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M Tonini

Publications and source records attributed to M Tonini.

At least 73 records · Page 4Linked to original sources
PubMed1994

Accommodation mediated by enteric inhibitory reflexes in the isolated guinea-pig small intestine.

1. The aim of the present study was to investigate whether the guinea-pig small intestine shows accommodation to infused fluid, similarly to other regions of the gastrointestinal tract. Tetrodotoxin, papaverine and transmitter antagonists were used to establish the existence of reflex pathways and the nature of the neurotransmitters involved. 2. Compliance, measured as the change in volume of infused fluid divided by the intraluminal pressure change, was reduced by tetrodotoxin (0.6 microM), indicating that there is an overall neurally mediated relaxation of the circular muscle in response to low rates of distension. Papaverine (10 microM) did not have any significant effect on compliance at the low rates of distension, suggesting that the circular muscle is fully relaxed. 3. At each rate of distension, 400 microM N omega-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor) significantly decreased the compliance of the intestinal wall, indicating that the circular muscle was relaxed by a nitric oxide-mediated mechanism. Apamin (0.5 microM), which blocks a component of inhibitory transmission, did not have a significant effect. 4. In control preparations, the intestinal wall was less compliant when distended by fluid at a fast rate, compared with the lower rates of distension. This was not due to changes in passive components of the intestinal wall or a myogenic response to rapid stretch. 5. When the intestine was distended rapidly, 1 microM hyoscine and 100 microM hexamethonium increased intestinal compliance. However, they had no detectable effect on compliance with low rates of distension.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Investigation into vanadate-induced potentiation of smooth muscle contractility in the rabbit isolated ileum.

The action of sodium orthovanadate (Na3VO4) on spontaneous mechanical activity of the longitudinal muscle was investigated in isolated segments of rabbit distal ileum. Vanadate (0.3-1000 microM) concentration-dependently enhanced the amplitude of phasic contractions (pendular movements) and caused the muscle tone to slightly increase at the highest concentrations. Both these effects were mimicked by the Ca2+ channel activator BAY K 8644 (10-1000 nM). Vanadate- and BAY K 8644-induced potentiation of mechanical activity was antagonized by the Ca2+ entry blocker nifedipine (3 nM). In Ca(2+)-free, K(+)-depolarized preparations, vanadate (100 microM) failed to contract the musculature, but potentiated the contractile response to applied calcium (CaCl2: 30-300 microM). The action of vanadate was similar to that of BAY K 8644 (3 nM) and was antagonized by nifedipine (0.1 nM). These results suggest that extracellular calcium is required for vanadate-induced smooth muscle excitation which, at least in part, appears to arise from facilitation of calcium influx through voltage-dependent Ca2+ channels.

Animals↗
PubMed1994

A pharmacological analysis of receptors mediating the excitatory response to 5-hydroxytryptamine in the guinea-pig isolated trachea.

1. Experiments were carried out to characterize the receptors mediating the indirect excitatory response to 5-hydroxytryptamine (5-HT) in the guinea-pig isolated trachea. 2. 5-HT caused concentration-dependent contractions of tracheal strips, and the resulting concentration-response curve was biphasic in nature. The first phase was obtained with agonist concentrations in the range of 0.01-3 nM and achieved a maximum which was 30% of the total 5-HT response, while the second phase was in the range 10 nM-1 microM. 3. Atropine (0.1 microM) and tetrodotoxin (TTX: 0.3 microM) significantly reduced both phases of the 5-HT curve. Morphine (10 microM), which can act to inhibit neuronal acetylcholine release, abolished the first phase and reduced the second phase. This suggests that the first phase is mainly neurogenic (cholinergic) in nature, while the second phase is in part neurogenic and in part due to direct activation of the effector cells. 4. The 5-HT2A receptor antagonist, ketanserin (0.01, 0.1 microM) markedly depressed the first phase and shifted the second phase to the right in a parallel manner, with some depression of the 5-HT response maximum. The less selective (5-HT1/5-HT2A) antagonist, methiothepin (0.1 microM) mimicked the action of ketanserin, albeit with less potency. Concomitant administration of ketanserin and methiothepin (each at 0.1 microM) produced an antagonism similar to that caused by ketanserin (0.1 microM) alone. 5. The 5-HT3 receptor antagonists, ondansetron (0.1 microM) and granisetron (0.01 microM) slightly but significantly inhibited the first phase of the 5-HT curve without altering the second phase. SDZ 205,557(0.3 MicroM), a 5-HT4 receptor antagonist, was ineffective.6. Our results suggest that neural 5-HT2A and, to a lesser extent, 5-HT3 receptor subtypes mediate the first phase of the 5-HT curve in the guinea-pig trachea. The second phase is mediated by 5-HT2Areceptors, which are probably located at both the neural and muscular level. No evidence for the participation of 5-HT1 receptors in the 5-HT response has been obtained.

