Altered Ca2+ handling in ventricular myocytes isolated from diabetic rats

Abstract

It has been suggested that alterations in intracellular Ca2+ homeostasis may be responsible for the development of diabetic cardiomyopathy. We have studied the effects of streptozotocin-induced diabetes on intracellular Ca2+ concentration ([Ca2+]i) in enzymically isolated rat ventricular myocytes. [Ca2+]i was measured using indo 1 or fluo 3. Both diastolic and peak systolic [Ca2+]i were reduced in diabetic compared with normal myocytes (by 52 and 43%, respectively). The decay phase of the systolic [Ca2+]i transient was slower in the diabetic myocyte compared with normal (time constant = 89.6 +/- 3.4 ms, n = 23, normal vs. 105.2 +/- 4.05 ms, n = 20, diabetic; P < 0.01). This led to a significant prolongation of the [Ca2+]i transient duration in the diabetic myocyte. In both normal and diabetic myocytes, increasing the frequency of electrical stimulation decreased peak systolic [Ca2+]i. The relationship between stimulation frequency and normalized peak systolic [Ca2+]i was the same for both normal and diabetic myocytes. We also found that the caffeine-induced Ca2+ release [used as an index of sarcoplasmic reticulum (SR) Ca2+ content] was significantly reduced in diabetic myocytes. These data indicate that SR Ca2+ content is decreased by diabetes. In the presence of thapsigargin (2.5 microM, an inhibitor of SR Ca(2+)-adenosinetriphosphatase), the magnitude and time course of stimulus-evoked [Ca2+]i transients were identical in both groups of myocytes, suggesting that Ca2+ influx and/or efflux across the plasma membrane is not significantly affected in diabetes. We conclude that 1) diabetes is associated with significant alterations in [Ca2+]i homeostasis and 2) the decrease in systolic [Ca2+]i and lengthening of the systolic [Ca2+]i transient result primarily from dysfunction of the SR.

Effect of Chronic Renal Failure on Cardiac Contractile Function, Calcium Cycling, and Gene Expression of Proteins Important for Calcium Homeostasis in the Rat

“…We particularly noted marked calcium insensitivity in these heart cells with the diastolic calcium value substantially elevated compared with sham-treated rats. It appears that it takes considerably longer periods of aortic constriction to produce abnormal systolic function and calcium insensitivity in these isolated myocytes than the induction of uremia by the 5/6 nephrectomy model that is associated with very similar BP elevation in the species and strain that we employed (42). Although most patients with chronic renal failure display normal (or even supranormal) systolic function (2), we suggest that the digitalis-like substances that circulate in such patients might mask underlying contractile problems (10).…”

Skin Autofluorescence and All-Cause Mortality in Stage 3 CKD

“…For example, AGEs affects cardiomyocyte function by altering intracellular protein function in animal models (34,35). Third, AGEs bind to cell membrane receptors (particularly the cell receptor for AGEs) and may induce several intracellular cascades, resulting in the release of cytokines (9), inflammation (36), tumor growth (37), neurodegenerative processes (38), and amyloidosis (39).…”

Inhibition of PI-3 kinase/Akt/mTOR, but not calcineurin signaling, reverses insulin-like growth factor I-induced protection against glucose toxicity in cardiomyocyte contractile function

“…Diastolic dysfunction is the most prominent cardiac abnormality and is characterized by prolonged relaxation and decreased compliance (Galderisi et al 1991, Ren & Bode 2000. Several mechanisms are suggested for the pathogenesis of glucose-triggered cardiac dysfunction including prolonged action potential, impaired excitation-contraction coupling, loss of myofilament Ca 2+ sensitivity, elevated oxidative stress, intracellular Ca 2+ dysregulation and dampened insulin-like growth factor I (IGF-1) signaling (Cai & Kang 2001, Esberg & Ren 2003, Lagadic-Gossmann et al 1996, Ren 2000. Most of these speculations have received convincing support from clinical and experimental studies using antioxidant, gene delivery and IGF-1 as therapeutic remedies for cardiovascular complications in diabetes (Goo et al 1996, Ren et al 1999a, Trost et al 2002, Norby et al 2002.…”