Stretch-elicited Na⁺/H⁺ exchanger activation: The autocrine/paracrine loop and its mechanical counterpart

The stretch of the cardiac muscle is immediately followed by an increase in the contraction strength after which occurs a slow force increase (SFR) that takes several minutes to fully develop. The SFR was detected in a wide variety of experimental preparations including isolated myocytes, papillary muscles and/or trabeculae, left ventricle strips of failing human myocardium, in vitro isovolumic and in vivo volume-loaded hearts. It was established that the initial increase in force is due to an increase in myofilament Ca²⁺ responsiveness, whereas the SFR results from an increase in the Ca²⁺ transient. However, the mechanism(s) for this increase in the Ca²⁺ transient has remained undefined until the proposal of Na⁺/H⁺ exchanger (NHE) activation by stretch. Studies in multicellular cardiac muscle preparations from cat, rabbit, rat and failing human heart have shown evidence that the stretch induces a rise in intracellular Na⁺ ([Na⁺]_i) through NHE activation, which subsequently leads to an increase in Ca²⁺ transient via reverse-mode Na⁺/Ca²⁺ (NCX) exchange. These experimental data agree with a theoretical ionic model of cardiomyocytes that predicted an increased Na⁺ influx and a concurrent increase in Ca²⁺ entry through NCX as the cause of the SFR to muscle stretch. However, there are aspects that await definitive demonstration, and perhaps subjected to species-related differences like the possibility of an autocrine/paracrine loop involving angiotensin II and endothelin as the underlying mechanism for stretch-induced NHE activation leading to the rise in [Na⁺]_i and reverse-mode NCX.