The role of nitric oxide in long-term potentiation of the nicotinic pathway of synaptic transmission in the isolated superior cervical ganglia of rat was studied. Long-term potentiation was induced by a brief tetanizing pulse (tetanus, 20 Hz/20 s) to the preganglionic nerve. The amplitude of the extracellularly recorded postganglionic compound action potential was used as an index of synaptic transmission. Pretreatment with the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (10 microM) or L-N(G)-nitro-arginine (10 microM) 30 min before tetanus, inhibited long-term potentiation. The inactive enantiomer of the nitric oxide synthase inhibitor, N(G)-nitro-D-arginine methyl ester (10 microM), failed to inhibit the long-term potentiation when given 30 min before the tetanus. Washout of L-N(G)-nitro-arginine, but not N(G)-nitro-L-arginine methyl ester, resulted in complete recovery of long-term potentiation. The nitric oxide synthase inhibitor had no significant effect on the basal ganglionic neurotransmission or post-tetanic potentiation. Furthermore, established long-term potentiation was blocked by superfusion of ganglia with N(G)-nitro-L-arginine methyl ester 1 h after a tetanus. Pretreatment of ganglia with the nitric oxide donor, sodium nitroprusside (100 microM), or the nitric oxide synthase substrate, L-arginine (1 mM), completely prevented the inhibitory effects of N(G)-nitro-L-arginine methyl ester on the tetanus-induced long-term potentiation. These findings present evidence for a requirement of nitric oxide for the maintenance but not induction of long-term potentiation in rat isolated superior cervical ganglia.