentolamine (0.3 microM) and propranolol (1 microM), responded to a train of stimuli (10 Hz for 2.5s) with a delayed neurogenic positive inotropic response which was insensitive to hexamethonium (10 microM) but abolished by either tetrodotoxin (1 microM), omega-conotoxin (0.1 microM), in vitro capsaicin desensitization or desensitization to calcitonin gene-related peptide (CGRP). 2. In these experimental conditions, gamma-aminobutyric acid (GABA) produced a concentration-related (10 microM-1 mM) positive inotropic response similar to that produced by electrical field stimulation. The effect of GABA was competitively antagonized by bicuculline methiodide (10 microM), a GABAA receptor antagonist. 3. The selective GABAA receptor agonists, muscimol and homotaurine mimicked the positive inotropic effect of GABA while baclofen, the selective GABAB receptor agonist, did not. 4. The action of GABA (1 mM) was abolished by either tetrodotoxin (1 microM), omega-conotoxin (0.1 microM), in vitro capsaicin desensitization or desensitization to CGRP, while it was unaffected by hexamethonium. In contrast, the inotropic response to CGRP was unaffected by tetrodotoxin, omega-conotoxin, bicuculline methiodide, hexamethonium or in vitro capsaicin desensitization, but was abolished by CGRP desensitization. 5. In the spontaneously beating guinea-pig right atrium, GABA (1 microM) produced a small and transient positive chronotropic effect that was no longer observed after in vitro desensitization with capsaicin (1 microM). 6. In the guinea-pig isolated perfused heart from reserpine-pretreated animals (with atropine, phentolamine and propranolol in the perfusion medium), GABA (1 microM) produced a transient tachycardia and a small increase in coronary flow. Both capsaicin (1 microM) and CGRP (1 microM) produced marked tachycardias and increases in coronary flow. After exposure to capsaicin (1 microM), no effect of GABA could be detected. 7. We conclude that, in the guinea-pig heart, GABAA receptors, presumably located on the preterminal region of capsaicin-sensitive sensory nerves, initiate a conducted impulse (since it is tetrodotoxin-sensitive) which leads to transmitter release (endogenous CGRP-like material) by activation of omega-conotoxin-sensitive, voltage-sensitive calcium channels and a functional response.

Animals↗
PubMed1989

A comparison of bradykinin- and capsaicin-induced myocardial and coronary effects in isolated perfused heart of guinea-pig: involvement of substance P and calcitonin gene-related peptide release.

1. Bradykinin and capsaicin were compared for their ability to elicit functional effects and to release sensory neuropeptides from guinea-pig isolated perfused hearts. 2. Both bradykinin (10 microM) and capsaicin (1 microM) produced a marked increase in coronary flow, a large positive chronotropic effect and a significant reduction in contractile strength. These actions were associated with a marked release of substance P-like immunoreactivity (SP-LI) and calcitonin gene-related-like immunoreactivity (CGRP-LI). The percentage of the tissue content of SP-LI and CGRP-LI released by each agent was similar, although bradykinin was less effective than capsaicin. The ratio of SP-LI/CGRP-LI released by both agents was similar to that present in cardiac tissue. 3. Neuropeptide release could be evoked only once with capsaicin but at least four times with bradykinin. Also, functional responses to capsaicin underwent desensitization. After either in vitro or systemic capsaicin pretreatment, the release of SP-LI and CGRP-LI by bradykinin was reduced and the positive chronotropic effect of bradykinin was significantly reduced, while the increase in coronary flow and negative inotropic responses remained unchanged. 4. Pretreatment with indomethacin (10 microM) strongly antagonized the release of SP-LI and CGRP-LI by bradykinin and reduced the increase in heart rate. 5. These findings suggest that activation by bradykinin (probably through indirect mechanisms) of capsaicin-sensitive sensory nerves in the heart, leads to a local release of sensory neuropeptides. These neuropeptides, in turn, could participate in determining the complex functional effects of this kinin on cardiac performance.

Animals↗
PubMed1989

Arachidonic acid-induced bronchomotor responses are partially mediated by release of sensory neuropeptides from capsaicin-sensitive structures.

Administration of arachidonic acid (AA) both in vitro and in vivo elicited prominent contractile responses in guinea-pig airways, which were markedly reduced after capsaicin desensitization. Furthermore, AA superfusion elicited a significant calcitonin gene-related peptide-like immunoreactivity release from isolated bronchi. It is suggested that at least part of the bronchomotor actions of AA rely upon stimulation of capsaicin-sensitive primary afferents.

Anesthesia↗
PubMed1989

Regional differences in the motor and inflammatory responses to capsaicin in guinea pig airways. Correlation with content and release of substance P-like immunoreactivity.

The motor and inflammatory effects of capsaicin, substance P, and neurokinin A, as well as the content and release of substance P-like immunoreactivity (SP-LI), were assessed in the upper and lower guinea pig trachea and in the main bronchus. Capsaicin-induced motor and inflammatory effects were greater in the lower than in the upper tract of the trachea and much more evident at the bronchial than at the tracheal level. On the other hand, no significant regional differences were observed in the potency and efficacy of tachykinins. SP-LI content was significantly greater in the lower than in the upper tract of the trachea and about five times greater in the bronchus than in the trachea. In each single tracheal preparation, a highly significant correlation was found between the motor effect of capsaicin (but not carbachol) and the SP-LI content. Furthermore, capsaicin-induced release of SP-LI was about eight times greater in bronchial than in tracheal tissues. In view of the strict correlation observed between magnitude of motor and inflammatory actions of capsaicin (but not substance P or neurokinin A) and SP-LI content and release, it is proposed that the regional differences in the response of guinea pig respiratory tissues to activation of capsaicin-sensitive sensory fibers might be mainly prejunctional in origin.

