Contractile Reserve and Intracellular Calcium Regulation in Mouse Myocytes From Normal and Hypertrophied Failing Hearts

Mouse myocyte contractility and the changes induced by pressure overload are not fully understood. We studied contractile reserve in isolated left ventricular myocytes from mice with ascending aortic stenosis (AS) during compensatory hypertrophy (4-week AS) and the later stage of early failure (7-week AS) and from control mice. Myocyte contraction and Ca(2+)(i) transients with fluo-3 were measured simultaneously. At baseline (0.5 Hz, 1.5 mmol/L Ca(2+)(o), 25 degrees C), the amplitude of myocyte shortening and peak-systolic Ca(2+)(i) in 7-week AS were not different from those of controls, whereas contraction, relaxation, and the decline of Ca(2+)(i) transients were slower. In response to the challenge of high Ca(2+)(o), fractional cell shortening was severely depressed with reduced peak-systolic Ca(2+)(i) in 7-week AS compared with controls. In response to rapid pacing stimulation, cell shortening and peak-systolic Ca(2+)(i) increased in controls, but this response was depressed in 7-week AS. In contrast, the responses to both challenge with high Ca(2+)(o) and rapid pacing in 4-week AS were similar to those of controls. Although protein levels of Na(+)-Ca(2+) exchanger were increased in both 4-week and 7-week AS, the ratio of SR Ca(2+)-ATPase to phospholamban protein levels was depressed in 7-week AS compared with controls but not in 4-week AS. This was associated with an impaired capacity to increase sarcoplasmic reticulum Ca(2+) load during high work states in 7-week AS myocytes. In hypertrophied failing mouse myocytes, depressed contractile reserve is related to an impaired augmentation of systolic Ca(2+)(i) and SR Ca(2+) load and simulates findings in human failing myocytes.