Regulation of mitochondrial [NADH] by cytosolic [Ca2+] and work in trabeculae from hypertrophic and normal rat hearts

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 κ280 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.