tropisetron and renzapride

The involvement of the recently characterized 5-HT4 receptor in the actions of 5-hydroxytryptamine (5-HT) on jejunal, ileal and colonic electrogenic ion secretion was investigated in the rat in-vivo. 5-HT and the 5-HT1-, 5-HT2- and 5-HT4-receptor agonist 5-methoxytryptamine (5-MeOT), induced a rise in transintestinal PD in all regions of the gut. However, the 5-HT4-receptor agonists renzapride and cisapride had no effect. Furthermore, the 5-HT4-receptor antagonists SDZ 205-557 (2-diethylaminoethyl-[2-methoxy-4-amino-5-chloro] benzoate), tropisetron and SB 204070 ([1-butyl-4-piperidinylmethyl]-8-amino-7-chloro-1,4- benzodioxan-5-carboxylate hydrochloride) did not affect the secretory response to either 5-HT or 5-MeOT in the jejunum, but did cause a small inhibition in the ileum and colon. It is concluded that 5-HT4 receptors do not make a contribution to the electrically monitored 5-HT intestinal secretory response in the rat jejunum in-vivo, but may play a small role in the ileum and colon.

Topics: 4-Aminobenzoic Acid; 5-Methoxytryptamine; Animals; Benzamides; Blood Pressure; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cisapride; Colon; Dioxanes; Dose-Response Relationship, Drug; Heart Rate; Ileum; Indoles; Intestinal Mucosa; Jejunum; Male; para-Aminobenzoates; Piperidines; Rats; Rats, Wistar; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Tropisetron

Intracellular electrophysiological methods were used to examine the effects of 5-hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT), 4-amino-5-chloro-2-methoxy-N-(4-[1-azabicyclo[3,3,1]nonyl]) benzamide hydrochloride (renzapride), cis-4-amino-5-chloro-N[1-[3- (4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl[-2-methoxybenzamide monohydrate (cisapride) and endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3- (1-methyl)ethyl-2-oxo-1 H-benzimidazole-1-carboxamidehydrochloride (BIMU 8) on noncholineric slow excitatory postsynaptic potentials (slow EPSPs) in myenteric afterhyperpolarization (AH) neurons of guinea pig ileum. 5-HT (0.01-1 microM) and 5-CT (0.001-0.1 microM) produced a concentration-dependent inhibition of slow EPSPs. The 5-HT1A receptor antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimidobutyl]piperazine (NAN-190) produced rightward shifts in 5-HT and 5-CT concentration-response curves; facilitation of slow EPSPs was never observed. 5-MeOT caused a depolarization and inhibited spike afterhyperpolarizations in a concentration-dependent manner but this effect was not blocked by the 5-HT3/5-HT4 receptor antagonist, tropisetron (1 microM). Renzapride (0.01-0.3 microM), cisapride (0.01-1.0 microM) and BIMU 8 (0.01-1.0 microM) did not change the membrane potential of any neuron tested. Renzapride and BIMU 8 did not change the amplitude of slow EPSPs. In 13 of 19 neurons cisapride did not change the amplitude of slow EPSPs; in 6 neurons cisapride (1 microM) reversibly inhibited the slow EPSP. Responses to substance P which mimicked the slow EPSP were not affected by cisapride.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 5-Methoxytryptamine; Animals; Benzamides; Benzimidazoles; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cisapride; Dose-Response Relationship, Drug; Electrophysiology; Guinea Pigs; Ileum; Indoles; Male; Membrane Potentials; Myenteric Plexus; Neurons; Piperazines; Piperidines; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Tropisetron

