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M Tonini

Publications and source records attributed to M Tonini.

At least 91 records · Page 5Linked to original sources
PubMed1990

A pharmacological analysis of the neuronal circuitry involved in distension-evoked enteric excitatory reflex.

Isolated segments of guinea-pig small intestine were set up in a partitioned bath to study the enteric excitatory reflex evoked by distension. The gut was distended by a rubber balloon inserted at the aboral end and contractions of the circular muscle were recorded at the oral end. The oral and aboral ends of the gut were separated by an intermediate compartment of the bath. Inflation of the intraluminal balloon with 0.075-0.35 ml water elicited reproducible and distension-dependent contraction. This enteric orally directed (ascending) excitatory reflex was abolished by tetrodotoxin irrespective of the compartment in which it was applied. Hyoscine (0.3 microM) almost abolished the enteric excitatory reflex when it was applied to the oral compartment. This indicates that the transmission from the final motor neurons to the circular muscle is mainly cholinergic, acting via muscarinic receptors. Hyoscine had no effect on the enteric excitatory reflex when added to the intermediate compartment. When hyoscine was added to the aboral compartment, it decreased the enteric excitatory reflex elicited by low distension stimuli to 70% of control and decreased the enteric excitatory reflex elicited by higher distension stimuli to 95% of control. This indicates that ganglionic transmission involving muscarinic receptors at the site of distension in the aboral bath contributes to the enteric excitatory reflex. Hexamethonium (100 microm) greatly depressed the enteric excitatory reflex when applied to any compartment indicating that nicotinic transmission is most important in the afferent, intermediate and efferent components of the reflex and that the reflex pathway involves a polysynaptic chain of cholinergic interneurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Effects of cisapride on cholinergic neurotransmission and propulsive motility in the guinea pig ileum.

The actions of cisapride on electrical behavior of single myenteric neurons and on the propulsive activity of segments of ileum were studied in vitro. Cisapride (10-300 nM) did not affect the membrane potential, resting properties, or active properties of S neurons. The amplitude of fast nicotinic excitatory postsynaptic potentials recorded from S cells was increased by cisapride in the concentration range of 10 nM to 1 microM. Higher cisapride concentrations (3-10 microM) reduced the amplitude of fast excitatory postsynaptic potentials. Potentiation of fast excitatory postsynaptic potentials by cisapride was antagonized by ICS 205-930 (1 microM) but was unaffected by GR 38032F (1 microM), both compounds being 5-HT3-receptor antagonists. Cisapride did not modify the electrical behavior of AH neurons except at the highest concentrations (3-10 microM), which caused hyperpolarization of some neurons. The propulsive efficiency (i.e., number of peristalses and total amount of fluid ejected per unit of time) of isolated segments of ileum was enhanced by cisapride (100 nM to 3 microM). Higher cisapride concentrations (6 or 10 microM) had a depressant action on propulsive activity. The stimulatory effect of cisapride on propulsion was not antagonized by ICS 205-930 (300 nM or 1 microM). These data indicate that cisapride facilitates cholinergic transmission in the myenteric plexus of guinea pig ileum and that this effect may be at least partially responsible for the increased propulsive efficiency observed in ileal segments.

Acetylcholine↗
PubMed1989

The role of GABAA receptor function in peristaltic activity of the guinea-pig ileum: a comparative study with bicuculline, SR 95531 and picrotoxinin.

1. The peristaltic activity of the guinea-pig ileum was studied in the absence and in the presence of the blockade of GABAA receptors. 2. Bicuculline (1-30 microM), improved at the highest concentrations the efficiency of peristalsis by enhancing the frequency of propulsive contractions and the amount of fluid ejected per unit of time. 3. Neither SR 95531 (0.3-10 microM), a novel GABAA receptor antagonist, which competitively antagonized 3-aminopropane sulphonic acid induced contractions in myenteric plexus-longitudinal muscle preparations (pA2 value: 6.47), nor picrotoxinin (1-30 microM) modified peristaltic parameters or influenced the potentiating effect of bicuculline on peristaltic activity. 4. In myenteric plexus-longitudinal muscle preparations, bicuculline (1-30 microM) enhanced the amplitude of electrically-induced cholinergic contractions without modifying submaximal contractions to applied acetylcholine. SR 95531 and picrotoxinin had no effect on twitch amplitude. In the presence of each of these compounds, bicuculline retained its potentiating effect. 5. The results obtained with SR 95531 and picrotoxinin question the view that GABAA receptors may exert a critical role in intestinal propulsion by modulating the activity of nerve pathways subserving peristalsis. Bicuculline potentiates the peristaltic activity of the ileum probably via a facilitatory effect on enteric cholinergic transmission that is independent of GABAA receptor blockade.

