Nitric oxide 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.

Recent work has tested the hypothesis that nitric oxide (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 guinea-pig 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 pig 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 humans 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 cGMP, PDE3-PKA signalling and mobilization of intracellular calcium. 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 humans indicates that direct stimulation of cardiac pacemaking by NO is functionally relevant for the control of HR in vivo.