Nicorandil opens mitochondrial K(ATP) channels not only directly but also through a NO-PKG-dependent pathway.
ABSTRACT Nicorandil, a hybrid of nitrate generator and potassium channel opener, protects ischemic myocardium by opening mitochondrial ATP sensitive potassium (mitoK(ATP)) channels. We recently found that nitric oxide (NO) opened K(ATP) channels in rabbit hearts by a protein kinase G (PKG) mechanism. This study examined whether the NO-donor property of nicorandil also contributes to opening of mitoK(ATP) channels through PKG. MitoK(ATP) channel opening was monitored in adult rabbit cardiomyocytes by measuring reactive oxygen species (ROS) production, an established marker of channel opening. Nicorandil increased ROS production in a dose-dependent manner. The selective mitoK(ATP) channel inhibitor 5-hydroxydecanoate (200 microM) completely blocked ROS production by nicorandil at all doses. The PKG inhibitor 8-bromoguanosine-3',5'-cyclic monophosphorothioate, Rpisomer (Rp-8-Br-cGMPs, 50 microM) shifted the dose-ROS production curve to the right with an increase of the EC(50) from 2.4 x 10(-5) M to 6.9 x 10(-5) M. Rp- 8-Br-cGMPs did not affect the increase in ROS production by the selective mitoK(ATP) channel opener diazoxide while it completely blocked increased ROS production from the NO donor S-nitroso-N-acetylpenicillamine (1 microM). Furthermore ODQ, an antagonist of soluble guanylyl cyclase, blocked nicorandil's ability to increase ROS generation. These results indicate that nicorandil, in addition to its direct effect on the channels, opens mitoK(ATP) channels indirectly via a NO-PKG signaling pathway.
Article: Redox balance and cardioprotection.[Show abstract] [Hide abstract]
ABSTRACT: Coronary artery disease is a major cause of morbidity and mortality in the Western countries. Acute myocardial infarction is a serious and often lethal consequence of coronary artery disease, resulting in contractile dysfunction and cell death. It is well known that unbalanced and high steady state levels of reactive oxygen and nitrogen species (ROS/RNS) are responsible for cytotoxicity, which in heart leads to contractile dysfunction and cell death. Pre- and post-conditioning of the myocardium are two treatment strategies that reduce contractile dysfunction and the amount of cell death considerably. Paradoxically, ROS and RNS have been identified as a part of cardioprotective signaling molecules, which are essential in pre- and post-conditioning processes. S-nitrosylation of proteins is a specific posttranslational modification that plays an important role in cardioprotection, especially within mitochondria. In fact, mitochondria are of paramount importance in either promoting or limiting ROS/RNS generation and reperfusion injury, and in triggering kinase activation by ROS/RNS signaling in cardioprotection. These organelles are also the targets of acidosis, which prevents mitochondrial transition pore opening, thus avoiding ROS-induced ROS release. Therefore, we will consider mitochondria as either targets of damage or protection from it. The origin of ROS/RNS and the cardioprotective signaling pathways involved in ROS/RNS-based pre- and post-conditioning will be explored in this article. A particular emphasis will be given to new aspects concerning the processes of S-nitrosylation in the cardioprotective scenario.Archiv für Kreislaufforschung 11/2013; 108(6):392. · 7.35 Impact Factor
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ABSTRACT: Insulin resistance (IR) of muscle cells is an early symptom of type 2 diabetes. It often results from excessive lipid accumulation in muscle fibers which under in vitro experimental conditions may be induced by incubation of muscle cells with palmitate. IR is manifested as a reduced response of cells to insulin expressed by lowered Akt kinase phosphorylation and decreased insulin-dependent glucose uptake. Stimulation of mitochondrial oxidative metabolism by mild dissipation of the mitochondrial potential is thought to increase fatty acid utilization and thereby prevent insulin resistance. Here it is shown that nicorandil and NS1619, which are openers of two different mitochondrial potassium channels, protect C2C12 myotubes from palmitate-induced insulin resistance. Preincubation of myotubes with 5-hydroxydecanoate abolishes the protective effect of nicorandil. The efficient concentrations of both openers are far below those commonly applied for cytoprotection. This is probably why their effects on the mitochondrial energy metabolism are small. These data suggest that opening of mitochondrial potassium channels could be a promising approach in prevention and therapy of insulin resistance related to dyslipidemia and obesity.Archives of Biochemistry and Biophysics 11/2013; · 3.37 Impact Factor
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