CARDIAC NORADRENERGIC NERVE-TERMINAL ABNORMALITIES IN DOGS WITH EXPERIMENTAL CONGESTIVE-HEART-FAILURE

Background. We have shown previously that norepinephrine (NE) uptake a ctivity is reduced in the failing right ventricle of animals with righ t heart failure (RHF) produced by tricuspid avulsion and progressive p ulmonary constriction. However, it is unknown whether this defect in n euronal NE uptake is related to reduction of noradrenergic nerve termi nals or whether these changes also occur in animals with left heart fa ilure (LHF). It is also unknown whether increased NE release in heart failure contributes to the noradrenergic nerve abnormalities. Methods and Results. We measured myocardial NE content, NE uptake function, an d noradrenergic nerve profiles in dogs with either RHF or LHF induced by rapid ventricular pacing. NE uptake activity was measured using [H- 3]NE, and noradrenergic nerve profiles were visualized by glyoxylic ac id (SPG)-induced histofluorescence and tyrosine hydroxylase immunocyto chemical staining. To study the effects of excess NE, we exposed norma l dogs to 8 weeks of chronic NE infusion using subcutaneous osmotic mi nipumps. RHF and LHF animals exhibited reduced myocardial contractile function and congestive heart failure, as evidenced by reduced cardiac output and elevated right atrial pressure. However, unlike that in LH F, left atrial pressure was not increased in RHF. The animals also sho wed an increase in plasma NE and a decrease in cardiac NE. In addition , SPG-induced histofluorescence correlated significantly with NE uptak e activity (r=.712, P<.001) and tyrosine hydroxylase immunoreactive pr ofiles (r=.569, P<.001) in the right ventricles of RHF dogs and in bot h ventricles of LHF dogs. The numbers of catecholaminergic profiles an d tyrosine hydroxylase profiles significantly correlated with cardiac filling pressures. Chronic infusion of NE decreased heart rate in norm al dogs but had no effect on either mean aortic pressure or left atria l pressure; like heart failure, it resulted in significant decreases i n myocardial NE uptake activity and numbers of SPG-induced catecholami nergic histofluorescence and immunoreactive tyrosine hydroxylase profi les. Conclusions. Myocardial NE uptake activity was reduced only in th e failing ventricles with elevated filling pressure in RHF and LHF. Th ese changes probably were caused by loss of noradrenergic nerve termin als in the failing ventricles, as evidenced by the reductions of catec holaminergic histofluorescence and tyrosine hydroxylase immunostained profiles. Furthermore, since similar reductions of myocardial NE uptak e and noradrenergic nerve profiles could be produced by chronic NE inf usion in normal dogs, elevated NE levels may play a role in the develo pment of cardiac noradrenergic nerve abnormalities in congestive heart failure.