In enteric synaptosomes of the rat the role of voltage-dependent Ca²⁺-channels (VDCCs) in K⁺-induced VIP release and nitric oxide synthesis was investigated. Basal VIP release was 39 ± 4 pg/mg and cofactor-substituted NOS activity was 7.0 ± 0.8 fmol/mg/min. K⁺-depolarization (65 mM) stimulated VIP release Ca²⁺-dependently (basal: 100%, K⁺: 172.2 ± 16.2%, P<0.05, n=5). K⁺-stimulated VIP release was reduced by blockers of the P-type (-agatoxin-IVA, 5 x 10^-8M) and N-type (-conotoxin-GVIA, 10^-6 M) Ca²⁺ channel by about 50 and 25%, respectively, but not by blockers of the L-type (isradipine, 10^-8 M), Q-type (-conotoxin-MVIIC, 10^-6 M) or T-type (Ni²⁺, 10^-6 M) Ca²⁺ channel. In contrast, NO synthesis was suppressed by -agatoxin-IVA, -conotoxin-GVIA and isradipine by about 79%, 70% and 70%, respectively, whereas Ni²⁺ and -conotoxin-MVIIC had no effect. These findings are suggestive of a coupling of depolarization-induced VIP release primarily to the P-, and N- type Ca²⁺ channel, whereas NO synthesis is presumably dependent on Ca²⁺ influx not only via the P-, N- but also via the L-type Ca²⁺ channel. In contrast, none of the Ca²⁺ channel blockers affected VIP release evoked by exogenous NO, suggesting that NO induces VIP secretion by a different mechanism presumably involving intracellular Ca²⁺ stores.