RESUMO
Antagonists of glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype, as well as of voltage-gated sodium channels, exhibit anticonvulsive and neuroprotective properties in vivo. One can postulate that a compound that combines both principles might be useful for the treatment of disorders of the central nervous system, like focal or global ischemia. Here, we present data on the effects of dimethyl-(2-[2-(3-phenyl-[1,2, 4]oxadiazol-5-yl)-phenoxy]ethyl)-amine hydrochloride (BIIR 561 CL) on neuronal AMPA receptors and voltage-dependent sodium channels. BIIR 561 CL inhibited AMPA receptor-mediated membrane currents in cultured cortical neurons with an IC50 value of 8.5 microM. The inhibition was noncompetitive. In a cortical wedge preparation, BIIR 561 CL reduced AMPA-induced depolarizations with an IC50 value of 10.8 microM. In addition to the effects on the glutamatergic system, BIIR 561 CL inhibited binding of radiolabeled batrachotoxin to rat brain synaptosomal membranes with a Ki value of 1.2 microM. The compound reduced sodium currents in voltage-clamped cortical neurons with an IC50 value of 5.2 microM and inhibited the veratridine-induced release of glutamate from rat brain slices with an IC50 value of 2.3 microM. Thus, BIIR 561 CL inhibited AMPA receptors and voltage-gated sodium channels in a variety of preparations. BIIR 561 CL suppressed tonic seizures in a maximum electroshock model in mice with an ED50 value of 2.8 mg/kg after s.c. administration. In a model of focal ischemia in mice, i.p. administration of 6 or 60 mg/kg BIIR 561 CL reduced the area of the infarcted cortical surface. These data show that BIIR 561 CL is a combined antagonist of AMPA receptors and voltage-gated sodium channels with promising anticonvulsive and neuroprotective properties.
Assuntos
Anticonvulsivantes/farmacologia , Benzodiazepinas , Neurônios/fisiologia , Fármacos Neuroprotetores/farmacologia , Oxidiazóis/farmacologia , Receptores de AMPA/fisiologia , Canais de Sódio/fisiologia , Animais , Ansiolíticos/farmacologia , Batraquiotoxinas/farmacocinética , Membrana Celular/fisiologia , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/fisiologia , Eletrochoque , Embrião de Mamíferos , Ácido Glutâmico/metabolismo , Técnicas In Vitro , Ataque Isquêmico Transitório/fisiopatologia , Ataque Isquêmico Transitório/prevenção & controle , Masculino , Mexiletina/farmacologia , Camundongos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/antagonistas & inibidores , Bloqueadores dos Canais de Sódio , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/fisiologia , Veratridina/farmacologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologiaRESUMO
1. This study describes the in vitro interaction of the muscarinic ligand McNeil-A-343 with two 5-hydroxytryptamine (5-HT) receptor subtypes, the 5-HT4 and 5-HT3 receptors, using functional as well as radioligand binding studies. 2. In the rat oesophageal muscularis mucosae, precontracted with carbachol, McNeil-A-343 was a competitive antagonist (pA2 6.2) of the 5-HT4 receptor which mediates the relaxation induced by 5-HT. The compound per se relaxed the oesophagus at high concentration only (> or = 10 microM), an effect unchanged by desensitization of the 5-HT4 receptor with 10 microM 5-methoxytryptamine. In the same preparation in the absence of tone, McNeil-A-343 displaced the carbachol concentration-response curve to the right, yielding an apparent affinity (pA2) of 4.9 for muscarinic receptors. 3. In the rat isolated superior cervical ganglion preparation, after blockade of muscarinic and nicotinic receptors, McNeil-A-343 caused a concentration-dependent depolarization that was unaffected by 100 nM ondansetron. The concentration-fast depolarization curve to 5-HT, mediated by the 5-HT3 receptor, was displaced to the right by McNeil-A-343, which showed an apparent affinity (pA2) of 4.8 for the 5-HT3 subtype. 4. In binding studies, McNeil-A-343 recognized a single population of 5-HT4 receptors in pig caudate nucleus, with a pKI of 5.9. The binding affinity of McNeil-A-343 for 5-HT3 receptors in NG 108-15 cells was approximately four times lower (pKI 5.3). Binding affinities (pKI) for muscarinic receptor subtypes in rat tissues were 5.3 (M1, cortex), 5.2 (M2, heart) and 4.9 (M3, submandibular glands), respectively. 5. McNeil-A-343 is an antagonist at 5-HT4 and 5-HT3 receptors; the interaction of the compound with these receptor subtypes (notably the 5-HT4) occurs in a range of concentrations which generally overlaps that relevant to the interaction with muscarinic receptors.
