Biomedical subjects

L Manzo

Publications and source records attributed to L Manzo.

At least 55 records · Page 3Linked to original sources

PubMed1993

Interaction of ethanol with muscarinic receptor-stimulated phosphoinositide metabolism during the brain growth spurt in the rat: role of acetaldehyde.

The developing brain is extremely sensitive to the neurotoxicity of ethanol; however, the mechanism(s) of its developmental neurotoxicity are still elusive. In the developing rat brain, ethanol exerts an age-, brain region-, and receptor-specific inhibitory effect on muscarinic receptor-stimulated phosphoinositide metabolism, which may be linked to some of the neurotoxic effects of ethanol found in children with fetal alcohol syndrome. Since some studies have suggested that the ethanol metabolite acetaldehyde may mediate, at least in part, the developmental effects of ethanol, in the present study we have examined whether acetaldehyde would inhibit carbachol-stimulated phosphoinositide metabolism in brain slices from immature rats. We also tested propionaldehyde, the corresponding aldehyde of n-propanol, another alcohol shown to cause microencephaly and to affect phosphoinositide metabolism in the developing rat. Neither acetaldehyde nor propionaldehyde, at concentrations up to 1 mM, had any inhibitory effect on this system, while the two alcohols did, as previously reported. These results suggest that ethanol itself may be the primary agent responsible for its developmental neurotoxicity.

1-Propanol↗

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↗

PubMed1993

Cyclic GMP formation induced by muscarinic receptors is mediated by nitric oxide synthesis in rat cortical primary cultures.

In rat primary cortical cultures, carbachol caused a time- and concentration-dependent increase in guanosine cyclic 3',5'-monophosphate (cGMP) levels, which was antagonized by the muscarinic antagonist atropine. Glutamate and sodium nitroprusside also caused large increases in cGMP levels, as previously reported. Two nitric oxide (NO) synthase inhibitors, L-NG-nitroarginine and L-NG-monomethylarginine, were tested for their ability to inhibit the carbachol- and the glutamate-induced cGMP formation. The cGMP response to carbachol was decreased by both compounds in a dose-dependent fashion. The effect of L-NG-nitroarginine was competitively reversed by addition of an excess of L-arginine. Similarly, the stimulatory effect of glutamate on cGMP levels was antagonized by L-NG-nitroarginine and L-NG-monomethylarginine. Hemoglobin, a scavenger of NO, also blocked the carbachol-stimulated cGMP production. These results indicate that muscarinic receptor-stimulated cGMP formation in rat cerebral cortex is mediated by NO.

Amino Acid Oxidoreductases↗

PubMed1993

Effects of inorganic and organic mercury on intracellular calcium levels in rat T lymphocytes.

The importance of cytosolic free calcium level ([Ca2+]i) in lymphocyte activation prompted us to investigate changes in [Ca2+]i in T cells caused by mercury compounds, which have been shown to have immunomodulatory and immunotoxic properties. Using fura-2 as fluorescent Ca2+ indicator, we found that both methyl-mercury (MeHg; 0.02-2 microM) and inorganic mercury (HgCl2; 0.01-1 microM) increased [Ca2+]i in lymphocytes from rat spleen in a concentration-dependent manner. The effect of MeHg was rapid and the increase of Ca2+ level was sustained in time, while HgCl2 caused a slow rise in [Ca2+]i. The effects of mercury compounds did not appear to be associated with alterations of membrane integrity, since there was no significant difference in the extent of MnCl2 quench between control and mercury-treated cells. However, HgCl2 (1 microM) and MeHg (2 microM) appeared to cause membrane damage at longer incubation times (15 min). When cells were incubated in Ca(2+)-free medium (in the presence of 1 mM EDTA) MeHg still increased [Ca2+]i, though to a lesser extent, while HgCl2 had no effect. Heparin, an inhibitor of inositol 1,4,5-trisphosphate-induced Ca2+ mobilization partially blocked this rise of [Ca2+]i, while carbonyl cyanide m-chlorophenylhydraxone (CCCP), an inhibitor of mitochondrial function, had a lesser effect. When added together, heparin and CCCP almost completely block the response to MeHg. These results suggest that MeHg and HgCl2 exert their effects of [Ca2+]i in different ways: MeHg-induced increases in [Ca2+]i are due to influx from outside the cells as well as to mobilization from intracellular stores, possibly the endoplasmic reticulum, and, to a minor extent, the mitochondria; on the other hand, HgCl2 causes only Ca2+ influx from the extracellular medium.