Animals↗
PubMed1994

Characterization of the 5-HT receptor potentiating neuromuscular cholinergic transmission in strips of human isolated detrusor muscle.

In human isolated detrusor strips, submaximal contractile responses evoked by electrical stimulation were resistant to hexamethonium (30 microM) and abolished by tetrodotoxin (0.6 microM) and hyoscine (1 microM), indicating the activation of postganglionic cholinergic nerves. In methysergide (1 microM) and ondansetron (3 microM) pretreated tissues, 5-hydroxytryptamine (5-HT) (0.3 nM-1 microM) caused a concentration-dependent increase in the amplitude of contractions (pEC50 = 8.1), which was antagonized by the selective 5-HT4 receptor antagonist GR 113808 (3, 10 and 30 nM) in a competitive manner. Schild analysis yielded a pA2 estimate of 8.9, a value comparable to that reported for GR 113808 in other animal and human peripheral tissues (8.8-9.7). Our findings indicate that neuromuscular cholinergic transmission in human isolated detrusor muscle is facilitated by neural 5-HT receptors belonging to the 5-HT4 subtype. The human urinary bladder can thus be regarded as an additional site in which 5-HT4 receptors are distributed.

Electric Stimulation↗
PubMed1994

Role of nitric oxide-dependent and -independent mechanisms in peristalsis and accommodation in the rabbit distal colon.

Previous findings, which have been confirmed in this study, indicate that nitric oxide (NO)-dependent and -independent (apamin-sensitive) mechanisms underlie the electrically induced non-adrenergic, noncholinergic (NANC) relaxation in the circular muscle of rabbit distal colon. Based on this evidence, we further investigated whether, and to what extent, these separate NANC components participate in the maintenance of circular muscle tone, reflex relaxations evoked by localized balloon distension or during peristalsis (descending inhibition) and in the accommodation of colonic wall in response to graded intraluminal fluid delivery. NG-nitro-L-arginine (L-NNA) (10-300 microM), apamin (100 nM) and tetrodotoxin (60 nM), enhanced the spontaneous low tone and phasic activity in circular muscle strips. In experiments on peristalsis, L-NNA (30 and 300 microM) shortened the latency of peristaltic wave initiation and increased the velocity of propulsion of an intraluminally distended balloon (range, 0.1-1 ml). The latter effect was mimicked by the NO scavenger oxyhemoglobin (30 microM). Velocity of propulsion was enhanced by apamin (100 nM) at low balloon distension (0.1 and 0.2 ml), whereas it was reduced at high distension volumes (1 ml), due to disruption of descending inhibition. A combination of L-NNA (300 microM) and apamin (100 nM) blocked peristalsis, due to persisting spasms of the circular muscle. L-NNA (300 microM) did not affect the amplitude of distension-evoked ascending reflex contraction and slightly inhibited the descending reflex relaxation. By contrast, the latter reflex was virtually abolished by apamin (100 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Interaction of the neurotoxic pesticides ivermectin and lindane with the enteric GABAA receptor-ionophore complex in the guinea-pig.

