INHIBITION OF NITRIC-OXIDE SYNTHASE SLOWS HEART-RATE RECOVERY FROM CHOLINERGIC ACTIVATION

The role of nitric oxide (NO) in the cholinergic regulation of heart r ate (HR) recovery from an aspect of simulated exercise was investigate d in atria isolated from guinea pig to test the hypothesis that NO may be involved in the cholinergic antagonism of the positive chronotropi c response to adrenergic stimulation. Inhibition of NO synthesis with N-G-monomethyl-L-arginine (L-NMMA: 100 mu M) 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 stim ulation (2 Hz). The half-times (t(1/2)) of responses were 3.99 +/- 0.4 1 s in control vs. 7.49 +/- 0.68 s in L-NMMA (P < 0.05). This was depe ndent on prior adrenergic stimulation (norepinephrine, 1 mu M). The ef fect 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 mu M) also slowed t he 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 mu M ZD-7288) of the hyperpolarization-activated current were s ignificantly faster compared with control. There was no additional eff ect of L-NMA or L-NMMA + L-arginine on vagal stimulation in groups tre ated with nifedipine, Cs+ Or ZD- 7288. We conclude that NO contributes to the cholinergic antagonism of the positive cardiac chronotropic ef fects of adrenergic stimulation by accelerating the HR response to vag al stimulation. This may involve an interplay between two pacemaking c urrents (L-type calcium channel current and hyperpolarization-activate d current. Whether NO modulates the vagal control of HR recovery from actual exercise remains to be determined.