Animals↗

PubMed1993

Modifications of Ca2+ signaling by inorganic mercury in PC12 cells.

The effects of different levels of inorganic mercury (Hg2+) on depolarization- or agonist-stimulated Ca2+ signals were studied in PC12 cells. Exposure to 50-300 nM Hg2+ did not alter the resting cytosolic free Ca2+ concentration ([Ca2+]i), but enhanced the Ca2+ response to KCL-induced depolarization. Patch-clamp experiments revealed that these Hg2+ concentrations increased the voltage-dependent Ca2+ current through L-type channels. Also, Hg2+ treatment amplified the intracellular [Ca2+]i transients elicited by extracellular ATP. In contrast, the Ca2+ increase stimulated by bradykinin was unaffected. At slightly higher concentrations (1 to 2 microM), Hg2+ caused a sustained rise of the resting [Ca2+]i. This increase did not occur in Ca(2+)-free medium and was prevented by pretreatment with NiCl2 or with the L-type Ca2+ channel blockers, verapamil and nifedipine. Hg2+ did not mobilize Ca2+ from intracellular stores sensitive to thapsigargin, 2,5-di-(tert-butyl)-benzohydroquinone, or caffeine. At 2 microM, Hg2+ inhibited the [Ca2+]i transients elicited by bradykinin, ATP, or KCl-induced depolarization. The loss of the intracellular Ca2+ response to bradykinin was independent from the Ca2+ overload elicit by Hg2+; instead, it was associated with inhibition of polyphosphoinositide generation. Exposure to the lower Hg2+ concentrations (0.3-0.5 microM) greatly potentiated NGF-induced PC12 cell differentiation. Conversely, treatment with 2 microM Hg2+ caused cell death. Our results show that inorganic mercury has selective and different effects on Ca2+ signaling in PC12 cells depending on the concentration, within a narrow range.

Adenosine Triphosphate↗

PubMed1992

Trace element reference values in tissues from inhabitants of the European Community. III. The control of preanalytical factors in the biomonitoring of trace elements in biological fluids.

In the context of a programme concerning the determination of trace elements in body fluids and tissues to establish trace element reference values, research has been undertaken on the control of preanalytical factors in order to develop sufficiently accurate and precise guidelines to be applied in routine work by using techniques such as graphite furnace atomic absorption spectroscopy (GFAAS). Aspects investigated are related to the risk of contamination during blood collection and the use of anticoagulants; the risk of losses during storage and freeze-drying as well as the possible risk of contamination arising from trace elements in airborne particulates of the laboratory environment. For the analysis of Al, Ba, Cd, Co, Cr, Mn, Mo, Ni, Sb, W, V and Zn in blood, Teflon cannula is the method of choice. The anticoagulants do not introduce disturbing contaminations of Rb, Se, Zn, while contaminations were observed for Co, Cr, Mn. Radiotracers in 'metabolized form' (radiolabelled rat or rabbit tissues from animals administered with radioisotopes) show that samples stored for 1 month at -20 degrees C have no significant trace metal losses. Strict ambient air quality standard has to be respected (continuous monitoring) due to the possibility of element contaminations inside the laboratory. The use of matrix modifiers could represent a toxicological risk to the operators. Critical factors should be considered ('metal sheets') for each element in each matrix. For instance 27 factors for Cr in serum have been suggested.

Air Pollutants, Occupational↗

PubMed1992

Guanine nucleotide- and muscarinic agonist-dependent phosphoinositide metabolism in synaptoneurosomes from cerebral cortex of immature rats.

