Ischemia-induced ventricular fibrillation in isolated perfused rat heart: role of alpha1A-adrenoceptor mediated activation of protein kinase C.
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.
Tölg
R
R
Medizinische Klinik II, Universitätsklinikum Lübeck, Germany. toelg@t-online.de
Schreieck
J
J
Kurz
T
T
Katus
H A
HA
Richardt
G
G
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications*; D010477:Perfusion; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D014693:Ventricular Fibrillation / Q000209:etiology* / Q000517:prevention & control
D000317:Adrenergic alpha-Antagonists; D004791:Enzyme Inhibitors; D011942:Receptors, Adrenergic, alpha; D011493:Protein Kinase C