Ischemia-induced ventricular fibrillation in isolated perfused rat heart: role of alpha(1A)-adrenoceptor mediated activation of protein kinase C

It previously has been reported in ischemic rat hearts that local release o f noradrenaline triggers ventricular fibrillation via alpha (1A)-adrenocept or stimulation. In order to elucidate the intracellular pathway mediating v entricular fibrillation in this setting, we used inhibitors or activators o f protein kinase C in the absence or presence of the alpha (1A)-adrenocepto r antagonist WB 4101. Regional ischemia was induced in isolated perfused ra t heart by ligature of the left coronary artery. Pharmacological interventi ons were tested by addition of drugs to the perfusate 10 min prior to ligat ure and throughout 30 min of ischemia while the epicardial electrocardiogra m was continuously monitored. Blockade of protein kinase C by polymyxin B ( 1 mu mol/l) significantly reduced ventricular fibrillation to 40% (from 87% in controls). Similar effects were seen with the protein kinase C inhibito rs staurosporine 10 nmol/l (46% vs. 91%) and cremophor RH 40 100 mu mol/l ( 33% vs. 77%). Activation of protein kinase C by 1,2-dioctanoyl-sn-glycerol (DOG, 10 mu mol/l) or phorbol 12-myristate 13-acetate (PMA, 10 nmol/l) did not affect ventricular fibrillation. In the presence of the alpha (1A)-adre noceptor antagonist WE 4101 (0.1 mu mol/l), which per se suppressed ventric ular fibrillation to 17%, both DOG and PMA increased the occurrence of vent ricular fibrillation to 73% and 75%, respectively, whereas the inactive pho rbol ester 4alpha-phorbol 12,13-didecanoate (4 alpha -PDD, 10 nmol/l) revea led no proarrhythmic effect. In summary, during regional ischemia in the is olated perfused rat heart, alpha (1A)-adrenoceptor stimulation induces vent ricular fibrillation mainly by activating protein kinase C.