Depletion of natriuretic peptide C receptors eliminates inhibitory effectsof C-type natriuretic peptide on evoked neurotransmitter efflux

Natriuretic peptides suppress evoked catecholamine efflux by a mechanism at tributed to activation of the natriuretic peptide receptor (NPR)-C, but thi s designation relies on the absolute specificity of truncated natriuretic p eptide 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 treatm ent suppressed NPR-C levels by 52 +/- 4% relative to missense treatment. Th e reduction of NPR-C levels suppressed evoked catecholamine efflux 33 +/- 6 % and eliminated the effect of C-type natriuretic peptide to suppress evoke d catecholamine efflux. The native peptide, C-type natriuretic peptide, red uced evoked catecholamine efflux 39 +/- 3% in cells with a normal complemen t of NPR-C. The NPR-C reduction failed 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 not prevent guanylyl cyclase activation in response to C-type natriuretic p eptide. These latter experiments indicate that the antisense treatment resu lted in a specific suppression of the NPR-C and did not affect alternative neuromodulatory pathways or guanylyl cyclase receptors. The novel aspects o f this study include both the inhibitory effect of NPR-C reduction on basal -evoked neurotransmitter efflux and the ablation of natriuretic peptide eff ects on neurotransmitter efflux by NPR-C reduction. The results are consist ent with the notion of a key signal-transducing role of the NPR-C in mediat ing inhibitory effects of natriuretic peptides on neurotransmitter efflux.