The analysis of plasma kinetics of the sympathetic neurotransmitter norepinephrine can be used to estimate sympathetic nervous "activity" (integrated nerve firing rate) for the body as a whole and for individual organs. In 12 patients with cardiac failure (left ventricular ejection fraction 10% to 39%), the mean arterial plasma norepinephrine concentration was 557 + 68 pg/ml (mean SE) compared with 211 + 21 pg/ml in 15 subjects without heart failure (p < .002). The difference was due to both increased release of norepinephrine to plasma (indicating increased "total" sympathetic activity) and reduced clearance of norepinephrine from plasma. The increase in sympathetic activity did not involve all organs equally. Cardiac (32 ± 9 vs 5 ± 1 ng/min; p < .002) and renal (202 ± 45 vs 66 ± 9 ng/min; p = .002) norepinephrine spillover were increased by 540% and 206%, respectively, but norepinephrine spillover from the lungs was normal. Adrenomedullary activity was also increased in the patients with heart failure, whose mean arterial plasma epinephrine concentration was 181 + 38 pg/ml compared with 71 ± 12 pg/ml in control subjects (p < .02). There is marked regional variation, inapparent from measurements of plasma norepinephrine concentration, in sympathetic nerve activity in patients with congestive heart failure. The finding of increased cardiorenal norepinephrine spillover has important pathophysiologic and therapeutic implications. Circulation 73, No. 4, 615421, 1986. THE CONSENSUS that sympathetic nervous overactivity is important in the pathophysiology of congestive heart failure is based in part on observations that the sympathetic neurotransmitter norepinephrine is present in plasma at increased concentration.1 The plasma concentration of norepinephrine, however, is determined by the rates of both release of norepinephrine to plasma and removal of norepinephrine from plasma. Norepinephrine plasma clearance might be reduced, and the plasma concentration thereby increased, because of the reduced cardiac output and organ blood flows that accompany congestive heart failure. A second difficulty in the study of the role of the sympathetic nervous system in congestive heart failure has been the inability of clinical research methods to estimate sympathetic activity in internal organs. Microneurographic electrophysiologic methods are available for the clinical study of nerve firing rates in subcutaneous nerves supplying skin and skeletal muscle,2 but the nerves to internal organs are not accessible for such testing.Measurement of sympathetic transmitter release is an alternative technique for quantifying sympathetic nerve activity in internal organs. We have developed a method3 using infusions of tritiated norepinephrine to determine both the rate at which norepinephrine spills into plasma and its rate of clearance from plasma. The technique has recently been applied to determine the rates of norepinephrine spillover from individual organs.4Although only a small fraction of the norepinephrine

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This study was performed to determine the relative contributions of plasma norepinephrine clearance and norepinephrine release to the increase in plasma norepinephrine concentration that occurs during exercise and to determine whether the high rates of cardiac norepinephrine release from the heart and kidney in patients with heart failure are associated with diminished reserve for regional sympathetic nervous stimulation. During supine steady-state bicycle exercise at 50% of maximum voluntary exercise capacity, the plasma norepinephrine concentration of six patients with congestive heart failure rose from 385±88 to 2,200±497 pg/ml, whereas that of nine normal subjects rose from 208±21 to 882±257 pg/ml. The change in plasma concentration in both groups was due to an increase in norepinephrine spillover to plasma without a change in plasma norepinephrine clearance. In patients with heart failure, cardiac spillover increased from 80 ± 26 to 528 ± 265 ng /min during exercise, and renal spillover rose from 146 ± 71 to 418 ± 69 ng/min. In the normal subjects, cardiac spillover rose from 5 ± 2 to 73 ± 23 ng/min, and renal spillover increased from 76 ± 27 to 275 ± 106 ng/min. There is no evidence of a reduced reserve for overall or regional sympathetic stimulation in patients with heart failure. Reduced reflex responses in these patients are more likely due to end-organ refractoriness than to inadequate stimulation. (Circulation 1988;78:516-521) E levated plasma norepinephrine concentration observed in patients with congestive heart failure is due to both reduced plasma norepinephrine clearance and increased spillover of norepinephrine to plasma. 1 Because reduced plasma clearance of norepinephrine is an important determinant of the baseline plasma concentration of norepinephrine, it might also be an important determinant of the increase in plasma norepinephrine that occurs during exercise. One would expect this effect to be more marked in patients with heart failure because of the intensity of splanchnic vasoconstriction during exercise in these patients.2There is also evidence of intense cardiorenal sympathetic nervous stimulation under resting conditions in patients with heart failure.' We hypothesized that the very high resting rates of norepinephrine spillover to plasma from the heart indicated maximal cardiac sympathetic stimulation. An inabil-