title: Mechanisms for blockade of in vivo activator production in the ischemic intestine and multi-organ failure.
abstract: Our recent results indicate that pancreatic enzymes in the ischemic intestine are involved in the production of in vivo activators, which stimulate cells in the cardiovascular system and initiate multiple organ failure. Since the intestine is a rich source of xanthine oxidase (XO), we investigated whether XO may be involved in the production of circulating activators in shock. The small intestine was perfused with saline (SAL group), a broad acting pancreatic enzyme inhibitor, ANGD (ANGD group), allopurinol (ALLOP group), or a combination of ANGD and allopurinol (ANGD + ALLOP group). 100 min of splanchnic arterial occlusion was followed by 120 min of reperfusion. Leukocytes from asymptomatic volunteers were incubated with plasma from experimental animals, and the fractions of pseudopod positive cells were counted as an indicator for the activator. ANGD served to preserve the arterial blood pressure (MAP) close to its control values (96.6 +/- 6.2 % in ANGD versus 60.9 +/- 6.2 % in SAL, 120 min after reperfusion, P < 0.05). In line with our previous experiments, ANGD decreased the formation of activator (30.5 +/- 4.8% in SAL versus 7.3 +/- 1.6 % in ANGD, 120 min after reperfusion, P< 0.05). Although allopurinol inhibited the XO in the small intestine, no protection from early indicators of multi-organ injury was detected. The recovery of MAP and reduced levels of plasma activator achieved in the ANGD + ANGD group was similar to those in the ALLOP group. These results indicate that XO may not serve as a significant source for plasma derived activators in an acute phase of shock after severe intestinal ischemia.
authors.affiliation: Department of Bioengineering and The Whitaker Institute for Biomedical Engineering, University of California San Diego, La Jolla 92093-0412, USA.
authors.forename: H
authors.initials: H
authors.lastname: Mitsuoka
authors.forename: G W
authors.initials: GW
authors.lastname: Schmid-Schönbein
mesh_terms: D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001550:Benzamidines; D001646:Bile / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D004386:Duodenum / Q000098:blood supply* / Q000473:pathology; D006146:Guanidines / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology*; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D009102:Multiple Organ Failure / Q000473:pathology / Q000503:physiopathology*; D009504:Neutrophils / Q000502:physiology*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014968:Xanthine Dehydrogenase / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D001550:Benzamidines; D006146:Guanidines; D011480:Protease Inhibitors; D000493:Allopurinol; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase; C032855:nafamostat