In isolated segments of guinea-pig small intestine, gamma-aminobutyric acid (GABA) (3-300 microM), the GABAA receptor agonist 3-aminopropane sulphonic acid (3-APS) (3-300 microM) and ivermectin (1-300 microM) caused concentration-dependent nerve-mediated cholinergic contractions sensitive to tetrodotoxin (1 microM) and hyoscine (1 microM). The EC50 values were 30.2 +/- 4.3, 24.6 +/- 3.1 and 4.8 +/- 0.6 microM, respectively. Picrotoxinin (10 microM), an allosteric blocker of the Cl- channel associated with GABAA receptors, non-competitively antagonized the contractile response caused by each agonist. Like picrotoxinin, lindane (10, 30 microM) caused a dose-related shift to the right of the concentration-response curve to GABA, 3-APS and ivermectin with depression of the maximum response. SR 95531 (3 microM), a competitive antagonist of GABAA receptors, caused a parallel dextral shift of the concentration-response curve to ivermectin with an apparent single point pA2 value of 6.5. Our results suggest that ivermectin and lindane, two neurotoxic pesticides interfering with central GABAErgic transmission, exert agonist and non-competitive antagonist properties at the enteric GABAA receptor-ionophore complex. This peripheral complex can thus be considered as an additional target for the action of both these compounds.

Animals↗
PubMed1992

Sites of action of morphine on the ascending excitatory reflex in the guinea-pig small intestine.

The effect of morphine on the ascending excitatory reflex of the circular muscle elicited by radial distension of the gut wall was studied in the isolated guinea-pig small intestine. A three compartment bath, in which an intermediate compartment divided the site of intraluminal stimulation (caudal compartment) from the site of reflex contraction recording (oral compartment), was used. Morphine (0.01-10 microM) applied independently to each compartment, caused a concentration-dependent depression (up to 90%) of the amplitude of distension-evoked reflex contractions. Concentration-response curves to morphine were shifted to the right by naloxone (30 nM) with an apparent pA2 value of about 8.5, which suggests an interaction with opioid mu-receptor subtypes. Our results indicate that morphine not only depressed transmission from excitatory motor neurons to the circular muscle but also neuro-neuronal transmission along the ascending excitatory reflex pathway.

Animals↗
PubMed1992

5-hydroxytryptamine4 receptor agonists facilitate cholinergic transmission in the circular muscle of guinea pig ileum: antagonism by tropisetron and DAU 6285.

The effect of 5-hydroxytryptamine (5-HT), BIMU 8 (endo-N-(8-methyl-8-azabicyclo [3.2.1.] oct-3-yl)-2,3-dihydro-3-(1-methyl)ethyl-2-oxo-1H-benzimidazole-1- carboxamide hydrochloride) and cisapride was studied on the electrically-induced neurogenic cholinergic twitch contractions in the guinea pig ileum circular muscle. These compounds caused a concentration-dependent increase in the amplitude of submaximal twitch contractions with the following rank order of potency: 5-HT greater than BIMU 8 = cisapride. The effect of 5-HT was competitively antagonized by tropisetron (ICS 205-930) (apparent pA2 value: 6.4), suggesting an interaction at 5-hydroxytryptamine4 (5-HT4) receptors. The novel benzimidazolone derivative DAU 6285 (endo-6-methoxy-8-methyl-8-azabicyclo [3.2.1.] oct-3-yl-2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylate hydrochloride), antagonized the effect of 5-HT, BIMU 8 and cisapride with apparent pA2 values in the range 7.1-7.3. Our findings demonstrate that cholinergic neurones innervating the circular coat are endowed with excitatory 5-HT4 receptors. DAU 6285 is approximately 5-9-fold more potent than tropisetron as antagonist at these receptors.

Animals↗
PubMed1992

Metabolic studies as a basis for the interpretation of metal toxicity.

