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Updated: Jul 14, 2026
Rodent Model of Intestinal Ischemia-Reperfusion Injury via Occlusion of the Superior Mesenteric Artery
Published on: October 20, 2023
Tezosentan attenuates organ injury and mesenteric blood flow decrease in endotoxemia and cecal ligation and puncture
Aysen Erdem1, A Meltem Sevgili, Filiz Akbiyik
1Department of Physiology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
Background:
Decreased mesenteric blood flow and multiple organ injury due to free radicals are the consequences of septic shock. Since the blockade of endothelin receptors was reported to exert beneficial effects, we investigated the effects of tezosentan, a novel dual endothelin receptor antagonist, in two different experimental models of septic shock induced either by the injection of Escherichia coli endotoxin (ETX, 20 mg/kg, i.p.) or by cecal ligation and puncture (CLP).
Study Design:
Swiss albino mice received tezosentan (10 mg/kg, i.p.) or its solvent saline (0.9% NaCl, w/v) twice at 2 and 22 h after ETX or CLP. At 24 h, the animals were anesthetized and the mesenteric blood flow was monitored for 15 min by using perivascular ultrasonic Doppler flowmeter. Then the animals were exsanguinated, and spleen, liver, and kidneys were isolated accordingly for histopathological examination. Thiobarbituric acid reacting substances and glutathione and myeloperoxides activities were also determined in the liver.
Results:
In both ETX and CLP models, there was a decrease in mesenteric blood flow which was blocked by tezosentan. Similarly, tezosentan significantly attenuated the histopathological injury inflicted by both models. Although the glutathione levels were decreased and thiobarbituric acid reacting substances and myeloperoxidase activity were increased by ETX and CLP, tezosentan has failed to block these alterations in a consistent manner. However, a significant interaction between CLP and tezosentan with regard to myeloperoxidase activity and glutathione should be taken as partial evidence to explain the underlying mechanism of protection offered by tezosentan against liver injury.
Conclusions:
Therefore, we concluded that tezosentan, by working via mechanisms mostly other than the blockade of free radical induced damage, is a useful treatment option for combating the deleterious effects of septic shock such as mesenteric ischemia as well as liver, spleen, and kidney injury.
Insights
Tezosentan, an endothelin receptor antagonist, improved mesenteric blood flow and reduced organ injury in septic shock models. It offers a promising treatment option beyond free radical blockade.
Area of Science:
- Pharmacology
- Critical Care Medicine
- Experimental Pathology
Background:
- Septic shock leads to decreased mesenteric blood flow and organ damage from free radicals.
- Endothelin receptor blockade shows potential therapeutic benefits.
- Tezosentan, a dual endothelin receptor antagonist, was investigated for its effects on septic shock.
Purpose of the Study:
- To evaluate the efficacy of tezosentan in experimental models of septic shock.
- To assess tezosentan's impact on mesenteric blood flow and organ injury.
- To explore the mechanisms underlying tezosentan's protective effects.
Main Methods:
- Two septic shock models were used: Escherichia coli endotoxin (ETX) and cecal ligation and puncture (CLP).
- Mice received tezosentan or saline, and mesenteric blood flow was measured.
- Histopathological examination of spleen, liver, and kidneys was performed, along with biochemical analyses.
Main Results:
- Tezosentan successfully blocked the decrease in mesenteric blood flow in both ETX and CLP models.
- Histopathological organ injury was significantly attenuated by tezosentan treatment.
- Tezosentan's effect on oxidative stress markers (glutathione, thiobarbituric acid reacting substances, myeloperoxidase) was inconsistent but suggested partial involvement in liver protection.
Conclusions:
- Tezosentan is a potential treatment for septic shock, effectively mitigating mesenteric ischemia and organ damage.
- The protective mechanisms of tezosentan appear to involve pathways beyond the direct blockade of free radical damage.
- Further investigation into tezosentan's multifaceted therapeutic actions is warranted.
