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-propyl-amino-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 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 X 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 alpha 2-adrenergic receptor antagonist
yohimbine, whereas the DA receptor antagonist,
sulpiride, had no effect, suggesting an action initiated at alpha 2-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.(ABSTRACT TRUNCATED AT 250 WORDS)