Abnormal myocyte Ca2+ homeostasis in rabbits with pacing-induced heart failure

To determine whether there are abnormalities in myocyte excitation-contraction coupling and intracellular Ca2+ concentration ([Ca2+](i)) homeostasis in pacing-induced heart failure (PF), we measured L-type Ca2+ current (I-Ca,I-L) and Na+/Ca2+ exchanger current (I-Na/Ca) with voltage clamp and measured intracellular Na+ concentration ([Na+](i)) and [Ca2+](i) with the use of sodium-binding benzofuran isophthalate (SBFI) and flue 3 in ventricular myocytes isolated from control and paced rabbits. The peak systolic and diastolic levels and the amplitude of electrically stimulated [Ca2+](i) transients (0.25 Hz, extracellular Ca2+ concentration = 1.08 mM) were significantly less in PF myocytes. Also, there was prolongation of the times to peak and decline of [Ca2+](i) transients. I-Ca,I-L density was markedly decreased in PF myocytes. I-Na/Ca at -40 mV elicited by rapid exposure to 0 Na+ solution with a rapid solution switcher was significantly reduced in PF myocytes, suggesting that the function of the Na+/Ca2+ exchanger is impaired in these myocytes. In PF myocytes the decline of the [Ca2+](i) transient when the Na+/Ca2+ exchanger was abruptly disabled was markedly prolonged compared with the decline in control myocytes, consistent with depressed sarcoplasmic reticulum (SR) Ca2+ ATPase function. RNase protection assay showed decreased levels of Na+/Ca2+ exchanger and SR Ca2+-ATPase mRNA in PF hearts, consistent with the function studies. We conclude that the functions of L-type Ca2+ channels, Na+/Ca2+ exchanger, and SR Ca2+-ATPase are impaired in myocytes from rabbit hearts with failure induced by rapid pacing. These abnormalities result in reduced [Ca2+](i) transients and systolic and diastolic dysfunction and appear to account for the abnormal ventricular function observed.