The effect of losartan treatment on the response of diabetic cardiomyocytes to ATP depletion

Abstract

The present work aimed to investigate the effect of losartan treatment of healthy and diabetic rats on cardiomyocyte response to ATP depletion. Cells were isolated from normoglycemic (N) and streptozotocin-injected (55 mg/kg) rats (D) treated or not treated with losartan (20 mg/kg/day in the drinking water; NL and DL, respectively) for 3 weeks. In each group of cells, enzyme activities such as glucose-6-phosphate (G6PDH) and glycerol-3-phosphate dehydrogenases (G3PDH), lactate/pyruvate, glycogen levels and citrate synthase were measured as an index of glycolytic dysregulation and mitochondrial mass, respectively. Cells were then challenged with NaCN (2 mM) in glucose-free Tyrode solution (metabolic intoxication, MI), a protocol to study ischemia at cell level. Under these conditions, the time to contractile failure up to rigor-type hyper-contracture in field-stimulated cells and K(ATP) current activation by patch-clamp recordings were measured. In comparison with N and NL, D cells presented higher G6PDH and cytoplasmic G3PDH activities, lactate/pyruvate, glycogen content but similar levels of citrate synthase, and decay time of contraction. When subjected to MI, D cells showed delayed activation of the K(ATP) current (25.7±7.1 min; p<0.001 vs. N and NL), increased time to contractile failure and rigor-type hyper-contracture (p<0.001 vs. N and NL). In cells from DL rats both functional (time to rigor and to K(ATP) current activation) and metabolic parameters, approached values similar to those measured in N and NL cells. These results demonstrate that diabetic cardiomyocytes from rats treated with losartan, maintain the capacity to respond promptly to ATP depletion reaching contractile failure, rigor-type hypercontracture and K(ATP) opening with a similar timing of N cells.