5-Hydroxytryptamine (5-HT) contracts and relaxes isolated stomach preparations. This study attempts to characterise receptors involved in the contractile response using electrically stimulated circular muscle strips from guinea pig stomach. Electrically induced contractions were abolished by atropine and tetrodotoxin. 5-HT enhanced contractions in corpus and fundus strips with pEC50% values (-log10 of the concentrations causing a 50% increase in twitch height) of 9.6 and 9.1, respectively. 5-Carboxamidotryptamine and 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), 5-HT1A receptor agonists, and alpha-methyl-5-HT, an agonist at 5-HT2 receptors, reduced contractions. The 5-HT3 receptor agonist, 2-methyl-5-HT, increased contractions. The effect of 2-methyl-5-HT but not of 5-HT was antagonized by the 5-HT3 receptor antagonist, tropisetron (10(-7) M). The 5-HT3 receptor antagonists, tropisetron, MDL 72222 (1 alpha H,3 alpha,5 alpha H-tropan-3-yl-3,5-dichlorobenzoate), grainsetron and ondansetron, did not modify twitch responses at concentrations below 10(-7) M. Renzapride and metoclopramide, agonists at 5-HT4 receptors, increased contractions and this effect was inhibited by the 5-HT4 receptor antagonist SDZ 205-557 (2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino) ethyl ester) with a pA2 of 7.4. The effect of 5-HT at a submaximal concentration of 10(-8) M was blocked by SDZ 205-557 (10(-6) M). It is concluded that electrically induced contractions in guinea pig stomach strips are enhanced by activation of 5-HT3- and 5-HT4 receptors and are diminished by 5-HT1 receptor agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 4-Aminobenzoic Acid; 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Atropine; Benzamides; Binding Sites; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Electric Stimulation; Female; Guinea Pigs; In Vitro Techniques; Indoles; Ligands; Male; Metoclopramide; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; para-Aminobenzoates; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Stomach; Tetrodotoxin; Tropanes; Tropisetron

Serotonin antagonists have been proven antisecretory in cholera toxin (CT)-induced hypersecretion in the small intestine of rodents. The pig small intestine is a good model for the human small intestine with regard to physiologic and pharmacologic processes.. The antisecretory effect of intraluminally administered methysergide, renzapride, ketanserin, granisetron, and tropisetron on CT-induced hypersecretion was tested in isolated pig jejunal loops in vivo.. Methysergide, ketanserin, and granisetron reduced the hypersecretory effect of CT maximally by 25%, 80%, and 50%, respectively. Tropisetron enhanced whereas renzapride did not alter the CT response. Combination of ketanserin and granisetron gave a maximal inhibitory effect of about 85%. Surprisingly, renzapride, granisetron, and tropisetron each induced hypersecretion. Taking into account the hypersecretory effect of the antagonists, they all reduced this CT-elicited hypersecretion.. Results suggest involvement of the 5-hydroxytryptamine-2 and 5-hydroxytryptamine-3 receptor subtypes as mediators in CT-induced hypersecretion in pig jejunum, and antidiarrheal therapeutic potentials of ketanserin and granisetron.

Topics: Animals; Animals, Newborn; Benzamides; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cholera Toxin; Diarrhea; Dose-Response Relationship, Drug; Drug Therapy, Combination; Granisetron; Indoles; Intestinal Secretions; Jejunum; Ketanserin; Methysergide; Serotonin Antagonists; Swine; Tropisetron

The purpose of this study was to compare the 5-hydroxytryptamine (5-HT) receptor subtypes involved in secretion of water and electrolytes (sodium, potassium, and chloride) induced by luminally administered serotonin in rat jejunum and ileum in vivo. Ketanserin partially inhibited and ICS 205-930 totally inhibited serotonin-evoked secretion. Ketanserin induced mild basal secretion while ICS 205-930 alone reduced basal absorption. There were no differences in the effects of ketanserin or ICS 205-930 on serotonin-induced secretion by rat jejunum versus ileum. Neither N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophanamide nor methysergide altered the secretory effect of serotonin in rat ileum. The substituted benzamides, cisapride, and BRL 24924, and the 5-HT4 agonist, 5-methoxytryptamide, induced water and electrolyte secretion. While BRL 24924 did not alter the subsequent serotonin-induced secretory fluxes, cisapride slightly inhibited the induced secretion. These results suggest that (1) in both segments of the intestine, 5-HT2, 5-HT3, and/or 5-HT4 receptor subtypes are involved in the regulation of intestinal transport of water and electrolytes under basal conditions; (2) serotonin-induced water and electrolyte secretion is mediated by pathways involving 5-HT2, 5-HT3, and 5-HT4 receptor subtypes in both rat jejunum and ileum; (3) 5-HT1 receptors do not seem to be involved in the mediation of intestinal water and electrolyte transport; (4) these effects are similar to those described for systemically administered 5-HT.

