Abstract
Our recent studies identified hitherto unknown, naturally occurring nucleotide: 4-pyridone-3-carboxamide-1-β-D-ribonucleoside triphosphate (4PYTP). This nucleotide was found to accumulate in the erythrocytes of patients with chronic renal failure, a condition that precipitates heart failure and atherosclerosis. We found also increase in plasma concentration of nucleoside precursor of 4PYTP: 4-pyridone-3-carboxamide-1-β-D-ribonucleoside (4PYR) in patients with renal failure. This study was aimed to evaluate metabolism and potential toxic effect of this nucleoside in cardiomyocytes and endothelial cells. We used human erythrocytes isolated from peripheral blood, human endothelial cell line HMEC-1 cell line and cardiomyocytes isolated from rat hearts. Cells were incubated with chemically synthesized 4PYR. Metabolic assessments were performed with HPLC or liquid chromatography/mass spectrometry. We demonstrated formation of 4PYTP in human erythrocytes during incubation with 4PYR. We noted however, preferential accumulation of monophosphate of 4PYR (4PYMP) over 4PYTP. Concentration of 4PYMP increased in the erythrocytes from below 5 μM to 76.9±7.1, 254.7±13.9 and 674.3±34.3 μM after 6h incubation with 0.1, 0.3 and 1 mM 4PYR. 4PYMP progressively accumulated in the cultured endothelial cells during incubation with 4PYR up to 72 h. Cardiomyocytes were also shown to accumulate 4PYMP. In all cell types formation of 4PYR nucleotides was accompanied by decrease in cellular ATP concentration. Furthermore, treatment with 4PYR and formation of its nucleotides in endothelial cells reduced NO synthase pathway while in cardiac myocytes resulted in prolongation of action potential. We conclude that endogenously formed 4PYR is effectively metabolized to nucleotide derivatives in the erythrocytes, cardiomyocytes and endothelium. Depletion of ATP in these cells accompanying 4PYR metabolism and deleterious effects on cell function suggests that accumulation of 4PYR and its enhanced metabolism to nucleotides in endothelium and cardiomyocyted may contribute to cardiovascular pathology observed in chronic renal failure.
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