The influence of oxidative stress on agonist-stimulated changes of intracellular free calcium and inositol trisphosphate in the neurosecretory PC12 cell line was investigated. The oxidant H2O2 modulated the bradykinin-induced calcium signal by decreasing the initial peak and the plateau phase in the same manner as tetraphorbolacetate, an activator of protein kinase C. Inositol trisphosphate formation, induced by bradykinin was also decreased by oxidative stress. Thiol protecting agents were able to restore the altered signal. In contrast to this, radical quenching substances had no influence on calcium signals in stressed cells. Inhibitors of several protein kinases, such as protein kinase C, protein kinase A, or cyclic GMP-dependent protein kinase showed the ability to protect the plateau phase of calcium signals against oxidative stress, but not the peak response. These results indicate that under the influence of oxidative stress multiple targets within the signal transduction cascades are affected.