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(Hypertension. 1997;30:398.)
© 1997 American Heart Association, Inc.

Articles

The Effects of Pathophysiological Increments in Brain Natriuretic Peptide in Left Ventricular Systolic Dysfunction

John G. Lainchbury; A. Mark Richards; M. Gary Nicholls; Penny J. Hunt; Hamid Ikram; Eric A. Espiner; Tim G. Yandle; Evan Begg

From the Departments of Medicine (J.G.L., A.M.R., M.G.N., E.B.), Endocrinology (P.J.H., E.A.E., T.G.Y.), and Cardiology (H.I.), Christchurch Hospital, Christchurch, New Zealand.

Correspondence to Prof A.M. Richards, Department of Medicine, Christchurch Hospital, PO Box 4345, Christchurch, New Zealand. E-mail bgriffin{at}chmeds.ac.nz

	Abstract

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Abstract Plasma levels of brain natriuretic peptide (BNP) are raised in patients with left ventricular impairment and may play a role in the adaptation to left ventricular impairment. Manipulation of BNP levels may have therapeutic potential. The effects of BNP have not been well studied in patients with left ventricular impairment. We studied the effects of low-dose BNP infusion, reproducing the increment in plasma BNP seen with progression from mild to severe heart failure in patients with impaired left ventricular systolic function. BNP was infused in a placebo-controlled, single-blind, crossover design at a rate of 3.3 pmol · kg^–1 · min^–1 over 4 hours to 8 patients with a history of congestive heart failure and persistent impairment of left ventricular systolic function (left ventricular ejection fraction <35%). Endocrine, renal, and hemodynamic effects were measured. Compared with time-matched placebo-control, BNP infusion decreased mean systemic arterial pressure (peak decrease, 17.1 mm Hg; P=.04), mean pulmonary artery pressure (peak decrease, 6.1 mm Hg; P=.007), mean pulmonary capillary wedge pressure (peak decrease, 5.5 mm Hg; P=.04), and systemic vascular resistance (peak decrease, 1400 dyne s^–1 · cm^-5; P=.015), but cardiac output and heart rate were unchanged. Urinary volume and urinary excretion of sodium and potassium were not altered. BNP infusion increased plasma cGMP (2.3-fold change, P=.002). Plasma atrial natriuretic peptide levels were increased for the first hour of BNP infusion (peak increase, 11.5 pmol/L; P=.005). Plasma aldosterone levels were unchanged during but increased over time-matched control levels after the end of the BNP infusion (peak increase, 90 pmol/L; P=.02). Plasma renin activity and cortisol and catecholamine levels were unchanged. Low-dose infusion of BNP causes favorable hemodynamic changes and relative neurohormonal suppression but has attenuated renal effects in patients with impaired left ventricular systolic function.

Key Words: natriuretic peptide, brain • ventricular function, left • hemodynamics • natriuresis • renin-angiotensin-aldosterone system • catecholamines

	Introduction

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Brain natriuretic peptide (BNP) is a cardiac hormone secreted predominantly from the ventricles.¹ Plasma BNP concentrations, like atrial natriuretic peptide (ANP), are increased in acute and chronic cardiac impairment in proportion to the degree of hemodynamic compromise.^{2 3 4 5 6} Important differences between BNP and ANP have been observed in humans. The plasma half-life of BNP is longer, and BNP has greater natriuretic and arterial pressure-lowering effects than ANP, but paradoxically causes lesser increments in plasma second-messenger levels (cGMP) and has a lesser suppressant effect than ANP on the secretion of aldosterone.^{7 8 9 10}