The toxicity of metal compounds has traditionally been regarded as a function of dose and potency of the metal itself. In recent years, however, it has become clear that several metals and metalloids undergo transformations in mammalian tissues and that metabolism may have important implications in clinical pharmacology, toxicology, and environmental health. In this paper, data obtained from recent metabolic studies are reviewed as a basis for the interpretation of biological effects and kinetic patterns of metals of major importance as environmental pollutants.

Animals↗
PubMed1992

Vigabatrin does not affect the intestinal absorption of phenytoin in rat duodeno-jejunal loops in situ.

The antiepileptic drug vigabatrin (GVG) is known to decrease significantly the serum concentration of concurrently administered phenytoin (PHT) in epileptic patients. To assess a possible mechanism for this interaction, the effect of GVG on the intestinal absorption of PHT was investigated by means of circulation experiments in an in situ rat duodeno-jejunal loop. GVG did not affect the rate of disappearance of PHT from the loop perfusing medium, providing evidence against occurrence of GVG-induced impairment of PHT absorption.

Aminocaproates↗
PubMed1992

Modulation of peristalsis in the guinea-pig isolated small intestine by exogenous and endogenous opioids.

1. A recording method was developed to measure physiological parameters of the preparatory and emptying phases of peristalsis in vitro. This method enabled measurement of: the compliance of the intestinal wall during the preparatory phase (a reflection of the resistance of the wall to distension); longitudinal muscle contraction during the preparatory phase; the threshold volume required to trigger the emptying phase; the maximal ejection pressure and the average power generated during the emptying phase, which reflects the rate at which the intestine performs work. Modulation of these parameters by exogenous and endogenous opioids acting at mu, kappa and delta opioid receptors was investigated. 2. The compliance of the intestinal wall during the preparatory phase was reduced by the mu opioid receptor agonist, [D-Ala2, N-methyl-Phe4, Gly5-ol] enkephalin (DAMGO) but not by the kappa agonist, dynorphin, or the delta agonist, [D-penicillamine2, D-penicillamine5] enkephalin (DPDPE). Reflex contraction of the longitudinal muscle during the preparatory phase was inhibited by DAMGO, dynorphin and DPDPE. The threshold volume required to trigger the emptying phase of peristalsis was increased by DAMGO, dynorphin and DPDPE. 3. The maximal ejection pressure generated during the emptying phase was reduced by dynorphin and DPDPE, but not by DAMGO. The average power generated by the intestine when emptying was not altered by any of the agonists. 4. Electrically stimulated contractions of longitudinal muscle in strips of longitudinal muscle-myenteric plexus were not inhibited by DPDPE. Similarly, DPDPE did not significantly inhibit electrically induced contraction of circular muscle in strips of circular muscle-myenteric plexus.5. Each of the agonist effects on peristaltic parameters was antagonized by the appropriate antagonist:D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) (mu), norbinaltorphimine (nor-BNI) (kappa), naltrindole(delta).6. It is concluded that mu and kappa agonists act primarily on excitatory circular and longitudinal muscle motor neurones. The delta agonist probably acts on enteric neurones presynaptic to excitatory circular and longitudinal muscle motor neurones.7. Antagonists for mu, delta and kappa receptors did not affect any parameters of peristalsis when the intestine emptied against a low resistance. However, when emptying against a high outflow resistance, the average power generated by the intestine was increased by the kappa antagonist, nor-BNI, but not by CTOP or naltrindole.8. It is concluded that endogenous opioids appear to have little role in peristalsis when the intestine is working against a low outflow resistance. However endogenous opioids, acting primarily at kappa receptors,provide a braking mechanism by inhibiting the emptying phase of peristalsis in conditions in which the intestine empties against a higher resistance.

Algorithms↗
PubMed1992

The influence of neuronal 5-hydroxytryptamine receptor antagonists on non-cholinergic ganglionic transmission in the guinea-pig enteric excitatory reflex.