Animals↗
PubMed1989

An in vitro study of the relationship between GABA receptor function and propulsive motility in the distal colon of the rabbit.

1. The effects of gamma-aminobutyric acid (GABA), 3-aminopropane sulphonic acid (3-APS) and baclofen on spontaneous, electrically-induced and propulsive motility were investigated in rabbit distal colon. 2. In unstimulated longitudinal (LMPs) and circular muscle strip preparations (CMPs) 3-APS (10-200 microM) and GABA caused a clear-cut relaxation susceptible to desensitization. Baclofen (10-200 microM) caused relaxation in a minority (30%) of preparations. The 3-APS response was sensitive to tetrodotoxin (TTX; 1 microM), SR 95531 (a novel competitive GABAA-receptor antagonist) (10 microM), picrotoxinin (30 microM), and insensitive to hyoscine (1 microM) and to a combination of prazosin (1 microM) and propranolol (1 microM). The baclofen response was antagonized by 5-aminovaleric acid (DAVA, 500 microM), TTX and hyoscine and resistant to GABAA-receptor and adrenoceptor blockade. GABAA-receptors were therefore associated with non-adrenergic non-cholinergic (NANC) inhibitory nerve activation while GABAB-receptors were involved in depression of cholinergic tone of smooth muscle. GABA (10-200 microM) elicited both above mentioned effects. 3. In LMPs, baclofen (10-200 microM) dose-dependently inhibited submaximal responses to both cholinergic and NANC inhibitory nerve stimulation. This effect was resistant to SR 95531 and picrotoxinin and prevented by DAVA and baclofen desensitization. GABA (10-200 microM) mimicked the action of baclofen. GABA inhibitory effects persisted in the presence of GABAA-receptor blockade. 4. In segments of distal colon, GABA and baclofen (1-200 microM), but not 3-APS (1-200 microM), dose-dependently decreased the velocity of propulsion of an intraluminally-distended balloon. This effect was antagonized by DAVA and GABA or baclofen desensitization and resistant to SR 95531 and picrotoxinin. These antagonists per se had no effect on propulsion. In preparations in which propulsion was slowed by hyoscine (1 microM), baclofen caused no consistent further depression of propulsive activity. 5. Our results show that GABAA- and GABAB-receptors are present in rabbit colon. GABAA-receptor stimulation activates NANC inhibitory nerves without apparently affecting propulsion. GABAB-receptors are associated with a reduction of neural (mainly cholinergic) activity subserving muscular tone and peristalsis and appear to be located on both cholinergic and NANC inhibitory nerves. However, the persisting propulsive activity during suppression of GABAA- and GABAB-receptor function suggests that GABA in enteric neurones is not crucial for the neural circuitry subserving colonic peristalsis in this species.

Amino Acids↗
PubMed1989

Interaction of the pyrethroid insecticides tetramethrin and cypermethrin with enteric cholinergic transmission in the guinea-pig.

In electrically-stimulated longitudinal muscle-myenteric plexus preparations of the guinea-pig ileum, the Type I pyrethroid insecticide tetramethrin (1-100 microM) caused a biphasic response consisting of an early transient increase followed by a sustained decrease in the amplitude of cholinergic contractions. The cholinergic potentiation was antagonized by phenytoin (3 microM), which also prevented the increase in twitch height caused by veratridine (30 nM). The late inhibitory effect of tetramethrin probably involved a direct action on the musculature since contractile responses to applied acetylcholine (100 nM) or histamine (300 nM) were also depressed by this compound. Cypermethrin (1-100 microM), a Type II pyrethroid, had only a minor enhancing effect on electrically evoked contractions. Cypermethrin (30, 60 microM), but not tetramethrin, antagonized the cholinergic response induced by the GABA-A receptor agonist 3-aminopropane sulphonic acid (1-100 microM). These results suggest that neural Na+ channels activation may underlie pyrethroid-induced potentiation of enteric cholinergic transmission. In small intestine, however, cypermethrin is also effective as a noncompetitive antagonist of GABA-A receptor mediated cholinergic contractions.