The pathophysiological significance of increments in circulating BNP in heart failure remains unclear. In human heart failure, in contrast to ANP,^{11 12 13} there are few reports of the bioactivity of administered BNP. In the two full articles in print,^{14 15} plasma BNP levels were increased to well beyond the pathophysiological range by the BNP infusions. In the article by Yoshimura et al,¹⁴ brief (30-minute) infusions of pharmacological doses (0.1 µg · kg^–1 · min^–1) of human BNP were administered to a poorly defined group of patients with congestive heart failure and well-sustained arterial pressure. Time-matched placebo-control data were not provided, but relative to preinfusion values, significant increases in cardiac stroke volume, a fall in left ventricular filling pressure, and no change in systemic arterial pressure were observed along with a significant natriuresis. The latter effect exceeded natriuresis induced in a normal control group receiving the same dose of BNP. This profile of bioactivity contrasts with that of ANP in which reduced systemic as well as intracardiac pressures and markedly attenuated natriuretic effects are seen in heart failure.^{11 12 13} The natriuretic effects reported by Yoshimura et al also contrast with the results seen in animal models of heart failure in which BNP infusions were given.^{16 17} In the more recent study by Marcus et al, BNP was infused to a group of patients with well-defined heart failure.¹⁵ Four incremental 90-minute infusions were used, with the highest dose being the same as that used by Yoshimura et al. Significant falls in both cardiac filling pressures and systemic arterial pressures were noted, and at the highest dose an increase in cardiac index was seen. Much more modest natriuresis and diuresis were observed compared with that recorded by Yoshimura et al. The effects of the BNP infusions on other neurohormonal systems were not reported. Therefore, the exact hemodynamic, renal, and endocrine effects of BNP infusion in patients with heart failure remain to be defined. In particular, the effects of pathophysiological as opposed to pharmacological increments have not been well studied.

Previous work from our group has confirmed the correlation between plasma BNP levels and degree of hemodynamic compromise in patients with cardiac disease.⁶ In that study a range of BNP levels was seen. Mildly increased BNP levels (plasma BNP, 10 to 20 pmol/L) were observed in those with mild hemodynamic impairment (cardiac index, >3.0 L · min^–1 · m^–2; pulmonary capillary wedge pressure, 15 to 20 mm Hg), and the highest levels of BNP (plasma BNP, 60 to 80 pmol/L) were seen in those with severe hemodynamic compromise (cardiac index, <2.0 L · min^–1 · m^–2; pulmonary capillary wedge pressure, 25 to 30 mm Hg). Therefore, in this study we set out to determine the hemodynamic, renal, and hormonal effects of human BNP infused over several hours at a dose reproducing the increment in plasma BNP observed with progression from mild to severe heart failure in placebo-controlled studies of patients with well-documented left ventricular impairment.

	Methods

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Study Patients
We examined eight men, aged 52 to 73 years, with stable treated chronic congestive heart failure (ischemic, n=6; idiopathic dilated cardiomyopathy, n=2). All patients had suffered a clinically and radiologically documented episode of left ventricular failure within the previous 5 years, and had left ventricular ejection fractions of <35% documented by echocardiography before taking part in the study. All were in New York Heart Association functional classes II or III, and had no other major systemic disorders (including no renal impairment). All eight men were taking furosemide (average dose 120 mg/d), six were taking angiotensin-converting enzyme inhibitors (enalapril, n=3, mean dose 16 mg/d; captopril, n=3, mean dose 83 mg/d), and one was taking digoxin (0.25 mg/d).

Study Protocol
Study participants gave written informed consent. The protocol was approved by the Southern Regional Health Authority Ethics Committee (Canterbury). Subjects were studied on two occasions separated by 2 weeks in a randomized, placebo-controlled, balanced-order, single-blind, crossover design on the fourth day of constant sodium (100 mmol/d) and potassium (60 mmol/d) diets. On the morning of each study day patients ate breakfast, presented to the study room, and completed a 24-hour urine collection at 8 AM. All medications were withheld for 24 hours. On each study day 100 mL of water was given orally every 2 hours between 8 AM and 6 PM, and 800 mL of fluid (5% dextrose in water) was administered intravenously in flushing the central line and in thermodilution determinations of cardiac output. Subjects remained seated throughout the day except for initial placement of intravascular cannulae (supine) and for passing urine (standing).

On presentation to the study room, a 7-F balloon flotation catheter was placed in the pulmonary artery via the subclavian vein for measurement of pulmonary artery, right atrial, and pulmonary capillary wedge pressures and of cardiac output by thermodilution (in triplicate). The brachial artery was cannulated for continuous direct measurement of arterial pressure, and two venous cannulae were placed (one in each forearm) for separate infusion of BNP/placebo and venous sampling. Heart rate and rhythm were continuously monitored by electrocardiography. Systemic and pulmonary vascular resistances were calculated by standard formulae.

After a baseline observation period of 90 minutes, subjects received a 4-hour infusion of synthetic human BNP (Bachem; 3.3 pmol · kg^–1 · min^–1 in Hemaccel [Behring], 10 mL/h) or vehicle alone. Monitoring and sampling were continued for 3 hours after the infusions were completed.

