METHODS AND RESULTS: Langendorff-perfused rat hearts were subjected to 30 minutes of global
ischemia followed by 30 minutes of reperfusion. The recovery of left ventricular developed pressure (LVDP),
creatine kinase (CK) release, and myocardial high energy
phosphates were measured in hearts perfused with or without NOS inhibitors, L-N(G)-monomethyl
arginine (
L-NMMA) or N(G)nitro-
L-arginine methylester (
L-NAME). NOS inhibitors exerted different effects on the recovery of LVDP and CK release depending on the concentration. The low dose of
L-NMMA improved the recovery of LVDP, decreased the CK release during reperfusion, and preserved the myocardial
adenosine triphosphate content after reperfusion. In contrast, the high dose of
L-NMMA had adverse effects.
L-NMMA reduced NO release in coronary effluent in a dose-dependent fashion. Both effects of
L-NMMA were abolished by excessive co-administration of
L-arginine and the same doses of D-N(G)-monomethyl
arginine (
D-NMMA) showed no effect on
ischemia-reperfusion injury. Therefore, both effects were due to NOS inhibition. In addition,
L-NMMA suppressed the myocardial
malondialdehyde accumulation, an
indicator of oxidative stress, which might be attributed to the beneficial effects by partial NOS inhibition. On the other hand, the high dose
L-NMMA significantly decreased coronary fl ow during aerobic perfusion and reperfusion. Therefore, it is conceivable that the vasoactive NOS inhibition contributes to the harmful effects, which might exceed the beneficial effects due to a decrease in oxidative stress.
CONCLUSION: The present results showed that NO inhibitors had dual effects on mechanical function and energy metabolism depending on the concentration. Non-vasoactive inhibition of NOS had beneficial effects due to the suppression of oxidative injury. However, strong vasoactive inhibition of NOS exacerbated the
ischemia-reperfusion injury.