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We investigated whether enhanced cardiac vagal responsiveness elicited by exercise training is dependent on neuronal nitric oxide synthase (NOS-1), since the NO-cGMP pathway facilitates acetylcholine release. Isolated atria with intact right vagal innervation were taken from male mice (18-22 weeks old) after a period of 10 weeks voluntary wheel-running (+EX, n = 27; peaked 9.8 +/- 0.6 km day(-1) at 5 weeks), and from mice housed in cages without wheels (-EX, n = 27). Immunostaining of whole atria for NOS-1 identified intrinsic neurones, all of which co-localized with choline acetyltransferase-positive ganglia. Western blot analysis confirmed that NOS-1 protein level was significantly greater in +EX compared to -EX atria (P < 0.05, unpaired t test). Basal heart rates (HR) were slower in +EX than in -EX atria (322 +/- 6 versus 360 +/- 7 beats min(-1); P < 0.05, unpaired t test) However, in +EX atria, HR responses to vagal stimulation (VNS, 3 and 5 Hz) were significantly enhanced compared to -EX atria (3 Hz, +EX: -76 +/- 8 beats min(-1) versus -EX: -62 +/- 7 beats min(-1); 5 Hz, +EX: -106 +/- 4 beats min(-1) versus -EX: -93 +/- 3 beats min(-1); P < 0.01, unpaired t test). Inhibition of NOS-1 with vinyl-L-N-5-(1-imino-3-butenyl)-L-ornithine (L-VNIO, 100 microM) or soluble guanylyl cyclase with 1H-[1, 2, 4]oxadiazolo[4, 3-a]quinoxalin-1-one (ODQ, 10 microM) abolished the difference in HR responses to VNS between +EX and -EX atria, and effects of L-VNIO were reversed by excess L-arginine (1 mM; P < 0.01, ANOVA). There were no differences between the HR responses to the bath-applied acetylcholine analogue carbamylcholine chloride in +EX and -EX atria (IC(50) concentrations were 5.9 +/- 0.4 microM (-EX) and 5.7 +/- 0.4 microM (+EX)), suggesting that the changes in vagal responsiveness resulted from presynaptic facilitation of neurotransmission. In conclusion, NOS-1 appears to be a key protein in generating the cardiac vagal gain of function elicited by exercise training.

Original publication




Journal article


J Physiol

Publication Date





225 - 232


Animals, Blotting, Western, Cyclic GMP, Guanylate Cyclase, Heart, Heart Rate, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nitric Oxide Donors, Nitric Oxide Synthase, Nitric Oxide Synthase Type I, Nitroprusside, Phenotype, Physical Conditioning, Animal, Solubility, Vagus Nerve