Assuntos
Cloreto de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamônio/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Cloreto de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamônio/metabolismo , Animais , Carbacol/farmacologia , Relação Dose-Resposta a Droga , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/metabolismoRESUMO
Alzheimer disease (AD) is a neurodegenerative disorder lacking an effective therapy. The etiology is controversial and among different drug strategies, the cholinergic approach has gained great interest owing to biochemical and pharmacological evidence of the crucial role of acetylcholine in cognitive functions. Several attempts exploiting the boosting of the cholinergic system are currently under way. Inhibitors of the acetylcholinesterase enzyme sustain the availability of the natural transmitter by limiting its removal from the synapse. In a different approach, exogenous agonists may substitute acetylcholine itself. In this way the issue of the extensive cholinergic cell loss occurring in AD and leading to a reduction of cholinergic functions, could be advantageously bypassed. Moreover the discovery of different muscarinic receptor subtypes, most notably the M1 subtype as that involved in the postsynaptic transmission, has offered new opportunities to face the problem in a very specific way. In this line of research, we have now identified BIMC 182 as a new functionally selective M1 agonist. Whereas its affinity for the different receptor subtypes is almost similar (radioreceptor binding), its functional selectivity is pointed out by specific "in vitro" models. BIMC 182 behaves as a full agonist at M1 (rat superior cervical ganglion, pD2 4.8) and as a partial agonist at M2 and M3 sites (g.p. heart pD2 = 5.4 and g.p. ileum pD2 = 4.5). The agonist profile is further confirmed in hm1 transfected CHO cells where the compound stimulates PI turnover. BIMC 182 penetrates well the brain as shown by the increase in the energy of the low frequency band (theta waves) in the cortical EEG of rabbits (3 mg/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Doença de Alzheimer/tratamento farmacológico , Agonistas Muscarínicos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Células CHO , Cricetinae , Feminino , Aprendizagem/efeitos dos fármacos , Masculino , Agonistas Muscarínicos/metabolismo , Agonistas Muscarínicos/uso terapêutico , Coelhos , Ratos , Receptores Muscarínicos/metabolismoRESUMO
We have investigated the in vivo motor stimulating and gastroprokinetic properties of the azabicycloalkyl benzimidazolone derivative BIMU 1 (3-ethyl-2,3-dihydro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-oxo-1H- benzimidazole-1-carboxamide hydrochloride) and its binding profile at 5-hydroxytryptamine3 and 5-hydroxytryptamine4 receptors, in an attempt to assess the serotonergic mechanism underlying its prokinetic action. BIMU 1 dose-dependently (0.01-0.3 mg/kg i.v.) increased the motility of a denervated pouch of canine stomach. This excitatory action was sensitive to muscarinic blockade. A similar stimulatory effect was exerted by the benzamidic prokinetic agent cisapride (0.03-0.3 mg/kg i.v.) but not by the 5-HT3 receptor antagonist ondansetron (up to 1 mg/kg i.v.). The significance for propulsive efficacy of the motor stimulating activity of BIMU 1 was evaluated in a model of gastric emptying of liquids in the conscious dog. The emptying rate of a non-caloric liquid meal instilled through a gastric fistula was accelerated by both BIMU 1 (0.01-1 mg/kg i.v. and 0.1-3 mg/kg p.o.) and cisapride (0.03-1 mg/kg i.v. and 0.3-10 mg/kg p.o.). Ondansetron (1 mg/kg i.v.) did not show any effect. The activity of the 5-HT4 receptor antagonist DAU 6285 was evaluated in the gastric emptying model per se and in interaction experiments on the accelerating action of BIMU 1 (0.3 mg/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Benzimidazóis/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes , Compostos Bicíclicos com Pontes/farmacologia , Antagonistas da Serotonina , Agonistas do Receptor de Serotonina/farmacologia , Estômago/efeitos dos fármacos , Animais , Antiulcerosos/farmacocinética , Antiulcerosos/farmacologia , Benzimidazóis/farmacocinética , Compostos Bicíclicos com Pontes/farmacocinética , Cisaprida , Cães , Relação Dose-Resposta a Droga , Feminino , Esvaziamento Gástrico/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Técnicas In Vitro , Masculino , Denervação Muscular , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Ondansetron/farmacocinética , Ondansetron/farmacologia , Piperidinas/farmacocinética , Piperidinas/farmacologia , Agonistas do Receptor de Serotonina/farmacocinética , Suínos , Células Tumorais CultivadasRESUMO
This study describes the antagonistic properties of himbacine, in comparison with those of pirenzepine, at muscarinic receptors mediating the depolarization of rat superior cervical ganglion, the inhibition of electrically-induced twitch contractions of rabbit vas deferens and the contraction of dog saphenous vein, currently classified as putative muscarinic M1 sites. The affinity of himbacine for the vas deferens site (pA2 8.08) was nearly ten times higher than those for the M1 receptors of rat ganglion and dog saphenous vein (pA2 7.14 and 7.16, respectively); affinity estimates for pirenzepine were similar throughout the different preparations. The present data are consistent with the allocation of ganglion and saphenous vein receptors into the M1 subclass; the profile of the vas deferens site, conversely, appears to be different, and possibly more closely related to that reported for the M4/m4 receptor.
Assuntos
Alcaloides/farmacologia , Parassimpatolíticos/farmacologia , Receptores Muscarínicos/metabolismo , Cloreto de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamônio/metabolismo , Cloreto de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamônio/farmacologia , Acetilcolina/metabolismo , Acetilcolina/farmacologia , Alcaloides/metabolismo , Animais , Ligação Competitiva , Cães , Feminino , Furanos , Masculino , Muscarina/análogos & derivados , Muscarina/metabolismo , Muscarina/farmacologia , Naftalenos , Parassimpatolíticos/metabolismo , Parassimpatomiméticos/metabolismo , Parassimpatomiméticos/farmacologia , Piperidinas , Pirenzepina/metabolismo , Pirenzepina/farmacologia , Coelhos , Ratos , Ratos Sprague-Dawley , Receptores Muscarínicos/efeitos dos fármacos , Veia Safena/efeitos dos fármacos , Veia Safena/metabolismo , Gânglio Cervical Superior/efeitos dos fármacos , Gânglio Cervical Superior/metabolismo , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/metabolismoRESUMO
The ability of WAL 2014 to elicit muscarinic responses was investigated in various in vitro and in vivo models. In CHO cells transfected with human m1- or m3- receptor genes, WAL 2014 was clearly more effective in stimulating the M1-mediated PI response. In isolated tissue preparations, WAL 2014 exhibited full agonist properties in the rabbit vas deferens (putative M1 receptor) and behaved like a partial agonist at M2 receptors in the atrium and M3 receptors in the ileum of guinea-pigs. In the pithed rat, in which the increase in blood pressure is mediated through a stimulation of M1 receptors in sympathetic ganglia, WAL 2014 produced a full dose response curve, whereas the reference compounds RS 86 and arecoline exhibited a bell-shaped behaviour. This is in accord with the view that WAL 2014 selectively activates M1 receptors in sympathetic ganglia, whereas conventional agonists in the same dose range stimulate both ganglionic M1 and vascular M3 receptors. The preferential neuron-stimulating properties were confirmed by EEG recording in the rabbit, in which muscarinic activation occurred at doses similar to those for ganglionic stimulation in the pithed rat. On the other hand, higher doses of WAL 2014 were needed to elicit muscarinic effects in peripheral effector organs, i.e. bradycardia, urinary bladder contraction and increase in airway resistance. It is concluded that WAL 2014 due to its preferential neuronal activity is a promising candidate for a cholinergic substitution therapy in Alzheimer's disease.
