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Stretching of cardiac muscle modulates contraction through the enhancement of the Ca²⁺ transient, but how this occurs is still not known. We found that stretching of myocytes modulates the elementary Ca²⁺ release process from ryanodine-receptor Ca²⁺-release channels (RyRCs), Ca²⁺ sparks and the electrically stimulated Ca²⁺ transient. Stretching induces PtdIns-3-OH kinase (PI(3)K)-dependent phosphorylation of both Akt and the endothelial isoform of nitric oxide synthase (NOS), nitric oxide (NO) production, and a proportionate increase in Ca²⁺-spark frequency that is abolished by inhibiting NOS and PI(3)K. Exogenously generated NO reversibly increases Ca²⁺-spark frequency without cell stretching. We propose that myocyte NO produced by activation of the PI(3)K–Akt–endothelial NOS axis acts as a second messenger of stretch by enhancing RyRC activity, contributing to myocardial contractile activation.