INHIBITION OF POTASSIUM-STIMULATED DOPAMINE RELEASE BY THE NITRIC-OXIDE GENERATOR ISOSORBIDE DINITRATE

In PC12 cells, isosorbide dinitrate (ISDN) and S-nitrosol-acetyl-penic illamine (SNAP), both nitric oxide (NO) generators, attenuated K+ (56 mM)-stimulated release of dopamine. The attenuation was not observed w ith isosorbide, an ISDN analog lacking NO generating capacity. In this model, A23187 (Ca2+ ionophore), Bay K8644 (Ca2+ slow channel agonist) and veratridine (Na+ channel agonist) stimulated dopamine release. Tr eatment with ISDN enhanced Bay K8644 and veratridine-evoked dopamine r elease, while ISDN had no significant effect on the A23187 response. I ncubation with 8-bromo-cGMP (membrane permeable cGMP analog) had no ef fect on basal or stimulated dopamine release in these cells, suggestin g NO's response was not mediated by cGMP. In additional studies, K+ (5 6 mM), Bay K8644 and veratridine elevated cytosolic free calcium level s ([Ca2+](i)). ISDN reduced K+-stimulated increase in [Ca2+](i), but e nhanced the increases of [Ca2+](i) induced by Bay K8644 or veratridine . These results suggest NO interacts with K+-induced membrane depolari zation (possibly by inhibiting membrane conductance to K+) to attenuat e Ca2+ influx and Ca2+-mediated dopamine secretion stimulated by K+.