XXXX stimulation of cardiac pacemaking in the sino-atrial node through the activation of a novel signalling pathway: overview of in vitro and in vivo evidence for a new basic mechanism in the control of heart rate.

@entity1 @entity1707 @entity6708 @entity840 @entity842 @entity460
Recent work has tested the hypothesis that @entity842 (NO) might play an important role in the control of heart rate (HR) by stimulating cardiac pacemaking in the sino-atrial node (SAN). In isolated @entity840 SAN cells and atrial preparations, nano-micromolar concentrations of NO donors were shown to elicit a NO-dependent increase of 20-30% in the beating rate. In the @entity1707 heart in situ, topical NO donor application to the SAN increased HR by ca. 10%, indicating that the direct positive chronotropic effect of NO is relevant in vivo. Indeed, a similar significant increase in HR (by 12%) was seen in @entity1 with intravenous NO donor infusion while blood pressure was clamped. Inhibition of NO synthase or depletion of its gene have been associated with a significant reduction in HR by ca. 10% in vitro and in vivo, consistent with a tonic positive chronotropic effect of endogenous NO. The direct stimulatory effect of NO on cardiac pacemaking is mediated by stimulation of the 'pacemaker' current I, in SAN cells via a novel cascade involving @entity6708 , PDE3-PKA signalling and mobilization of intracellular @entity460 . In conclusion, recent studies have demonstrated for the first time that NO exerts a direct positive chronotropic effect through the activation of a novel signal transduction pathway in SAN cells. Evidence in animals and in @entity1 indicates that direct stimulation of cardiac pacemaking by NO is functionally relevant for the control of HR in vivo.