A partitioned bath made it possible to separate the site of recording of the ascending excitatory reflex of the ileal circular muscle (oral compartment) from the site of reflex induction (caudal compartment), evoked by inflating an intraluminal balloon. In the caudal compartment, blockade of cholinergic ganglionic transmission by hexamethonium (100 microM) and hyoscine (0.3 microM) caused an approximately 65% reduction in the amplitude of reflex contractions, suggesting that the remaining response was mediated by non-cholinergic transmission near the distension site. This non-cholinergic component of ganglionic transmission was insensitive to the action of methiothepin (1 microM), ondansetron (1 microM), tropisetron (1.5 microM), DAU 6285 (1 microM) and renzapride (1 microM), agents that antagonize the action of 5-hydroxytryptamine (5-HT) at neural 5-HT1-like, 5-HT3, 5-HT4 and putative 5-HT1P receptors. These findings suggest that the neural pathways subserving non-cholinergic ganglionic transmission in the ascending excitatory reflex in the guinea-pig ileum do not involve 5-HT as neurotransmitter.

Animals↗
PubMed1992

Calcium entry blockade as a mechanism for chlordimeform-induced inhibition of motor activity in the isolated guinea-pig ileum.

Central and peripheral alpha 2-adrenoceptors, including those of the gastrointestinal tract, have been indicated as a toxicity target of formamidine pesticides in mammals. In this study, the inhibitory effect of chlordimeform on twitch contractions from electrically-stimulated longitudinal muscle-myenteric plexus preparations (LMMPs) of the guinea-pig ileum was found to be resistant to the action of the alpha 2-adrenoceptor antagonist idazoxan. This drug was also ineffective on chlordimeform-induced inhibition of peristalsis recorded in whole ileal segments. As expected, idazoxan antagonized the inhibitory effect of the alpha 2-adrenoceptor agonist clonidine on twitch contractions and peristaltic activity. Chlordimeform reduced the amplitude of direct mechanical responses to a variety of spasmogens such as acetylcholine, histamine and substance P, suggesting a muscular site of action. Moreover, Ca(2+)-free, K(+)-depolarized LMMPs, chlordimeform inhibited submaximal contractions caused by addition of exogenous calcium, through an action apparently similar to that of the Ca2+ entry blocker nifedipine. Both chlordimeform- and nifedipine-induced inhibition of calcium contractions were reversed by the calcium channel activator BAY K 8644. This compound also partially prevented the inhibitory action of chlordimeform on peristaltic activity. On the whole, these results indicate that chlordimeform-induced depression of motor activity in the guinea-pig ileum is, at least in part, related to inhibition of transmembrane Ca2+ fluxes responsible for smooth muscle contraction.

Adrenergic alpha-Antagonists↗
PubMed1992

Benzimidazolone derivatives: a new class of 5-hydroxytryptamine4 receptor agonists with prokinetic and acetylcholine releasing properties in the guinea pig ileum.

The influence of three azabicycloalkyl benzimidazolone derivatives, DAU 6236, BIMU 1 and BIMU 8, which act as agonists at central 5-hydroxytryptamine (5-HT)4 receptors, has been investigated on cholinergic neuromuscular transmission and peristalsis in the guinea pig small intestine. In the longitudinal muscle myenteric plexus preparations, these compounds caused a concentration-dependent (range 1-300 nM) enhancement of the amplitude of nerve-mediated cholinergic submaximal contractions to electrical stimulation. In comparison to the potentiating effect of 5-methoxytryptamine (a reference 5-HT4 receptor agonist), the rank order of agonist potency was BIMU 8 = BIMU 1 greater than DAU 6236 = 5-methoxytryptamine. In whole ileal segments, DAU 6236, BIMU 1 and BIMU 8 increased markedly (maximum increase, 200%) the frequency of peristalsis within the range of 0.1 to 3 microM. Micromolar concentrations of ICS 205-930, which is a low affinity antagonist of 5-HT4 receptors, were required to antagonize the facilitatory effect on cholinergic transmission caused by benzimidazolone derivatives and 5-methoxytryptamine (pA2 values, 6.5 in average) and to reverse the increase in the frequency of peristalsis induced by DAU 6236, BIMU 1 and BIMU 8. By contrast, the potent and selective 5-HT3 receptor antagonist ondansetron (1 microM) was ineffective. Our findings indicate that benzimidazolone derivatives act as agonists in the guinea pig ileum causing enhancement of acetylcholine release and peristaltic activity. The neural receptor site involved in the action of benzimidazolone derivatives and which showed low affinity for ICS 205-930 is probably identical to the putative 5-HT4 receptor subtype agonized by indoleamines and substituted benzamide derivative prokinetic agents.

