Cardiovascular pharmacology Blockers of sulfonylureas receptor 1 subunits may lead to cardiac protection against isoprenaline-induced injury in obese rats Yige Bao a , Xiaodong Sun b , Yerong Yu b,n , Shuyuan Lu a , Yang Wu a a West China School of Medicine, Sichuan University, Chengdu, China b Department of Endocrinology and Metabolism, West China Hospital, Chengdu, China article info Article history: Received 5 February 2012 Received in revised form 18 June 2012 Accepted 20 June 2012 Available online 2 July 2012 Keywords: Obesity Ischemic injury SUR1 Nonselective cation channel K ATP channel abstract Recent studies have found that blockers of sulfonylureas receptor 1(SUR1) might have cardiac ischemic protective effects. We evaluated the effects of a selective SUR1 blocker gliclazide on cardiac function and arrhythmia after isoprenaline-induced myocardial injury in obese rats. Diet-induced obese rats received isoprenaline or saline shots subcutaneously. Gliclazide or saline was given q12h for 48 h to rats received isoprenaline. We measured ECG and hemodynamic parameters and collected blood samples for CK-MB, glucose and lipid profile determination, and then harvested hearts for water content, histological and immunohistochemical analysis and infarct size measurements. The obese rats’ hearts receiving isoprena- line-induced myocardial injury showed up-regulated SUR-1 expression in the peri-microvascular area. Obese rats receiving gliclazide lavage had less severe arrhythmia (ASI: 4.00 70.61 vs. 2.14 70.39, P o0.05) and myocardial edema (water percentage: 85.16 70.46% vs. 81.56 70.57%, P o0.05). Less infarct size (47.6712.8% vs. 32.779.1%, P o0.05) and improved diastolic function (LVEDP: 6.8670.85% vs. 2.5171.09%, P o0.05; (dp/dt) max : 1663.67387.91 mmHg/s vs. 2834.87290.76 mmHg/s, P o0.05) were also observed in rats receiving gliclazide lavage. Blocking of the SUR1 thus exerts a protective effect on the isoprenaline-induced myocardial injury in obese rats. That SUR1 blocker leads to ischemic protection suggesting a critical biological role of SUR1 in regulating the function of the cardiovascular system than previously recognized under pathophysiological conditions. & 2012 Elsevier B.V. All rights reserved. 1. Introduction In recent decades, the prevalence of obesity in the world has risen to epidemic/pandemic proportions. Risks of cardiovascular diseases are substantially higher under obesity, but the weight loss is associated with benefits in all of the obesity-related comorbidities. However, most weight loss interventions are associated with weight re-gain and are therefore not successful in the longer term. It is for these reasons that exploring mechan- isms and new treatments of obesity related cardiovascular dis- eases remains a crucial role in improving the prognosis of obesity. Sulfonylureas receptor 1(SUR1) is one of the receptors of sulfonylureas (SUs), a widely used hypoglycemic agent, and new understanding of molecular cloning studies responsible for ion channels has provided novel insights into biophysical and phar- macological properties of SUR1 subunits. SUR1 has further been recognized as the regulatory subunit of a newly discovered calcium-activated nonselective cation channel (NSC Ca ), identified in cultured human and mouse endothelial cells in central nervous systems subjected to hypoxia (Chen et al., 2003). Another recent discovery focusing on the heart have shown that SUR1 is one of the regulatory subunit of K ATP channels (abundantly expressed in the heart but are generally thought to consist of Kir6.2/SUR2A sub- units) and serves as an ATP-binding cassette transporter. Other recent studies have also found the presence of SUR1 subunits in mouse cardiac tissue and a surprising protection from myocardial ischemia-reperfusion in SUR1-null mice (Lefer et al., 2009). We hypothesized that SUR1 regulated cardiac NSC Ca channel and/ or K ATP channel is involved in heart ischemic injury and inhibiting these channels with a highly selective SUR1 blocker may have beneficial cardio-protective effects. We created an isoprenaline- induced myocardial injury model on diet-induced obese Wistar rats to observe the possible up-regulation of SUR1 subunits in the myocardium. The effects of low-dose gliclazide on infarct size, cardiac function and arrhythmia was examined by blocking SUR1 to shut down SUR1-regulated cardiac K ATP channel and/or NSC Ca channel. 2. Materials and methods 2.1. Experimental animals Four-week-old male Wistar rats (200–220 g body weight) obtained from the Experimental Animal Center of the Chengdu Contents lists available at SciVerse ScienceDirect journal homepage: www.elsevier.com/locate/ejphar European Journal of Pharmacology 0014-2999/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejphar.2012.06.039 n Corresponding author at: Sichuan University, Department of Endocrinology and Metabolism, West China. School of Medicine, #37 Guoxue Road, Chengdu 610041, China. Tel.: þ86 28 85422357; fax: þ86 28 85423459. E-mail address: yerongyu@scu.edu.cn (Y. Yu). European Journal of Pharmacology 690 (2012) 142–148