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

The role ofnitric oxide (NO) in the cholinergic regulation of heart rate(HR) recovery from an aspect of simulated exercise wasinvestigated in atria isolated from guinea pig to test the hypothesisthat NO may be involved in the cholinergic antagonism of the positivechronotropic response to adrenergic stimulation. Inhibition of NOsynthesis withN^G-monomethyl-L-arginine(L-NMMA, 100 µM) significantlyslowed the time course of the reduction in HR without affecting themagnitude of the response elicited by bath-applied ACh (100 nM) orvagal 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 inL-NMMA(P < 0.05). This was dependent onprior adrenergic stimulation (norepinephrine, 1 µM). The effect ofL-NMMA was reversed byL-arginine (1 mM; t_1/2 4.62 ± 0.39 s). The calcium-channelantagonist nifedipine (0.2 µM) also slowed the kinetics of thereduction in HR caused by vagal nerve stimulation. However, thet_1/2 for the reduction in HR with antagonists (2 mM Cs⁺ and 1 µM ZD-7288) of thehyperpolarization-activated current were significantlyfaster compared with control. There was no additional effect ofL-NMMA orL-NMMA+L-arginineon vagal stimulation in groups treated with nifedipine,Cs⁺, or ZD-7288. Weconclude that NO contributes to the cholinergic antagonism of thepositive cardiac chronotropic effects of adrenergic stimulation byaccelerating the HR response to vagal stimulation. This may involve aninterplay between two pacemaking currents (L-type calcium channelcurrent and hyperpolarization-activated current). Whether NO modulatesthe vagal control of HR recovery from actual exercise remains to bedetermined.