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Hypertension is associated with reduced cardiac vagal activity and decreased atrial guanylate cyclase and cGMP levels. Neuronal production of NO facilitates cardiac parasympathetic transmission, although oxidative stress caused by hypertension may disrupt this pathway. We tested the hypothesis that peripheral vagal responsiveness is attenuated in the spontaneously hypertensive rat (SHR) because of impaired NO-cGMP signaling and that gene transfer of neuronal NO synthase (nNOS) into cholinergic intracardiac ganglia can restore neural function. Cardiac vagal heart rate responses in the isolated SHR atrial/right vagus preparation were significantly attenuated compared with age-matched normotensive Wistar-Kyoto rats. [(3)H] acetylcholine release was also significantly lower in the SHR. The NO donor, sodium nitroprusside, augmented vagal responses to nerve stimulation and [(3)H] acetylcholine release in the Wistar-Kyoto rat, whereas the soluble guanylate cyclase inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxaline-1-one attenuated [(3)H] acetylcholine release in Wistar-Kyoto atria. No effects of sodium nitroprusside or 1H-(1,2,4)oxadiazolo(4,3-a)quinoxaline-1-one were seen in the SHR during nerve stimulation. In contrast, SHR atria were hyperresponsive to carbachol-induced bradycardia, with elevated production of atrial cGMP. After gene transfer of adenoviral nNOS into the right atrium, vagal responsiveness in vivo was significantly increased in the SHR compared with transfection with adenoviral enhanced green fluorescent protein. Atrial nNOS activity was increased after gene transfer of adenoviral nNOS, as was expression of alpha(1)-soluble guanylate cyclase in both groups compared with adenoviral enhanced green fluorescent protein. In conclusion, a significant component of cardiac vagal dysfunction in hypertension is attributed to an impairment of the postganglionic presynaptic NO-cGMP pathway and that overexpression of nNOS can reverse this neural phenotype.

Original publication




Journal article



Publication Date





380 - 388


Acetylcholine, Animals, Cyclic GMP, Electric Stimulation, Ganglia, Gene Transfer Techniques, Guanylate Cyclase, Heart, Heart Atria, Hypertension, Male, Myocardium, Nitric Oxide, Nitric Oxide Donors, Nitric Oxide Synthase Type I, Nitroprusside, Parasympathetic Nervous System, Rats, Rats, Inbred SHR, Rats, Inbred WKY, Vagus Nerve