Differential response of A 68930 and sulpiride in stress-induced gastric ulcers in rats.
Dopamine is linked to gastrointestinal functions. However, its exact nature in stress-induced gastric pathology is still not clear. In the present study, an attempt has been made to identify the effects of dopamine in stress-induced gastric ulcers, and concurrent alterations in various ulcer-influencing factors such as plasma corticosterone levels, gastric mucosal PGE(2) content and proton pump activity. The dopamine D(1) receptor agonist (A 68930) and antagonist (SCH 23390), and D(2) receptor agonist (quinpirole) and antagonist (sulpiride) were used to evaluate their effects on acute stress (single immobilization for 150 min) and chronic unpredictable stress (two different types of stressors for 7 days) induced gastric ulcers in rats. Acute and chronic unpredictable stress significantly increased the gastric ulcer severity, adrenal hypertrophy and corticosterone levels, while gastric mucosal dopamine levels were decreased. Pretreatment of sulpiride (60 mg/kg) significantly reverted the acute stress-induced alterations, while A 68930 (0.25mg/kg) significantly restored the acute and chronic unpredictable stress-induced alterations. In contrast, administration of SCH 23390 (0.1-0.5mg/kg) and quinpirole (0.1-0.5mg/kg) failed to alter acute stress-induced alterations. Further, A 68930 and sulpiride showed different response on proton pump inhibition under in-vitro condition. A 68930 (10-50 microg/ml) inhibited the gastric H(+) K(+)-ATPase activity comparable to positive control omeprazole, while sulpiride (10-50 microg/ml) had no effect. A 68930 also normalized the decreased gastric PGE2 content observed during chronic unpredictable stress. The histopathological evaluation of gastric mucosal tissue supported the observations regarding the gastroprotective effect of sulpiride during acute stress and of A 68930 during both acute and chronic unpredictable stress conditions. Our results provide important insights into the mechanism of dopamine-regulated pathways, which cause an overall pathophysiology of gastric stress ulcers and implicating the importance of D(1) agonist in ulcer protection. Thus, current study highlights the need to evaluate anti-stress and anti-ulcer agents in terms of their ability to modulate dopaminergic transmissions.
Rasheed
Naila
N
Division of Pharmacology, Central Drug Research Institute, C.S.I.R. P.B. No. 173, Lucknow 226001, India.
Ahmad
Ausaf
A
Singh
Neetu
N
Singh
Pratibha
P
Mishra
Vaibhav
V
Banu
Naheed
N
Lohani
Mohtashim
M
Sharma
Sharad
S
Palit
Gautam
G
D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002839:Chromans / Q000494:pharmacology* / Q000627:therapeutic use; D003345:Corticosterone / Q000097:blood; D015232:Dinoprostone / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D005753:Gastric Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D008297:Male; D009929:Organ Size / Q000187:drug effects; D017494:Proton Pumps / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D012149:Restraint, Physical; D013276:Stomach Ulcer / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D013315:Stress, Psychological / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D013469:Sulpiride / Q000494:pharmacology*
D002839:Chromans; D065127:Dopamine D2 Receptor Antagonists; D017494:Proton Pumps; D017447:Receptors, Dopamine D1; D013469:Sulpiride; C065380:A 68930; D017506:H(+)-K(+)-Exchanging ATPase; D015232:Dinoprostone; D003345:Corticosterone