Nicorandil attenuates the mitochondrial Ca 2+ overload with accompanying depolarization of the mitochondrial membrane in the heart
| Autor: | Yuki Hirota, Haruaki Nakaya, Hiroe Nakazawa, Hideyuki Ishida, Toshiaki Sato, Chokoh Genka, Naoko Higashijima |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
medicine.medical_specialty
Heart Ventricles Vasodilator Agents In Vitro Techniques Pharmacology Mitochondrion Mitochondria Heart Ouabain Membrane Potentials Rats Sprague-Dawley Glibenclamide Adenosine Triphosphate Internal medicine Glyburide Potassium Channel Blockers medicine Animals Myocytes Cardiac Nicorandil Inner mitochondrial membrane Membrane potential Cardioprotection Chemistry Depolarization General Medicine Myocardial Contraction Rats cardiovascular system Cardiology Calcium Hydroxy Acids Decanoic Acids medicine.drug |
| Zdroj: | Naunyn-Schmiedeberg's Archives of Pharmacology. 369:192-197 |
| ISSN: | 1432-1912 0028-1298 |
| Popis: | The anti-anginal drug nicorandil has been demonstrated to protect the myocardium against ischemic injury in both experimental and clinical studies. Although nicorandil seems to protect the myocardium via activation of mitochondrial ATP-sensitive K+ (mitoKATP) channels, the mechanisms underlying its cardioprotection have remained elusive. We therefore examined whether nicorandil depolarizes the mitochondrial membrane and attenuates the mitochondrial Ca2+ overload. With the use of a Nipkow confocal system, the mitochondrial Ca2+ concentration ([Ca2+]m) and the mitochondrial membrane potential (DeltaPsim) in rat ventricular myocytes were measured by loading cells with rhod-2 and JC-1 respectively. The number of cell hypercontractures resulting from mitochondrial Ca2+ overload was counted. Exposing cells to ouabain (1 mM) evoked mitochondrial Ca2+ overload and increased the intensity of rhod-2 fluorescence to 180+/-15% of baseline ( p0.001). Nicorandil (100 microM) significantly attenuated the ouabain-induced mitochondrial Ca2+ overload (129+/-4% of baseline; p0.001 vs. ouabain). Nicorandil decreased the DeltaPsim during application of ouabain, thereby reducing the intensity of JC-1 fluorescence to 89+/-2% of baseline ( p0.05). Exposure of myocytes to ouabain eventually resulted in cell hypercontracture (51+/-2%). This ouabain-induced cell hypercontracture was blunted by application of nicorandil (37+/-2%, p0.05 vs. ouabain). Moreover, these effects of nicorandil were abolished by 5-hydroxydecanoate (500 microM), a putative mitoKATP channel blocker, and by glibenclamide (10 microM), a nonselective KATP channel blocker. Our results suggest that nicorandil attenuates the matrix Ca2+ overload with accompanying depolarization of the mitochondrial membrane. Such effect might potentially be attributed to the mechanism of cardioprotection afforded by nicorandil. |
| Databáze: | OpenAIRE |
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