INFLUENCE OF PHORBOL ESTERS ON STIMULATION-INDUCED NORADRENALINE RELEASE AND CONTRACTILE-FORCE OF ISOLATED GUINEA-PIG ATRIA

Phorbol-12,13-dibutyrate (PDB) and phorbol-12-myristate-13-acetate (PMA) increased the field-stimulation-induced efflux of radioactivity from guinea-pig atria preloaded with 7-[H-3]-noradrenaline. The efflux was more than doubled by 10(-7) mol/l of either compound. Phorbol-12-myristate-13-acetate-4-O-methylether (PME), which has no effect on the protein kinase C (PKC), did not modify the stimulation-induced efflux of radioactivity, while a slight reduction was seen with 70-mu-M of the PKC inhibitor polymyxin B. In the presence of polymyxin B, the effects of PMA and PDB were greatly attenuated. In addition, PDB had a concentration-dependent negative inotropic effect (EC50 7,0 X 10(-10) mol/l). Pretreatment with polymyxin B shifted the concentration-response curve for PDB to the right (EC50 4,6 X 10(-9) mol/l). No negative inotropic effect was seen with PMA or PME. The results suggest that all effects of the phorbol esters were mediated by a stimulation of PKC. The different lipophilicity of PMA and PDB or a different influence on the various isozymes of PKC may account for the diverging postjunctional effects of the two compounds.