SUPERIOR MESENTERIC-ARTERY BLOOD-FLOW AND INDOMETHACIN-INDUCED INTESTINAL INJURY AND INFLAMMATION

Intestinal injury caused by nonsteroidal anti-inflammatory drugs (NSAI Ds) is associated with increased mucosal permeability, microvascular i njury, focal intravascular thrombus formation, fibrin deposition, and neutrophil infiltration. Ulcerations and adhesions are also prominent features of this injury. Although NSAID-induced inhibition of prostagl andin formation has been suggested to produce ischemic injury and infl ammation, no studies have directly assessed intestinal blood flow in e xperimental NSAID-induced enteropathy. This study tested the hypothesi s that indomethacin-induced small bowel injury and inflammation result from intestinal ischemia. With the use of pulsed Doppler flowmetry, s uperior mesenteric artery blood flow was continuously monitored in con scious rats after doses of indomethacin known to promote acute and the n chronic small bowel inflammation (7.5 mg/kg, 2 sc doses spaced 24 h apart). After 72 h, rats were anesthetized and a section of small bowe l was removed for histology and intestinal myeloperoxidase activity me asurements. Mean arterial blood pressure was not affected until 32 h a fter indomethacin, when it decreased 20% (P < 0.05 to P < 0.01). Susta ined blood flow changes first occurred at 20 h, when an increase of 15 % (P < 0.01) was observed, whereas flow resistance decreased. Flow res istance continued to decrease for the remainder of the 72-h period, an d there was an accompanying blood flow increase to +40% (P < 0.05 to P < 0.01). Intestinal ulcers developed in 86% of indomethacin-treated r ats. Adhesions, dilation, and thickening of the distal jejunum and pro ximal ileum were observed in most indomethacin-treated rats. Histologi cal grading of intestinal injury yielded scores of 7.1 +/- 1.2 and zer o for indomethacin-treated and vehicle-injected rats, respectively (P < 0.01). Myeloperoxidase activity was greater in indomethacin-treated rats (6.7 +/- 1.9 vs. 1.8 +/- 0.3 U/cm, P < 0.05). These results sugge st that indomethacin-induced enteropathy is associated with an increas e, not a decrease, in superior mesenteric artery blood flow. Therefore , ischemia does not appear to be a mechanism by which subcutaneous ind omethacin administration produces small intestinal injury and inflamma tion.