Angiotensin II inhibits the forearm vascular response to increased arterial pressure in humans.

OBJECTIVES: This study tested the hypothesis that angiotensin II may inhibit the forearm vascular resistance response to an increase in arterial pressure in normal humans. BACKGROUND: Angiotensin II inhibits baroreflex-mediated reductions in heart rate and peripheral sympathetic activity during increases in arterial pressure in experimental animals. If present in humans, such effects could contribute to the pathophysiologic role of angiotensin II in hypertension and heart failure. METHODS: Two investigations were performed. In the first, forearm vascular resistance responses were compared during equipressor infusions of angiotensin II and phenylephrine. In the second, heart rate, forearm vascular resistance and systemic venous norepinephrine spillover responses were compared during head-down tilt and head-down tilt plus phenylephrine with concomitant angiotensin II or vehicle infusions. RESULTS: In the first study, forearm vascular resistance increased from 44 +/- 12 (mean +/- SD) to 54 +/- 13 U (p < 0.05) during angiotensin II but did not change during phenylephrine infusions (39 +/- 8.5 to 40 +/- 14 U) that increased mean arterial pressure comparably (88 +/- 9.8 to 103 +/- 14 mm Hg during angiotensin II, p < 0.001; 91 +/- 7.6 to 104 +/- 9.2 mm Hg during phenylephrine, p < 0.001). In the second study, the decrease in heart rate and forearm vascular resistance during the combination of head-down tilt and phenylephrine were both attenuated during concomitant angiotensin II compared with vehicle infusions: delta HR/delta MAP = -2.2 beats/min per mm Hg during vehicle and -0.87 beats/min per mm Hg during angiotensin II (p = 0.07); delta FVR/delta MAP = -2.8 U/mm Hg during vehicle and -0.19 U/mm Hg during angiotensin II (p = 0.01), where delta HR = change in heart rate; delta MAP = change in mean arterial pressure; and delta FVR = change in forearm vascular resistance. Norepinephrine spillover declined during vehicle infusions (612 +/- 367 to 418 +/- 196 ng/min, p < 0.05) but not during angiotensin II infusions despite a greater increase in mean arterial pressure when the subpressor angiotensin II was combined with head-down tilt and phenylephrine (6.0 +/- 7.0 mm Hg during vehicle; 14 +/- 9.4 mm Hg during angiotensin II, p < 0.01). CONCLUSIONS: Both pressor and nonpressor infusions of angiotensin II immediately inhibit the forearm vascular response to mild baroreflex loading in normal humans. If present over the long term, such effects could contribute to inappropriate peripheral resistance in diseases such as hypertension and congestive heart failure.

Angiotensin II and sympathetic activity in patients with congestive heart failure.

OBJECTIVES: This study was designed to determine the effects of intravenous angiotensin II infusions and the short-term effects of enalaprilat on venous plasma norepinephrine and norepinephrine spillover in patients with stable chronic congestive heart failure. BACKGROUND: Angiotensin II has been shown experimentally to stimulate norepinephrine release. Such effects, if present in humans with congestive heart failure, could be of pathophysiologic and pharmacologic importance. METHODS: In study 1, 60-min angiotensin II (5 ng/kg per min) infusions were administered in eight patients with chronic New York Heart Association functional class II and III congestive heart failure. Heart rate, arterial pressure, forearm venous plasma norepinephrine, norepinephrine clearance (estimated from the clearance of tritiated norepinephrine) and norepinephrine spillover were measured after 30 min in the supine position and after 15 min each of head-up and head-down tilt. All patients were studied in a double-blind manner on two occasions with vehicle control infusions. In study 2, 14 patients comparable to those in the first study had similar measurements made in the supine position before and 30 and 60 min after the administration of enalaprilat (1 mg intravenously). Eight patients received a double-blind vehicle control. RESULTS: In study 1, there were no effects of angiotensin II on heart rate, plasma norepinephrine, norepinephrine clearance or norepinephrine spillover compared with the vehicle control when the patient was in the supine position. Mean arterial pressure increased from 85 +/- 13 to 95 +/- 10 mm Hg with angiotensin II. During upright tilt, plasma norepinephrine and norepinephrine spillover increased comparably with angiotensin II and the vehicle control. During head-down tilt, plasma norepinephrine decreased with both angiotensin II and the vehicle control. Norepinephrine spillover remained elevated relative to control values on both study days during head-down tilt. In study 2, both enalaprilat and vehicle control administration were associated with a slight decrease in mean arterial pressure (5 +/- 2 vs. 3 +/- 4 mm Hg, p = NS), but no changes were seen in plasma norepinephrine. Norepinephrine clearance and spillover decreased comparably with time after both enalaprilat and vehicle control. CONCLUSIONS: Neither the infusion of angiotensin II nor the acute administration of enalaprilat significantly alters the activity of the sympathetic nervous system as reflected by plasma norepinephrine or systemic venous norepinephrine spillover in patients with chronic congestive heart failure. These data weaken the hypothesis that angiotensin II is an important regulator of sympathetic activity in congestive heart failure.

Dissociation of sympathetic responses to baroreceptor loading and unloading in compensated congestive heart failure secondary to ischemic or nonischemic dilated cardiomyopathy.

