Cardiac function is known to be impaired in diabetes. Alterations in intracellular calcium handling have been suggested to play a pivotal role. This study aimed to test the hypothesis that β-adrenergic activation can reveal the functional derangements of intracellular calcium handling of the 4-week diabetic heart. Langendorff perfused hearts of 4-week streptozotocin-induced diabetic rats were subjected to the β-adrenoceptor agonist isoproterenol. Cyclic changes in [Ca 2+] i levels were measured throughout the cardiac cycle using Indo-1 fluorescent dye. Based on the computational analysis of the [Ca 2+] i transient the kinetic parameters of the sarcoplasmic reticulum Ca 2+-ATPase and the ryanodine receptor were determined by minimizing the squared error between the simulated and the experimentally obtained [Ca 2+] i transient. Under unchallenged conditions, hemodynamic parameters were comparable between control and diabetic hearts. Isoproterenol administration stimulated hemodynamic function to a greater extent in control than in diabetic hearts, which was exemplified by more pronounced increases in rate of pressure development and decline. Under unchallenged conditions, [Ca 2+] i amplitude and rate of rise and decline of [Ca 2+] i as measured throughout the cardiac cycle were comparable between diabetic and control hearts. Differences became apparent under β-adrenoceptor stimulation. Upon β-activation the rate-pressure product showed a blunted response, which was accompanied by a diminished rise in [Ca 2+] i amplitude in diabetic hearts. Computational analysis revealed a reduced function of the sarcoplasmic reticulum Ca 2+-ATPase and Ca 2+-release channel in response to β-adrenoceptor challenge. Alterations in Ca 2+ i handling may play a causative role in depressed hemodynamic performance of the challenged heart at an early stage of diabetes.
- Calcium handling
- Computational modeling
- Diabetic cardiomyopathy
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Pharmacology, Toxicology and Pharmaceutics(all)