Voltage dependence of the Ca2+ transient in endocardial and epicardial myocytes from the left ventricle of Goto–Kakizaki type 2 diabetic rats

Abstract

Diabetes mellitus is a major global health disorder and, currently, over 450 million people have diabetes with 90% suffering from type 2 diabetes. Left untreated, diabetes may lead to cardiovascular diseases which are a leading cause of death in diabetic patients. Calcium is the trigger and regulator of cardiac muscle contraction and derangement in cellular Ca homeostasis, which can result in heart failure and sudden cardiac death. It is of paramount importance to investigate the regional involvement of Ca in diabetes-induced cardiomyopathy. Therefore, the aim of this study was to investigate the voltage dependence of the Ca transients in endocardial (ENDO) and epicardial (EPI) myocytes from the left ventricle of the Goto-Kakizaki (GK) rats, an experimental model of type 2 diabetes mellitus. Simultaneous measurement of L-type Ca currents and Ca transients was performed by whole-cell patch clamp techniques. GK rats displayed significantly increased heart weight, heart weight/body weight ratio, and non-fasting and fasting blood glucose compared to controls (CON). Although the voltage dependence of L-type Ca current was unaltered, the voltage dependence of the Ca transients was reduced to similar extents in EPI-GK and ENDO-GK compared to EPI-CON and ENDO-CON myocytes. TPK L-type Ca current and Ca transient were unaltered. THALF decay of L-type Ca current was unaltered; however, THALF decay of the Ca transient was shortened in ENDO and EPI myocytes from GK compared to CON rat hearts. In conclusion, the amplitude of L-type Ca current was unaltered; however, the voltage dependence of the Ca transient was reduced to similar extents in EPI and ENDO myocytes from GK rats compared to their respective controls, suggesting the possibility of dysfunctional sarcoplasmic reticulum Ca transport in the GK diabetic rat hearts.

Calcium Signaling in the Ventricular Myocardium of the Goto-Kakizaki Type 2 Diabetic Rat

“…In our recently published data, L-type Ca 2+ current and Ca 2+ transients were simultaneously measured in endocardial (ENDO) and epicardial (EPI) myocytes from the left ventricle of GK rats [ 74 ]. Consistent with previous findings [ 48 ], the amplitude of L-type Ca 2+ current, over a wide range of test potentials, was unaltered in ENDO and EPI myocytes from the left ventricle of GK rat.…”

“…Interestingly, while a reduction in the amplitude of L-type Ca + current has been reported in earlier studies on a diabetic heart [ 75 , 76 ], it does not necessarily explain the reduced Ca 2+ transients. This is because many reports show no change in L-type Ca 2+ current despite the reduction in both contractions and Ca 2+ transients [ 48 , 74 , 77 – 79 ]. Instead, reduction of Ca 2+ transients and the consequent contractile dysfunction may be due to depletion of SR Ca 2+ , which may result from RYR-dependent Ca 2+ leak, an increased Ca 2+ extrusion through NCX, or a reduced function of SERCA [ 61 , 80 ].…”

Calcium signaling in endocardial and epicardial ventricular myocytes from streptozotocin‐induced diabetic rats

“…Ventricular myocytes were obtained by enzymatic and mechanical dispersal techniques in accordance with previously described protocols 24,27,28 . Animals were euthanized with a guillotine.…”

“…On stabilization of heart contraction, perfusion was switched to Ca 2+ -free cell isolation solution containing egtazic acid (0.1 mmol/L) for 4 min, and then to cell isolation solution containing Ca 2+ (0.05 mmol/L), type 1 collagenase (0.60 mg/mL) and type XIV protease (0.075 mg/mL) for 6 min. On completion of enzymatic treatment, hearts were detached from the Langendorff perfusion system and the left ventricle was further dissected as described in earlier studies 27,28 . Thin sections were carefully dissected by fine scissors from the outermost layer (EPI) and innermost layer (ENDO) of the left ventricle.…”

“…To date, only a few studies have explored the transmural effect of STZ-induced diabetes on Ca 2+ signaling in ventricular myocytes [26][27][28] . For this reason, the current work was undertaken to investigate the progressive regional effects of diabetes on ventricular myocytes.…”