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This Article Full Text Full Text (PDF) All Versions of this Article: 294/1/H354    most recent 00898.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Choate, J. K. Articles by Anderson, C. R. Search for Related Content PubMed PubMed Citation Articles by Choate, J. K. Articles by Anderson, C. R.

Sympathetic control of heart rate in nNOS knockout mice

¹Department of Physiology, School of Biomedical Sciences, Monash University; and ²Department of Anatomy and Cell Biology, University of Melbourne, Parkville, Australia

Submitted 2 August 2007 ; accepted in final form 15 October 2007

Inhibition of neuronal nitric oxide synthase (nNOS) in cardiac postganglionic sympathetic neurons leads to enhanced cardiac sympathetic responsiveness in normal animals, as well as in animal models of cardiovascular diseases. We used isolated atria from mice with selective genetic disruption of nNOS (nNOS^–/–) and their wild-type littermates (WT) to investigate whether sympathetic heart rate (HR) responses were dependent on nNOS. Immunohistochemistry was initially used to determine the presence of nNOS in sympathetic [tyrosine hydroxylase (TH) immunoreactive] nerve terminals in the mouse sinoatrial node (SAN). After this, the effects of postganglionic sympathetic nerve stimulation (1–10 Hz) and bath-applied norepinephrine (NE; 10^–8–10^–4 mol/l) on HR were examined in atria from nNOS^–/– and WT mice. In the SAN region of WT mice, TH and nNOS immunoreactivity was virtually never colocalized in nerve fibers. nNOS^–/– atria showed significantly reduced HR responses to sympathetic nerve activation and NE (P < 0.05). Similarly, the positive chronotropic response to the adenylate cyclase activator forskolin (10^–7–10^–5 mol/l) was attenuated in nNOS^–/– atria (P < 0.05). Constitutive NOS inhibition with L-nitroarginine (0.1 mmol/l) did not affect the sympathetic HR responses in nNOS^–/– and WT atria. The paucity of nNOS in the sympathetic innervation of the mouse SAN, in addition to the attenuated HR responses to neuronal and applied NE, indicates that presynaptic sympathetic neuronal NO does not modulate neuronal NE release and SAN pacemaking in this species. It appears that genetic deletion of nNOS results in the inhibition of adrenergic-adenylate cyclase signaling within SAN myocytes.

neuronal nitric oxide synthase; autonomic nervous system; sinoatrial node