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 ß-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 ß-adrenoceptor agonist isoproterenol. Cyclic changes in [Ca2+]i levels were measured throughout the cardiac cycle using Indo-1 fluorescent dye. Based on the computational analysis of the [Ca2+]i transient the kinetic parameters of the sarcoplasmic reticulum Ca2+-ATPase and the ryanodine receptor were determined by minimizing the squared error between the simulated and the experimentally obtained [Ca2+]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, [Ca2+]i amplitude and rate of rise and decline of [Ca2+]i as measured throughout the cardiac cycle were comparable between diabetic and control hearts. Differences became apparent under ß-adrenoceptor stimulation. Upon ß-activation the rate-pressure product showed a blunted response, which was accompanied by a diminished rise in [Ca2+]i amplitude in diabetic hearts. Computational analysis revealed a reduced function of the sarcoplasmic reticulum Ca2+-ATPase and Ca2+-release channel in response to ß-adrenoceptor challenge. Alterations in Ca2+i handling may play a causative role in depressed hemodynamic performance of the challenged heart at an early stage of diabetes.
Op den Buijs, J., Miklós, Z., Riel, van, N. A. W., Prestia, C. M., Szenczi, O., Toth, A., ... Ivanics, T. (2005). Beta-Adrenergic activation reveals impaired cardiac calcium handling at early stage of diabetes. Life Sciences, 76(10), 1083-1098. https://doi.org/10.1016/j.lfs.2004.08.018