Gastric antisecretory and antiulcer effects of WHR1582A, a compound exerting alpha-2 adrenoceptor agonist activity.
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.
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001241:Aspirin; D002217:Carbachol / Q000494:pharmacology; D003000:Clonidine / Q000494:pharmacology; D003543:Cysteamine; D017259:Dimaprit; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects*; D007213:Indomethacin; D008026:Ligation; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012110:Reserpine; D013276:Stomach Ulcer / Q000139:chemically induced; D013312:Stress, Physiological / Q000150:complications; D013890:Thiourea / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000897:Anti-Ulcer Agents; D010671:Phenylurea Compounds; D015016:Yohimbine; D003543:Cysteamine; C052029:1-(2,6-dimethylphenyl)-3-isobutoxyamidinourea; D012110:Reserpine; D002217:Carbachol; D013890:Thiourea; D003000:Clonidine; D001241:Aspirin; D009638:Norepinephrine; D007213:Indomethacin; D017259:Dimaprit