It previously has been reported in ischemic rat hearts that local release of
noradrenaline triggers
ventricular fibrillation via alpha1A-adrenoceptor stimulation. In order to elucidate the intracellular pathway mediating
ventricular fibrillation in this setting, we used inhibitors or activators of
protein kinase C in the absence or presence of the alpha1A-adrenoceptor antagonist
WB 4101. Regional
ischemia was induced in isolated perfused rat heart byligature of the left coronary artery. Pharmacological interventions were tested by addition of drugs to the perfusate 10 min prior to
ligature and throughout 30 min of
ischemia while the epicardial electrocardiogram was continuously monitored. Blockade of
protein kinase C by
polymyxin B (1 micromol/l) significantly reduced
ventricular fibrillation to 40% (from 87% in controls). Similar effects were seen with the
protein kinase C inhibitors
staurosporine 10 nmol/l (46% vs. 91%) and
cremophor RH 40 100 micromol/l (33% vs. 77%). Activation of
protein kinase C by
1,2-dioctanoyl-sn-glycerol (DOG, 10 micromol/l) or
phorbol 12-myristate 13-acetate (PMA, 10 nmol/l) did not affect
ventricular fibrillation. In the presence of the alpha1A-adrenoceptor antagonist
WB 4101 (0.1 micromol/l), which per se suppressed
ventricular fibrillation to 17%, both DOG and PMA increased the occurrence of
ventricular fibrillation to 73% and 75%, respectively, whereas the inactive
phorbol ester 4alpha-phorbol 12,13-didecanoate (4alpha-PDD, 10 nmol/l) revealed no proarrhythmic effect. In summary, during regional
ischemia in the isolated perfused rat heart, alpha1A-adrenoceptor stimulation induces
ventricular fibrillation mainly by activating
protein kinase C.