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.
- [show abstract] [hide abstract]
ABSTRACT: Cardiomyocyte death secondary to transient ischaemia occurs mainly during the first minutes of reperfusion in the form of contraction band necrosis. Research on the mechanisms leading to sarcolemmal rupture and necrosis during initial reperfusion identified several promising pharmacological targets directed either to correct the alterations in Ca(2+) handling occurring during this period (Na(+)/H(+)-exchanger, reverse mode of Na(+)/Ca(2+)-exchanger, sarcoplasmic reticulum) or to interfere with its consequences [hypercontracture, calpain activation, and mitochondrial permeability transition pore (mPTP) opening]. However, despite the fact that pharmacological tools against some of these targets have consistently demonstrated that it is possible to reduce infarct size in experimental studies by interventions applied at the time of reperfusion, the translation of these approaches to clinical practice has failed due in part to the lack of drugs able to be tested in humans. Recently, the benefits of both post-conditioning and inhibition of mPTP have been supported by proof-of-concept trials demonstrating the clinical applicability of strategies aimed at preventing lethal reperfusion injury. These promising results should stimulate efforts to develop drugs testable in humans against known, unexploited targets involved in reperfusion injury and to identify and validate additional ones.Cardiovascular research 05/2009; 83(2):169-78. · 5.80 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The calcium-sensitizing drug levosimendan increases myocardial contractility and, by activating K(+)-channels, dilates pulmonary vessels. In the acute setting, levosimendan is clinically used to treat right heart failure in pulmonary hypertension. As K(+)-channel activation elicits several beneficial effects in the vascular system, we hypothesized that levosimendan also attenuates the remodeling process in the monocrotaline model of rat pulmonary hypertension. Animal subgroups received levosimendan, the K(+)-channel opener nicorandil, or levosimendan together with the K(+)-adenosine triphosphate (ATP)-sensitive potassium channel (K(ATP)) blocker glibenclamide. Morphometric analyses revealed that levosimendan and nicorandil attenuated the increased pulmonary vascular medial wall thickness after monocrotaline challenge. Accordingly, in vivo BrdU assays revealed that levosimendan significantly diminished proliferation of pulmonary arterial smooth muscle cells (PASMCs), and this effect was attenuated by glibenclamide. Levosimendan also reduced right ventricular hypertrophy, but this effect was not glibenclamide sensitive and not recapitulated by nicorandil. In cell culture, levosimendan had a direct inhibitory effect on the platelet-derived growth factor (PDGF)-induced proliferation of PASMCs, which however required high concentrations of the compound, pointing towards an endothelial effect. Indeed, levosimendan increased cyclic guanosine monophosphate (cGMP) in human umbilical vein endothelial cells (HUVECs) and impaired the tumor necrosis factor-α (TNF-α)-induced inflammatory expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2), and monocyte chemotactic protein-1 (MCP-1). In luciferase reporter gene assays in HUVECs, levosimendan dose-dependently attenuated the TNF-α-stimulated increase of proinflammatory transcription factors activator protein 1 (AP1), hypoxia-inducible factor-1α (HIF-1α), and nuclear factor-κB (NF-κB). Levosimendan attenuates pulmonary vascular remodeling, presumably by an antiproliferative and anti-inflammatory effect which is mediated by cellular hyperpolarization. The compound also has a direct inhibitory effect on cardiac hypertrophy, which is however K(+)-channel independent.European Journal of Intensive Care Medicine 05/2011; 37(8):1368-77. · 5.17 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Nicorandil, a unique dual pharmacological mechanism anti-anginal agent with adenosine triphosphate sensitive potassium (K(ATP)) channel agonist and nitrate-like properties, provides cardiologists with a means of managing angina pectoris patients effectively and provides long-term cardioprotection. The aim of this review is to provide an update on the efficacy of treatment with nicorandil, which counteracts cardiac damage in patients with acute or chronic ischaemic heart disease, congestive heart failure and arrhythmia, with particular emphasis on that induced by ischaemic preconditioning (in which strong protection against ischaemia-reperfusion injury is afforded by a brief preliminary ischaemic period). First, the rationale for nicorandil treatment and its pharmacological effects on the vasculature and cardiomyocytes are reviewed. The mechanisms underlying ischaemic preconditioning, with a focus on those that involve the K(ATP) channel pathway, such as mitochondrial permeability transition pores, sub-lethal reactive oxygen species generation and nitric oxide production are then discussed. Next, clinical practice related to ischaemic preconditioning and pharmacological preconditioning with nicorandil as well as other favourable mechanisms of improvement of prognosis, in which it plays a role in improving endothelial function, modulating autonomic nervous system activity and stabilizing plaque are summarized. Finally, the tolerability of nicorandil is discussed.Drugs 06/2011; 71(9):1105-19. · 4.63 Impact Factor