Review Mechanisms by which K ATP channel openers produce acute and delayed cardioprotection Yigang Wang, Husnain Khawaja Haider, Nauman Ahmad, Muhammad Ashraf T Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0529, USA Abstract Mitochondria are being increasingly studied for their critical role in cell survival. Multiple diverse signaling pathways have been shown to converge on the K + -sensitive ATP channels as the effectors of cytoprotection against necrosis and apoptosis. The role of potassium channel openers in regulation and transformation of cell membrane excitability, action potential and electrolyte transfer has been extensively studied. Cardiac mitoK ATP channels are the key effectors in cardioprotection during ischemic preconditioning, as yet with an undefined mechanism. They have been hypothesized to couple myocardial metabolism with membrane electrical activity and provide an excellent target for drug therapy. A number of K ATP channel openers have been characterized for their beneficial effects on the myocardium against ischemic injury. This review updates recent progress in understanding the physiological role of K ATP channels in cardiac protection induced by preconditioning and highlights relevant questions and controversies in the light of published data. D 2005 Published by Elsevier Inc. Keywords: K ATP ; Mitochondria; K ATP channel; Cardioprotection Contents 1. Introduction ........................................................... 253 2. Sarcolemmal K ATP channels and their role in cardiac protection ................................ 254 3. Mitochondrial K ATP channels and their role in cardiac protection ............................... 255 4. Involvement sarcK ATP and mitoK ATP channels in ischemic preconditioning .......................... 256 5. Role of NO in the activation of mitoK ATP channels ...................................... 256 6. Role of NF-nB in activation of mitoK ATP channels ...................................... 257 7. Role of protein kinase C in activation of mitoK ATP channels ................................. 257 8. Pharmacological structure and K ATP channel openers ..................................... 257 9. Role of mitoK ATP channels in chronic preconditioning ..................................... 260 10. MitoK ATP channels as an end effector of protection ...................................... 260 11. Summary and further directions ................................................ 260 Acknowledgement ........................................................... 260 References ............................................................... 260 1. Introduction Two decades after identification of ATP-sensitive K + channels in membrane patches prepared from isolated guinea pig ventricular myocyte (Noma, 2001) their presence 1537-1891/$ - see front matter D 2005 Published by Elsevier Inc. doi:10.1016/j.vph.2005.02.008 T Corresponding author. Tel.: +1 513 558 0145; fax: +1 513 558 0807. E-mail address: Muhammad.Ashraf@UC.Edu (M. Ashraf). Vascular Pharmacology 42 (2005) 253–264 www.elsevier.com/locate/vph