Acetylcholine↗
PubMed1991

Two subtypes of enteric non-opioid sigma receptors in guinea-pig cholinergic motor neurons.

In the longitudinal muscle-myenteric plexus preparation (LMMP) of the guinea-pig ileum, the non-opioid sigma receptors agonists, 1,3-di-ortho-tolylguanidine (DTG) and (+)N-allyl-N-normetazocine [(+)SKF 10,047], had opposite effects on nerve-mediated cholinergic contractions caused by electrical field stimulation. DTG (0.1-10 microM) inhibited and (+)SKF 10,047 (0.1-10 microM) markedly enhanced these contractile responses. Both effects were evaluated in the presence (0.5 or 1 microM) of the putative antagonists at central sigma sites: haloperidol, rimcazole, BMY 14802 and dextromethorphan. Haloperidol and dextromethorphan were ineffective. Rimcazole antagonized the effect of both DTG and (+)SKF 10.047. BMY 14802 antagonized the (+)SKF 10.047-mediated excitatory response only. These results suggest that two sigma receptor subtypes are present in enteric cholinergic motor neurons innervating the longitudinal coat. Rimcazole and BMY 14802 may provide useful tools for the characterization of peripheral non-opioid sigma receptors.

Animals↗
PubMed1991

Biliary excretion of barium in the rat.

Biliary excretion of barium was studied in Sprague-Dawley bile-duct-cannulated rats injected intravenously with 1.8 micrograms Ba/rat as 133Ba-labeled barium chloride. Approximately 0.5% of the barium dose was excreted into bile within 2 h. The time-course profile of biliary excretion of the radiotracer closely reflected that of plasma concentrations. Biliary barium levels reached their peak in the first 15-min period after administration and rapidly declined thereafter. The plasma-to-bile barium-concentration ratio was approx 1 at 2 h after injection. There was no tendency of barium to concentrate in liver, and the 133Ba levels in stomach and small intestine largely exceeded hepatic levels. There is evidence indicating that barium is predominantly excreted with feces following parenteral administration in rats and humans. The results of this study suggest that biliary excretion is of little quantitative importance and that physiological routes other than bile contribute to elimination of barium by the digestive tract.

Animals↗
PubMed1991

Muscarinic M2 receptors in rat brain labeled with [3H] AF-DX 384.

The muscarinic antagonist AF-DX 384 (5,11-dihydro-11-(((2-(2-((dipropylamino)methyl)-1- piperidinyl)ethyl)amino)carbonyl)-6H-pyrido(2,3b)(1,4)-benzodiazepin+ ++-6-one methansulfonate) was used to label cholinergic muscarinic receptors of the M2 subtype in rat brain. In the brainstem [3H] AF-DX 384 labeled a single population of binding sites with Kd = 3-4 nM and Bmax = 430-610 fmol/mg of protein. The pharmacological profile of these sites was similar to that observed with the muscarinic M2 agonist [3H] AF-DX 116. Muscarinic M2 receptors were unequally distributed in rat brain regions: in brainstem, about 80% of total muscarinic receptors (measured with [3H] quinuclidinyl benzilate) were labeled by [3H] AF-DX 384, while in other brain areas they represented only a fraction of total binding. Because of its high specific binding, high affinity and specificity, [3H] AF-DX 384 represents a useful novel ligand to study M2 receptors in brain tissue.

Animals↗