Intracellular sodium determines frequency-dependent alterations in contractility in hypertrophied feline ventricular myocytes

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 292; no. 2; pp. H1129 - H1138
• Main Authors: Mills, Geoffrey D, Harris, David M, Chen, Xiongwen, Houser, Steven R
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.02.2007
• Subjects: Action Potentials; Animals; Calcium - metabolism; Cardiac Pacing, Artificial; Cardiology; Cardiomegaly - metabolism; Cardiomegaly - physiopathology; Cats; Cells; Circulatory system; Disease Models, Animal; Heart Rate; Heart Ventricles - metabolism; Heart Ventricles - physiopathology; Hypertrophy, Left Ventricular - metabolism; Hypertrophy, Left Ventricular - physiopathology; Intracellular Fluid - metabolism; Medical disorders; Microdialysis; Myocardial Contraction; Myocytes, Cardiac - metabolism; Patch-Clamp Techniques; Sodium; Sodium - metabolism; Sodium-Calcium Exchanger - metabolism; Time Factors
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00375.2006

1 Temple University School of Medicine and 2 Thomas Jefferson University, Philadelphia, Pennsylvania Submitted 8 April 2006 ; accepted in final form 25 September 2006 Hypertrophy and failure (H/F) in humans and large mammals are characterized by a change from a positive developed force-frequency relationship (+FFR) in normal myocardium to a flattened or negative developed force-frequency relationship (–FFR) in disease. Altered Ca 2+ homeostasis underlies this process, but the role of intracellular Na + concentration ([Na + ] i ) in H/F and frequency-dependent contractility reserve is unclear. We hypothesized that altered [Na + ] i is central to the –FFR response in H/F feline myocytes. Aortic constriction caused left ventricular hypertrophy (LVH). We found that as pacing rate was increased, contraction magnitude was maintained in isolated control myocytes (CM) but decreased in LVH myocytes (LVH-M). Quiescent LVH-M had higher [Na + ] i than CM (LVH-M 13.3 ± 0.3 vs. CM 8.9 ± 0.2 mmol/l; P < 0.001) with 0.5-Hz pacing (LVH-M 14.9 ± 0.5 vs. CM 10.8 ± 0.4 mmol/l; P < 0.001) but were not different at 2.5 Hz (17.0 ± 0.7 vs. control 16.0 ± 0.7 mmol/l; not significant). [Na + ] i was altered by patch pipette dialysis to define the effect of [Na + ] i on contraction magnitude and action potential (AP) wave shape at slow and fast pacing rates. Using AP clamp, we showed that LVH-M require increased [Na + ] i and long diastolic intervals to maintain normal shortening. Finally, we determined the voltage dependence of contraction for Ca 2+ current ( I Ca )-triggered and Na + /Ca 2+ exchanger-mediated contractions and showed that there is a greater [Na + ] i dependence of contractility in LVH-M. These data show that increased [Na + ] i is essential for maintaining contractility at slow heart rates but contributes to small contractions at fast rates unless rate-dependent AP shortening is prevented, suggesting that altered [Na + ] i regulation is a critical contributor to abnormal contractility in disease. cardiac function; calcium handing Address for reprint requests and other correspondence: S. R. Houser, Cardiovascular Research Center, MRB 204, Temple Univ. School of Medicine, 3400 N. Broad St., Philadelphia, PA 19140 (e-mail: srhouser{at}temple.edu )