Treatment with AT(1) receptor blocker restores diabetes-induced alterations in intracellular Ca(2+) transients and contractile function of rat myocardium.
We investigated the effect of treatment with an angiotensin II receptor blocker, candesartan-cilexetil, on the mechanical and electrophysiological properties of cardiomyocytes isolated from streptozotocin-induced diabetic (STZ) rats. Contractile activity and electrophysiological properties were measured in papillary muscle and ventricular cardiomyocytes from normoglycemic and STZ-induced diabetic rats given vehicle or 5mg/kg/day candesartan-cilexetil for 4 weeks. Alterations in the kinetics of contractile activity and intracellular Ca(2+) transients were observed as well as a typical prolongation of action potential duration and significant decrease of potassium currents in diabetic rat heart preparations. Candesartan-cilexetil treatment recovered significantly prolonged action potential and depressed potassium currents in diabetic rats. It was also shown that treatment with AT(1) blocker restored altered kinetics of both the Ca(2+) transients in cardiomyocytes and the contractile activity in papillary muscle strips of diabetic rats. We also showed that incubation of cardiomyocytes from diabetic rats with a protein kinase C (PKC) inhibitor bisindolylmaleimide I (BIM) had a similar effect to candesartan treatment on the Ca(2+) transients. Thus, angiotensin II receptor blockade protects the heart from the development of cellular alterations typically related with diabetes, and this action of AT(1) receptors seems to be related with the activity of PKC.
Ozdemir
Semir
S
Department of Biophysics, School of Medicine, Ankara University, Sihhiye, 06100 Ankara, Turkey.
Ugur
Mehmet
M
Gürdal
Hakan
H
Turan
Belma
B
D000200:Action Potentials / Q000187:drug effects*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage*; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D002118:Calcium / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D013777:Tetrazoles / Q000008:administration & dosage*
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C077793:candesartan cilexetil; D002118:Calcium