Venous blood samples were taken for measurement of plasma BNP, ANP, N-terminal ANP, cGMP, plasma renin activity, aldosterone, cortisol, and catecholamines at 30- to 60-minute intervals throughout the study. Additional samples were taken at the beginning and end of the BNP infusion at 2-, 4-, 8-, and 15-minute intervals for determination of plasma half-life of BNP. Total volume of blood taken for analysis on each study day was 250 mL.

Hormone and cGMP concentrations were measured as previously described.^{18 19 20 21 22} Plasma BNP was measured by radioimmunoassay.³ Briefly, BNP was extracted from 2 mL plasma using Vycor glass (Crown Corning, Science Products Division; mean extraction 70%). The assay used, radiolabeled BNP purified by high-performance liquid chromatography ([¹²⁵I]-hBNP-32) and a specific antiserum (Phoenix Pharmaceuticals), had a minimum detection limit of 0.45 fmol/tube and an IC₅₀ of 9 fmol/tube. Cross-reactivity with hANP (99 to 126) was less than 0.001%. Samples from individual subjects were assayed together to minimize the effects of interassay variation. The intra-assay coefficient of variation was 5%.

Baseline plasma concentrations of BNP were subtracted from all concentrations before pharmacokinetic analysis. The pharmacokinetics of BNP in plasma were modeled using TOPFIT.²³ A two-compartment model best described the data and was applied to both the accumulation phase (during the infusion) and the elimination phase. A weighting function of 1/y was used to correct for the variance observed in the assay at higher concentrations. Values were estimated for each individual for the following parameters: t1/2 (min), t1/2ß (min), volume of distribution central compartment (Vc, L/kg), volume of distribution steady state (Vss, L/kg), mean residence time (MRT, min), and clearance (liters per kilogram per minute). The mean±SEM values for the group were calculated.

Plasma sodium, potassium, glucose, albumin, and creatinine were measured on venous blood taken before, during, and after the infusions. Packed cell volume was measured by the microhematocrit method at hourly intervals. Patients passed urine at set times (at beginning and end of infusions and at end of recordings) and at other times as required. The urine collections during, and for the 3 hours after the infusions, were pooled for measurement of sodium, potassium, and creatinine.

Echocardiographic examinations were obtained at baseline, midinfusion, and at least 1 hour postinfusion for measurement of left ventricular dimensions, mitral valve diastolic flow, and left ventricular ejection fraction (by M-mode and acoustic quantification).

Statistical Analysis
The data were analyzed by two-way ANOVA with treatment (BNP or placebo) and time as repeated measures. P<.05 was considered significant. Values are expressed as mean±SEM.

	Results

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The infusions were generally well tolerated. Two patients experienced brief symptomatic hypotension during BNP infusion. Both recovered within 10 minutes of lying supine without cessation of infusion or the need for additional intravenous fluid. All patients’ results were included in analyses, except the pharmacokinetic analysis in which one patient had a number of missing data points and could not be made to fit the model used, and was therefore excluded from pharmacokinetic analysis.

Twenty-four-hour urine indices were not significantly different before active and placebo days (results before BNP and placebo, respectively: sodium, 82±15 versus 80±6 mmol/24 h; creatinine, 11±1.2 versus 11±1.1 mmol/24 h; volume, 1468±242 versus 1664±273 mL/24 h).

Urinary potassium was slightly higher before the placebo phase (52±5 versus 42±4 mmol/24 h, P=.05).

Hormone and Biochemical Results
Mean baseline plasma BNP levels (19.6±6 pmol/L) were approximately fourfold higher than the mean for normals in our assay (normals, 4.8±0.2 pmol/L; n=168). Baseline levels of BNP correlated with baseline mean pulmonary artery pressure (r=.79, n=8, P=.017) and mean pulmonary wedge pressure (r=.77, n=8, P=.024).

The mean rate of BNP infusion confirmed by radioimmunoassay of infusates was 3.3±0.2 pmol · kg^–1 · min^–1.

Plasma BNP levels were stable for the hour before both placebo and BNP infusions (Fig 1). Peak BNP levels were achieved within 180 to 240 minutes of infusion (mean peak BNP=80.9±8.3 pmol/L). Plasma BNP fell rapidly after cessation of the infusion. Calculated t1/2 for BNP was 10.2±2.5 minutes, and t1/2ß was 90.9±14.8 minutes. The Vc and Vss were 1.04±0.28 L/kg and 2.32±0.37 L/kg, respectively, or 72.8 L/70 kg and 162.4 L/70 kg. The MRT was 169±7.7 minutes, and the mean clearance was 0.05±0.006 L · kg^–1 · min^–1 or 3.51 L · min^–1 · 70 kg^–1.

