EFFECT OF KAPPA-OPIOID AGONIST RU-51599 ON OSMOTIC AND NONOSMOTIC STIMULATED ARGININE-VASOPRESSIN RELEASE AND GENE-REGULATION IN SMALL-CELLLUNG-CARCINOMA CELLS

Arginine vasopressin (AVP) is synthesized in the hypothalamus, stored in the posterior pituitary, and osmotic and non-osmotic stimuli releas e AVP into the circulation for antidiuretic and vascular actions on ta rget tissue. The kappa-opioid agonist, RU 51599, exhibits a potent diu retic activity in both experimental animals and humans. This diuretic activity is characterized by a water diuresis without an associated in crease in electrolyte excretion. Studies with cultured rat hypothalamo -neurohypophysial system explant showed that AVP mRNA level changed in parallel to the RU 51599-induced changes in AVP secretory rate. There are, however, no hypothalamic neuronal cell lines to study AVP gene r egulation system, and it is not known whether RU 51599, regulates AVP secretion and biosynthesis under osmotic and non-osmotic stimulatory c onditions of AVP release. The effect of RU 51599 on AVP release, AVP m RNA, and AVP gene promoter activity in osmotic and non-osmotic conditi ons was therefore studied using cultured small cell lung carcinoma (SC LC) cell lines. RU 51599 significantly inhibited AVP release by osmoti c stimulation (330 mOsm) and non-osmotic stimulators, angiotensin II ( AII) and endothelin 3 (ET3). However, RU 51599 did not show any effect on the AVP mRNA and AVP gene promoter activity stimulated by high osm olality and ET3. These results indicate, therefore, that RU 51599 supp resses AVP secretion by inhibition at the step of AVP release during o smotic and non-osmotic stimulation but does not affect the AVP gene tr anscription level in the SCLC cells.