Inhibition of nitric oxide synthase slows heart rate recovery from cholinergic activation

Claire E. Sears, Julia K. Choate, David J. Paterson

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The role of nitric oxide (NO) in the cholinergic regulation of heart rate (HR) recovery from an aspect of simulated exercise was investigated in atria isolated from guinea pig to test the hypothesis that NO may be involved in the cholinergic antagonism of the positive chronotropic response to adrenergic stimulation. Inhibition of NO synthesis with N(G)-monomethyl-L- arginine (L-NMMA, 100 μM) significantly slowed the time course of the reduction in HR without affecting the magnitude of the response elicited by bath-applied ACh (100 nM) or vagal nerve stimulation (2 Hz). The half-times (t(1/2)) of responses were 3.99 ± 0.41 s in control vs. 7.49 ± 0.68 s in L- NMMA (P < 0.05). This was dependent on prior adrenergic stimulation (norepinephrine, 1 μM). The effect of L-NMMA was reversed by L-arginine (1 mM; t(1/2) 4.62 ± 0.39 s). The calcium-channel antagonist nifedipine (0.2 μM) also slowed the kinetics of the reduction in HR caused by vagal nerve stimulation. However, the t(1/2) for the reduction in HR with antagonists (2 mM Cs+ and 1 μM ZD-7288) of the hyperpolarization-activated current were significantly faster compared with control. There was no additional effect of L-NMMA or L-NMMA + L-arginine on vagal stimulation in groups treated with nifedipine, Cs+, or ZD-7288. We conclude that NO contributes to the cholinergic antagonism of the positive cardiac chronotropic effects of adrenergic stimulation by accelerating the HR response to vagal stimulation. This may involve an interplay between two pacemaking currents (L-type calcium channel current and hyperpolarization-activated current). Whether NO modulates the vagal control of HR recovery from actual exercise remains to be determined.

Original languageEnglish
Pages (from-to)1596-1603
Number of pages8
JournalJournal of Applied Physiology
Issue number5
Publication statusPublished - May 1998
Externally publishedYes


  • Autonomic nervous system
  • Cardiac
  • Guinea pig

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