Polymyxin B, a protein kinase C inhibitor, abolishes preconditioning-induced protection against contractile dysfunction in the isolated blood perfused rat heart.
The aims of this study were (1) to determine the characteristics of preconditioning against contractile dysfunction in a blood perfused isolated heart model in the presence of a physiologic combination of substrates, and (2) to determine if protein kinase C (PKC) is involved in preconditioning in this model. In order to investigate these aims, isolated isovolumic, blood perfused rat hearts (balloon-in-LV, n = 6/group) were perfused normoxically for 30 min and then divided into three groups and subjected to: (1) a further 30 min of perfusion (control group) (2) a further 20 min of perfusion + 5 min of ischaemia and 5 min of reperfusion (1 x preconditioned group) and (3) 3 x (5 min of ischaemia+5 min of reperfusion) (3 x preconditioned group). All hearts were then subjected to 30 min of ischaemia and 30 min of reperfusion. Contractile function, myocardial oxygen consumption (MVO2), lactate release and creatine kinase release were all assessed. To determine if PKC is involved in the mechanism of preconditioning in this model, the control and 3 x preconditioned group experiments were repeated in the presence of polymyxin B (50 microM), a relatively specific PKC inhibitor. Final recovery of LVDP was 31 +/- 12, 67 +/- 6 and 60 +/- 5% in the control, 1 x and 3 x preconditioned groups, respectively. Protection of contractile function was accompanied by both a preservation of diastolic function and the ratio of MVO2 to contractile function (ratio of metabolic:mechanical efficiency). However, lactate release was decreased only in the 3 x preconditioned group. Polymyxin B abolished preconditioning-induced protection against contractile and diastolic dysfunction and the protection of the ratio of MVO2 to contractile function. Lactate release was still however reduced in the polymyxin B-preconditioned group. Thus, preconditioning-induced protection against contractile dysfunction appears to be accompanied by a preservation of both diastolic function and the metabolic: mechanical efficiency and is effective in the presence of a physiologic combination of substrates. However, limitation of glycolysis during ischaemia, as assessed by lactate release, appears to be an epiphenomenon of the preconditioning protocol and is not consistently related to protection. PKC activation appears to be pivotal to the mechanism of protection against contractile dysfunction, since administration of polymyxin B abolished any protection.
Cave
A C
AC
Cardiac Muscle Research Laboratory, Boston University School of Medicine, MA 02118, USA.
Apstein
C S
CS
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology*; D010101:Oxygen Consumption; D011113:Polymyxins / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D011113:Polymyxins; D011493:Protein Kinase C