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Nitric oxide (NO), a ubiquitous cell signalling molecule, plays an important role in the regulation of cardiovascular function. NO is produced by all cell types in the heart and is widely implicated in vasodilation, inflammation,
ischemic preconditioning and cell death. Mounting evidence now suggests that NO also provides protection against cardiac
arrhythmia. Pharmacological studies using NO precursors and NO donors have observed an anti-arrhythmic effect,
while inhibitors of NO biosynthesis increase arrhythmia, or attenuate anti-arrhythmic actions in a variety of animal models.
Additionally, genetic studies from animals deficient in nitric oxide synthase (NOS) enzymes have found increased
susceptibility to pharmacological or ischemia-induced arrhythmia while transgenic mice overexpressing certain NOS
isozymes may be protected. In the human population polymorphisms in NOS enzymes, or differences in the levels of endogenous
inhibitors of NO synthesis may also be important determinants of arrhythmic susceptibility. The precise mechanisms
of NO-mediated protection from arrhythmia are still under investigation but may include reductions in calcium
overload, regulation of gap junction/connexin expression, reductions in oxidative stress, and regulation of sympathetic activity.
This review examines the pharmacological, genetic, and clinical evidence of a role for NO in reducing cardiac arrhythmia
and discusses possible mechanisms of NO-mediated protection against arrhythmia.