Depletion of Natriuretic Peptide C Receptors Eliminates Inhibitory Effects of C-Type Natriuretic Peptide on Evoked Neurotransmitter Efflux

摘要

Natriuretir peptides suppress evoked catecholamine efflux by a mechanism attributed to ctivation of the natriuretic peptide receptor (NPR)-C,but this designation relies on the absolute specificity of trucncated natriuretic peptide analogs for the NPR-C. The NPR-C involvement in evoked catecholamine efflux was defined better in this study by selectively ablating the NPR-C in pheochromocytoma cells with antisense oligodeoxynucleotides. This treatment suppressed NPR-C levels by 52+-4% relative to missense treatment. The reduction of NPR-C levels suppressed evoked cataecholamine efflux 33+-6% and eliminated the effect of C-type natriuretic peptide to suppress evoked catecholamine efflux. The native peptide, C-type natriuretic peptide, reduced evoked catechloamine efflux 39+-3% in cell with a normal complement of NPR-C. The NPR-C reductionfailed to alter neuromodulatory effects of N-nitro-L-arginine methyl ester or an active fragment of the NPR-C receptor administered in permeabilized cells. Furthermore, the NPR-C reduction did nto prevent guanylyl cyclase activation in response to C-type natriuretic peptide. These latter experiments indicate that the antisens treatment resulted in a specific suppression of the NPR-C and did not affect alternative neuromodulatory pathways or guanylyl cyclase receptors. The novel aspects of this study include both the inhibitory effect of NPR-C reduction on basal-evoked neurotransmitter efflux and the ablation of natriuretic peptide effects on neurotransmitter efflux by NPR-C reduction. The results are consistent with the notion of a key signal-transducing role of the NPR-C in mediating inhibitory effects of natriuretic peptides on neurotransmitter efflux.