Many cardiac interventional procedures, such as coronary angioplasty, stenting, and thrombolysis, attempt to reintroduce blood flow (reperfusion) to an ischemic region of myocardium. However, the reperfusion is accompanied by a complex cascade of cellular and molecular events resulting in oxidative damage, termed
myocardial ischemia-reperfusion (I/R) injury. In this study, we evaluated the ability of
HO-4038, an
N-hydroxypiperidine derivative of
verapamil, on the modulation of myocardial tissue oxygenation (Po(2)), I/R injury, and key signaling molecules involved in cardioprotection in an in vivo rat model of acute
myocardial infarction (MI). MI was created in rats by ligating the left anterior descending coronary artery (LAD) for 30 min followed by 24 h of reperfusion.
Verapamil or
HO-4038 was infused through the jugular vein 10 min before the induction of
ischemia. Myocardial Po(2) and the
free-radical scavenging ability of
HO-4038 were measured using electron paramagnetic resonance spectroscopy.
HO-4038 showed a significantly better scavenging ability of reactive
oxygen radicals compared with
verapamil. The cardiac contractile functions in the I/R hearts were significantly higher recovery in
HO-4038 compared with the
verapamil group. A significant decrease in the plasma levels of
creatine kinase and
lactate dehydrogenase was observed in the
HO-4038 group compared with the
verapamil or untreated I/R groups. The left ventricular
infarct size was significantly less in the
HO-4038 (23 +/- 2%) compared with the untreated I/R (36 +/- 4%) group.
HO-4038 significantly attenuated the hyperoxygenation (36 +/- 1 mmHg) during reperfusion compared with the untreated I/R group (44 +/- 2 mmHg). The HO-4038-treated group also markedly attenuated
superoxide production, increased
nitric oxide generation, and enhanced Akt and Bcl-2 levels in the reperfused myocardium. Overall, the results demonstrated that
HO-4038 significantly protected hearts against I/R-induced cardiac dysfunction and damage through the combined beneficial actions of
calcium-channel blocking,
antioxidant, and prosurvival signaling activities.