title: beta-Adrenergic activation reveals impaired cardiac calcium handling at early stage of diabetes.
abstract: 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 beta-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 beta-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 beta-adrenoceptor stimulation. Upon beta-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 beta-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.
authors.affiliation: Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
authors.forename: Jorn
authors.initials: J
authors.lastname: op den Buijs
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Miklós
authors.forename: Natal A W
authors.initials: NA
authors.lastname: van Riel
authors.forename: Christina M
authors.initials: CM
authors.lastname: Prestia
authors.forename: Orsolya
authors.initials: O
authors.lastname: Szenczi
authors.forename: András
authors.initials: A
authors.lastname: Tóth
authors.forename: Ger J
authors.initials: GJ
authors.lastname: Van der Vusse
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
authors.forename: László
authors.initials: L
authors.lastname: Ligeti
authors.forename: Tamás
authors.initials: T
authors.lastname: Ivanics
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D013311:Streptozocin
chemical_list: D011943:Receptors, Adrenergic, beta; D013311:Streptozocin; D002118:Calcium