1. The whole cell patch clamp was used to measure calcium current in isolated chick sympathetic ganglion neurons. Previous results showed that somatostatin inhibits calcium currents (ICa) in a voltage-dependent manner. The effect of somatostatin rapidly desensitizes. In addition, the action of somatostatin on the calcium current is inhibited by activation of protein kinase C (PKC). Because substance P (SP) has been shown to activate PKC in the chick sympathetic neurons, we here test the effects of SP on the calcium current and on the modulatory action of somatostatin. 2. At a concentration of 1 microM, SP had small, variable effects on ICa. 3. SP in the presence of guanosine 5'-triphosphate-gamma-S, or at higher concentrations (10 microM), inhibited ICa in a voltage-dependent manner, similar to the action of somatostatin. 4. Rather than inhibiting the action of somatostatin, SP (1 microM) potentiated the response to somatostatin. This effect of SP was only observed after the response to somatostatin had partially desensitized. SP had no effect on nondesensitized responses to somatostatin. 5. Desensitization of the somatostatin response involved a shift in its dose-response curve toward higher somatostatin concentrations as well as a decrease in the maximal response. SP appears to counteract the shift of the dose-response curve selectively. 6. The potentiation of the somatostatin response by SP is blocked by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), but not by Calphostin C, Compound 5, k252a, protein kinase C (PKC)19-36, or adenylyl-imidodiphosphate (AMP-PNP), suggesting that phosphorylation is not involved and that the H-7 action does not depend on kinase inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)