Himura Y, Felten S Y, Kashiki M, Lewandowski T J, Delehanty J M, Liang C S
Department of Medicine (Cardiology Unit), University of Rochester Medical Center, NY 14642.
Circulation. 1993 Sep;88(3):1299-309. doi: 10.1161/01.cir.88.3.1299.
We have shown previously that norepinephrine (NE) uptake activity is reduced in the failing right ventricle of animals with right heart failure (RHF) produced by tricuspid avulsion and progressive pulmonary constriction. However, it is unknown whether this defect in neuronal NE uptake is related to reduction of noradrenergic nerve terminals or whether these changes also occur in animals with left heart failure (LHF). It is also unknown whether increased NE release in heart failure contributes to the noradrenergic nerve abnormalities.
We measured myocardial NE content. NE uptake function, and noradrenergic nerve profiles in dogs with either RHF or LHF induced by rapid ventricular pacing. NE uptake activity was measured using [3H]NE, and noradrenergic nerve profiles were visualized by glyoxylic acid (SPG)-induced histofluorescence and tyrosine hydroxylase immunocytochemical staining. To study the effects of excess NE, we exposed normal dogs to 8 weeks of chronic NE infusion using subcutaneous osmotic minipumps. RHF and LHF animals exhibited reduced myocardial contractile function and congestive heart failure, as evidence by reduced cardiac output and elevated right atrial pressure. However, unlike that in LHF, left atrial pressure was not increased in RHF. The animals also showed an increase in plasma NE and a decrease in cardiac NE. In addition, SPG-induced histofluorescence correlated significantly with NE uptake activity (r = .712, P < .001) and tyrosine hydroxylase immunoreactive profiles (r = .569, P < .001) in the right ventricles of RHF dogs and in both ventricles of LHF dogs. The numbers of catecholaminergic profiles and tyrosine hydroxylase profiles significantly correlated with cardiac filling pressures. Chronic infusion of NE decreased heart rate in normal dogs but had no effect on either mean aortic pressure or left atrial pressure; like heart failure, it resulted in significant decreases in myocardial NE uptake activity and numbers of SPG-induced catecholaminergic histofluorescence and immunoreactive tyrosine hydroxylase profiles.
Myocardial NE uptake activity was reduced only in the failing ventricles with elevated filling pressure in RHF and LHF. These changes probably were caused by loss of noradrenergic nerve terminals in the failing ventricles, as evidenced by the reductions of catecholaminergic histofluorescence and tyrosine hydroxylase immunostained profiles. Furthermore, since similar reductions of myocardial NE uptake and noradrenergic nerve profiles could be produced by chronic NE infusion in normal dogs, elevated NE levels may play a role in the development of cardiac noradrenergic nerve abnormalities in congestive heart failure.
我们之前已经表明，在通过三尖瓣撕脱和进行性肺收缩产生右心衰竭（RHF）的动物的衰竭右心室中，去甲肾上腺素（NE）摄取活性降低。然而，尚不清楚神经元NE摄取的这种缺陷是否与去甲肾上腺素能神经末梢的减少有关，或者这些变化是否也发生在左心衰竭（LHF）的动物中。也不清楚心力衰竭时NE释放增加是否导致去甲肾上腺素能神经异常。
我们测量了快速心室起搏诱导的RHF或LHF犬的心肌NE含量、NE摄取功能和去甲肾上腺素能神经分布。使用[3H]NE测量NE摄取活性，通过乙醛酸（SPG）诱导的组织荧光和酪氨酸羟化酶免疫细胞化学染色观察去甲肾上腺素能神经分布。为了研究过量NE的影响，我们使用皮下渗透微型泵使正常犬接受8周的慢性NE输注。RHF和LHF动物表现出心肌收缩功能降低和充血性心力衰竭，心输出量降低和右心房压力升高证明了这一点。然而，与LHF不同，RHF中左心房压力没有升高。这些动物还表现出血浆NE增加和心脏NE减少。此外，在RHF犬的右心室和LHF犬的两个心室中，SPG诱导的组织荧光与NE摄取活性（r = 0.712，P < 0.001）和酪氨酸羟化酶免疫反应性分布（r = 0.569，P < 0.001）显著相关。儿茶酚胺能分布和酪氨酸羟化酶分布的数量与心脏充盈压显著相关。慢性输注NE可降低正常犬的心率，但对平均主动脉压或左心房压力无影响；与心力衰竭一样，它导致心肌NE摄取活性以及SPG诱导的儿茶酚胺能组织荧光和免疫反应性酪氨酸羟化酶分布的数量显著降低。
心肌NE摄取活性仅在RHF和LHF中充盈压升高的衰竭心室中降低。这些变化可能是由于衰竭心室中去甲肾上腺素能神经末梢的丧失所致，儿茶酚胺能组织荧光和酪氨酸羟化酶免疫染色分布的减少证明了这一点。此外，由于在正常犬中慢性输注NE可产生类似的心肌NE摄取和去甲肾上腺素能神经分布减少，NE水平升高可能在充血性心力衰竭时心脏去甲肾上腺素能神经异常的发生中起作用。
