Enhanced modulation of hypotension in endotoxemia by concomitant nitric oxide synthesis inhibition and nitric oxide...

Elevated nitric oxide (NO) levels appear to be a primary cause of the sepsis related hypotension. We tested a hypothesis that a concomitant NO synthesis inhibition (NOSI) and NO scavenging (NOSC) could effectively modulate this hypotension. Anesthetized SD rats were subjected to endotoxemic shock by intravenous administration of endotoxin (LPS; 10mg/kg). Three hours post-LPS, the animals were randomly divided into three groups and infused with 25mg/kg of N-amino-L-methyl ester (NAME; a NO synthesis inhibitor, N = 4), 130 mg/kg human hemoglobin (Hb; a NO scavenger, N = 6), or a mixture of both (130mgHb/kg and 25mg NAME/kg, N = 4). Changes in mean blood pressure (MBP) and erythrocyte and plasma nitrosyl Hb (HbNO) levels were followed. The initial MBP increase of the combined treatment was significantly greater than Hb or NAME alone (P < 0.05, t-test) and was maintained significantly above the pre-treatment values (P < 0.05, paired t-test) 2hrs after treatment. All post-LPS erythrocyte samples exhibited the characteristic electron spin resonance signals of HbNO at 3.4 kGauss indicating NO formation in endotoxemia. The HbNO signal was also detected in plasma of rats treated with Hb alone or with Hb and NAME indicating the infused Hb reacted with NO. These results indicate that concomitant NOSI and NOSC is more effective than NOSI or NOSC alone in modulating the hypotension of sepsis as it combines two distinct but mutually complementary anti-NO mechanisms.