Enhanced Na + -Ca 2+ Exchange in the Infarcted Heart

Abstract Cellular Ca 2+ regulation is abnormal in diseased hearts. We designed this study to assess the role of the Na + -Ca 2+ exchanger in excitation-contraction coupling in surviving myocardium of the infarcted heart. We measured cellular contractions and whole-cell currents in single left ventricular myocytes isolated from the hearts of rabbits with healed myocardial infarction (MI). Eight weeks after MI, rabbits had left ventricular dysfunction without overt heart failure. Myocytes isolated from regions adjacent to the infarcted zone were significantly longer than cells from control hearts. At low stimulation rates (0.5 Hz), the amplitude of field-stimulated contractions was increased (11.6±0.5% versus 10.2±0.6% resting cell length), whereas the time to peak shortening and action potential duration were prolonged in the MI cells. When stimulation frequency was increased to 2.0 Hz, cellular shortening did not change or decreased in myocytes from infarcted hearts, whereas control cells had a positive shortening-interval relationship. Cells from infarcted hearts had a significantly decreased (31%) L-type Ca 2+ current ( I Ca ) density but no change in the current-voltage relationship or the kinetics of I Ca inactivation. Maximal Na + -Ca 2+ exchange current density was significantly increased (32%) in the cells from infarcted hearts. Sarcoplasmic reticulum (SR) Ca 2+ content during a stable train of contractions, as estimated from caffeine-induced inward currents, was slightly increased ( P =NS) in the MI myocytes. To determine whether Na + -Ca 2+ exchange influenced SR Ca 2+ content, cells were clamped at potentials between −70 and +90 mV for 400 ms. The amplitude of the contraction during a subsequent clamp step to +10 mV was then measured as an index of SR loading that occurred during the preceding clamp step. Steps to positive potentials produced greater augmentation of the subsequent contraction in MI than in control myocytes. In myocytes from the infarcted heart, increased activity of the Na + -Ca 2+ exchanger may promote Ca 2+ entry or decrease Ca 2+ extrusion. This relative augmentation of inward Ca 2+ flux by the exchanger may enhance SR Ca 2+ loading and thus support contractility that would otherwise be impaired as a result of decreased Ca 2+ current. However, Ca 2+ influx by the exchanger may contribute to the prolongation of contractions in myocytes from infarcted hearts.