ET_A receptor blockade protects the small intestine against ischaemia/reperfusion injury in dogs via an enhancement of antioxidant defences

The aim of the present study was to determine whether the ET_A receptor antagonist LU135252 can protect the mesenterium against ischaemia/reperfusion (I/R) damage. Direct occlusion of the superior mesenteric artery was performed for 30min in two groups of dogs. Declamping was followed by 90min of reperfusion. Mesenteric release of ET-1 was studied in series 1 (n = 6). In series 2, 5min before cross-clamping, the treated group (n = 7) received an intravenous bolus of LU135252 (5mg/kg), whereas the control group (n = 6) was given vehicle. Mean arterial blood pressure and mesenteric blood flow were recorded. Mesenteric venous and systemic arterial serum lactate and glucose, plasma creatine kinase and free radical concentrations were determined at 15min intervals. Ischaemia for 30min induced a significant increase (P<0.05) in mesenteric ET-1 release (1594±526pg/min, compared with 343±258pg/min at baseline), which had returned to baseline after 20min of reperfusion. LU135252 administration significantly decreased mesenteric blood flow during ischaemia (204±23%) compared with controls (320±34%, P<0.05). In contrast, mesenteric blood flow was higher in the treated group (120±19% compared with 82±7%; P<0.05) after 90min of reperfusion. Mesenteric lactate production was reduced by ET_A antagonist administration under ischaemia (0.77±0.02mmol/l) compared with controls (1.36±0.04mmol/l; P<0.01). Lower levels of venous creatine kinase were present in the treated group during ischaemia as well as after reperfusion (120±7% compared with 150±16%; P<0.01). Administration of LU135252 also improved the total scavenger capacity of the mesenteric bed during ischaemia [(15.9±3.9)×10⁶ compared with (6.4±3.6)×10⁶ relative light units; P<0.05] and early reperfusion [(8.7±3.1)×10⁶ compared with (1.1±2.9)×10⁶ relative light units]. Thus ET-1 is involved in I/R-induced disturbances in the intestine. LU135252 seems to counteract these changes, in part by increasing the antioxidant capacity of the mesenterium.