Inhibition of Insulin Release from Rat Pancreatic Islets by Drugs that Are Analogues of Dopamine

Various synthetic dopamine (DA) analogues have been shown to produce glucose intolerance and inhibit the compensatory increase in serum insulin during an oral glucose tolerance test (OGTT). To investigate the possibility that there is a direct action of dopamine analogues to inhibit glucose-stimulated insulin release from the endocrine pancreas, the following compounds were compared with the effects of epinephrine (EPI) on isolated rat pancreatic islets: apomorphine (APO), pergolide, lergotrile, TL-99 (2-dimethylamino-6,7-dihydroxytetralin), and RDS-127 (2-di-n-propylamino-4,7-dimethoxyindane). EPI, TL-99, and pergolide inhibited insulin release in a concentration-dependent fashion (10 ⁻⁷–10⁻⁵ M), whereas lergotrile inhibited at K)10⁻⁵ M but not at 10⁻⁶ M. RDS-127 and APO were ineffective at 10 ⁻⁵ M, but produced a greater than 50% inhibition at 2 × 10⁻⁴;M. The potencies of the DA analogues fell into two groups: compounds that are approximately as active as EPI (e.g., TL-99 and pergolide) or compounds that are relatively inactive (e.g., APO, lergotrile, and RDS-127). The inhibitory actions of EPI, TL-99, and pergolide were blocked by the α₂-adrenergic receptor antagonist yohimbine, whereas the DA receptor antagonist, sulpiride, had no effect, suggesting an action initiated at α₂-adrenergic receptors. Drugs from both groups produced marked glucose intolerance and inhibited the compensatory increase in insulin during an OGTT. Adrenodemedullation blocked the glucose intolerance and inhibition of insulin release caused by RDS-127, whereas these effects of TL-99 were not attenuated. These data, obtained in vitro and in vivo, show that selective dopamine agonists, such as RDS-127, reduce glucose-stimulated insulin release indirectly through adrenal medullary secretions, whereas the effect of less selective agonists, such as TL-99, directly inhibit the release of insulin from the endocrine pancreas.