RESUMO
The gastric antisecretory and antiulcer effects of a novel compound, [1-(2,-dimethylphenyl)-3-isobutoxyamidinourea]hydrochloride (WHR1582A), are described. WHR1582A was active in preclinical ulcer models induced by 18-hr pylorus ligation, aspirin, indomethacin, reserpine, stress or cysteamine. WHR1582A inhibited acid secretion in the pylorus-ligated rat and in the anesthetized, lumen-perfused rat. The antisecretory effects of WHR1582A were antagonized by yohimbine, RX781094A and phentolamine. Propranolol, prazosin, corynanthine, methysergide, sulpiride and pimozide were unable to block its activity. WHR1582A blocked acid secretion stimulated by 2-deoxy-D-glucose but was inactive against the direct parietal cell stimulants carbachol and dimaprit. WHR1582A also inhibited electrically stimulated contractions that were mediated via the vagus in the isolated rat stomach preparation. The antisecretory activity of WHR1582A was not due to a reduction in gastric mucosal blood flow. These results demonstrate that WHR1582A is an effective antiulcer-antisecretory agent that exerts its gastric effects through the activation of alpha-2 adrenoceptors located presynapitcally on the vagus.
Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Antiulcerosos/farmacologia , Ácido Gástrico/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Animais , Aspirina , Carbacol/farmacologia , Clonidina/farmacologia , Cisteamina , Dimaprit , Indometacina , Ligadura , Masculino , Contração Muscular/efeitos dos fármacos , Norepinefrina/farmacologia , Ratos , Ratos Endogâmicos , Reserpina , Úlcera Gástrica/induzido quimicamente , Estresse Fisiológico/complicações , Tioureia/farmacologia , Ioimbina/farmacologiaRESUMO
1-(2,6-Dimethylphenyl)-3-methylamidinourea hydrochloride (WHR-1142A), lidamidine hydrochloride), a novel antidiarrheal agent, inhibited contractile activity in isolated guinea pig ileum stimulated by acetylcholine, histamine, serotonin, dimethylphenylpiperazinium, prostaglandin E2, BaCl2 and KCl. WHR-1142A also blocked spontaneous and stimulated contractile activity measured with extraluminal strain gauges in the duodenum, ileum and colon of dogs. Studies on the autonomic effects of WHR-1142A indicated little, if any, peripheral adrenergic stimulatory or cholinergic blocking activity. Inhibition of intestinal motility by WHR-1142A was not antagonized by naloxone. WHR-1142A also showed no morphine-like analgesic effects and was devoid of any H1-antihistamine activity. WHR-1142A appears to be a pharmacologically unique antidiarrheal agent.
Assuntos
Amidinas/farmacologia , Antidiarreicos/farmacologia , Analgésicos , Animais , Fármacos do Sistema Nervoso Autônomo , Difenoxilato/farmacologia , Cães , Duodeno/efeitos dos fármacos , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Cobaias , Antagonistas dos Receptores Histamínicos H1 , Liberação de Histamina/efeitos dos fármacos , Íleo/efeitos dos fármacos , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Naloxona/farmacologia , CoelhosRESUMO
1-(2,6-Dimethylphenyl)-3-methyl-amidinourea hydrochloride (WHR-1142A, lidamidine hydrochloride) was shown to have potent antimotility, antidiarrheal and intestinal antisecretory activity in mice, rats and dogs. Antimotility activity was demonstrated in charcoal intestinal motility, gastric emptying and gastric and intestinal intraluminal pressure studies. Antidiarrheal activity was evaluated in castor oil-, prostaglandin E2-, carbachol-, and serotonin-induced diarrhea. Intestinal secretion induced by cholera toxin was inhibited by WHR-1142A. In general, WHR-1142A was more potent than diphenoxylate and loperamide although species differences were noted. The ED50 for inhibition of castor oil-induced diarrhea was 1.8 mg/kg p.o. and the duration of action at 16 mg/kg p.o. was at least 6 h. Unlike diphenoxylate, WHR-1142A showed no tolerance.
