Previous studies have shown that the newly found endogenous inhibitor (NCXIF) of the cardiac Na/Ca exchanger (NCX1) is capable of regulating the muscle strip's contractility and relaxation. Here, the effects of purified NCXIF were tested on single cell shortening-lengthening (by using the IR CCD camera coupled with the two-edge video-detector) and [Ca](i)-transients (by monitoring the changes in fluo-3 fluorescence). A perfusion of isolated cardiomyocytes (paced at 0.5-1.0 Hz) with NCXIF results in 4-6-fold enhancement in the amplitude of cell shortening-lengthening reaching the steady-state levels within 5-8 min (n = 20, p < 0.009). Simultaneous recordings of cell shortening-lengthening and [Ca](i)-transients from the same cell show that the amplitude enhancement is associated with accelerated decay of both signals. Therefore, the NCXIF-dependent modulation of the single cell contractility is primarily governed by Ca-related mechanisms. The observed data are consistent with a proposal suggesting that the inhibition of NCX1 by NCXIF results in Ca-dependent activation of SERCA (SR Ca ATPase), yielding the accelerated decay of the [Ca](i)-transients. The subsequent increase in the SR Ca content may result in enhanced Ca-release reflecting the manifested promotion of [Ca](i)-transients. More systematic study is required for confirming this working hypothesis. (c) 2006 Elsevier Inc. All rights reserved.