Assuntos
Neurônios/efeitos dos fármacos , Parassimpatomiméticos/farmacologia , Quinuclidinas/farmacologia , Animais , Células CHO , Cricetinae , Estado de Descerebração , Cães , Feminino , Cobaias , Hemodinâmica/efeitos dos fármacos , Masculino , Coelhos , Ratos , Receptores Muscarínicos/efeitos dos fármacos , TransfecçãoRESUMO
The antagonistic properties of DAU 6285, an azabicycloalkyl benzimidazolone derivative, at putative 5-hydroxytryptamine4 (5-HT4) receptors were investigated in in vitro preparations of guinea-pig ileum and human atrium, in comparison to ICS 205-930. DAU 6285 behaved as a competitive antagonist in all the preparations examined. Its affinity (pA2) ranged between 6.50 and 7.12 in the test models considered. The affinity of ICS 205-930 was 2-3 fold lower. At variance with ICS 205-930, DAU 6285 displayed a weak affinity for 5-HT3 receptors (pKi = 6.1, rat cortex; pA2 less than 5, guinea-pig ileum). In the guinea-pig ileum, DAU 6285 (10 microM) did not exert antimuscarinic, antihistaminic, antinicotinic or myolytic activity. Moreover, it did not bind to other 5-HT receptor subtypes, or to adrenergic, dopaminergic, benzodiazepine, nicotine, GABA receptors. DAU 6285 may represent a suitable tool for studies in the field of 5-HT4 receptors.
Assuntos
Benzimidazóis/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes , Compostos Bicíclicos com Pontes/farmacologia , Antagonistas da Serotonina , Animais , Cobaias , Humanos , Íleo/efeitos dos fármacos , Técnicas In Vitro , Indóis/farmacologia , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , TropizetronaRESUMO
The pharmacological profile of six representative members of a novel class of 5-HT3 receptor antagonists is described. The compounds are esters and amides of benzimidazolone-1-carboxylic acid with a basic azabicycloalkyl moiety (compounds 1-3) and their respective ethyl derivatives (compounds 4-6). In isolated preparations (rabbit heart and guinea pig ileum) all compounds antagonized the 5-HT3 receptor-mediated effects of serotonin, with potencies comparable with those of the reference compounds, ICS 205.930 and GR 38032F (-log IC50 9.30-11.9 and 6.8-8.20, in heart and ileum, respectively). In the anaesthetised rat, all agents potently inhibited the Bezold-Jarisch reflex whether given i.v. or i.d. I.v. administration of compounds prevented cisplatin-induced emesis in dogs (ID50 ranging from 3.7 to 147 micrograms/kg). All agents accelerated gastric emptying of solids in rats (ED50 about 10-160 micrograms/kg i.p.). In addition, compounds 4 and 5 were able to stimulate 5-HT4 receptors in the isolated guinea pig ileum, as well as enhance contractile activity in the Heidenhain gastric pouch of dogs, showing clearcut prokinetic properties.
