Phorbol ester-induced ventricular fibrillation in the Langendorff-perfused rabbit heart: antagonism by staurosporine and glibenclamide.
Using a paced Lagendorff-perfused rabbit heart paradigm, we investigated the role of protein kinase C (PKC) in the development of ventricular fibrillation (VF) in hearts subjected to hypoxia (12 min) and re-oxygenation (40 min). We studied the effect of putative activators and inhibitors of PKC on the incidence of VF. Hearts exposed to 4 beta-phorbol,12,13-dibutyrate (PDBu), isophorbol or the membrane permeant diacylglycerol analog, 1-oleoyl-2-acetyl-rac-glycerol (OAG), during the prehypoxic phase had an increased incidence of VF during the hypoxic and reoxygenation periods. The incidence of VF was 90%, 83% and 75% in hearts exposed to PDBu, isophorbol and OAG, respectively (P < 0.05 vs control). Perfusion of hearts with PDBu was associated with a significant increase in the membrane fraction of cardiac PKC activity. In the presence of the inactive phorbol ester 4 alpha-phorbol didecanoate, the incidence of VF was 17% (P > 0.05 vs control). PKC activators were profibrillatory at concentrations that did not affect cardiac function: neither left ventricular developed pressure nor coronary perfusion pressure were affected. The effect of PDBu was antagonized by staurosporine: the incidence of VF was 17% in PDBu+staurosporine treated hearts (P < 0.05 vs control). To further study the profibrillatory effect of PDBu, hearts were exposed to PDBu in the presence of the ATP-dependent potassium channel antagonist glibenclamide. The latter prevented PDBu-induced VF. The results show that under the conditions employed, PDBu-induced activation of PKC induces redistribution of PKC activity and is associated with the development of VF.
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University of Michigan Medical School, Ann Arbor 48109-0626.
Fagbemi
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Chi
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Friedrichs
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Lucchesi
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D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D004075:Diglycerides / Q000633:toxicity; D005905:Glyburide / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D010477:Perfusion; D015240:Phorbol 12,13-Dibutyrate / Q000633:toxicity*; D010703:Phorbol Esters / Q000633:toxicity; D010704:Phorbols / Q000633:toxicity; D020110:Pinacidil; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011817:Rabbits; D019311:Staurosporine; D014693:Ventricular Fibrillation / Q000139:chemically induced* / Q000517:prevention & control
D000470:Alkaloids; D004075:Diglycerides; D006146:Guanidines; D007546:Isoquinolines; D010703:Phorbol Esters; D010704:Phorbols; D010879:Piperazines; C008876:phorbol-12,13-didecanoate; D015240:Phorbol 12,13-Dibutyrate; D020110:Pinacidil; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C038237:1-oleoyl-2-acetylglycerol; D011493:Protein Kinase C; D019311:Staurosporine; D005905:Glyburide; C033085:phorbol