Tetrahydrobiopterin (BH4) exerts cardioprotective effects in ischemia/reperfusion injury when given at reperfusion

Abstract

Myocardial ischemia followed by reperfusion (I/R) in the presence of polymorphonuclear leukocytes (PMNs) results in a marked cardiac contractile dysfunction. The effects of BH4 (cofactor of endothelial nitric oxide (NO) synthase) or dihydrobiopterin (BH2, i.e., oxidized BH4) were examined in isolated ischemic (20 min) and reperfused (45 min) rat hearts reperfused with PMNs. I/R+PMN hearts perfused with BH4 (10μM) during the first 5 min of reperfusion (n=6), left ventricular developed pressure (LVDP) significantly recovered to 85±8% of baseline compared to control I/R+PMN hearts (53±7%, n=9) at 45 min post-reperfusion (P<0.01). Moreover, the cardioprotection of BH4 was blocked by a NO synthase inhibitor NG–nitro-L-arginine methyl ester (50 μM). By contrast, I/R+PMN hearts perfused with BH2 (100 μM, n=7), LVDP only recovered to 64±9% of baseline, which was similar to control I/R + PMN hearts. The effects of BH4 and BH2 on I/R+PMN cardiac contractile function may be correlated with increased endothelial NO release by BH4 and decreased NO release by BH2, respectively, from non ischemic rat aortic segments. In summary, our preliminary data show that BH4, not BH2, significantly attenuates PMN-induced decreased LVDP following I/R, suggesting that hearts receiving BH4 during the first 5 min of reperfusion may promote eNOS to produce NO to maintain endothelial function to limit reperfusion injury. This study was supported by NHLBI Grant 1R15HL-76235-01 and Center For Chronic Disorders Of Aging. Philadelphia College of Osteopathic Medicine.