INTERACTION BETWEEN NEURONAL NITRIC-OXIDE SYNTHASE AND INHIBITORY G-PROTEIN ACTIVITY IN HEART-RATE REGULATION IN CONSCIOUS MICE

Nitric oxide (NO) synthesized within mammalian sinoatrial cells has be en shown to participate in cholinergic control of heart rate (HR). How ever, it is not known whether NO synthesized within neurons plays a ro le in HR regulation. HR dynamics were measured in 24 wild-type (WT) mi ce and 24 mice in which the gene for neuronal NO synthase (nNOS) was a bsent (nNOS(-/-) mice), Mean HR and HR variability were compared in su bsets of these animals at baseline, after parasympathetic blockade wit h atropine (0.5 mg/kg i.p.), after beta-adrenergic blockade with propr anolol (1 mg/kg i.p.), and after combined autonomic blockade. Other an imals underwent presser challenge with phenylephrine (3 mg/kg i.p.) af ter beta-adrenergic blockade to test for a baroreflex-mediated cardioi nhibitory response, The latter experiments were then repeated after in activation of inhibitory G proteins with pertussis toxin (PTX) (30 mu g/kg i.p.). At baseline, nNOS(-/-) mice had higher mean HR (711+/-8 vs . 650+/-8 bpm, P = 0.0004) and lower HR variance (424+/-70 vs. 1,112+/ -174 bpm(2), P = 0.001) compared with WT mice. In nNOS-/- mice, atropi ne administration led to a much smaller change in mean HR (-2+/-9 vs. 49+/-5 bpm, P = 0.0008) and in HR variance (64+/-24 vs. -903+/-295 bpm (2), P = 0.02) than in WT mice. In contrast, propranolol administratio n and combined autonomic blockade led to similar changes in mean HR be tween the two groups. After beta-adrenergic blockade, phenylephrine in jection elicited a fall in mean HR and rise in HR variance in WT mice that was partially attenuated after treatment with PTX. The response t o presser challenge in nNOS(-/-) mice before PTX administration was si milar to that in WT mice. However, PTX-treated nNOS(-/-) mice had a dr amatically attenuated response to phenylephrine. These findings sugges t that the absence of nNOS activity leads to reduced baseline parasymp athetic tone, but does not prevent baroreflex-mediated cardioinhibitio n unless inhibitory G proteins are also inactivated. Thus, neuronally derived NO and cardiac inhibitory G protein activity serve as parallel pathways to mediate autonomic slowing of heart rate in the mouse.