Assuntos
Benzimidazóis/farmacologia , Antagonistas da Serotonina , Animais , Cisplatino/efeitos adversos , Cães , Relação Dose-Resposta a Droga , Feminino , Esvaziamento Gástrico/efeitos dos fármacos , Cobaias , Coração/efeitos dos fármacos , Íleo/efeitos dos fármacos , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Coelhos , Ratos , Ratos Endogâmicos , Serotonina/farmacologia , Estômago/efeitos dos fármacos , Vômito/induzido quimicamente , Vômito/prevenção & controleRESUMO
The antiemetic activity of DAU 6215, a novel antagonist of 5-HT3 receptors, was investigated in animal models of cytotoxic treatment-evoked emesis and compared with the antiemetic activity of ondansetron and metoclopramide. In dogs, vomiting was induced by i.v. cisplatin; in ferrets, the emetic response was elicited by i.v. doxorubicin or X-ray exposure. Pretreatment with 0.1-1 mg/kg DAU 6215 given i.v. or p.o. prevented the vomiting response to the different emetic agents. In the dog, the antiemetic potency of metoclopramide was 30 times lower than that of DAU 6215. Ondansetron was less potent than DAU 6215 against cisplatin and doxorubicin but was equally effective in the radiotherapy protocol. In this model, lengthening of the pretreatment time to 2 h did not affect the antiemetic efficacy of DAU 6215, whereas it decreased that of ondansetron. The results demonstrate that DAU 6215 is a highly effective and long-lasting inhibitor of cytotoxic treatment-induced emesis in different animal species.
Assuntos
Antieméticos/uso terapêutico , Benzimidazóis/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes , Compostos Bicíclicos com Pontes/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/radioterapia , Antagonistas da Serotonina/uso terapêutico , Animais , Cisplatino/efeitos adversos , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Avaliação Pré-Clínica de Medicamentos , Feminino , Furões , Imidazóis/uso terapêutico , Masculino , Metoclopramida/uso terapêutico , Neoplasias Experimentais/complicações , Ondansetron , Fatores de Tempo , Vômito/etiologia , Vômito/prevenção & controleRESUMO
The effect of the serotonin precursor 5-hydroxytryptophan (5-HTP) on jejunal migrating myoelectric complexes (MMCs) was investigated in conscious rats. Subcutaneous administration of low doses of 5-HTP (1-2 mg/kg) shortened the period between migrating complexes, whereas high doses of the compound (4-8 mg/kg) disrupted the MMC pattern. The serotonin (5-HT2) antagonist methysergide (8 mg/kg s.c.) did not alter basal MMC, neither did it prevent the effect of a low dose of 5-HTP; conversely, it antagonized the disruption due to the high dose. The 5-HT3 antagonist ICS 205-930 (30 micrograms/kg s.c.) decreased MMC frequency; administration of 2 mg/kg 5-HTP following ICS 205-930 brought the frequency of myoelectric complexes back to basal values. Both effects of 5-HTP were prevented by the decarboxylase inhibitor benserazide (85 mg/kg i.p.), which per se caused a transient inhibition of spiking activity. The results suggest that rat MMCs can be influenced in a composite fashion by progressively increasing concentrations of 5-HT, which in turn activate different receptor subtypes. A peripheral neuronal receptor, probably belonging to the 5-HT3 subclass, mediates the increase in MMC frequency observed after low doses of 5-HTP; higher levels of serotonin activate 5-HT2 receptors, causing disruption of cycling activity. Additionally, 5-HT3 receptors, but not 5-HT2, appear to be relevant for the regulation of the MMC pattern by the endogenous amine.
Assuntos
5-Hidroxitriptofano , Jejuno/fisiologia , Músculos/fisiologia , Receptores de Serotonina/fisiologia , Serotonina/fisiologia , Animais , Benserazida , Eletroencefalografia , Indóis , Jejuno/efeitos dos fármacos , Jejuno/inervação , Masculino , Metisergida , Músculos/efeitos dos fármacos , Músculos/inervação , Ratos , Ratos Endogâmicos , Antagonistas da Serotonina , TropizetronaRESUMO
An in vivo model for evaluating spasmolytic activity in the anaesthetized rat has been developed. A peculiarity of this model is the injection of parasympathetic agonists directly into the abdominal aorta. Acetylcholine and carbachol produced constant contractions of the ascending colon, while the cardiovascular system was affected only to a small extent. The contractions could be selectively antagonized by antimuscarinic drugs administered by either intravenous or intraduodenal route. Antagonists at other receptor systems were ineffective. The present procedure provides a reliable test model which mimics, in the rat, the technique of close intra-arterial injection of spasmogen feasible only in bigger animals.
