© 2000 American Heart Association, Inc.
Cellular Biology |
Contractile Reserve and Intracellular Calcium Regulation in Mouse Myocytes From Normal and Hypertrophied Failing Hearts
From the Department of Medicine (K.I., X.Y., M.T., B.H.L.), Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Mass; and Division of Cardiology (Z.S., W.H.B.), University of Utah Health Sciences Center (Salt Lake City).
Correspondence to Beverly H. Lorell, MD, Cardiovascular Division, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215. E-mail blorell{at}caregroup.harvard.edu
Abstract—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 [Ca2+]i transients with fluo-3 were measured simultaneously. At baseline (0.5 Hz, 1.5 mmol/L [Ca2+]o, 25°C), the amplitude of myocyte shortening and peak-systolic [Ca2+]i in 7-week AS were not different from those of controls, whereas contraction, relaxation, and the decline of [Ca2+]i transients were slower. In response to the challenge of high [Ca2+]o, fractional cell shortening was severely depressed with reduced peak-systolic [Ca2+]i in 7-week AS compared with controls. In response to rapid pacing stimulation, cell shortening and peak-systolic [Ca2+]i increased in controls, but this response was depressed in 7-week AS. In contrast, the responses to both challenge with high [Ca2+]o and rapid pacing in 4-week AS were similar to those of controls. Although protein levels of Na+-Ca2+ exchanger were increased in both 4-week and 7-week AS, the ratio of SR Ca2+-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 Ca2+ 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 [Ca2+]i and SR Ca2+ load and simulates findings in human failing myocytes.
Key Words: myocytes • contractility • sarcoplasmic reticulum • Ca2+-ATPase • heart failure • hypertrophy
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