Guanine nucleotide-, neurotransmitter-, and fluoride-stimulated accumulation of [3H]inositol phosphates ([3H]InsPs) was measured in [3H]inositol-labeled synaptoneurosomes from cerebral cortex of immature (7-day-old) and adult rats, in order to clarify the role of GTP-binding proteins (G-proteins) in modulating phosphoinositide (PtdIns) metabolism during brain development. GTP(S) [Guanosine 5'-O-(3-thio)triphosphate] time- and concentration-dependently stimulated PtdIns hydrolysis. Its effect was potentiated by full (carbachol, metacholine) and partial (oxotremorine) cholinergic agonists through activation of muscarinic receptors. The presence of deoxycholate was required to demonstrate agonist potentiation of the guanine nucleotide effect. The response to GTP(S) was higher in adult than in immature rats, while the effect of cholinergic agonists was similar at the two ages examined. At both ages, histamine potentiated the effect of GTP(S), while norepinephrine was ineffective. At both ages, guanosine 5'-O-(2-thio)diphosphate [GDP(S)] and pertussis toxin significantly decreased GTP(S)-induced [3H]InsPs formation. The phorbol ester phorbol 12-myristate 13-acetate (PMA), on the other hand, did not inhibit the guanine nucleotide response in synaptoneurosomes from immature rats. NaF mimicked the action of GTP(S) in stimulating PtdIns hydrolysis. Its effect was not affected by carbachol and was highly synergistic with that of AlCl3, according to the concept that fluoroaluminate (AlF4-) is the active stimulatory species. No quantitative differences were found in the response to these salts between immature and adult animals. These results provide evidence that, in both the immature and adult rat brain, neuroreceptor activation is coupled to PtdIns hydrolysis through modulatory G-proteins.

Aging↗

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

Thiol modification and cell signalling in chemical toxicity.

Exposure of cells to thiol oxidizing agents can result in the modification of key proteins involved in cell signalling. Such changes have been shown to affect agonist-stimulated phosphoinositide metabolism, activation of protein kinases and intracellular Ca2+ signals, which result in abnormalities in cell metabolisms and growth. Here, we show that moderate levels of oxidants potentiate growth signals and either enhance cell proliferation or facilitate cell differentiation, whereas inhibition of growth signals by higher oxidant concentrations can block cell proliferation and activate programmed cell death (PCD). Finally, a general alteration of multiple signalling pathways associated with increased catabolic reactions results in cell death by necrosis. Our data suggest that oxidant interaction with cell signalling systems may exert opposite effects, depending on the dose, and that oxidative reactions may either mimic growth factor stimulation and stimulate cell proliferation or inhibit growth signals and activate PCD, in the same cell systems.

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

Effects of thallium on primary cultures of testicular cells.

The objective of this in vitro study was to examine the response of mixed cultures of Sertoli and germ cells to treatment with thallium (Tl) at the range of concentrations that, in previous studies, was shown in vivo to affect reproduction. Cultures were prepared from the testis of Sprague-Dawley rats. Cultures containing approximately 3.75 x 10(6) cells/ml were treated with Tl concentrations corresponding to 35, 7, and 1.4 micrograms Tl/g testis, estimated from protein content of cultures. Observations at 24, 48, and 72 h after treatment showed a significant release of germ cells into the culture medium that was both concentration and time dependent. Cultures treated with 35 micrograms Tl/g testis showed a threefold increase in germ-cell detachment compared with controls after only 24 h of exposure. As the treatment time increased to 48 h of exposure, even cultures exposed at the lowest Tl concentration (1.4 micrograms Tl/g testis) showed significant loss of germ cells. After 48 h, cultures exposed to 7 micrograms Tl/g testis exhibited a 2.5-fold increase in germ-cell detachment, and those exposed to 35 micrograms Tl/g testis exhibited a 10-fold increase over controls. Morphological investigations of cell cultures showed evident loss of germ cells with significant reduction in prepachytene and pachytene spermatocytes and changes in the shape of Sertoli cells. These results are in agreement with in vivo studies, in which thallium treatment at comparable exposure levels manifested its earliest toxic testicular effects in Sertoli and germ cells. They also demonstrate the usefulness of this in vitro culture technique to assess toxic testicular damage rapidly.

Animals↗

PubMed1992

Cytotoxic and genotoxic effects of styrene-7,8-oxide in neuroadrenergic Pc 12 cells.

