Choate J K, Danson E J, Morris J F, Paterson D J
Department of Physiology, Monash University, Victoria 3800, Australia.
Am J Physiol Heart Circ Physiol. 2001 Dec;281(6):H2310-7. doi: 10.1152/ajpheart.2001.281.6.H2310.
The role of nitric oxide (NO) in the vagal control of heart rate (HR) is controversial. We investigated the cholinergic regulation of HR in isolated atrial preparations with an intact right vagus nerve from wild-type (nNOS+/+, n = 81) and neuronal NO synthase (nNOS) knockout (nNOS-/-, n = 43) mice. nNOS was immunofluorescently colocalized within choline-acetyltransferase-positive neurons in nNOS+/+ atria. The rate of decline in HR during vagal nerve stimulation (VNS, 3 and 5 Hz) was slower in nNOS-/- compared with nNOS+/+ atria in vitro (P < 0.01). There was no difference between the HR responses to carbamylcholine in nNOS+/+ and nNOS-/- atria. Selective nNOS inhibitors, vinyl-L-niohydrochloride or 1-2-trifluoromethylphenyl imidazole, or the guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one significantly (P < 0.05) attenuated the decrease in HR with VNS at 3 Hz in nNOS+/+ atria. NOS inhibition had no effect in nNOS-/- atria during VNS. In all atria, the NO donor sodium nitroprusside significantly enhanced the magnitude of the vagal-induced bradycardia, showing the downstream intracellular pathways activated by NO were intact. These results suggest that neuronal NO facilitates vagally induced bradycardia via a presynaptic modulation of neurotransmission.
一氧化氮（NO）在迷走神经对心率（HR）的控制中所起的作用存在争议。我们利用来自野生型（nNOS+/+，n = 81）和神经元型一氧化氮合酶（nNOS）基因敲除（nNOS-/-，n = 43）小鼠的完整右迷走神经，在离体心房标本中研究了HR的胆碱能调节。在nNOS+/+心房中，nNOS通过免疫荧光与胆碱乙酰转移酶阳性神经元共定位。在体外，与nNOS+/+心房相比，nNOS-/-心房在迷走神经刺激（VNS，3和5 Hz）期间HR的下降速率较慢（P < 0.01）。nNOS+/+和nNOS-/-心房对氨甲酰胆碱的HR反应没有差异。选择性nNOS抑制剂盐酸乙烯-L-精氨酸或1-（2-三氟甲基苯基）咪唑，或鸟苷酸环化酶抑制剂1H-[1,2,4]恶二唑并[4,3-a]喹喔啉-1-酮显著（P < 0.05）减弱了nNOS+/+心房在3 Hz VNS时HR的下降。在VNS期间，NOS抑制对nNOS-/-心房没有影响。在所有心房中，NO供体硝普钠显著增强了迷走神经诱导的心动过缓的幅度，表明由NO激活的下游细胞内信号通路是完整的。这些结果表明，神经元型NO通过对神经传递的突触前调节促进迷走神经诱导的心动过缓。
