期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：6
页码：3507-3512
DOI：10.1073/pnas.2627986100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Voltage-gated Na+ channels are composed of pore-forming and auxiliary {beta} subunits. The majority of Na+ channels in the heart contain tetrodotoxin (TTX)-insensitive Nav1.5 subunits, but TTX-sensitive brain-type Na+ channel subunits are present and functionally important in the transverse tubules of ventricular myocytes. Sinoatrial (SA) nodal cells were identified in cardiac tissue sections by staining for connexin 43 (which is expressed in atrial tissue but not in SA node), and Na+ channel localization was analyzed by immunocytochemical staining with subtype-specific antibodies and confocal microscopy. Brain-type TTX-sensitive Nav1.1 and Nav1.3 subunits and all four {beta} subunits were present in mouse SA node, but Nav1.5 subunits were not. Nav1.1 subunits were also present in rat SA node. Isolated mouse hearts were retrogradely perfused in a Langendorff preparation, and electrocardiograms were recorded. Spontaneous heart rate and cycle length were constant, and heart rate variability was small under control conditions. In contrast, in the presence of 100 nM TTX to block TTX-sensitive Na+ channels specifically, we observed a significant reduction in spontaneous heart rate and markedly greater heart rate variability, similar to sick-sinus syndrome in man. We hypothesize that brain-type Na+ channels are required because their more positive voltage dependence of inactivation allows them to function at the depolarized membrane potential of SA nodal cells. Our results demonstrate an important contribution of TTX-sensitive brain-type Na+ channels to SA nodal automaticity in mouse heart and suggest that they may also contribute to SA nodal function and dysfunction in human heart.
