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Activity of selective dopamine DA1 and DA2 agonists and antagonists on experimental gastric lesions and gastric acid
1Department of Pharmacology, University of Manitoba, Faculty of Medicine, Winnipeg, Canada.
Abstract:
Selective dopamine (DA) DA1 and DA2 receptor agonists and antagonists were examined for their effects on cold-stress gastric lesions, 100% ethanol gastric lesions and basal gastric acid secretion. The selective DA1 agonist SKF 38393 [R-(+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol.HCl] attenuated cold-stress and ethanol lesions and blocked basal acid output. The protective effects of SKF 38393 were reversed by the cyclooxygenase inhibitors indomethacin, sodium meclofenamate, by the peripherally selective DA receptor antagonist domperidone and by the tissue sulfhydryl blocker, N-ethylmaleimide. The DA1 antagonist, SCH 23390, worsened lesion formation and augmented gastric acid secretion. N-0437 [S-(-)-2-N-propyl-N-2-thienylethylamino)-5-hydroxytetralin], a DA2 agonist, was less potent than SKF 38393 at reducing experimental gastric lesion formation, but slightly more potent at attenuating gastric secretion. The DA2 antagonist, eticlopride, was inactive in all models. Based upon these in vivo data, we suggest that: 1) the gut DA receptor may be of the DA1 subtype and 2) that activation of gut DA1 receptors produces gastroprotection by several mechanisms, at least one of which is by reducing gastric acid output.
Insights
Dopamine DA1 receptor activation protects the stomach from injury by reducing acid secretion. This effect is mediated by cyclooxygenase and sulfhydryl groups, suggesting a novel therapeutic target for gastroprotection.
Area of Science:
- Gastroenterology
- Pharmacology
- Neuroscience
Background:
- The role of dopamine receptors in gastric function is not fully understood.
- Dopamine (DA) receptors are implicated in various physiological processes, including gastrointestinal functions.
Purpose of the Study:
- To investigate the effects of selective dopamine DA1 and DA2 receptor agonists and antagonists on gastric lesions and acid secretion.
- To elucidate the specific dopamine receptor subtype involved in gastroprotection and its mechanisms.
Main Methods:
- In vivo studies using cold-stress and ethanol-induced gastric lesion models in rodents.
- Assessment of basal gastric acid secretion.
- Pharmacological interventions with selective DA1/DA2 agonists/antagonists, cyclooxygenase inhibitors, and sulfhydryl blockers.
Main Results:
- The selective DA1 agonist SKF 38393 attenuated both cold-stress and ethanol-induced gastric lesions and reduced basal gastric acid secretion.
- The protective effects of SKF 38393 were reversed by cyclooxygenase inhibitors, the peripheral DA receptor antagonist domperidone, and N-ethylmaleimide.
- The DA1 antagonist SCH 23390 exacerbated lesion formation and increased gastric acid secretion.
- The DA2 agonist N-0437 showed less potency in lesion reduction but was more potent in reducing gastric secretion compared to SKF 38393.
- The DA2 antagonist eticlopride had no effect in any model.
Conclusions:
- The gut dopamine receptor involved in gastroprotection is likely the DA1 subtype.
- Activation of gut DA1 receptors confers gastroprotection through multiple mechanisms, including the reduction of gastric acid output.
- These findings suggest that targeting gut DA1 receptors may offer a novel therapeutic strategy for managing gastric disorders.