To determine if peripheral angiotensin II (Ang II) prejunctional receptors facilitating NE release exist in humans, we used 13H INE kinetic methodology to measure forearm NE spillover during intrabrachial arterial Ang II infusions in eight normal male subjects. We used the following protocol to optimize conditions for demonstrating these receptors: (a) lower body negative pressure (-15 mmHg) to increase sympathetic nerve activity to skeletal muscle; and (b) intraarterial nitroprusside to maintain a high constant forearm blood flow (-10 ml/ min* 100 ml) to maximize the proportion of neuronally released NE that spills over into the circulation. During lower body negative pressure, the following were infused intraarterially for three consecutive 20-min periods: saline, Ang II (4 ng/min), and Ang 11( 16 ng/min). During the Ang II infusions, forearm venous NE increased significantly from 173 to 189 and 224 pg/ml (P < 0.01), and forearm NE spillover increased from 384 to 439 and 560 ng/min. 100 ml (P < 0.05 for high Ang II). Forearm NE clearance was unchanged. During low and high dose Ang II, the plasma venous Ang II concentrations were 25 and 97 pM, respectively. Since normal subjects increase plasma Ang II from 4 to 20-22 pM with exercise, standing, or diuretic administration, and patients with severe congestive heart failure can have a plasma Ang II of -25 pM at rest, we suggest that Ang II might facilitate NE release in severe congestive heart failure, especially under conditions of stress. (J. Clin. Invest. 1994. 93:684-691.) Key words: congestive heart failure* angiotensin-converting enzyme inhibitors . 13H1-norepinephrine kinetics . norepinephrine spillover

During dynamic exercise, blood flow to exercising muscle is closely matched to metabolic demands. This is made possible by metabolic vasodilation, vasoconstriction in inactive vascular beds, and a rise in cardiac output. The sympathetic nervous system plays an important role in regulating this exercise response. In this study, we used steady-state infusions of tritiated norepinephrine ([3H]NE) to determine the magnitude and time course of the arterial NE spillover response to sustained upright bicycle exercise at low (n = 11) and moderate-to-high (n = 14) exercise intensity (25 and 65% of maximum work load, respectively) in normal young subjects. In addition, we sought to examine whether exercise was associated with a change in NE clearance. During 30 min of low-level exercise, arterial NE spillover increased from 1.45 +/- 0.13 to 3.14 +/- 0.30 nmol.min-1 x m-2 (P < 0.01) and appeared to plateau at 20-30 min of exercise; NE clearance remained unchanged. During 20 min of moderate-to-high-intensity exercise, we found a substantial and progressive rise of arterial NE spillover from 2.15 +/- 0.27 to 13.52 +/- 1.62 nmol.min-1 x m-2 (P < 0.01). NE clearance decreased from 0.91 +/- 0.05 to 0.80 +/- 0.05 l.min-1 x m-2 (P < 0.05). These data suggest that, during dynamic exercise, sympathetic nervous system activity is related to exercise intensity, and there appears to be an interaction between the effects of exercise intensity and duration on NE spillover. In addition, at moderate-to-high exercise intensity, a small decrease of NE clearance contributes to the rise in plasma NE.

These results support the conclusion that two dimensional echo/Doppler techniques can be used to estimate rapidly and non-invasively the degree of left ventricular damage produced in living rats with myocardial infarction when compared to non-infarcted controls.

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To determine whether prejunctional angiotensin II receptors facilitate norepinephrine (NE) release during exercise, normal volunteers exercised at approximately 25 or approximately 65% of maximal O2 consumption (VO2max) on two occasions. Steady-state NE kinetics were determined at rest and during exercise by using infusions of [3H]NE. Arterial plasma NE and [3H]NE were determined for calculation of NE spillover and clearance. Before the second bout of exercise at approximately 25% of VO2max later that day, enalaprilat (n = 8) or nitroprusside (n = 5) was administered intravenously to lower blood pressure to a comparable level and saline was infused as a time control (n = 4). Exercise at 25% of VO2max increased heart rate from 73 to 100 beats/min, plasma NE from 296 to 626 pg/ml, and NE spillover from 1.56 to 3.32 nmol.min-1.m-2. The exercise effect was significant in each subgroup. At rest and during exercise, the decrease in blood pressure and the increase in plasma NE and NE spillover were similar with enalaprilat and nitroprusside. There was no drug effect in the saline group. In a separate group (n = 7), exercise at approximately 65% of VO2max increased heart rate from 76 to 170 beats/min, plasma NE from 338 to 2,656 pg/ml, and NE spillover from 1.87 to 11.65 nmol.min-1.m-2. In this group, 3 days of oral enalapril did not affect the NE spillover response to exercise. Because the angiotensin-converting enzyme inhibitor did not attenuate the NE spillover response to exercise, we conclude that at the exercise levels tested, prejunctional angiotensin II receptors do not appear to facilitate NE release.

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