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Timolol treatment of diabetic rats improved basal cardiac function and responses to β3‐ but not β1‐ and β2‐receptors stimulations
Author(s) -
TUNCAY ERKAN,
ZEYDANLI ESMA NUR,
TURAN BELMA
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1098.4
Subject(s) - timolol , endocrinology , medicine , ryanodine receptor , diabetic cardiomyopathy , ryanodine receptor 2 , agonist , streptozotocin , chemistry , basal (medicine) , calcium in biology , cardiomyopathy , receptor , diabetes mellitus , heart failure , intraocular pressure , surgery
We aimed to investigate whether defective intracellular Ca 2+ ‐handling is improved by timolol in diabetic cardiomyopathy. In diabetic cardiomyopathy, the defects identified in the heart function from diabetic animals include alteration of Ca 2+ signaling via changes in critical processes that regulate intracellular Ca 2+ concentration. These defects result partially from a dysfunction of cardiac ryanodine receptor calcium release channel (RyR2). In a rat model of chronic diabetes induced by streptozotocin, we evaluated effects of timolol (25 mg/kg, daily; for 3 months) on left ventricular dysfunction and β 1 ‐, β 2 ‐, β 3 ‐agonist responsiveness using isolated perfuded hearts, papillary muscle, and cardiomyocytes. Normal cardiac function including left ventricular developed pressure, action potential duration was well preserved in timolol‐treated diabetic rats. Defective β 3 ‐agonist responsiveness but not specific β 1 ‐ and β 2 ‐agonist responsiveness was impored in the treated diabetic rats. Timolol‐treatment also improved altered kinetic parameters of Ca 2+ transients, depressed Ca 2+ loading of sarcoplasmic reticulum, basal intracellular Ca 2+ level and depressed level of L‐type Ca 2+ currents were significantly restored. In addition, hyperphosphorylated levels of RyR2, protein kinase A, and Ca 2+ /calmodulin‐dependent protein kinase, and depleted protein level of calstabin2 were restored to control levels. Furtheremore, timolol treatment prevented diabetes‐induced increased oxidized protein‐thiol levels in heart‐tissue. Our data suggest that these beneficial effects of timolol on diabetic‐heart appear, at least in part, to be related to improvement of β 3 ‐adrenergic receptors and restoration of RyR2 macromolecular‐complex via an antioxidant‐like effect. (Supported by TUBITAK SBAG‐107S427).