IMIDAZOLINES STIMULATE RELEASE OF INSULIN FROM RIN-5AH CELLS INDEPENDENTLY FROM IMIDAZOLINE I-1 AND I-2 RECEPTORS

The effect on insulin release of efaroxan, an alpha(2)-adrenoceptor an tagonist and a highly potent drug at imidazoline I-1 receptors, and th e effects of seven other imidazoline compounds selective for the imida zoline I-1 or I-2 receptors, were studied in the rat insulinoma cell l ine RIN-SAH. The cells released insulin in response to glucose (0.3-10 mM), and efaroxan (100 mu M) potentiated glucose-induced insulin rele ase. (-)-Adrenaline completely displaced the binding of [I-125]p-iodoc lonidine to membranes of RIN-SAH cells, indicating that these cells do not express imidazoline I-1 receptors. Cirazoline and idazoxan (100 m u M), both highly potent drugs at imidazoline I-2 receptors, and the g uanidines guanoxan and amiloride (200 mu M), also promoted insulin rel ease from RIN-SAH cells. Irreversible blockade of imidazoline I-2 rece ptors with 10 mu M clorgyline did not prevent the stimulatory effects of cirazoline or idazoxan; however, these compounds completely reverse d the inhibition by diazoxide (250 mu M), an opener of ATP-dependent K + channels (K-ATP(+) channels), of glucose-induced insulin release. Th ese data indicate that the imidazoline/guanidine compounds promote ins ulin release from RIN-SAH cells, by interacting with a novel binding s ite related to K-ATP(+) channels that does not represent any of the kn own imidazoline I-1 or I-2 receptors.