Natriuretic peptides suppress adrenergic neurotransmission by a mechanism sensitive to pertussis toxin, suggesting that GTP-binding proteins are involved in the response. The major GTP-binding proteins present in the pheochromocytoma (PC12) cells used in this report are Go alpha and Gi alpha2. We tested the hypothesis that the more abundant GTP-binding protein, Go alpha, mediates natriuretic peptide effects in PC12 cells by selectively ablating Go alpha from the cells with antisense oligodeoxynucleotides. The results indicate that a selective ablation of Go alpha with this technique eliminated C-type natriuretic peptide (CNP) effects and suppressed dopamine efflux evoked by a depolarizing stimulus. However, the activation of guanylyl cyclase (GC) by CNP was sustained after the Go alpha ablation. Further, Nomega-nitro-L-arginine methyl ester suppressed evoked dopamine efflux equally in the presence and absence of Go alpha. These results suggest that CNP attenuates evoked catecholamine efflux from PC12 cells by a mechanism requiring Go alpha but independent of GC activation. (Hypertension. 1999;33:124-129.).