This study tested the hypothesis that abnormalities of baroreceptor-mediated suppression of sympathetic activity may persist in chronic congestive heart failure (CHF) despite pharmacologic treatment and clinical stability. Plasma norepinephrine and norepinephrine kinetics (using 3HNE infusions) were measured during head-up and head-down tilt in 8 patients with chronic CHF and 6 normal control subjects. In response to upright tilt, normal subjects increased plasma norepinephrine (270 +/- 45 to 413 +/- 60 pg/ml, p less than 0.001) and norepinephrine spillover (540 +/- 103 to 781 +/- 124 ng/min, p less than 0.001). Patients also increased plasma norepinephrine (436 +/- 105 to 600 +/- 112 pg/ml, p less than 0.05) and norepinephrine spillover (802 +/- 180 to 1,037 +/- 370 ng/min). During head-down tilt, plasma norepinephrine decreased in normal subjects (from 413 +/- 60 to 256 +/- 26 pg/ml, p less than 0.001). The decrease was due entirely to a decrease in norepinephrine spillover (781 +/- 124 to 466 +/- 40 ng/min, p less than 0.001). In contrast, there was no significant change in norepinephrine spillover (1,037 +/- 370 to 949 +/- 338 ng/min) during head-down tilt in patients with CHF. These data suggest that suppression of sympathetic activity during baroreceptor loading may be defective in CHF despite relative preservation or correction of the response to baroreceptor unloading.

Effect of a pressor infusion of angiotensin II on sympathetic activity and heart rate in normal humans.

We tested the hypothesis that pressor infusions of angiotensin II (AII) could stimulate the sympathetic nervous system as reflected by norepinephrine (NE) spillover in humans. AII was infused at 5 ng/kg/min in six healthy volunteers, with vehicle and phenylephrine infusions as controls, on 3 separate days. Heart rate, mean arterial pressure, plasma NE, NE clearance, and NE spillover were assessed before and after 30-minute infusions of AII, vehicle, or phenylephrine in the supine position and then after 15 minutes of head-up and 15 minutes of head-down tilt. Both AII and phenylephrine raised mean arterial pressure (88 +/- 9.6 to 103 +/- 14 mm Hg, p less than 0.001, and 91 +/- 7.6 to 104 +/- 9.2 mm Hg, p less than 0.001, respectively), whereas heart rate fell only with phenylephrine (60 +/- 6 to 51 +/- 6.3 beats/min, p less than 0.001). Neither plasma NE nor NE spillover was affected by either infusion, and NE clearance declined slightly with both. No changes occurred in any variable during vehicle infusions in the supine position. During upright tilt, NE spillover increases were attenuated by both AII and phenylephrine while NE clearance changes were slightly greater, leaving plasma NE increases similar on each day. During head-down tilt, NE and NE spillover declined comparably on each study day.(ABSTRACT TRUNCATED AT 250 WORDS)

Subpressor angiotensin II infusions do not stimulate sympathetic activity in humans.

Angiotensin II (ANG II) exerts significant direct and indirect pressor and chronotropic effects in experimental animals. The indirect effects have been shown to be due to interactions with the sympathetic nervous system at several levels. To test the hypothesis that ANG II in subpressor doses enhances the activity of the sympathetic nervous system in humans either at rest or in response to a stimulus from baroreceptor unloading, we measured mean arterial pressure (MAP), heart rate (HR), plasma norepinephrine (NE), and plasma NE kinetics during infusions of ANG II at 2 ng.kg-1. min-1 [or 5% dextrose in water (D5/W) control in six healthy volunteers in the supine position and during 60 degrees head-up tilt. No changes in any measured variable occurred during either infusion in the supine position. During upright tilt with D5/W, HR increased (58 +/- 8.4 to 68 +/- 7.7 beats/min, P less than 0.005), MAP rose slightly (90 +/- 3.9 to 94 +/- 4.0 mmHg, P less than 0.005), and plasma NE increased (213 +/- 3.8 to 366 +/- 83 pg/ml, P less than 0.005). The responses of the variables to tilt during ANG II were not different from those with D5/W.(ABSTRACT TRUNCATED AT 250 WORDS)

Norepinephrine spillover to plasma during steady-state supine bicycle exercise. Comparison of patients with congestive heart failure and normal subjects.

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.

Effect of autonomic blockade on the hemodynamic responses of normal human subjects to acute intravenous milrinone.

We studied the hemodynamic effects of four doses of milrinone, administered by intravenous (i.v.) infusion alone and after autonomic blockade with prazosin, propranolol, atropine, and clonidine. Plasma concentrations of milrinone (50-600 ng/ml) were similar to those used for the treatment of cardiac failure and were unaltered by autonomic blockade. When given alone, milrinone induced dose-dependent increases in heart rate (maximum increase 21 +/- 4, SEM, beats/min) and cardiac output (CO) (maximum 44 +/- 9%) and reduced systemic vascular resistance (SVR) by a maximum of 32 +/- 5%. After autonomic blockade, milrinone caused a similar fall in SVR and a smaller but significant (7 +/- 2 beats/min) rise in heart rate, but no change in CO. The increase in CO produced in normal humans by acute i.v. infusions of milrinone depends on intact cardiovascular reflexes.

Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity.

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 less than .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 less than .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 less than .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.

Noradrenaline release and sympathetic nervous system activity.

Measurements of the plasma concentration of noradrenaline, or more specifically the rate at which noradrenaline enters plasma, provide a useful guide to sympathetic nervous system function in humans. The overall rate of release of noradrenaline to plasma gives an overview of sympathetic nervous system activity (integrated nerve firing rate), detecting generalized changes, whether occurring as a reflex response, produced by drugs, or accompanying disease processes. The pattern of sympathetic nervous activation, however, is not delineated, only the net change in neurotransmitter release. Measurement of regional rates of noradrenaline release allows the clinical assessment of organ-specific sympathetic nervous tone, and consequently more penetrating analysis of sympathetic nervous system pathophysiology in disease states. The major problem in interpreting regional noradrenaline spillover measurements lies in the difficulty in differentiating those changes in noradrenaline spillover due to altered nerve firing, from those due to extraneous factors which might also affect spillover, such as the possible influence of blood flow on noradrenaline washout.