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Effects of cytosolic $NADH/NAD^{+}$levels on sarcoplasmic reticulum $Ca^{2+}$release in permeabilized rat ventricular myocytes
| Content Provider | Scilit |
|---|---|
| Author | Zima, Aleksey V. Copello, Julio A. Blatter, Lothar A. |
| Copyright Year | 2004 |
| Description | Journal: The Journal of physiology In the heart ischaemic conditions induce metabolic changes known to have profound effects on $Ca^{2+}$ signalling during excitation–contraction coupling. Ischaemia also affects the redox state of the cell. However, the role of cytosolic redox couples, such as the $NADH/NAD^{+}$ redox system, for the regulation of $Ca^{2+}$ homeostasis has remained elusive. We studied the effects of NADH and $NAD^{+}$ on sarcoplasmic reticulum (SR) $Ca^{2+}$ release in permeabilized rat ventricular myocytes as well as on $Ca^{2+}$ uptake by SR microsomes and ryanodine receptor (RyR) single channel activity. Exposure of permeabilized myocytes to NADH (2 mm; [Ca^{2+}$]_{cyt}$= 100nm) decreased the frequency and the amplitude of spontaneous $Ca^{2+}$ sparks by 62% and 24%, respectively. This inhibitory effect was reversed by $NAD^{+}$ (2 mm) and did not depend on mitochondrial function. The inhibition of $Ca^{2+}$ sparks by NADH was associated with a 52% decrease in SR $Ca^{2+}$ load. Some of the effects observed with NADH may involve the generation of superoxide anion (O_{2}$^{−}$·) as they were attenuated to just a transient decrease of $Ca^{2+}$ spark frequency by superoxide dismutase (SOD). O_{2}$^{−}$· generated in situ from the xanthine/xanthine oxidase reaction caused a slowly developing decrease of $Ca^{2+}$ spark frequency and SR $Ca^{2+}$ load by 44% and 32%, respectively. Furthermore, in studies with cardiac SR microsomes NADH slowed the rate of ATP-dependent $Ca^{2+}$ uptake by 39%. This effect also appeared to depend on O_{2}$^{−}$· formation. Single channel recordings from RyRs incorporated into lipid bilayers revealed that NADH (2 mm) inhibited the activity of RyR channels by 84%. However, NADH inhibition of RyR activity was O_{2}$^{−}$·-independent. In summary, an increase of the cytoplasmic $NADH/NAD^{+}$ ratio depresses SR $Ca^{2+}$ release in ventricular cardiomyocytes. The effect appears to be mediated by direct NADH inhibition of RyR channel activity and by indirect NADH inhibition (O_{2}$^{−}$· mediated) of SR $Ca^{2+}$-ATPase activity with a subsequent decrease in SR $Ca^{2+}$ content. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1664876/pdf |
| Ending Page | 741 |
| Page Count | 15 |
| Starting Page | 727 |
| ISSN | 00223751 |
| e-ISSN | 14697793 |
| DOI | 10.1113/jphysiol.2003.055848 |
| Journal | The Journal of physiology |
| Issue Number | 3 |
| Volume Number | 555 |
| Language | English |
| Publisher | Wiley-Blackwell |
| Publisher Date | 2004-03-09 |
| Access Restriction | Open |
| Subject Keyword | Journal: The Journal of physiology Single Channel Sr Microsomes Channel Activity Decrease in Sr |
| Content Type | Text |
| Resource Type | Article |
| Subject | Physiology Sports Science |
