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Updated: Aug 12, 2026
Acute Myocardial Infarction in Rats
Published on: February 16, 2011
Wortmannin, a potent antineutrophil agent, exerts cardioprotective effects in myocardial ischemia/reperfusion
1Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Abstract:
Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in a marked cardiac contractile dysfunction. Wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase, suppresses superoxide production from PMNs. Therefore, we hypothesized that wortmannin could attenuate PMN-induced cardiac dysfunction by suppression of superoxide production from PMNs. We examined the effects of wortmannin in isolated ischemic (20 min) and reperfused (45 min) rat hearts perfused with PMNs. Wortmannin at 10, 20, or 40 nM given to hearts during the first 5 min of reperfusion, significantly improved left ventricular developed pressure (P < .01), and the maximal rate of development of left ventricular developed pressure (P < .01) compared with ischemic/reperfused hearts perfused with PMNs in the absence of wortmannin. In addition, wortmannin significantly reduced PMN infiltration into the myocardium by 50 to 75% (P < .001). Superoxide radical release also was significantly reduced in N-formylmethionyl-leucylphenylalanine-stimulated PMNs pretreated with 10 or 40 nM wortmannin by 70 and 95%, respectively (P < .001 versus untreated PMNs). Rat PMN adherence to rat superior mesenteric artery endothelium exposed to 2 U/ml thrombin was significantly attenuated by 10 to 40 nM wortmannin compared with untreated vessels (P < .001). These results provide evidence that wortmannin can significantly attenuate PMN-induced cardiac contractile dysfunction in the ischemic/reperfused rat heart via attenuation of PMN infiltration into the myocardium and suppression of superoxide release by PMNs.
Insights
Wortmannin, a phosphatidylinositol 3-kinase inhibitor, reduces cardiac dysfunction caused by ischemia-reperfusion and polymorphonuclear leukocytes (PMNs). It attenuates PMN infiltration and superoxide release, protecting the heart.
Area of Science:
- Cardiovascular Research
- Inflammation Biology
- Pharmacology
Background:
- Ischemia-reperfusion injury exacerbates cardiac contractile dysfunction, particularly with polymorphonuclear leukocyte (PMN) involvement.
- PMNs contribute to cardiac dysfunction through superoxide production and myocardial infiltration.
- Wortmannin, a phosphatidylinositol 3-kinase inhibitor, is known to suppress PMN superoxide production.
Purpose of the Study:
- To investigate the potential of wortmannin to attenuate PMN-induced cardiac dysfunction during ischemia-reperfusion.
- To determine if wortmannin's protective effects are mediated by suppressing PMN superoxide production and infiltration.
Main Methods:
- Isolated rat hearts underwent 20 minutes of ischemia followed by 45 minutes of reperfusion with PMNs.
- Wortmannin (10, 20, or 40 nM) was administered during early reperfusion.
- Measurements included left ventricular developed pressure, PMN infiltration, superoxide radical release from PMNs, and PMN adherence to endothelium.
Main Results:
- Wortmannin significantly improved cardiac contractile function (left ventricular developed pressure and its maximal rate of development).
- Wortmannin markedly reduced PMN infiltration into the myocardium (50-75%) and superoxide release from stimulated PMNs (70-95%).
- Wortmannin also attenuated PMN adherence to thrombin-activated endothelium.
Conclusions:
- Wortmannin effectively attenuates PMN-induced cardiac contractile dysfunction in an ischemia-reperfusion model.
- The cardioprotective effects of wortmannin are linked to reduced PMN infiltration and suppressed PMN superoxide production.
- Wortmannin demonstrates therapeutic potential for mitigating ischemia-reperfusion injury involving inflammatory cells.
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