Mitochondrial Physiology Network 10.9: 95 (2005) - download pdf

The metabolic activators of  mitochondrial ATP-dependent potassium channel and its role in cardioprotection.

Galina D Mironova¹, IB Krylova², AE Negoda¹, OM Rodionova², EV Kachaeva¹, NP Evdokimova² , NS Sapronov²

¹Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region, 142290 Russia; ²Institute of Experimental Medicine, Russian Academy of Medical Sciences, St. Petersburg, Russia. - mironova@iteb.ru

    Cardiac disorders are a common cause of death in technically developed countries, so the search for principally new ways of their prevention and treatment is a problem of great concern. A development of new approaches based on the data of basic studies obtained lately is important in this perspective. It is well know that synthetic activators of the mitochondrial ATP-dependent K⁺ channel (mitoK_ATP) have a clear cardioprotecting properties and prevented ATP disintegration in experimental myocardial ischemia [1]. In our earlier research we found that uridine-5¢-diphosphate (UDP) is a physiological activator of the mitoK_ATP [2].

    The goal of this study is to investigate a possible role of metabolic activators of mitoK_ATP in cardioprotection. We studied the cardioprotective properties of the precursors of UDP, uridine and uridine-5¢-monophosphate (UMP). These precursors opposed to UDP possess the capacity to penetrate into the cell. On a model of acute myocardial infarction in rats the anti-ischemic activity of these preparations was revealed. It was shown that  the myocardium infarct zone decreased in 1.9 and 3.5 times for uridine and UMP, respectively. The changes of the T-wave amplitude, electrophysiological characteristic of myocardium injuries during infarction, confirmed these data. The results obtained showed the same trend of changes of the T-wave amplitude under the treatment of the preparations. The inhibitors of mitoK_ATP  glibenclamide and 5-hydroxydecanoic acid (5-HD) prevented the cardioprotective effect of uridine and UMP. This suggests that mitoK_ATP is involved in the realization of the anti-ischemic effect of uridine and its phosphonucleotide. It was also found that uridine and UMP affect the development of occlusion arrhythmias in rats, the effect of UMP being more pronounced. Since the antiarrhythmic action of 5-HD was less manifested, than the effect of glibenclamide we suppose that their antiarrhythmic action  is associated mainly with the activation of the cell membrane ATP-dependent potassium channel (cellK_ATP). Thus both preparations can be considered as potential cardiotropic agents, but the mechanism of their action can be different.

     Supported by Russia Foundation of Basic Research grant No/ 04-04-97281.

1.    O’Rourke (2004) Evidence for mitochondrial K⁺ channels and their role in cardioprotection. Circ. Res. 94: 420-432.

2.  Mironova GD, Negoda A, Marinov BS, Paucek P, Costa ADT, Grigoriev SM, Skarga YY, Garlid KD (2004) Functional distinctions between the mitochondrial ATP-dependent K⁺ channel (mito K_ATP) and its inward rectifier subunit (mito KIR). J. Biol. Chem. 279: 32562-32568.