Expression of type 1 plasminogen activator inhibitor and nitric oxide generation in ischemic preconditioning of rat liver.
AIMS: Nitric oxide (NO) has protective effects against ischemia-reperfusion (I/R) injury and plays an important role in ischemic preconditioning. Type 1 plasminogen activator inhibitor (PAI-1) regulates plasminogen activators, which may have cytotoxic effects in I/R injury. I/R injury is reduced by the inhibition of fibrinolytic enzymes. To clarify the mechanism of ischemic preconditioning, PAI-1 induction and NO generation were studied in hepatic ischemic preconditioning. METHODS: Total hepatic ischemia was achieved by Pringle's maneuver. FK409 was used as an NO donor. Plasma alanine aminotransferase (ALT) and hyaluronic acid (HA) were measured to estimate hepatic damage and serum nitrite (NO(2)(-)) and nitrate (NO(3)(-)) were also determined to assess NO generation. Reserve transcription-polymerase chain reaction (RT-PCR) and in situ hybridization were carried out to determine the quantitative changes in the expression of PAI-1 mRNA. Plasma PAI-1 concentration was determined using an enzyme-linked immunosorbent assay (ELISA) system. RESULTS: No increase in ALT or HA was found with 5 min I/R. NO and PAI-1 in plasma and PAI-1 mRNA in liver were not increased in the ischemic period, but were increased during the reperfusion period. Infusion of FK409 stimulated induction of PAI-1 mRNA dose dependently. In situ hybridization studies indicated that hepatocytes expressed PAI-1 mRNA after I/R treatment. CONCLUSIONS: I/R increased the concentration of plasma PAI-1. Reperfusion following ischemia was needed for the induction of PAI-1 mRNA and increase of plasma NO concentration. FK409 stimulated PAI-1 mRNA induction in the liver. These results indicate that PAI-1 is a component of the ischemic preconditioning mechanisms, which is stimulated by NO generation.
Watanabe
Yoshifumi
Y
Third Department of Surgery, Nihon University School of Medicine, Tokyo, Japan
Takahashi
Hideo
H
Uno
Shigeyuki
S
Takano
Seigo
S
Nakagawa
Shigeki
S