These results provide evidence that HMG-CoA reductase inhibitors are potent and effective cardioprotective agents that inhibit leukocyte-endothelial cell interactions and preserve cardiac contractile function and coronary perfusion after myocardial ischemia and reperfusion. Moreover, these effects are unrelated to the cholesterol-lowering action of this agent and appear to be mediated by enhanced endothelial release of NO.

In the present study, the cardioprotective effects of insulin-like growth factor I (IGF-I) were examined in a murine model of myocardial ischemia reperfusion (i.e., 20 min + 24 hr). IGF-I (1-10 micrograms per rat) administered 1 hr prior to ischemia significantly attenuated myocardial injury (i.e., creatine kinase loss) compared to vehicle (P < 0.001). In addition, cardiac myeloperoxidase activity, an index of neutrophil accumulation, in the ischemic area was significantly attenuated by IGF-I (P < 0.001). This protective effect of IGF-I was not observed with des-(1-3)-IGF-I. Immunohistochemical analysis of ischemic-reperfused myocardial tissue demonstrated markedly increased DNA fragmentation due to programmed cell death (i.e., apoptosis) compared to nonischemic myocardium. Furthermore, IGF-I significantly attenuated the incidence of myocyte apoptosis after myocardial ischemia and reperfusion. Therefore, IGF-I appears to be an effective agent for preserving ischemic myocardium from reperfusion injury and protects via two different mechanisms--inhibition of polymorphonuclear leukocyte-induced cardiac necrosis and inhibition of reperfusion-induced apoptosis of cardiac myocytes.

The microcirculation undergoes a profound degree of endothelial dysfunction within minutes (i.e., 2.5 to 5 min) following reperfusion of ischaemic vasculature. This has been documented in the coronary and mesenteric microcirculation. The endothelial dysfunction is characterized by a loss in basal and agonist-mediated nitric oxide (NO) produced by the vascular endothelium. The loss of NO results in upregulation of cell adhesion molecules (CAMs) particularly P-selectin 10-20 min following reperfusion. Thus, CAM upregulation renders the endothelium sticky, and a marked degree of leukocyte adherence (particularly neutrophils) occurs 20 min following reperfusion. This enhanced involvement of neutrophils leads to neutrophil infiltration into the underlying tissue (e.g., myocardium) within 2-3 h of reperfusion. The infiltration of neutrophils leads to reperfusion injury (i.e., necrosis) which is significant at 3 h but becomes profound at 4.5 h following reperfusion. Cardiac necrosis can be significantly attenuated by treatment with NO, an organic NO donor, L-arginine, or specific blockers of CAMs given just prior to reperfusion. This approach is a promising one for a variety of types of reperfusion injury.

We measured changes in basal release of nitric oxide and its effect on polymorphonuclear leukocyte (PMN) adherence to endothelial cells (ECs) in a feline model of myocardial ischemia (90 minutes) and reperfusion. Basal release of nitric oxide from the left anterior descending coronary artery (LAD) after myocardial ischemia/reperfusion and from the control left circumflex coronary artery (LCX) was assessed by NG-nitro L-arginine methyl ester (L-NAME) -induced vasocontraction. L-NAME induced a significant EC-dependent vasocontraction in control LCX rings (0.28±0.04 g), which was fully reversed by L-arginine but not D-arginine. L-NAME-induced vasocontraction of LAD rings was not significantly changed after 90 minutes of myocardial ischemia without reperfusion. However, 10 minutes of reperfusion reduced the L-NAME-induced vasocontraction to 0.13±0.04 g (p<0.05), and this was restored by addition of 3 mM L-arginine but not D-arginine. Longer periods of reperfusion progressively decreased L-NAME-induced vasocontraction. After 270 minutes of reperfusion, L-NAME-induced vasocontraction was virtually abolished. Myocardial ischemia without reperfusion did not increase PMN adherence to ECs. However, PMN adherence to LAD ECs was significantly increased after 20 minutes of reperfusion (39±6 to 105±9 PMNs/mm2, p<0.01), and incubation of LAD segments with L-arginine significantly attenuated this increase in PMN adherence. After 270 minutes of reperfusion, PMN adherence to LAD ECs was further increased to 224+ 10 PMNs/mm2 (p<0.001). This increase in PMN adherence was almost completely blocked by MAb R15.7, a monoclonal antibody against CD18 of PMNs, and was significantly attenuated by MAb RR1/1, a monoclonal antibody against intercellular adhesion molecule-1 of ECs (p<0.01). These results indicate that decreased basal release of endothelium-derived relaxing factor after myocardial ischemia/reperfusion precedes enhanced PMN adherence to the coronary endothelium, which may lead to PMN-induced myocardial injury. (Circulation Research 1993;72:403-412 release from coronary vascular endothelium is significantly impaired in myocardial ischemia followed by reperfusion.8-10 However, basal release of NO in myocardial ischemia and reperfusion has not been studied in this setting.It is now well recognized that polymorphonuclear leukocytes (PMNs) play an important role in myocardial injury associated with ischemia and reperfusion."1 Accumulating evidence suggests that PMNs also contribute to endothelial dysfunction after reperfusion of the coronary vasculature.12 Recently, NO has been shown to be an endogenous inhibitor of leukocyte chemotaxis,"3 adherence,6 and activation.'4 Since normal endothelial cells release NO basally and this NO may prevent PMNs from adhering to endothelial cells, it is conceivable that reduced basal NO release after myocardial reperfusion may promote or allow PMN adherence to endothelial cells, leading to neutrophil-induced reperfusion injury.Therefore, the purposes of this study were 1) to determine the time cours...