Chelerythrine, a potent inhibitor of protein kinase C, was evaluated for its effect on cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aorta. Chelerythrine activated basal PDE2 and inhibited activated PDE2, PDE4 and PDE5. The effect of chelerythrine (10 microM) was also investigated on vasorelaxation induced by a beta-adrenoceptor agonist or a PDE3 inhibitor. Chelerythrine attenuated the isoprenaline-mediated relaxation whereas it potentiated the relaxation induced by SK & F 94120 (5-(4)acetamidophenyl)pyrazin-2(1 H)-one, a PDE3 inhibitor). The present study demonstrates that chelerythrine, at a concentration generally reported in the literature to inhibit protein kinase C, interacts with cyclic nucleotide phosphodiesterases and consequently modulates vasorelaxation. These results cast some doubt on the use of chelerythrine as a specific inhibitor of protein kinase C.