1. Azelnidipine protects HL-1 cardiomyocytes from hypoxia/reoxygenation injury by enhancement of NO production independently of effects on gene expression.
- Author
-
Minato H, Endo R, Kurata Y, Notsu T, Kinugasa Y, Wakimizu T, Tsuneto M, Shirayoshi Y, Ninomiya H, Yamamoto K, Hisatome I, and Otsuki A
- Subjects
- Animals, Mice, Gene Expression Regulation drug effects, Nitric Oxide Synthase Type III metabolism, Action Potentials drug effects, Cell Hypoxia, Cell Line, Dihydropyridines pharmacology, Myocytes, Cardiac drug effects, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Nitric Oxide metabolism, Azetidinecarboxylic Acid pharmacology, Azetidinecarboxylic Acid analogs & derivatives, Calcium Channel Blockers pharmacology, Apoptosis drug effects, Myocardial Reperfusion Injury metabolism, Myocardial Reperfusion Injury prevention & control, Myocardial Reperfusion Injury genetics, Myocardial Reperfusion Injury pathology
- Abstract
It remains to be elucidated whether Ca
2+ antagonists induce pharmacological preconditioning to protect the heart against ischemia/reperfusion injury. The aim of this study was to determine whether and how pretreatment with a Ca2+ antagonist, azelnidipine, could protect cardiomyocytes against hypoxia/reoxygenation (H/R) injury in vitro. Using HL-1 cardiomyocytes, we studied effects of azelnidipine on NO synthase (NOS) expression, NO production, cell death and apoptosis during H/R. Action potential durations (APDs) were determined by the whole-cell patch-clamp technique. Azelnidipine enhanced endothelial NOS phosphorylation and NO production in HL-1 cells under normoxia, which was abolished by a heat shock protein 90 inhibitor, geldanamycin, and an antioxidant, N-acetylcysteine. Pretreatment with azelnidipine reduced cell death and shortened APDs during H/R. These effects of azelnidipine were diminished by a NOS inhibitor, L-NAME, but were influenced by neither a T-type Ca2+ channel inhibitor, NiCl2 , nor a N-type Ca2+ channel inhibitor, ω-conotoxin. The azelnidipine-induced reduction in cell death was not significantly enhanced by either additional azelnidipine treatment during H/R or increasing extracellular Ca2+ concentrations. RNA sequence (RNA-seq) data indicated that azelnidipine-induced attenuation of cell death, which depended on enhanced NO production, did not involve any significant modifications of gene expression responsible for the NO/cGMP/PKG pathway. We conclude that pretreatment with azelnidipine protects HL-1 cardiomyocytes against H/R injury via NO-dependent APD shortening and L-type Ca2+ channel blockade independently of effects on gene expression., (© 2024. Springer Nature Japan KK, part of Springer Nature.)- Published
- 2024
- Full Text
- View/download PDF