Muscle stretch is a principal determinant of cardiac performance. Lengthening the sarcomere, the basic contractile unit in cardiac muscle, results in enhanced Ca2+-binding to Troponin C and an immediate increase in contractile force in response to the release of Ca2+ from the sarcoplasmic reticulum (SR). Cardiac muscle stretch also modulates contraction via enhancement of excitation-Ca2+-release process, but how this occurs remains obscure. We found that myocyte stretch modulates the elementary Ca2+-release process from ryanodine-receptor-Ca2+-release-channels (RyRC), Ca2+-sparks, and the electrically-stimulated Ca2+-transient. Stretch induces PI3-kinase-dependent phosphorylation of both Akt and eNOS, NO production, and a proportionate increase in Ca2+-spark frequency that is abolished by inhibiting NOS and PI3-kinase. Exogenously-generated NO reversibly increases Ca2+-spark frequency without cell stretch. We propose that myocyte NO produced by activation of the PI3-kinase-Akt-eNOS axis acts as a second messenger of stretch by enhancing RyRC activity, contributing to myocardial contractile activation. This set of mechanisms could serve as a physiologic sensor of cardiac stretch by generating NO, providing a novel link between cardiac muscle length and EC coupling. This stretch-mediated NO pathway could also be viewed in the larger context of a spectrum of adaptive myocardial load-dependent signalling events involving autocrine/paracrine activation of the PI3K-Akt axis diverging to various downstream effectors. The resultant eNOS activation could modulate contractility in the near term but also the induction of genes leading to hypertrophy in the longer term, and promote cell survival. Accordingly, alterations in these mechanisms could contribute to pathological changes in cardiac performance and/or structure. For instance, defects in EC coupling due to a reduced ability of ICa to trigger calcium release from the SR in hypertensive cardiac hypertrophy and heart failure could be correlated with decreases in eNOS protein abundance proportional to the severity of LV dysfunction. Thus, based on the mechanisms identified here, we would propose that the loss of the endogenous NO mechanisms could contribute significantly to the development of functional impairments of cardiac muscle when other compensatory mechanisms fail.
