Cardiovascular Pharmacology Pharmacological preconditioning with nicorandil and pioglitazone attenuates myocardial ischemia/reperfusion injury in rats Lamiaa A. Ahmed ⁎, Hesham A. Salem, Amina S. Attia, Azza M. Agha Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt abstract article info Article history: Received 10 November 2010 Received in revised form 22 February 2011 Accepted 14 April 2011 Available online 28 April 2011 Keywords: Arrhythmias Ischemia Nicorandil Pioglitazone Preconditioning Reperfusion The present investigation was designed to study the cardioprotective effects of nicorandil and pioglitazone preconditioning in myocardial ischemia/reperfusion-induced hemodynamic, biochemical and histological changes in rats. Oral doses of nicorandil (3 or 6 mg/kg) and pioglitazone (10 or 20 mg/kg) were administered once daily for 5 consecutive days. Rats were then subjected to myocardial ischemia/reperfusion (40 min/ 10 min). Heart rate and ventricular arrhythmias were recorded during ischemia/reperfusion progress. At the end of reperfusion, plasma creatine kinase-MB activity and total nitrate/nitrite were determined. In addition, lactate, adenine nucleotides, thiobarbituric acid reactive substances, reduced glutathione and myeloperox- idase activity were estimated in the heart left ventricle. Finally, histological examination was performed to visualize the protective cellular effects of different pretreatments. Nicorandil (3 or 6 mg/kg) was effective in attenuating the ischemia/reperfusion-induced ventricular arrhythmias, creatine kinase-MB release, lactate accumulation and oxidative stress. Nicorandil (3 mg/kg) was more effective in improving the energy production and lowering the elevated myeloperoxidase activity. Both doses of pioglitazone (10 or 20 mg/kg) were equally effective in reducing lactate accumulation and completely counteracting the oxidative stress. Pioglitazone (10 mg/kg) was more effective in improving energy production and reducing ventricular arrhythmias, plasma creatine kinase-MB release and total nitrate/nitrite. It seems that selective mitochondrial K ATP channel opening by lower doses of nicorandil and pioglitazone in the present study provided more cardioprotection against ventricular arrhythmias and biochemical changes induced by ischemia/reperfusion. Histological examination revealed also better improvement by the lower dose of nicorandil than that of pioglitazone. © 2011 Elsevier B.V. All rights reserved. 1. Introduction The major goals of therapeutic intervention during myocardial infarction are prevention of lethal ventricular arrhythmias and preservation of myocardial tissue from irreversible damage (Lepran et al., 1996). Most cardioprotective strategies are designed to reduce oxidative stress and Ca 2+ overload to protect the heart against ischemia/reperfusion injury (Perrault and Menasché, 1999). Another successful approach in the experimental setting is myocardial preconditioning. Ischemic preconditioning is achieved by exposure of the myocardium to transient sublethal ischemia which can protect the organ from a subsequent prolonged ischemic insult (Murry et al., 1986). Preconditioning has been demonstrated to attenuate reperfu- sion arrhythmias (Shiki and Hearse, 1987), reduce necrosis (Schott et al., 1990) and improve postischemic function (Cohen et al., 1991). Activation of mitochondrial rather than sarcolemmal K ATP channel has been suggested in several studies as a principle mechanism of ischemic preconditioning (Gross and Fryer, 1999). This has lead to the hypothesis that drugs that open mitochondrial K ATP channel can mimic preconditioning (pharmacological preconditioning) (Hearse, 1995). Nicorandil and pioglitazone are among the drugs with this property that have been tested with generally positive results (Gross and Fryer, 1999). Nicorandil is an anti-anginal agent that has been demonstrated to protect heart against ischemic damage in both experimental (Ima- gawa et al. 1998) and clinical studies (Ito et al. 1999). Several lines of evidence suggest that opening of mitochondrial K ATP channels elicits preservation of mitochondrial integrity with subsequent protection of cellular function (Akao et al., 2002). In addition to its K ATP channel opening activity, nicorandil is a NO donor (Taira, 1989). NO inhibits apoptosis through regulating Bcl-2 family proteins (Suschek et al., 1999). It has also been reported that nicorandil has anti-free radical and neutrophil-modulating activities in vitro. The cardioprotection by European Journal of Pharmacology 663 (2011) 51–58 ⁎ Corresponding author at: Faculty of Pharmacy, Kasr El Aini St., Cairo, Postal code: 11562, Egypt. Fax: +20 2 23628426. E-mail addresses: lamiaahmed2004@yahoo.com (L.A. Ahmed), heshamalysalem@yahoo.com (H.A. Salem), draminasalem@yahoo.com (A.S. Attia), azzaagha@yahoo.com (A.M. Agha). 0014-2999/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2011.04.038 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar