Sympathetic control of heart rate in nNOS knockout mice

Julia Choate, Susan M Murphy, Rebecca Feldman, Colin R Anderson

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16 Citations (Scopus)


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 sino-atrial node (SAN). Following 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 were virtually never co-localised in nerve fibres. 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 (AC) activator forskolin (10(-7) - 10(-5) mol/L) was attenuated in nNOS(-/-) atria (P <0.05). Constitutive NOS inhibition with L-nitroarginine (L-NA, 0.1 micromol/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, plus the attenuated HR responses to neuronal and applied NE indicates that pre-synaptic 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-AC signalling within SAN myocytes. Key words: heart rate, autonomic nervous system, nitric oxide, sinoatrial node.
Original languageEnglish
Pages (from-to)H354 - H361
Number of pages8
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number1
Publication statusPublished - 2008

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