Topics: 5-Methoxytryptamine; Animals; Benzamides; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cisapride; Ileum; Indoles; Jejunum; Ketanserin; Male; Methysergide; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin; Tropisetron; Water-Electrolyte Balance

(1-S,8-S)-N-[(hexahydro-1H-pyrrolizin-1-yl)methyl]-6-chloroimi+ ++- dazo[1,2-a]pyridine-8-carboxamide hydrochloride (SC-53606) acts as an antagonist of 5-hydroxytryptamine4 (5-HT4) receptor-mediated relaxation of carbachol-induced contractions in rat esophageal tunica muscular mucosae, but does not possess 5-HT4 agonist activity. SC-53606 demonstrated a pA2 value against 5-HT in this tissue of 7.91 +/- 0.08 (Ki = 12.3 +/- 1.17 nM). Similar pA2 values of 7.68 +/- 0.06, 7.67 +/- 0.06 and 7.63 +/- 0.05 were determined for the synthetic 5-HT4 receptor agonists SC-53116, 5-methoxytryptamine and renzapride, respectively. In addition, slopes of Schild plots for antagonism of these four agonists by SC-53606 were 1.07 +/- 0.02, 0.98 +/- 0.03, 1.04 +/- 0.02 and 0.96 +/- 0.06, respectively, and did not deviate from unity. The pA2 values for 5-HT4 antagonism against 5-HT were determined to be 6.80 +/- 0.09 for tropisetron and 7.36 +/- 0.08 for 2-methoxy-4-amino-S- chlorobenzoic acid-2-(diethylamino)ethyl ester SDZ 205-557), indicating that SC-53606 is more a potent 5-HT4 antagonist than either of the reference antagonists. Radioligand binding studies also demonstrated that SC-53606 is a selective antagonist with more affinity for 5-HT4 than for other 5-HT receptors. Displacement of radioligand binding from 5-HT1 and 5-HT2 receptors by SC-53606 was less than 50% at a 10 microM concentration. Similarly, SC-53606 displayed little binding affinity at alpha 1, alpha 2 and beta adrenergic, dopamine1, dopamine2 and muscarinic cholinergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 4-Aminobenzoic Acid; Animals; Benzamides; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Carbachol; Esophagus; Imidazoles; In Vitro Techniques; Indoles; Male; Mucous Membrane; Muscle Contraction; Muscle, Smooth; para-Aminobenzoates; Pyrroles; Rats; Receptors, Cell Surface; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Tropisetron; Tryptamines

Three chemical classes of serotonin 5-HT4 receptor agonists have been identified so far: 5-substituted indoles (e.g. 5-HT), benzamides (e.g. renzapride) and benzimidazolones (e.g. BIMU 8). In a search for 5-HT4 receptor antagonists, we have discovered that the benzimidazolone derivative DAU 6285 (for structure see text), is 3-5 times more potent than tropisetron in blocking 5-HT, renzapride and BIMU 8 induced stimulation of adenylate cyclase activity in mouse embryo colliculi neurons. Schild plot analysis yielded Ki values of 220, 181 and 255 nmol/l, respectively. In addition, DAU 6285 showed poor activity as a 5-HT3 receptor ligand with respect to tropisetron, as demonstrated by in vitro binding studies (Ki, 322 vs 2.8 nmol/l) and by its antagonistic activity in the Bezold-Jarisch reflex test (ID50, 231 vs 0.5 micrograms/kg, i.v.). No significant binding (Ki greater than 10 mumol/l) of DAU 6285 to serotonergic 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT2 receptors as well as to adrenergic alpha 1, alpha 2, dopaminergic D1, D2 or muscarinic M1-M3 receptor subtypes was found. The data indicate that DAU 6285 has a somewhat higher affinity than tropisetron for 5-HT4 receptors, a property confirmed in functional tests, and much lower affinity than tropisetron for 5-HT3 receptors. The compound represents a new interesting tool for investigating the pharmacological and physiological properties of 5-HT4 receptors.

Topics: Animals; Benzamides; Benzimidazoles; Brain; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cells, Cultured; Cyclic AMP; Embryo, Mammalian; Heart Rate; Indoles; Kinetics; Mesencephalon; Mice; Rats; Receptors, Serotonin; Reflex; Serotonin; Serotonin Antagonists; Stimulation, Chemical; Tropisetron

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.

Topics: Animals; Benzamides; Benzimidazoles; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Female; Guinea Pigs; Indoles; Intestine, Small; Male; Methiothepin; Muscle Contraction; Ondansetron; Serotonin Antagonists; Synaptic Transmission; Tropisetron

The effect of 5-hydroxytryptamine and renzapride was studied on the peristaltic reflex elicited in vitro in the guinea-pig ileum. Both agents evoked the reflex at subthreshold intraluminal pressures (50% of threshold) and were blocked by ICS 205-930 (3 microM), but not ondansetron (5 microM). This novel finding suggests strongly that the prokinetic action of renzapride and gut motility stimulating action of 5-hydroxytryptamine are mediated via agonism at the putative 5-HT4 receptor.

