title: Restoration of diabetes-induced abnormal local Ca2+ release in cardiomyocytes by angiotensin II receptor blockade.
abstract: Stimulation of local renin-angiotensin system and increased levels of oxidants characterize the diabetic heart. Downregulation of ANG II type 1 receptors (AT(1)) and enhancement in PKC activity in the heart point out the role of AT(1) blockers in diabetes. The purpose of this study was to evaluate a potential role of an AT(1) blocker, candesartan, on abnormal Ca(2+) release mechanisms and its relationship with PKC in the cardiomyocytes from streptozotocin-induced diabetic rats. Cardiomyocytes were isolated enzymatically and then incubated with either candesartan or a nonspecific PKC inhibitor bisindolylmaleimide I (BIM) for 6-8 h at 37 degrees C. Both candesartan and BIM applied on diabetic cardiomyocytes significantly restored the altered kinetic parameters of Ca(2+) transients, as well as depressed Ca(2+) loading of sarcoplasmic reticulum, basal Ca(2+) level, and spatiotemporal properties of the Ca(2+) sparks. In addition, candesartan and BIM significantly antagonized the hyperphosphorylation of cardiac ryanodine receptor (RyR2) and restored the depleted protein levels of both RyR2 and FK506 binding protein 12.6 (FKBP12.6). Furthermore, candesartan and BIM also reduced the increased PKC levels and oxidized protein thiol level in membrane fraction of diabetic rat cardiomyocytes. Taken together, these data demonstrate that AT(1) receptor blockade protects cardiomyocytes from development of cellular alterations typically associated with Ca(2+) release mechanisms in diabetes mellitus. Prevention of these alterations by candesartan may present a useful pharmacological strategy for the treatment of diabetic cardiomyopathy.
authors.affiliation: Department of Biophysics, School of Medicine, Ankara University, Sihhiye, 06100, Ankara, Turkey.
authors.forename: Nazmi
authors.initials: N
authors.lastname: Yaras
authors.forename: Ayca
authors.initials: A
authors.lastname: Bilginoglu
authors.forename: Guy
authors.initials: G
authors.lastname: Vassort
authors.forename: Belma
authors.initials: B
authors.lastname: Turan
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001713:Biphenyl Compounds; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D009202:Cardiomyopathies / Q000209:etiology / Q000517:prevention & control; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D011506:Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D013438:Sulfhydryl Compounds; D013777:Tetrazoles; D002110:Caffeine; D011493:Protein Kinase C; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; C088060:bisindolylmaleimide; C081643:candesartan; D002118:Calcium