Assuntos
Músculo Liso/efeitos dos fármacos , Parassimpatolíticos , Parassimpatomiméticos , Acetilcolina/farmacologia , Anestesia , Animais , Aorta Abdominal , Pressão Sanguínea/efeitos dos fármacos , Colo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Injeções Intra-Arteriais , Masculino , Contração Muscular/efeitos dos fármacos , Parassimpatomiméticos/administração & dosagem , Ratos , Ratos EndogâmicosRESUMO
The present study investigates the spasmolytic properties of cimetropium bromide, compared to atropine, on human and canine large bowel. The drug behaved as a competitive antagonist of muscarinic-mediated contractions in isolated colonic preparations from both species, with affinity values (pA2) ranging between 7.41 and 7.82. When administered intravenously to conscious dogs provided with a colonic Thiry fistula, cimetropium was a potent inhibitor of large bowel motility evoked by both exogenous and endogenous stimuli. The compound (10-100 micrograms/kg) counteracted colonic motor response to neostigmine administration with an ID50 of 27.9 micrograms/kg; both tonic and phasic components of contractile response were affected. In a comparable range of doses (3-100 micrograms/kg), the drug inhibited motor activity elicited by intraluminal distension.
Assuntos
Doenças do Colo/fisiopatologia , Derivados da Escopolamina/farmacologia , Espasmo/fisiopatologia , Animais , Cães , Motilidade Gastrointestinal/efeitos dos fármacos , Humanos , Técnicas In Vitro , Muscarina/antagonistas & inibidores , Neostigmina/farmacologia , Parassimpatolíticos , Estimulação Física , Reflexo/fisiologiaRESUMO
The role played by muscarinic receptor subtypes in the regulation of the migrating myoelectric complex was investigated in 7 dogs chronically implanted with bipolar electrodes along the small intestine. Pirenzepine (3-300 micrograms/kg i.v.) and atropine (1-30 micrograms/kg i.v.) were used as selective and unselective antagonist, respectively. Atropine (30 micrograms/kg) significantly delayed the onset of the next complex. On the contrary, pirenzepine displayed a biphasic action: low doses (less than 100 micrograms/kg) shortened the cycle period, whereas at 300 micrograms/kg the drug behaved like atropine. Pirenzepine affected the cycle period in the low-dose range by reducing the length of phase I. Both atropine and pirenzepine impaired the migration of the ongoing complex, and significantly reduced the migration velocity of the following one. These findings suggest that the initiation of the migrating myoelectric complex in the dog is under an inhibitory influence mediated by the M1 muscarinic receptor subtype; on the other hand, M2 receptor activation is needed for the onset of the activity front. Finally, both receptor subtypes determine the normal migration of phase III.