Topics: Animals; Benzamides; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Guinea Pigs; In Vitro Techniques; Indoles; Male; Peristalsis; Receptors, Serotonin; Serotonin; Tropisetron

The effects of 5-carboxamidotryptamine (5-CT) and the gastrokinetic benzamides renzapride and cisapride on contractile force were investigated using isolated paced right atrial appendages from patients treated with beta-adrenoceptor blocking agents who were undergoing open heart surgery. These effects were compared to those of 5-hydroxytryptamine (5-HT). The effects of the drugs on atrial cyclic AMP levels and cyclic AMP-dependent protein kinase ratios were also investigated. The drugs all increased contractile force of rank order of potency was 5-HT greater than renzapride greater than cisapride greater than 5-CT. The maximum responses, expressed as a fraction of the response to 200 mumol/l (-)-isoprenaline, were 5-HT 0.6, 5-CT 0.6, renzapride 0.4 and cisapride greater than or equal to 0.2, suggesting that the latter two are partial agonists. 5-HT, 5-CT and renzapride but not cisapride caused significant shortening of time to peak force. The effects of the four drugs were blocked by mumolar concentrations of ICS 205-930, suggesting an involvement of 5-HT4 receptors. As expected of partial agonists both renzapride and cisapride caused simple competitive antagonism of the positive inotropic effects of 5-HT. The estimated equilibrium dissociation constants pKP (-log mol/l KP) were 6.7 for renzapride and 6.2 for cisapride. 5-CT at concentrations up to 10 mumol/l did not antagonise the effects of 5-HT. In the presence of (+/-)-propranolol 0.4 mumol/l, 5-HT 10 mumol/l, 5-CT 100 mumol/l, renzapride 10 mumol/l and cisapride 40 mumol/l significantly increased cyclic AMP levels. 5-HT and renzapride also significantly increased cyclic AMP-dependent protein kinase activity, whereas 5-CT caused only marginal stimulation and cisapride was ineffective. The results confirm the existence of a human right atrial 5-HT receptor that is similar in nature to, but not necessarily identical with, the 5-HT4 receptor of mouse embryonic colliculi neurones. The main difference is that in human right atrium the benzamides are less potent and efficacious than 5-HT and that cisapride is less potent and less efficacious than renzapride while in mouse embryonic colliculi these two benzamides are equipotent with and more efficacious agonists than 5-HT. We designate the human right atrial 5-HT receptor 5-HT4-like. The human right atrial 5-HT4-like receptor greatly resembles porcine sinoatrial and left atrial 5-HT4-like receptors and also appears to be similar to 5-HT4-like receptors of gu

Topics: Benzamides; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cisapride; Cyclic AMP; Embryo, Mammalian; Female; Heart Atria; Humans; Indoles; Male; Middle Aged; Myocardial Contraction; Piperidines; Protein Kinases; Receptors, Serotonin; Serotonin; Structure-Activity Relationship; Tropisetron

We studied the effect of 5-hydroxytryptamine 3 (5-HT3) receptor antagonists on gastrointestinal (GI) motor activity in conscious dogs with force transducers implanted chronically. During the digestive state, GR38032F, BRL 43694 and ICS 205-930 did not affect GI motor activity at all at doses up to 1 mg/kg, whereas BRL 24924 at 1.0 mg/kg i.v. significantly stimulated GI motor activity from the stomach to the colon. When GR38032F, BRL 43694 or ICS 205-930 was given i.v. at doses of 0.1 to 1.0 mg/kg during the phase I period, no direct effect was observed on GI motor activity, but the treatment inhibited the occurrence of the subsequent phase III activity in the stomach completely and inhibited it partially in the duodenum without affecting the plasma motilin concentration. GR38032F, BRL 43694 and ICS 205-930 did not influence the caudal migration of phase III activity in the small intestine. In contrast, BRL 24924 at doses of 0.1 to 1.0 mg/kg i.v. significantly stimulated GI motor activity during the phase I period. On the other hand, when GR38032F, BRL 43694 or ICS 205-930 was given during natural or motilin-induced phase III activity, the total contractions in the stomach and partial contractions in the duodenum were inhibited but the caudal propagation of phase III activity in the small intestine was not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzamides; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Digestion; Dogs; Dose-Response Relationship, Drug; Female; Gastrointestinal Motility; Granisetron; Imidazoles; Indazoles; Indoles; Infusions, Intravenous; Injections, Intravenous; Male; Motilin; Motor Activity; Muscle Contraction; Muscle, Smooth; Ondansetron; Serotonin Antagonists; Time Factors; Tropisetron