Exposure of Pc 12 cells to styrene-7,8-oxide (SO) (0.5-1 mM) caused a rapid increase in cytosolic Ca2+, depletion of intracellular glutathione and ATP, DNA damage and loss of cell viability. Lower SO concentrations (less than or equal to 100 microM), did not cause loss of cell viability or affect cell growth rate. However, at 30 and 100 microM, SO stimulated the formation of alkali-sensitive, DNA single-strand breaks (SSB). DNA SSB were fully repaired when cells exposed to 30 microM SO were subsequently incubated for 3 h in fresh medium, whereas DNA repair was only partial after exposure to 100 microM SO. When cells exposed to 30 or 100 microM SO were incubated with the inhibitors of repair synthesis 1-beta-D-arabinofuranosyl-cytosine (AraC) and hydroxyurea (HU), SSB accumulated, indicating the involvement of the excision-repair system in the removal of DNA lesions. A SO adduct with guanine at the N7 position was detected in the DNA extracted from treated cells. SO did not induce the formation of double-strand breaks, interstrand cross-links, or DNA-protein cross-links. Although cells exposed to 30 or 100 microM SO underwent normal cell division, latent DNA damage was retained for up to 14 subsequent replicative cycles. In addition, SO-treated cells partially lost their normal ability to differentiate in response to nerve growth factor (NGF) stimulation. NGF failed to induce differentiation in cells that had replicated for 20 generations after exposure to 100 microM SO. Spontaneous differentiation stimulated by high-density culture was also inhibited in SO-treated cells. These results indicate that non-lethal concentrations of SO can cause modifications that compromise the ability of Pc 12 cells to respond to NGF and differentiate.

Adrenal Gland Neoplasms↗

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

Inhibition of muscarinic receptor- and G-protein-dependent phosphoinositide metabolism in cerebrocortical membranes from neonatal rats by ethanol.

Phosphoinositide (PtdIns) metabolism activated by cholinergic muscarinic receptors appears to play a role in brain development and has been recently suggested as a possible biochemical target for the developmental neurotoxicity of ethanol (EtOH). Recent experimental evidence indicates that, in rat brain, muscarinic receptor stimulation is coupled to PtdIns hydrolysis through regulatory GTP-binding proteins (G-proteins). We investigated the effect of various alcohol concentrations (10-500 mM) on guanine nucleotide-, fluoride-, and muscarinic-dependent PtdIns hydrolysis in [3H]inositol-labelled cerebral cortical membranes from neonatal (7-day-old) and adult rats. At both ages, EtOH exerted slight inhibitory effects on GTP(S) (100 microM)- and NaF (5 mM)-induced [3H]inositol phosphates accumulation. The presence of GTP(S) was necessary to unmask the stimulatory effect of the muscarinic agonist carbachol. Under these experimental conditions EtOH markedly inhibited carbachol (100 microM)-induced PtdIns hydrolysis. This effect was concentration-dependent and was more pronounced in the cortex from immature animals, where a statistically significant inhibition was observed at EtOH concentrations as low as 50 mM, comparable to the hematic concentrations reached following in vivo administration of doses of ETOH able to induce developmental neurotoxicity. These results confirm that EtOH exerts an age-specific inhibition of muscarinic-dependent PtdIns metabolism and suggest that this action might be exerted through an interaction with receptor-G-protein coupling.

Animals↗

PubMed1992

Comparative studies on the neuro- and reproductive toxicity of acrylamide and its epoxide metabolite glycidamide in the rat.

The neurotoxicity of acrylamide (AA) has been the subject of extensive studies at the morphological and functional levels in both animals and man. The concern for human exposure to monomeric AA derives partly from its extensive use in molecular biology laboratories where, in the United States alone, 100,000-200,000 persons are potentially exposed. Initial work in this laboratory aiming at the development of techniques for using hemoglobin adducts as biomarkers for human exposure to AA, revealed the formation of glycidamide as a reactive epoxide metabolite of acrylamide in the rat (Chem. Res. Toxicol. 3, 406, 1990). In rats treated with 0-100 mg/kg of AA significant dose-rate effects were observed on adduct formation by both AA and glycidamide. The high rate of formation of the metabolite, especially at low doses where approximately 60% of AA was converted to glycidamide in vivo, prompted us to investigate its potential role in the induction of neurotoxic and reproductive effects attributed to AA exposure. In initial neurotoxicological experiments, the effects of the parent compound (8-14 days, 25 and 50 mg/kg/day) and the metabolite (8-14 days, 50 and 100 mg/kg/day) were compared. While at the higher dose both compounds affected the rats' performance on the rotarod, only acrylamide had a significant effect in the hindlimb splay test, which is considered a more sensitive indicator of peripheral neuropathy. On the other hand, a stronger effect was seen for glycidamide than for AA on the male reproductive system, especially on sperm cell viability.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrylamide↗

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↗