Regulation of Mitochondrial [NADH] by Cytosolic [Ca²⁺] and Work in Trabeculae From Hypertrophic and Normal Rat Hearts

From the Department of Physiology, Loyola University–Chicago, School of Medicine, Maywood, Ill (R.B., D.M.B.), and Medizinische Klinik III, Universität Freiburg, Freiburg, Germany (L.S.M.).

Correspondence to Rolf Brandes, Department of Physiology, Loyola University–Chicago, School of Medicine, 2160 S First Ave, Maywood, IL 60153. E-mail rbrande{at}luc.edu

Abstract—Pressure overload hypertrophy has previously been shown to reduce contractility but paradoxically to increase O₂ consumption rates at a given force. Because O₂ consumption rates are related to mitochondrial [NADH] ([NADH]_m), we tested the hypothesis that with hypertrophy, control of [NADH]_m may be altered. Left ventricular trabeculae were isolated from banded and control rat hearts, and fluorescence spectroscopy was used to monitor [NADH]_m and cytosolic [Ca²⁺] ([Ca²⁺]_c). The hearts from banded rats developed hypertrophy (heart-to-body weight ratio increased from 4.1±0.1 to 4.9±0.1 mg/g) and hypertension (systolic arterial pressure increased from 117±4 to 175±5 mm Hg). Muscle workload was increased by stepwise increases in pacing frequency (up to 2 Hz). After increased work, [NADH]_m fell and then slowly recovered toward control levels. When work was decreased, [NADH]_m overshot control values and then slowly returned. The Ca²⁺-independent initial fall was larger for trabeculae from rats with hypertrophied hearts than from control rats (eg, 17±2% versus 11±1% when work was increased by increasing the frequency from 0.25 to 1 Hz). At 1 Hz, average [Ca²⁺]_c was 280 nmol/L, and the Ca²⁺-dependent [NADH]_m recovery was larger for trabeculae from rats with hypertrophied hearts (17±4% versus 10±2%) despite similar average [Ca²⁺]_c. At steady state after Ca²⁺-dependent recovery, there was no difference in [NADH]_m (fall of 1±2% versus 1±1%). Furthermore, the Ca²⁺-dependent overshoot was larger for trabeculae from hypertrophied than from control hearts (increase of 14±2% versus 9±2% when frequency was decreased from 1 to 0.25 Hz). We conclude that (1) there is initially a larger imbalance in NADH production versus consumption rate in hypertrophy (because NADH fell more) and (2) the Ca²⁺-dependent recovery mechanism is enhanced in hypertrophy (because NADH recovered and overshot more), thus compensating for the larger imbalance.

Key Words: muscle • force • ATP hydrolysis • oxidative phosphorylation • indo-1 fluorescence

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