Drugs that enhance gastrointestinal motility include the benzamide drugs metoclopramide, cisapride and renzapride (BRL-24924). Because these agents also are serotonin-3 (5-HT3) receptor antagonists, which can promote gastric emptying in some species, the motor-stimulating properties of benzamide agents may be due to this mechanism. Metoclopramide (0.3-3.0 mg/kg i.v.), cisapride (0.03-1.0 mg/kg i.v.) and BRL-24924 (0.01-0.1 mg/kg i.v.) were evaluated for their relative motility-stimulating and 5-HT3 receptor antagonist activities in conscious dogs and were compared with selective 5-HT3 antagonist antiemetic compounds ICS-205-930, (3 alpha-tropanyl)1-H-indole-3-carboxylic acid ester and granisetron (BRL-43694). Gastric antral contractions and intestinal myoelectric motility were determined in response to drugs, as were their effects on solid and liquid emptying in a gamma scintigraphic model of gastroparesis. 5-HT3 receptor antagonist potency was examined by deriving ED50 values for inhibition of cisplatin emesis. All drugs were 5-HT3 antagonists as they blocked cisplatin emesis with relative potencies of BRL-43694 = ICS-205-930 greater than BRL-24924 greater than cisapride = metoclopramide. The order of potency for stimulating fasted dog antral contractile activity, however, was BRL-24924 = cisapride greater than metoclopramide greater than ICS-205-930 = BRL-43694. Maximally effective doses of BRL-24924 (0.1 mg/kg i.v.) and cisapride (0.67 mg/kg i.v.) in the antrum also stimulated intestinal myoelectrical activity, whereas ICS-205-930 (0.5 and 2.0 mg/kg i.v.) was not active.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzamides; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cisapride; Cisplatin; Dogs; Dose-Response Relationship, Drug; Female; Gastric Emptying; Gastrointestinal Motility; Indoles; Injections, Intravenous; Male; Metoclopramide; Piperidines; Receptors, Serotonin; Serotonin Antagonists; Tropisetron

5-Hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT) and the gastrointestinal kinetic benzamides renzapride and cisapride caused tachycardia in spontaneously beating right atria of piglet in the presence of 400 nmol/l (+/-)-propranolol and 6 mumol/l cocaine. The maximum tachycardia caused by agonists, compared to that evoked by 200 mumol/l (-)-isoprenaline, was 63% for 5-HT, 50% for 5-CT, 50% for renzapride and 28% for cisapride. The rank order of potency was 5-HT greater than renzapride greater than cisapride greater than 5-CT. The effects of the agonists, but not those of (-)-isoprenaline, were antagonised by 3 alpha-tropanyl-1H-indole-3-carboxylic acid (ICS 205930); the pKB of ICS 205930 (vs 5-HT) was 6.9. These characteristics suggest that piglet sinoatrial 5-HT receptors are similar to "so-called" 5-HT4 receptors previously described in mouse colliculi neurons. Piglet sinoatrial 5-HT4-like receptors resemble the human atrial 5-HT receptors that mediate positive inotropic effects of 5-HT.

Topics: Animals; Benzamides; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cardiotonic Agents; Cisapride; Female; Heart; Heart Atria; Humans; In Vitro Techniques; Indoles; Male; Piperidines; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Sinoatrial Node; Swine; Tropisetron

