Regulation of Mitochondrial [NADH] by Cytosolic [Ca 2+ ] and Work in Trabeculae From Hypertrophic and Normal Rat Hearts

Abstract

Abstract —Pressure overload hypertrophy has previously been shown to reduce contractility but paradoxically to increase O 2 consumption rates at a given force. Because O 2 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 [Ca 2+ ] ([Ca 2+ ] 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 Ca 2+ -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 [Ca 2+ ] c was ≈280 nmol/L, and the Ca 2+ -dependent [NADH] m recovery was larger for trabeculae from rats with hypertrophied hearts (17±4% versus 10±2%) despite similar average [Ca 2+ ] c . At steady state after Ca 2+ -dependent recovery, there was no difference in [NADH] m (fall of 1±2% versus 1±1%). Furthermore, the Ca 2+ -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 Ca 2+ -dependent recovery mechanism is enhanced in hypertrophy (because NADH recovered and overshot more), thus compensating for the larger imbalance.