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1.
Indian J Exp Biol ; 2005 Feb; 43(2): 167-71
Artigo em Inglês | IMSEAR | ID: sea-60597

RESUMO

Nitric oxide (NO) is an important neurotransmitter in the gut and has been demonstrated to be a key physiological mediator of non-adrenergic non-cholinergic (NANC) relaxation of gastrointestinal smooth muscle. In the present study the effect of PDE 5 inhibitor sildenafil on the gastrointestinal function (gastric emptying and intestinal transit) has been demonstrated in mice. Sildenafil (0.5-2 mg/kg, po) did not alter the percent gastric emptying however, in higher doses (5, 10 and 30 mg/kg, po) it inhibited the gastric emptying. On acute administration (0.5-5 mg/kg, po) it did not alter the intestinal transit but in higher doses (10 and 30 mg/kg, p.o.) delayed the intestinal transit. Further, the inhibitory effect of sildenafil was significantly blocked by L-NAME (10 mg/kg, ip), a non-selective NOS inhibitor and methylene blue (1 mg/kg, ip), a guanylate cyclase inhibitor. These findings suggest the participation of NO-cGMP transduction pathway in the inhibitory effect of sildenafil (higher doses) on the gastrointestinal smooth muscles and its potential application in patients with nutcracker oesophagus, hypertensive lower oesophageal sphincter (LOS), achalsia and diabetic gastroparesis or colitis where there is a loss of nNOS.


Assuntos
Administração Oral , Animais , GMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Feminino , Esvaziamento Gástrico/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Masculino , Camundongos , Músculo Liso/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Piperazinas/farmacologia , Purinas , Transdução de Sinais/efeitos dos fármacos , Sulfonas
2.
Indian J Exp Biol ; 2004 Jun; 42(6): 567-9
Artigo em Inglês | IMSEAR | ID: sea-63185

RESUMO

Biliary, ureteric and intestinal colic are extremely common clinical conditions associated with smooth muscle spasm. In the present study, antispasmodic activity was carried out against acetylcholine (10-640 ng/ml)-induced contractions on guinea pig ileum. Acetylcholine (10-640 ng/ml) induced concentration-dependent contraction of smooth muscle. Diclofenac, in varying concentration (9.4 x 10(-5) mol/l and 14.1 x 10(-5) mol/l) shifted the concentration response curve of acetylcholine to the right without suppressing the maximal response. However, in higher concentration diclofenac (18.9 x 10(-5) mol/l) blocked the response in an unsurmountable fashion. Further, analgin (11.09 x 10(-5), 16.63 x 10(-5) and 22.18 x 10(-5) mol/l) in equimolar concentrations did not alter the concentration response curve of acetylcholine, but in higher concentration analgin (44.36 x 10(-5) mol/l) also blocked the response in an unsurmountable fashion. Pitofenone (2.5 x 10(-6) mol/l) also, shifted the concentration response curve of acetylcholine to right in a parallel fashion with no change in maximal response. The present study confirms the potent antispasmodic activity of diclofenac-pitofenone combination in comparison to analgin-pitofenone in molar equivalent concentration (in comparison to diclofenac) against acetylcholine-induced contractions of guinea pig ileum.


Assuntos
Acetilcolina/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Benzofenonas/farmacologia , Colinérgicos/metabolismo , Diclofenaco/farmacologia , Dipirona/farmacologia , Relação Dose-Resposta a Droga , Feminino , Cobaias , Íleo/efeitos dos fármacos , Masculino , Contração Muscular , Músculo Liso/efeitos dos fármacos , Parassimpatolíticos/farmacologia , Espasmo/tratamento farmacológico
3.
Indian J Exp Biol ; 2004 Apr; 42(4): 361-7
Artigo em Inglês | IMSEAR | ID: sea-59881

RESUMO

Acetylcholine and cholinomimetic agents with predominant muscarinic action are known to increase the concentration of cGMP by activation of nitric oxide signaling pathway in the nociceptive conditions. The present study was aimed to investigate the NO-cGMP-PDE5 pathway in nociceptive conditions in the experimental animals. Nociceptive threshold was assessed by acetic acid-induced writhing assay (chemonociception) or carrageenan-induced hyperalgesia. Sildenafil [1-5 mg/kg, ip, 50-200 microg/paw, intraplantar (ipl)] produced dose dependent antinociception in both the tested models. Coadministration of acetylcholine (50 mcg/paw, ipl) or cholinomimetic agent, neostigmine (0.1 mcg/kg, ip and 25 ng/paw, ipl) augmented the peripheral antinociceptive effect of sildenafil. This effect was sensitive to blockade by L-NAME (20 mg/kg, ip, 100 microg/paw, ipl), a non-selective NOS inhibitor and methylene blue (1 mg/kg, ip), a guanylate cyclase inhibitor, which per se had little or no effect in both the models of nociception. Further, the per se analgesic effect of acetylcholine and neostigmine was blocked by both L-NAME and methylene blue in the models of nociception, suggesting the activation of NO-cGMP pathway. Also, both L-NAME and methylene blue blocked the per se analgesic effect of sildenafil. These results indicate the peripheral accumulation of cGMP may be responsible for antinociceptive effect, and a possible interaction between cholinergic agents and PDE5 system in models of nociception.


Assuntos
3',5'-GMP Cíclico Fosfodiesterases/metabolismo , Ácido Acético/farmacologia , Acetilcolina/farmacologia , Animais , Carragenina/farmacologia , Colinérgicos/metabolismo , Inibidores da Colinesterase/farmacologia , GMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Inibidores Enzimáticos/farmacologia , Feminino , Guanilato Ciclase/antagonistas & inibidores , Hiperalgesia/induzido quimicamente , Masculino , Azul de Metileno/farmacologia , Camundongos , NG-Nitroarginina Metil Éster/farmacologia , Neostigmina/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Dor/induzido quimicamente , Medição da Dor , Inibidores de Fosfodiesterase/farmacologia , Piperazinas/uso terapêutico , Purinas , Ratos , Sulfonas
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