Animals↗
PubMed1988

Differential localization of 5-HT1 receptors on myenteric and submucosal neurons.

Intracellular recordings were made from guinea pig enteric neurons, and the effects of 5-hydroxytryptamine (5-HT) and the 5-HT1 selective agonists 5-carboxyamidotryptamine (5-CT) and 8-hydroxy-2-(n-dipropylamino)tetralin (DPAT) were studied on membrane potential and synaptic potentials. Most myenteric AH neurons were hyperpolarized when these agonists were applied by superfusion; this hyperpolarization was due to an increase in potassium conductance. Membrane hyperpolarizations to 5-HT, 5-CT, or DPAT were never observed in submucous neurons. Fast nicotinic excitatory postsynaptic potentials (EPSPs) and slow EPSPs recorded from S neurons in the myenteric plexus were suppressed by 5-HT, 5-CT, and DPAT; slow EPSPs in myenteric AH neurons were also inhibited by these agonists. Fast and slow EPSPs recorded from submucous S neurons were not affected by 5-CT or DPAT. However, slow EPSPs recorded from submucous AH neurons were readily blocked by 5-CT and DPAT. The results indicate that 5-HT1 receptors are located on the cell bodies of myenteric but not submucosal neurons. The nerve terminals that release the mediator or mediators of fast and slow synaptic potentials in myenteric neurons also have 5-HT1 receptors and presumably arise from other myenteric neurons; the nerve terminals responsible for the slow EPSP to AH neurons seem to be the only elements of the submucous plexus that express 5-HT1 receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Involvement of substance P in the excitatory action of GABAA agonists on cholinergic neurons in the guinea-pig ileum.

The possible involvement of substance P (SP) in cholinergic contractions induced by GABAA agonists in the guinea-pig ileum was further investigated. Responses evoked by 3-aminopropane sulphonic acid (3-APS) or muscimol consisted of a rapid phasic contraction followed in 70% of preparations by a tonic contraction, usually smaller in amplitude but considerably longer in duration. Phasic and tonic components were sensitive to bicuculline, neurogenic (cholinergic) in nature and susceptible to desensitization. Capsaicin (0.2 microM) pretreatment and SP receptor desensitization caused by 3 different priming SP concentrations (10 nM, 30 nM, 100 nM), depressed both components of the 3-APS-induced response, the magnitude of antagonism being greater for tonic contractions. Similar findings were obtained by using 10 microM (D-Pro4,D-Trp7.9)SP-(4-11), even though the degree of antagonism caused by this SP antagonist was consistently lower. These results indicate that depression of SP receptor function achieved by three different procedures decreases cholinergic contractile responses to GABAA agonists in the guinea-pig ileum. This provides further support for the hypothesis that GABAA receptor activation evokes both direct and indirect stimulation of enteric cholinergic neurons and that SP and/or a related peptide play an important role in mediating the indirect component of the cholinergic response.

Animals↗
PubMed1987

Depressant action of oxybutynin on the contractility of intestinal and urinary tract smooth muscle.

Experiments were carried out in-vitro using segments of guinea-pig ileum, taenia caeci, ureter and detrusor. In the ileum, oxybutynin (30, 100 nM) competitively antagonized acetylcholine-induced contractions but did not alter those induced by histamine. Higher concentrations of oxybutynin (up to 10 microM) induced a non-competitive depression of responses to both agonists and caused a parallel shift to the right of the Ca2+-induced contractions in taenia caeci strips bathed in a Ca2+-free, high-K+ medium. In the ureter, oxybutynin (1-10 microM) impaired rhythmic muscular contractions in normal medium and after CaCl2 addition in Ca2+-free medium. Similarly to verapamil (10, 30 microM), oxybutynin (10, 30 microM) depressed both the cholinergic and non-adrenergic, non-cholinergic components of the electrically-induced contractions of detrusor strips. It is concluded that oxybutynin has anticholinergic properties and, at higher concentrations, exerts a direct spasmolytic activity possibly mediated by blockade of the transmembrane Ca2+ fluxes responsible for smooth muscle contraction.

Acetylcholine↗
PubMed1986

Inhibitory action of capsaicin on cholinergic responses induced by GABAA agonists in the guinea-pig ileum.

