When isolated rat islets were cultured for 18 h prior to use, the putative
imidazoline binding site
ligand,
RX871024 caused a dose-dependent increase in insulin secretion at both 6 mM and 20 mM
glucose. By contrast, a second
ligand,
efaroxan, was ineffective at 20 mM
glucose whereas it did stimulate insulin secretion in response to 6 mM
glucose. Exposure of islets to
RX871024 (50 microM) for 18 h, resulted in loss of responsiveness to this
reagent upon subsequent re-exposure. However, islets that were unresponsive to
RX871024 still responded normally to
efaroxan. The
imidazoline antagonist,
KU14R, blocked the
insulin secretory response to
efaroxan, but failed to prevent the stimulatory response to
RX871024. By contrast with its effects in cultured islets,
RX871024 inhibited
glucose-induced
insulin release from freshly isolated islets.
Efaroxan did not inhibit insulin secretion under any conditions studied. In freshly isolated islets, the effects of
RX871024 on insulin secretion could be converted from inhibitory to stimulatory, by
starvation of the animals. Inhibition of insulin secretion by
RX871024 in freshly isolated islets was prevented by the
cyclo-oxygenase inhibitors indomethacin or
flurbiprofen. Consistent with this,
RX871024 caused a marked increase in islet
PGE2 formation.
Efaroxan did not alter islet
PGE2 levels. The results suggest that
RX871024 exerts multiple effects in the pancreatic beta-cell and that its effects on insulin secretion cannot be ascribed only to interaction with a putative
imidazoline binding site.