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Updated: Oct 2, 2026
Model of Ischemia and Reperfusion Injury in Rabbits
Published on: November 3, 2023
Inhibition of cyclo-oxygenase-2 exacerbates ischaemia-induced acute myocardial dysfunction in the rabbit
Giuseppe Rossoni1, Marcelo N Muscara, Giuseppe Cirino
1Department of Pharmacological Sciences, University of Milan, Milan, Italy.
Abstract:
1. The effects of treatment with a number of cyclo-oxygenase inhibitors, (celecoxib, meloxicam, DuP-697 and aspirin) on ischaemia-reperfusion-induced myocardial dysfunction were examined using an in vitro perfused rabbit heart model. 2. Ischaemia resulted in myocardial dysfunction, as indicated by a significant increase in left ventricular end diastolic pressure and marked changes in coronary perfusion pressure and left ventricular developed pressure. In the post-ischaemic state, coronary perfusion pressure increased dramatically, left ventricular developed pressure recovered to a small degree and there were significant increases in creatinine kinase release (indicative of myocardial damage) and prostacyclin release. 3. Pretreatment with aspirin, or with drugs that selectively inhibit cyclo-oxygenase-2 (celecoxib, meloxicam and DuP-697), resulted in a concentration-dependent exacerbation of the myocardial dysfunction and damage. Exacerbation of myocardial dysfunction and damage was evident with 10 microM concentrations of the cyclo-oxygenase-2 inhibitors, which inhibited prostacyclin release but did not affect cyclo-oxygenase-1 activity (as measured by whole blood thromboxane synthesis). 4. NCX-4016, a nitric oxide-releasing aspirin derivative, significantly reduced the myocardial dysfunction and damage caused by ischaemia and reperfusion. Beneficial effects were observed even at a concentration (100 microM) that significantly inhibited prostacyclin synthesis by the heart. 5. The results suggest that prostacyclin released by cardiac tissue in response to ischaemia and reperfusion is derived, at least in part, from cyclo-oxygenase-2. Cyclo-oxygenase-2 plays an important protective role in a setting of ischaemia-reperfusion of the heart.
Insights
Cyclo-oxygenase-2 inhibitors worsen heart damage during ischemia-reperfusion. However, nitric oxide-releasing aspirin derivatives offer protection, suggesting cyclo-oxygenase-2 plays a vital role in cardiac protection during such events.
Area of Science:
- Cardiovascular Pharmacology
- Biochemistry
- Myocardial Pathophysiology
Background:
- Ischemia-reperfusion injury is a significant cause of myocardial damage.
- Cyclo-oxygenase (COX) enzymes play a role in inflammation and cardiovascular function.
- Selective COX-2 inhibitors are used clinically, but their role in ischemia-reperfusion is not fully understood.
Purpose of the Study:
- To investigate the effects of cyclo-oxygenase inhibitors on ischemia-reperfusion-induced myocardial dysfunction and damage.
- To determine the role of cyclo-oxygenase-2 (COX-2) in mediating cardiac protection during ischemia-reperfusion.
- To evaluate the potential therapeutic benefits of a nitric oxide-releasing aspirin derivative.
Main Methods:
- Utilized an in vitro perfused rabbit heart model to simulate ischemia-reperfusion.
- Administered various cyclo-oxygenase inhibitors, including selective COX-2 inhibitors (celecoxib, meloxicam, DuP-697) and aspirin.
- Assessed myocardial dysfunction through left ventricular pressure measurements and measured cardiac damage via creatinine kinase release and prostacyclin release.
Main Results:
- Ischemia-reperfusion led to significant myocardial dysfunction and damage, evidenced by increased left ventricular end-diastolic pressure and creatinine kinase release.
- Pretreatment with selective COX-2 inhibitors exacerbated myocardial dysfunction and damage in a concentration-dependent manner, inhibiting prostacyclin release without affecting COX-1 activity.
- NCX-4016, a nitric oxide-releasing aspirin derivative, significantly attenuated ischemia-reperfusion-induced myocardial dysfunction and damage.
Conclusions:
- Cardiac prostacyclin release during ischemia-reperfusion is, at least partly, mediated by COX-2.
- COX-2 appears to play a protective role in the heart during ischemia-reperfusion injury.
- Nitric oxide-releasing aspirin derivatives demonstrate potential therapeutic value in mitigating cardiac damage from ischemia-reperfusion.
