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 30 min in two groups of dogs. Declamping was followed by 90 min of reperfusion. Mesenteric release of ET-1 was studied in series 1 (n=6). In series 2, 5 min before cross-clamping, the treated group (n=7) received an intravenous bolus of LU135252 (5 mg/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 15 min intervals. Ischaemia for 30 min induced a significant increase (P<0.05) in mesenteric ET-1 release (1594+/-526 pg/min, compared with 343+/-258 pg/min at baseline), which had returned to baseline after 20 min 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 90 min of reperfusion. Mesenteric lactate production was reduced by ET(A) antagonist administration under ischaemia (0.77+/-0.02 mmol/l) compared with controls (1.36+/-0.04 mmol/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)x10(6) compared with (6.4+/-3.6)x10(6) relative light units; P<0.05] and early reperfusion [(8.7+/-3.1)x10(6) compared with (1.1+/-2.9)x10(6) 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.
Department of Cardiovascular Surgery, Semmelweis University, Városmajor ut.68, H-1122 Budapest, Hungary. tean74@hotmail.com
Terézia B
TB
Andrási
Violetta
V
Kékesi
Anna
A
Blázovics
István
I
Dóbi
Gábor
G
Szabó
Alexander
A
Juhász-Nagy
D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D007077:Ileal Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017538:Mesenteric Artery, Superior; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D010666:Phenylpropionates / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D044022:Receptor, Endothelin A; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
D000975:Antioxidants; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; C107831:darusentan