Pretreatment of the guinea-pig ileum with capsaicin resulted consistently in depression of the neurogenic cholinergic contractions induced by the GABAA receptor agonists 3-aminopropane sulphonic acid (3-APS) and muscimol. Since capsaicin acts mainly by releasing and depleting substance P from its stores in intestinal nerves, it is likely that substance P plays a role in the response caused by GABAA-mimetic compounds, On the whole, our results suggest that excitatory responses to 3-APS and muscimol result from both direct and indirect activation of intrinsic intestinal cholinergic neurons innervating smooth muscle cells.

Animals↗
PubMed1986

A re-appraisal of the mode of action of 5-HT in inhibiting GABA-induced cholinergic contractions in the guinea-pig ileum.

In the guinea-pig ileum, pretreatment with 5-hydroxytryptamine (5-HT) (5 microM) for 4-5 min inhibited both 5-HT- and gamma-aminobutyric acid (GABA)-induced cholinergic contractions without consistently altering those induced by electrical field stimulation. Cisapride (1 micron) antagonized 5-HT-induced cholinergic contractions but left those induced by GABA or twitch responses unchanged. These results indicate that the 5-HT action in inhibiting GABA-induced cholinergic responses may arise at the interneuronal level, thus suggesting that GABA may also indirectly activate cholinergic terminal neurons. These findings rule out the possibility of 5-HT acting as an intermediate transmitter in this type of response.

Animals↗
PubMed1985

Depression by morphine of the excitability of intrinsic inhibitory neurons in the guinea-pig colon.

The mechanical responses to morphine were examined in isolated preparations of longitudinal and circular muscle of the guinea-pig colon. In the longitudinal coat, morphine induced a relaxation which was prevented by naloxone, hyoscine and tetrodotoxin. Conversely, in the circular coat morphine caused a contraction which was antagonized by naloxone, mimicked by tetrodotoxin and left unaltered by hyoscine, chlorpheniramine and methysergide. In both muscular layers, morphine depressed (and tetrodotoxin abolished) the non-adrenergic relaxation induced by field stimulation. The action of morphine in the two preparations can thus be explained in terms of inhibition of the tonic excitatory cholinergic or inhibitory non-adrenergic neural control prevailing in the longitudinal and circular muscle respectively.

Animals↗
PubMed1984

Changes in sensitivity to the inhibitory effects of adrenergic agonists on intestinal motor activity after chronic sympathetic denervation.

The concentration-effect relationships of adrenergic agonists in inhibiting muscular tone, carbachol-induced contraction of circular muscle strips and nerve-mediated motor activity during the peristaltic reflex have been studied in intact and sympathetically denervated preparations of isolated guinea-pig colon. The order of potencies of adrenergic agonists was different for muscular and nerve-mediated effects, being clonidine greater than noradrenaline greater than methoxamine greater than isoprenaline for the inhibition of peristalsis and isoprenaline greater than noradrenaline greater than methoxamine greater than clonidine for the relaxation of circular muscle. Denervation supersensitivity was specific for the adrenergic agonists and developed both to the muscular and nerve-mediated effects, involving both alpha and beta receptors. The degree of potentiation was similar for noradrenaline and isoprenaline when measured for the muscular effects but was significantly higher for noradrenaline than for isoprenaline or methoxamine when measured for peristalsis inhibition. No potentiation could be observed for papaverine and for the muscular effects of methoxamine and phenylephrine. The increase in potency of noradrenaline ranged from a 26-fold increase for the inhibition of propulsion velocity to a 2.5-fold increase for the inhibition of carbachol-induced contraction. A much narrower range was observed for isoprenaline. Potentiation could also be observed for the inhibitory effect of noradrenaline on acetylcholine release. Clonidine was the most potent agonist against peristaltic reflex and the weakest agonist in relaxing circular muscle. Denervated preparations became subsensitive to the inhibitory effect of clonidine on peristaltic reflex. The potency of clonidine relative to noradrenaline was 488 in intact preparations and only 3.1 in denervated organs.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1984

5-hydroxytryptamine desensitization fails to modify GABA-induced inhibitory responses in the guinea-pig colon.

