Histamine: A promoter of xanthine oxidase activity in intestinal ischemia/reperfusion

Abstract

Xanthine oxidase (XO)-derived oxygen radicals are thought to play an important role in the intestinal injury resulting from ischemia and reperfusion. In vitro data shows enhanced XO activity in the presence of histamine. Histamine is known to be released during intestinal ischemia and reperfusion. The purpose of this study was to evaluate the relationship between histamine and XO in vivo in intestinal ischemia/reperfusion injury. Using an established model of gut ischemia and reperfusion, portal venous plasma was obtained and assayed for histamine levels, XO activity, and xanthine dehydrogenase (XD) activity following injury. Intestinal ischemia for 120 minutes resulted in a 200% increase in plasma histamine levels (263.4 ± 36.9 nmol/mL control, v 548.7 ± 35.1 nmol/mL experimental, P < .05). Reperfusion for 15 minutes resulted in a further increase in plasma histamine (to 658.3 ± 33.9 nmol/mL), compared with 120 minutes of ischemia alone. No significant change in plasma XO activity resulted after simple ischemia for 120 minutes. However, XO activity doubled within 15 minutes of reperfusion of the ischemic intestine (6.37 ± 0.53 nmol O 2 − per milliliter per minute v 3.12 ± 0.25 nmol O 2 − per milliliter per minute, P < .05). Reperfusion for 60 minutes resulted in the maximal observed increase in plasma XO activity (9.49 ± 0.67 nmol O 2 − per milliliter per minute). Analysis of XD activity demonstrated no significant decrease compared with controls until 120 minutes of ischemia and 60 minutes of reperfusion (1.62 ± 0.49 nmol uric acid per milliliter per minute at 60 minutes of reperfusion, versus 5.02 ± 0.52 nmol uric acid per milliliter per minute control, P < .05). These data suggest that enhanced XO activity due to calcium and protease-dependent conversion from XD results relatively late in the course of this ischemia/reperfusion injury, after the histamine-associated early increase in plasma XO activity. In summary, intestinal ischemia followed by reperfusion results in parallel elevations of plasma histamine and XO activity. The early increase in XO activity is independent of conversion from XD but is temporally related to elevations in plasma histamine. These data suggest a role for histamine as a pathogenic mediator of intestinal ischemia/reperfusion injury.