View larger version (18K): [in this window] [in a new window]   Figure 1. Mean (±SEM) plasma concentrations of BNP, cGMP, ANP, and aldosterone (ALDO) during infusion of BNP (3.3 pmol · kg–1 · min–1) (•) or placebo (). Plasma BNP was increased by BNP infusion (P=.001). Plasma cGMP differed significantly between phases (P=.002). Plasma ANP was higher over the first hour of infusion on the BNP day (P=.005). Plasma aldosterone differed significantly between phases after the conclusion of the infusions (P=.02).

Plasma cGMP levels increased to twice control levels during BNP infusions (P=.002) and returned close to time-matched control values 120 minutes postinfusion (Fig 1).

Plasma ANP rose above placebo-related levels for the first hour of the BNP infusion (P=.005, Fig 1). In contrast, N-terminal ANP levels tended to fall during the BNP infusions (P=.17) (Table).

View this table: [in this window] [in a new window]   Table 1. Plasma Cortisol, Renin Activity, Catecholamines, Albumin, Hematocrit, and N-Terminal ANP

Plasma aldosterone levels were similar at baseline and throughout the infusion phase, but after the conclusion of the BNP infusions, they rose above time-matched control values (P=.02, Fig 1). Plasma renin activity and cortisol and catecholamine levels did not significantly differ between study days (Table). There were no significant effects on plasma Na, K, Cr, glucose, and albumin or on hematocrit (Table).

Hemodynamics
Mean systemic arterial and pulmonary artery pressures were lowered significantly by BNP (P=.04 and P=.007, respectively). Both remained significantly lower on the active day from termination of the infusions over the remaining 3 hours of recordings (P=.03 and P=.02, respectively; Fig 2). Mean pulmonary capillary wedge pressure was lowered by BNP (P=.04, Fig 2). Cardiac output, mean right atrial pressure, and heart rate did not differ significantly between active and placebo days. Calculated systemic vascular resistance fell on the active day (P=.015, maximum difference between active and placebo 18.6% [2937 versus 1537 dyne·s^–1 · cm^-5]), but calculated pulmonary vascular resistance was unchanged.

View larger version (23K): [in this window] [in a new window]   Figure 2. Mean (±SEM) values of mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP), mean pulmonary capillary wedge pressure (PCWP), cardiac output (C.O.), and heart rate during infusions of BNP (3.3 pmol · kg–1 · min–1) (•) or placebo (). Mean arterial pressure, pulmonary artery pressures, and pulmonary capillary wedge pressure differed significantly between study phases (P=.04, P=.007, and P=.04, respectively). There was no difference in cardiac output or heart rate between phases.

Renal Effects
Urinary Na excretion was higher on the BNP infusion day (3.6±1 mmol/h versus 2.2±0.6 mmol/h), but this difference was not significant (P=.25). K excretion and urinary volumes did not differ significantly between the two study days (Fig 3), and creatinine clearance was unchanged (data not shown).

View larger version (11K): [in this window] [in a new window]   Figure 3. Mean (±SEM) urinary sodium and potassium excretion and urine volume during and for 3 hours after a 4-hour infusion (total 7 hours) of BNP (3.3 pmol · kg–1 · min–1, shaded bars) or placebo (open bars). There were no significant differences between study phases for these urinary variables.

Echocardiographic Results
Left ventricular systolic and diastolic volumes as determined by echocardiographic acoustic quantification were reduced by BNP infusions (peak infusion end systolic volume with BNP=154±15 mL, placebo=184±16 mL, P=.03; peak infusion end-diastolic volume with BNP=202±17 mL, placebo=240±20 mL, P=.01). Ejection fraction and mitral valve diastolic flow values were not altered by BNP.