In segments of guinea-pig colon, treated with 1 microM hyoscine, a 5-HT desensitization procedure that decreased the potency of 5-HT 41-fold in relaxing the longitudinal musculature, failed to modify the non-adrenergic GABA-induced inhibitory responses, suggesting that the action of GABA in this preparation is not 5-HT-mediated. These results are at variance with those obtained in the guinea-pig ileum where 5-HT seems to play a role in GABA-induced cholinergic contractions.

Animals↗
PubMed1983

5-HT mediated GABA excitatory responses in the guinea-pig proximal ileum.

GABA (3--100 microM) and 5-HT (0.03--30 microM) caused concentration-dependent transient contractions of the longitudinal muscle of the guinea-pig ileum. The contractile response to GABA was antagonized by hyoscine (2.2 microM). TTX (0.7 microM), bicuculline (3 microM), furosemide (25 microM) and desensitization to GABA itself, while hexamethonium (20 microM) and methysergide (20 microM) were without effect. The contractile response to 5-HT was antagonized by hyoscine (2.2 microM), TTX (0.7 microM) and desensitization to 5-HT itself and was unaffected by bicuculline (10 microM), hexamethonium (20 microM), furosemide (25 microM) and methysergide (20 microM). A desensitization procedure that caused a 84.7-fold increase in the 5-HT EC50 also resulted in a 74.1-fold increase of the GABA EC50. Desensitization to GABA caused a reduction of 5-HT induced response but only in preparations desensitized by high (50 microM) concentrations of GABA. The results indicate that GABA-induced contractions in the guinea-pig ileum are mediated by activation of cholinergic motor neurones. This effect appears to be mediated by interneuronal release of 5-HT rather than by a direct stimulatory action of GABA on the effector neurones.

Animals↗
PubMed1983

Reduction of phenytoin clearance caused by cimetidine.

The effect of cimetidine on the disposition kinetics of phenytoin was investigated in 7 healthy volunteers. Each subject received a single intravenous dose of phenytoin on two occasions, in the control state, and during concurrent treatment with cimetidine 1 200 mg/day for 6 days. A slight but statistically significant decrease both in the rate of elimination and total body clearance of phenytoin was observed during the administration of cimetidine. The effect is probably due to inhibition of metabolism.

Adult↗
PubMed1983

Purine receptors in the guinea-pig internal anal sphincter.

1 In the isolated internal anal sphincter of the guinea-pig, adenosine 5'-triphosphate (ATP) and adenosine induced a concentration-dependent and tetrodotoxin-insensitive relaxation. 2 Pretreatment with theophylline (25-50 microM) had no significant effect on the concentration-response curves obtained with either purine compound. 3 Reactive blue 2 (25-100 microM) shifted the curve to ATP to the right in a dose-dependent fashion leaving that to adenosine unaltered. The antagonism appeared to be non-competitive. 4 Neither reactive blue 2 nor purine receptor occupation by ATP or adenosine altered the electrically-induced non-adrenergic, non-cholinergic inhibitory response. 5 The actions of ATP and adenosine in the guinea-pig internal anal sphincter appear to be mediated by separate receptors. These receptors are not involved in the nerve-mediated relaxation.

Adenosine↗
PubMed1983

Dilazep: an inhibitor of adenosine uptake with intrinsic calcium antagonistic properties.

Concentrations of dilazep which were ineffective in altering the muscular tone of the guinea-pig taenia caeci (0.03, 0.3 microM) or the phasic mechanical activity of the rabbit proximal ileum (0.03 microM) markedly potentiated the inhibitory action of adenosine on both these parameters. Dilazep, 0.3 microM or greater, dose-dependently inhibited the mechanical activity of the proximal ileum. This inhibitory action was probably mediated by more than one mechanism, as shown by the fact that theophylline (50, 100 microM) antagonized the effect at lower dilazep concentrations (up to 3 microM) leaving essentially unchanged the response to higher concentrations (6, 10 microM). Similarly, the responses to low doses of dilazep were reduced after desensitization of the organ to adenosine, whilst the responses to higher doses were unaffected by this procedure. In a Ca2+-free, high-K+ medium, dilazep (1-10 microM) caused a parallel shift to the right of the Ca2+-induced contractions of the guinea-pig taenia caeci. Adenosine showed only slight Ca2+-antagonistic properties within the mM range of concentrations. These findings suggest that, at the higher concentration tested, dilazep exhibits Ca2+-antagonistic properties unrelated to its adenosine-mediated mode of action.

Adenosine↗