Intravenous bolus injections of 5-hydroxytryptamine (5-HT; 3, 10 and 30 micrograms kg-1), 5-methoxytryptamine (5-MeO-T; 3, 10 and 30 micrograms kg-1), renzapride (BRL 24924; 3, 10, 30 and 100 micrograms kg-1) and isoprenaline (0.03, 0.1 and 0.3 micrograms kg-1) to anaesthetized pigs increased heart rate by, respectively, 22 +/- 3, 44 +/- 3 and 65 +/- 4 beats min-1 (5-HT; n = 17); 12 +/- 1, 26 +/- 2 and 44 +/- 4 beats min-1 (5-MeO-T; n = 15), 5 +/- 2, 11 +/- 2, 18 +/- 4 and 37 +/- 5 beats min-1 (renzapride; n = 8) and 17 +/- 2, 46 +/- 3 and 75 +/- 3 beats min-1 (isoprenaline; n = 13). The responses to 5-HT, 5-MeO-T and renzapride were antagonized by ICS 205-930 (1 and 3 mg kg-1, i.v.), which did not modify the increases in heart rate by isoprenaline. Renzapride showed tachyphylaxis and attenuated the responses to 5-HT. These findings indicate that 5-HT elicits tachycardia in the pig by acting on a novel receptor, either similar or identical to the 5-HT4 receptor identified in mouse brain colliculi.

Topics: Anesthesia; Animals; Benzamides; Blood Pressure; Brain; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Heart; Heart Rate; In Vitro Techniques; Indoles; Isoproterenol; Myocardium; Receptors, Serotonin; Serotonin; Swine; Tropisetron

Administration of serotonin (5-hydroxytryptamine, 5-HT) to pyramidal cells of the CA1 region of the hippocampus results in a hyperpolarizing response which is followed by a rebound depolarization and a decrease in the calcium-activated afterhyperpolarization (AHP). While the hyperpolarizing response has been previously shown to be mediated by receptors of the 5-HT1A subtype, the identity of the receptor(s) involved in the depolarizing response and decrease of the AHP have not been identified. In the present study the effectiveness of a series of 5-HT receptor antagonists in blocking the membrane depolarization and reduction of the AHP was assessed. While a variety of 5-HT1 and 5-HT2 antagonists were found to be ineffective, the substituted benzamide BRL 24924 was found to be a potent and selective antagonist of the 5-HT-induced depolarization and decrease in the AHP in this region. This effect however appeared unrelated to the ability of this compound to block 5-HT3 receptors, as ICS 205-930 and MDL 72222 were markedly less efficacious in blocking these effects of 5-HT. Upon blockade of 5-HT1A receptors, 5-HT elicits a depolarization which is accompanied by a marked increase in excitability. These effects were also dose-dependently antagonized by BRL 24924. The present results thus suggest the presence in the CA1 region of the hippocampus of a novel 5-HT receptor at which BRL 24924 functions as a selective antagonist and which is capable of mediating slow excitatory responses in central neurons.

Topics: Animals; Benzamides; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Calcium; Hippocampus; In Vitro Techniques; Indoles; Male; Neurons; Pyramidal Tracts; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Tropanes; Tropisetron

1. The substituted benzamides, zacopride and BRL 24924 induced dose-dependent increases of the total EEG-energy of rats when applied intracerebroventricularly (i.c.v.) with ED50 values of 8.0 +/- 0.6 and 3.6 +/- 0.9 micrograms, respectively. Not only the energy of the low frequency hippocampal theta rhythm but also that of the other frequency bands was increased. 2. In contrast to i.c.v. application intraperitoneal administration of zacopride or BRL 24924 (1 and 10 mg kg-1) did not lead to an increase in EEG-energy. 3. The increase in EEG-energy induced by zacopride (10 micrograms, i.c.v.) was blocked by ICS 205-930 (1 microgram, i.c.v.). Neither the 5-HT3 receptor agonist 2-methyl-5-hydroxytryptamine (30 micrograms, i.c.v.) nor the selective 5-HT3 receptor antagonist MDL 72222 (30 micrograms, i.c.v.) had any effect upon rat EEG. 4. Scopolamine (0.01 micrograms and 0.1 micrograms, i.c.v.) dose-dependently antagonized the effect of zacopride (10 micrograms, i.c.v.). 5. An agonist action of zacopride and BRL 24924 and inhibition of these effects by ICS 205-930 but not by MDL 72222 was recently described in isolated colliculi neurones from neonatal mice. The receptor involved was described as '5-HT4'. The present results indicate that the central effects of zacopride and BRL 24924 may be due to activation of such a 5-HT receptor.

