Gö 6983 exerts cardioprotective effects in myocardial ischemia/reperfusion.
Ischemia followed by reperfusion (I/R) in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac contractile dysfunction. Inhibiting protein kinase C (PKC) inhibits the release of superoxide from PMNs. The compound Gö 6983 is an inhibitor of all five PKC isoforms present in PMNs. Therefore, we hypothesized that Gö 6983 could attenuate PMN-induced cardiac dysfunction by suppression of superoxide production from PMNs. We studied isolated rat hearts following ischemia (20 minutes) and reperfusion (45 minutes) infused with activated PMNs. In hearts reperfused with PMNs and Gö 6983 (100 nM, n = 7), left ventricular developed pressure (LVDP) and the rate of LVDP (+dP/dt max) recovered to 89 +/- 7% and 74 +/- 2% of baseline values, respectively, at 45 minutes postreperfusion compared with I/R hearts (n = 9) receiving PMNs alone, which only recovered to 55 +/- 3% and 45 +/- 5% of baseline values for LVDP and +dP/dtmax, respectively (P < 0.01). Gö 6983 (100 nM) significantly reduced PMN adherence to the endothelium and infiltration into the myocardium compared with I/R + PMN hearts (P < 0.01), and significantly inhibited superoxide release from PMNs by 90 +/- 2% (P < 0.01). In the presence of PMNs, Gö 6983 attenuated post-I/R cardiac contractile dysfunction, which may be related in part to decreased superoxide production.
Peterman
Ellen E
EE
Department of Pathology, Philadelphia College of Osteopathic Medicine Philadelphia, Pennsylvania 19131-1694, USA.
Taormina
Philip
P
Harvey
Margaret
M
Young
Lindon H
LH
D000818:Animals; D002227:Carbazoles / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles; D008297:Male; D008301:Maleimides; D008954:Models, Biological; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism
C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; D002227:Carbazoles; D002316:Cardiotonic Agents; D007211:Indoles; D008301:Maleimides; D013481:Superoxides; D011493:Protein Kinase C