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Subcellular localization of nitric oxide (NO) synthases with effector molecules is an important regulatory mechanism for NO signalling. In the heart, NO inhibits L-type Ca²⁺ channels but stimulates sarcoplasmic reticulum (SR) Ca²⁺ release^,,, leading to variable effects on myocardial contractility. Here we show that spatial confinement of specific NO synthase isoforms regulates this process. Endothelial NO synthase (NOS3) localizes to caveolae^,,, where compartmentalization with β-adrenergic receptors and L-type Ca²⁺ channels allows NO to inhibit β-adrenergic-induced inotropy^,. Neuronal NO synthase (NOS1), however, is targeted to cardiac SR. NO stimulation of SR Ca²⁺ release via the ryanodine receptor (RyR) in vitro, suggests that NOS1 has an opposite, facilitative effect on contractility. We demonstrate that NOS1-deficient mice have suppressed inotropic response, whereas NOS3-deficient mice have …