Mechanical load is an important regulator of cardiac force. Stretching human atrial and ventricular trabeculae elicited a biphasic force increase: an immediate increase (Frank-Starling mechanism) followed by a further slow increase (slow force response, SFR). In ventricle, the SFR was unaffected by AT-and ET-receptor antagonism, by inhibition of protein-kinase-C, PI-3-kinase, and NOsynthase, but attenuated by inhibition of Na + /H + -(NHE) and Na + /Ca 2+ -exchange (NCX). In atrium, however, neither NHE-nor NCX-inhibition affected the SFR. Stretch elicited a large NHE-dependent [Na + ] i increase in ventricle but only a small, NHE-independent [Na + ] i increase in atrium. Stretchactivated non-selective cation channels contributed to basal force development in atrium but not ventricle and were not involved in the SFR in either tissue. Interestingly, inhibition of AT-receptors or pre-application of angiotensin II or endothelin-1 reduced the atrial SFR. Furthermore, stretch increased phosphorylation of atrial myosin light chain 2 (MLC2) and inhibition of myosin light chain kinase (MLCK) attenuated the SFR in atrium and ventricle. Thus, in human heart both atrial and ventricular myocardium exhibit a stretch-dependent SFR that might serve to adjust cardiac output to increased workload. In ventricle, there is a robust NHE-dependent (but angiotensin II-and endothelin-1-independent) [Na + ] i increase that is translated into a [Ca 2+ ] i and force increase via NCX. In atrium, on the other hand, there is an angiotensin II-and endothelin-dependent (but NHE-and NCX-independent) force increase. Increased myofilament Ca 2+ sensitivity through MLCK-induced phosphorylation of MLC2 is a novel mechanism contributing to the SFR in both atrium and ventricle.

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