A 4-Amino Analogue of Tetrahydrobiopterin Attenuates Endotoxin-Induced Hemodynamic Alterations and Organ Injury in Rats

Abstract

Most recently we have shown that 4-aminotetrahydrobiopterin (4-ABH4), an analogue of tetrahydrobiopterin (cofactor of NO synthase), even administered 2 h after endotoxin challenge, improves survival rate in rats. The following experiment was performed to examine the effects of 4-ABH4 with respect to endotoxin-induced hemodynamic alterations and organ failure. At 2 h after endotoxic challenge (10 mg kg(-1) body weight) animals received 4-ABH4 at a dose of 1, 10, or 100 mg kg(-1) body weight. The controls were treated similarly but received saline at the same volume. Eight hours after endotoxin challenge cardiac index and stroke volume were significantly increased in animals treated with 10 mg 4-ABH4 compared to controls (0.23 +/- 0.06 vs. 0.16 +/- 0.04 mL min(-1) kg(-1) and 0.29 +/- 0.05 vs. 0.22 +/- 0.03 mL beat(-1)) while mean arterial pressure and peripheral vascular resistance index did not significantly differ among the groups. Plasma alanine aminotransferase (ALT) and creatinine levels were significantly increased in endotoxin controls compared with laboratory controls (ALT: 1643 +/- 1436 vs. 74 +/- 17 U L(-1); Creatinine: 91 +/- 29 vs. 42 +/- 3 micromol L(-1)) which was attenuated in animals treated with 10 mg kg(-1) 4-ABH4 (ALT: 417 +/- 318 U L(-1); Creatinine: 78 +/- 26 micromol L(-1)). Moreover, endotoxin-induced lung edema and intestinal necrosis were significantly reduced by 4-ABH4. Our study provides information that tetrahydrobiopterin analogue, 4-ABH4, improves LPS induced hemodynamic conditions and organ injury. This may, at least in part, account for the previously observed protection of rats by 4-ABH4 against endotoxin-induced mortality in the same endotoxic shock model.