Jumrussirikul P, Dinerman J, Dawson T M, Dawson V L, Ekelund U, Georgakopoulos D, Schramm L P, Calkins H, Snyder S H, Hare J M, Berger R D
Department of Medicine, Department of Neurology, Department of Neuroscience, Department of Physiology, and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland 21287, USA.
J Clin Invest. 1998 Oct 1;102(7):1279-85. doi: 10.1172/JCI2843.
Nitric oxide (NO) synthesized within mammalian sinoatrial cells has been shown to participate in cholinergic control of heart rate (HR). However, it is not known whether NO synthesized within neurons plays a role in HR regulation. HR dynamics were measured in 24 wild-type (WT) mice and 24 mice in which the gene for neuronal NO synthase (nNOS) was absent (nNOS-/- mice). Mean HR and HR variability were compared in subsets of these animals at baseline, after parasympathetic blockade with atropine (0.5 mg/kg i.p.), after beta-adrenergic blockade with propranolol (1 mg/kg i.p.), and after combined autonomic blockade. Other animals underwent pressor challenge with phenylephrine (3 mg/kg i.p.) after beta-adrenergic blockade to test for a baroreflex-mediated cardioinhibitory response. The latter experiments were then repeated after inactivation of inhibitory G proteins with pertussis toxin (PTX) (30 microgram/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 bpm2, P = 0.001) compared with WT mice. In nNOS-/- mice, atropine 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 bpm2, P = 0.02) than in WT mice. In contrast, propranolol administration and combined autonomic blockade led to similar changes in mean HR between the two groups. After beta-adrenergic blockade, phenylephrine injection elicited a fall in mean HR and rise in HR variance in WT mice that was partially attenuated after treatment with PTX. The response to pressor challenge in nNOS-/- mice before PTX administration was similar to that in WT mice. However, PTX-treated nNOS-/- mice had a dramatically attenuated response to phenylephrine. These findings suggest that the absence of nNOS activity leads to reduced baseline parasympathetic tone, but does not prevent baroreflex-mediated cardioinhibition 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.
哺乳动物窦房结细胞内合成的一氧化氮（NO）已被证明参与心率（HR）的胆碱能控制。然而，尚不清楚神经元内合成的NO是否在心率调节中发挥作用。对24只野生型（WT）小鼠和24只缺乏神经元型一氧化氮合酶（nNOS）基因的小鼠（nNOS-/-小鼠）进行心率动态测量。比较这些动物亚组在基线、用阿托品（0.5mg/kg腹腔注射）进行副交感神经阻滞后、用普萘洛尔（1mg/kg腹腔注射）进行β-肾上腺素能阻滞后以及联合自主神经阻滞后的平均心率和心率变异性。在用苯肾上腺素（3mg/kg腹腔注射）进行升压挑战后，对其他动物进行β-肾上腺素能阻滞，以测试压力反射介导的心脏抑制反应。在用百日咳毒素（PTX）（30μg/kg腹腔注射）使抑制性G蛋白失活后，重复进行后者的实验。在基线时，与WT小鼠相比，nNOS-/-小鼠的平均心率更高（711±8对650±8次/分钟，P = 0.0004），心率方差更低（424±70对1112±174次/分钟²，P = 0.001）。在nNOS-/-小鼠中，给予阿托品后平均心率（-2±9对49±5次/分钟，P = 0.0008）和心率方差（64±24对-903±295次/分钟²，P = 0.02）的变化比WT小鼠小得多。相反，给予普萘洛尔和联合自主神经阻滞导致两组之间平均心率的类似变化。在β-肾上腺素能阻滞后，注射苯肾上腺素导致WT小鼠的平均心率下降和心率方差增加，在用PTX治疗后部分减弱。在给予PTX之前，nNOS-/-小鼠对升压挑战的反应与WT小鼠相似。然而，用PTX处理的nNOS-/-小鼠对苯肾上腺素的反应明显减弱。这些发现表明，nNOS活性的缺失导致基线副交感神经张力降低，但除非抑制性G蛋白也失活，否则不会阻止压力反射介导的心脏抑制。因此，神经元衍生的NO和心脏抑制性G蛋白活性作为平行途径介导小鼠心率的自主减慢。
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