title: 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.
authors.affiliation: Dept. of Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Alfarano
authors.forename: Silvia
authors.initials: S
authors.lastname: Suffredini
authors.forename: Ornella
authors.initials: O
authors.lastname: Fantappiè
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mugelli
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cerbai
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Manni
authors.forename: Laura
authors.initials: L
authors.lastname: Raimondi
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
chemical_list: D015221:Potassium Channels; D000255:Adenosine Triphosphate; D019808:Losartan