Animals↗
PubMed1989

Regional differences of adenylate cyclase stimulation by calcitonin and calcitonin gene-related peptide in the human kidney.

Calcitonin (CT) gene-related peptide (CGRP)-like immunoreactivity was detected in both the cortex and medullo-papillary portion of human kidneys. The two forms of human CGRP as well as rat CGRP were capable of stimulating renal cortical adenylate cyclase activity in a concentration-related manner, with a half-maximally effective concentration (EC50) similar to that of human CT and approximately 100-1000 times higher than that of salmon CT. However, in the medullo-papillary portion, in which both salmon CT and human CT were inactive, the two forms of human and rat CGRP increased adenylate cyclase activity by 100%, with EC50 values ranging from 36 nmol/L to 1 mumol/L. In cortical membrane preparations the effect of CGRP was additive to that of salmon CT. We concluded that regional differences exist in the effect of CT and CGRP in human renal tissue and that in the medullo-papillary portion and possibly in the cortex, CGRP stimulates adenylate cyclase activity through a CT-independent mechanism.

Adenylyl Cyclases↗
PubMed1988

Neurokinin A-(4-10): a potent bronchospastic agent virtually devoid of sialologic properties in anaesthetized guinea-pigs.

The ability of substance P, neurokinin A and its C-terminal fragment, neurokinin A-(4-10), to elicit NK-1 (salivation) and NK-2 (bronchospasm) receptor-mediated responses was investigated in anaesthetized guinea-pigs. Neurokinin A-(4-10) produced a dose-related increase in tracheal insufflation pressure and its maximal effect was similar to that elicited by neurokinin A and significantly greater than that of substance P. On the other hand substance P induced a potent dose-dependent increase of salivation while neurokinin A was significantly less potent. Neurokinin A-(4-10) did not exert any sialologic effect even at the dose of 100 nM/kg. These findings indicate that neurokinin A-(4-10) might be a valuable pharmacological tool for characterizing the involvement of NK-1 and NK-2 receptors in physiological responses in vivo.

Anesthesia↗
PubMed1988

Vascular effects of capsaicin in isolated perfused rat mesenteric bed.

The effects of intra- and extraluminal capsaicin administration were evaluated in isolated perfused rat mesenteric bed. Capsaicin (10 nM-1 microM) produced a potent concentration-dependent relaxation of the tonic vasoconstriction induced by norepinephrine (1 microM) but not by high-K+ (60 mM). The capsaicin-induced relaxation was nearly abolished in preparations pretreated in vitro with a high concentration of capsaicin (1 microM, for 10 min, 1 h before). Capsaicin-induced relaxation was reduced but not abolished in preparations obtained from rats pretreated neonatally with capsaicin. The capsaicin effects were unaffected by atropine, guanethidine, propranolol, hexamethonium or tetrodotoxin. The observation that capsaicin (0.1 microM)-induced relaxation was virtually abolished in presence of the proteolytic enzyme alpha-chymotrypsin (1 U/ml) supports the involvement of neuropeptide(s) in this response. Bolus injections of calcitonin gene-related peptide (CGRP) elicited a potent and rapidly ensuing relaxation which underwent tachyphylaxis. However, no cross-desensitization with capsaicin was observed. It is concluded that activation of capsaicin-sensitive sensory fibers could release neuropeptides locally with a potent effect on intestinal blood flow.

Animals↗
PubMed1988

The effect of nifedipine on spontaneous, drug-induced and reflexly-activated contractions of the rat urinary bladder: evidence for the participation of an intracellular calcium store to micturition contraction.

1. The effect of nifedipine on spontaneous and stimulated motility of the rat urinary bladder has been investigated in vitro (isolated detrusor strips) and in vivo (micturition reflex). 2. Nifedipine inhibited tone and spontaneous activity of the isolated rat bladder, its effect being greater in indomethacin-treated preparations. Nifedipine suppressed the KCl induced phasic and tonic contraction and inhibited by 60-80% the carbachol- or ATP- induced contractions. Nifedipine reduced by about 70% amplitude of the nerve-mediated bladder contractions. 3. Exposure to Ca free medium containing EDTA suppressed tone and spontaneous activity of the rat bladder. In these conditions the response to KCl or ATP was rapidly abolished while a response to carbachol was still evident even after a long exposure to the Ca free medium. 4. In vivo, nifedipine affected reflex micturition e.g. increased volume threshold and slightly reduced amplitude of micturition contraction. In addition, nifedipine reduced voiding efficiency e.g. increased residual volume after micturition. These effects were evident following ligation of the ureters because in normal conditions nifedipine induced a marked diuresis which masked its effect on volume threshold. 5. These findings indicate that in the rat urinary bladder Ca from both intra- and extracellular pools is mobilized during spontaneous or stimulated contractions. Mobilization of an intracellular Ca pool by cholinomimetics or other neurotransmitter(s) may be responsible for the nifedipine-resistant component of the voiding contraction in vivo.

Adenosine Triphosphate↗