Assuntos
Intestino Delgado/fisiologia , Receptores Muscarínicos/fisiologia , Animais , Atropina/farmacologia , Cães , Eletrofisiologia , Feminino , Masculino , Pirenzepina/farmacologiaRESUMO
1. Intravenous injection of the muscarinic agonist, McN-A-343, in conscious dogs equipped with an ileal Thiry fistula produced a dose-related inhibition of intestinal phasic contractile activity, and an increase in heart rate. 2. The inhibitory action of McN-A-343 on motility was antagonized with different potencies by antimuscarinic drugs. The non-selective drug, N-methylatropine, blocked the McN-A-343 effect as well as the reflex phasic activity. The M1-selective compound, pirenzepine (1-30 micrograms kg-1), was a potent antagonist of the McN-A-343 effect, whereas the cardioselective M2-antagonist, AF-DX 116, and the smooth muscle selective compound, 4-diphenylacetoxy-N-methyl piperidine (4-DAMP), were completely ineffective at the doses tested. 3. The McN-A-343-induced inhibition of intestinal motility was blocked by locally applied lignocaine, suggesting the involvement of a neural inhibitory pathway. The resistance to hexamethonium and (alpha 1-, alpha 2- and beta-) adrenoceptor blocking drugs excluded transmission through a nicotinic synapse or release of catecholamines. 4. McN-A-343-induced tachycardia was also the result of muscarinic receptor activation. It was very sensitive to antagonism by 4-DAMP, while being completely unaffected by AF-DX 116. Pirenzepine displayed an intermediate profile, reducing tachycardia at doses fully active in reversing the agonist-mediated effect on intestinal motility. Propranolol partially reduced McN-A-343 tachycardia, suggesting catecholamine release. 5. The two McN-A-343 effects investigated in the present study appear to be mediated by different muscarinic receptor subtypes. While the inhibitory action on intestinal motility results from stimulation of Ml-muscarinic receptors, the tachycardia is mediated by receptors blocked selectively by 4-DAMP.
Assuntos
Cloreto de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamônio/farmacologia , Motilidade Gastrointestinal/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Compostos de Amônio Quaternário/farmacologia , Receptores Muscarínicos/análise , Animais , Cães , Feminino , Masculino , Antagonistas Muscarínicos , Receptores Muscarínicos/fisiologia , Receptores Nicotínicos/efeitos dos fármacos , Simpatolíticos/farmacologiaRESUMO
Parotid saliva secretion was studied in conscious dogs in which a chronic fistula of the parotid duct was provoked by a simple surgical procedure. To validate the technique employed, the responsiveness of the gland to various stimuli was examined. The volume of secretion was measured as well as the concentrations of Na+, K+ and calcium. Secretion was elicited by administering bethanechol i.v. or by feeding a meat meal. These stimuli, applied repetitively in the same animal, evoked reproducible secretory responses. In addition, the dose-response curve to bethanechol could also be constructed. The parotid secretion is controlled by muscarinic receptor activation, as illustrated by atropine blockade and its insensitivity to adrenergic drugs. The preparation is a versatile model which allows to investigate secretion evoked by both direct and reflex activation. The advantages of the preparation, which avoids invasive techniques, are accurate measurements and reproducible responses over long periods in a conscious animal.
Assuntos
Glândula Parótida/metabolismo , Saliva/metabolismo , Animais , Compostos de Betanecol/farmacologia , Cães , Relação Dose-Resposta a Droga , Feminino , Alimentos , Modelos Biológicos , Fístula das Glândulas Salivares , Simpatomiméticos/farmacologiaRESUMO
The effects of phentolamine, yohimbine and prazosin on laparotomy induced intestinal motor disturbances were studied in anaesthetised fasted rats previously equipped with electrodes, chronically implanted on the duodenum and jejunum. During continuous recording of interdigestive myoelectric activity, laparotomy under thiopental anaesthesia (Nesdonal 40 mg/kg ip) induced a primary phase of total inhibition of spiking activity lasting 26.1 +/- 1.3 min (mean +/- SE) followed by a period of disorganised activity, the first propagated migrating myoelectric complex (MMC) occurring 71.4 +/- 7.9 min after laparotomy. Phentolamine (3 mg/kg), or yohimbine (1 mg/kg) given im before laparotomy decreased by 48 and 49%, respectively, the duration of postsurgical inhibition, with a normal MMC pattern occurring immediately after. In contrast, there was only a shortening of the postlaparotomy initial inhibition of spiking activity after im prazosin (100 micrograms/kg), with a late (50-60 min) recovery of the MMC pattern. These results suggest that the initial inhibition of intestinal motility induced by laparotomy may involve alpha-1 and alpha-2 adrenoceptors, while the disruption of the MMC pattern is mainly caused by the activation of alpha-2 receptors.
Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Motilidade Gastrointestinal/efeitos dos fármacos , Animais , Sistema Digestório/efeitos dos fármacos , Fenômenos Fisiológicos do Sistema Digestório , Laparotomia , Masculino , Condução Nervosa/efeitos dos fármacos , Fentolamina/farmacologia , Prazosina/farmacologia , Ratos , Ratos Endogâmicos , Receptores Adrenérgicos/efeitos dos fármacos , Receptores Adrenérgicos/fisiologia , Ioimbina/farmacologiaRESUMO
The spasmolytic activity of N-Butyl Hyoscine (NBH) (1) has been investigated in conscious dogs provided with ileal or colonic Thiry fistulas in which motility was stimulated by intraluminal distension. In ileal motility experiments, phasic motility index (PMI), intestinal tonus, contraction frequency and heart rate were monitored. Intravenous administration of NBH (10 to 100 micrograms/kg) depressed PMI (ED50 35.1 micrograms/kg) and the other motility parameters. Heart rate increases were observed at 100 micrograms/kg. Application of NBH directly into the fistula (300 to 3000 micrograms/kg) caused a long-lasting, potent inhibition (31-72%) of PMI; tonus and contraction frequency were only slightly affected, while heart rate was not altered. When NBH was administered into an ileal fistula adjacent to the one from which motility was recorded, changes of PMI and other parameters were observed only after a massive dose of the drug (10000 micrograms/kg). In colonic fistula experiments, intraluminal NBH administration (300 to 3000 micrograms/kg) depressed colonic motility (39-59%), without affecting heart rate. It is concluded that NBH present in the intestine, although poorly absorbed, exerts local spasmolytic action.
Assuntos
Brometo de Butilescopolamônio/farmacologia , Colo/fisiologia , Motilidade Gastrointestinal/efeitos dos fármacos , Íleo/fisiologia , Parassimpatolíticos/farmacologia , Derivados da Escopolamina/farmacologia , Animais , Colo/efeitos dos fármacos , Cães , Feminino , Frequência Cardíaca/efeitos dos fármacos , Íleo/efeitos dos fármacos , Injeções Intravenosas , Masculino , Tono Muscular/efeitos dos fármacos , Fatores de TempoRESUMO
Cimetropium displaced 3H-NMS binding from membranes derived from gastrointestinal smooth muscle. The affinity of cimetropium for intestinal muscarinic receptors was in the range 70-100 nM. The competitive antagonism of cimetropium was demonstrated in guinea-pig ileum and taenia coli stimulated by bethanechol. Comparing pA2 values, cimetropium (8.19 and 7.91, resp.) was 0.3 times as potent as atropine (8.52 and 8.41, resp.). Cimetropium displayed strong inhibitory effects towards BaCl2 and 5-hydroxytryptamine induced contractions of the guinea-pig ileum. The compound was devoid of antihistaminic or Ca++ channel blocking activity. A binding study performed in vivo confirmed the ability of i.v. cimetropium to displace 3H-N-methylscopolamine binding from muscarinic receptors in peripheral organs. In addition, when injected into ileal loops, cimetropium displaced 3H-NMS binding solely from the surrounding tissue of the loop, indicating a topical effect of the compound.
Assuntos
Parassimpatolíticos/farmacologia , Derivados da Escopolamina/farmacologia , Animais , Cálcio/farmacologia , Colo/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Cobaias , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/metabolismo , Potássio/farmacologia , Ratos , Ratos Endogâmicos , Receptores Muscarínicos/efeitos dos fármacos , Receptores Muscarínicos/metabolismoRESUMO
The authors report the stimulatory effects provoked by caerulein on caecum and colon motilities in sheep which are quite opposite to those exerted by the same peptide on the forestomach and abomasal sections. By means of various pharmacological tools these effects are suggested to be attributable to a direct effect of caerulein on the smooth muscle of these viscera through the involvement of receptors different from those ones on which CCK may be antagonizable by proglumide or cGMP pretreatments.