Topics: Animals; Benzamides; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Electroencephalography; Indoles; Injections, Intraventricular; Male; Rats; Rats, Inbred Strains; Scopolamine; Serotonin Antagonists; Tropisetron

Adult guinea pig hippocampal membranes contain two 5-hydroxytryptamine (5-HT) receptors positively coupled with an adenylate cyclase. One is a typical 5-HT1A receptor and the second is a nonclassical 5-HT receptor that we previously proposed to call 5-HT4. Here, we show that 4-amino-5-chlor-2-methoxy-benzamide derivatives are agonists of 5-HT4 receptors in guinea pig hippocampal membranes. Their effects on the adenylate cyclase of these membranes are not additive with those of 5-HT but are additive with those of RU 24969, a typical 5-HT1 agonist. The effects of benzamides, as well as those of 5-HT, on 5-HT4 receptors are not blocked by 5-HT1, 5-HT2, or 5-HT3 antagonists except ICS 205 903, which does so with a low affinity (1 microM). The potency of benzamides (cisapride greater than BRL 24924 greater than zacopride greater than BRL 20627 greater than metoclopramide) is similar to their effect of 5-HT4 receptors positively coupled with an adenylate cyclase of fetal mouse colliculi neurons.

Topics: Adenylyl Cyclases; Animals; Benzamides; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Enzyme Activation; Guinea Pigs; Hippocampus; In Vitro Techniques; Indoles; Male; Receptors, Serotonin; Serotonin; Signal Transduction; Spiperone; Structure-Activity Relationship; Tropisetron

A non-classical 5-hydroxytryptamine (5-HT) receptor that we have previously proposed to call 5-HT4 and which mediates stimulation of adenylate cyclase activity in mouse embryo colliculi neurons in primary culture was also stimulated by substituted benzamide derivatives such as metoclopramide and BRL 24924 ([ (+/-)-(endo)]-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo-[3.3.1]-non- 4-yl)-benzamide hydrochloride). The non-additivity of the effects of 5-HT and BRL 24924 on cAMP formation and the inhibition by ICS 205 930, a potent 5-HT3 antagonist, suggest that 5-HT and BRL 24924 act on the same receptor. In light of these results, we think that a similarity may exist between the non-classical 5-HT receptor, coupled with an adenylate cyclase in colliculi neurons, and the non-classical 5-HT receptor, involved in gastric and ileum motility which is specifically stimulated by substituted benzamide derivatives in the same order of potency (metoclopramide, BRL 24924).

Topics: Adenylyl Cyclases; Animals; Benzamides; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Bridged-Ring Compounds; Cyclic AMP; Embryo, Mammalian; Female; Indoles; Metoclopramide; Mice; Neurons; Pregnancy; Serotonin Antagonists; Tropisetron

Topics: Animals; Benzamides; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dogs; Gastrointestinal Motility; Granisetron; Imidazoles; In Vitro Techniques; Indazoles; Indoles; Motilin; Ondansetron; Rabbits; Serotonin Antagonists; Tropisetron

5-HT3 receptor antagonists may have both antiemetic and gastric and intestinal motility stimulating properties, but they differ in their relative potencies and efficacies for these two activities. Since the 5-HT3 receptor is present on enteric neurons, intracellular recordings of myenteric neuronal transmembrane potential were used to assess the actions of four proposed motility stimulating drugs, metoclopramide, BRL 24924, ICS 205-930 and cisapride. BRL 24924 (10(-6) M), ICS 205-930 (10(-7) M) and cisapride (5 x 10(-6) M) each antagonized the 5-HT3-mediated fast depolarization of myenteric neurons. Metoclopramide (10(-5) M) was less consistent in its ability to antagonize this response, and the response often returned in the continued presence of metoclopramide. In the present study, BRL 24924 (10(-6) M) and, as previously shown, cisapride (5 x 10(-6) M) antagonized the slow depolarization of myenteric neurons induced by 5-HT. Metoclopramide (10(-5) M), BRL 24924 (10(-6) M) and cisapride (5 x 10(-6) M), but not ICS 205-930 (10(-7) M) depolarized myenteric neurons within the first 2 min of contact with myenteric neurons. These data support the view that there are separate receptors that may be responsible for the prokinetic actions of these drugs and a series of 5-HT3-mediated actions which include antiemesis.

Topics: Animals; Benzamides; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cisapride; Electrophysiology; Gastrointestinal Motility; Guinea Pigs; In Vitro Techniques; Indoles; Male; Metoclopramide; Myenteric Plexus; Neurons; Piperidines; Receptors, Serotonin; Serotonin Antagonists; Stimulation, Chemical; Tropisetron