Calcium handling and sarcoplasmic-reticular protein functions during heart-failure transition in ventricular myocardium from rats with hypertension

The objective of this study was to determine the primary event that occurs in Ca2+-regulatory sarcoplasmic-reticular (SR) proteins during subacute tra nsition from concentric/mechanically-compensated left ventricular (LV) hype rtrophy to eccentric/decompensated hypertrophy. Using Dahl salt-sensitive r ats with hypertension, changes of myocardial contraction, intracellular Ca2 + transients, SR Ca2+ up-take, protein levels of SR Ca2+ ATPase (SERCA2), p hospholamban, and calsequestrin (CSQ), and mRNA levels of SERCA2 and CSQ we re serially determined and compared between the established stage of LV hyp ertrophy (LVH) and the subsequent stage of overt LV dysfunction (CHF). In L VH, isolated LV papillary muscle preparations showed an equal peak-tension level and a mild prolongation of the isometric tension decay compared to th ose of age-matched controls. The Ca2+ transients as measured by aequorin we re unchanged. The Ca2+ uptake of isolated SR vesicles and the protein/mRNA levels of SR proteins were also equivalent to those of the controls. In con trast, in CHF, the failing myocardium showed a further prolongation of the contraction time course and a 39% reduction of the peak-tension development . The Ca2+ transients showed changes consisting of a decrease in the peak l evel and a prolongation of the time course. In addition, the SR Ca2+ uptake was decreased by 41%. Despite these functional changes, the protein and mR NA levels of the SR components remained equivalent to those of the age-matc hed controls. Thus, in this hypertensive animal, 1) at the LVH stage, myoca rdial contractility and intracellular capability to regulate Ca2+ remained normal; 2) at the CHF stage, impaired SR Ca2+ handling and the subsequent r eduction of myocardial contraction were in progress; and 3) impairments of SR function occurred at the post-translational protein level rather than at the transcriptional/translational levels. Our findings support the role of SR proteins as the primary determinant of the contractile dysfunction that occurs during the heart-failure transition; however, post-translational mo dulators of these SR elements may also be critical. (C) 2001 Elsevier Scien ce Inc. All rights reserved.