	Discussion

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The baseline levels of plasma BNP observed in this study were similar to those seen previously in patients with well-compensated cardiac impairment, and the peak levels achieved with BNP infusion were similar to those found in patients with severe hemodynamic impairment.^{3 6} Our infusions of BNP caused significant falls in blood pressure, pulmonary artery pressure, left ventricular filling pressure, and cardiac dimensions without concomitant change in cardiac output, ejection fraction, heart rate, renin-angiotensin-aldosterone system activity, plasma catecholamines, urine volume, or urine electrolyte excretion. These data are strongly reminiscent of results previously reported during administration of ANP (at doses severalfold those incorporated in the current study) in similar patients.^{11 12 13 24}

Comparison With Previously Published Results
Our results stand in contrast to those of Yoshimura et al,¹⁴ who reported a substantial natriuretic and diuretic response greater than that seen in normal volunteers receiving the same dose of BNP, but no alteration in systemic pressures, and a fall in cardiac filling pressures.¹ A number of differences between studies may reconcile the discrepant findings. Yoshimura et al provide no time-matched control data, and the natriuresis and diuresis reported was confined to a total duration of 1 hour. In addition, mean arterial pressure was relatively high in their heart failure patients. In comparison with the current experiment, a much higher dose of BNP, causing a 20-fold rise in plasma BNP concentrations, was used. In our own study, falls in blood pressure did not commence until after the first hour of BNP infusions, and it is therefore not surprising that Yoshimura et al recorded no effect on blood pressure during a brief 30-minute infusion. This lack of fall in systemic arterial pressure and, therefore, presumably renal perfusion pressure coupled with the pharmacological levels of BNP, may well produce the natriuresis observed. The study by Marcus et al¹⁵ confirms the significant hemodynamic effects of BNP infusions in patients with impaired left ventricular function. They observed significant falls in systemic arterial pressure and cardiac filling pressure with BNP infusions over a range of doses, with effects on these parameters seen at doses similar to those used in the current study. In contrast to the current study, they recorded an increase in cardiac index, but this was seen only at infusion rates approximately 3 to 10 times those in the present study. This group of workers also observed a significant natriuresis and diuresis with BNP infusion, but these effects were much less than those seen in the study by Yoshimura et al. Peak plasma levels of BNP were approximately 20-fold greater than placebo in the study by Marcus et al, yet the increase in sodium excretion with BNP infusion was small (urine sodium excretion 2.6±2.4 mEq/h and 1.4±1.2 mEq/h for BNP and placebo, respectively). These findings plus those in the present study suggest that the natriuretic effects of BNP are attenuated in heart failure, particularly when compared with the effects of infused BNP in normal volunteers and hypertensive patients.^{25 26}

Urinary Hyporesponsiveness
The urinary hyporesponsiveness to natriuretic peptides in heart failure is not fully understood. It has been variously attributed to reduced renal artery perfusion pressure,^{27 28} downregulation of guanylate cyclase–linked natriuretic peptide receptors,^{24 29 30 31 32} attenuated renal cGMP production,³⁰ an intracellular defect distal to cGMP production,^{33 34} reduced delivery of natriuretic peptides to the distal nephron,³⁴ a deficiency of intrarenal kinins,³⁵ and the anti-natriuretic/anti-diuretic actions of angiotensin II,^{36 37} the renal sympathetic system,^{38 39} and vasopressin, all of which may be stimulated in severe grades of cardiac failure. With respect to renal artery perfusion pressure, it is notable that mean systemic arterial pressure was not low in either our study group or that reported by Yoshimura et al. Furthermore, we noted no correlation between basal arterial pressures (and therefore presumably renal perfusion pressure) and the subsequent natriuretic response to infused BNP within our study group. We therefore suggest that mechanisms other than, or additional to, the level of renal perfusion pressure explain the attenuated natriuretic response to natriuretic peptides in cardiac impairment.

Mechanism of Hemodynamic Effects
The mechanisms underlying the BNP-induced reductions in systemic and right-sided cardiac pressures that we observed cannot be definitively characterized from our data. However, the absence of change in renin and aldosterone concentrations and in plasma norepinephrine and heart rate during the course of infusions suggests that inhibition of the sympathetic nervous system or the renin-angiotensin-aldosterone system is not the primary cause of the reduction in pressures. On the other hand, it is notable that a substantial fall in arterial pressure occurred without a change in these compensatory systems, suggesting a relative suppression of response by renin and also of the baroreflex-mediated sympathetic response. Apropos of this the postinfusion increase in plasma aldosterone levels above control values in the current study does point to relative suppression of aldosterone during the course of BNP infusions. These findings are similar to those previously reported with ANP.^{11 12 13}

The decline in arterial pressure in the absence of a change in cardiac output indicates a fall in vascular resistance. The absence of change in hematocrit or plasma albumin suggests that rapid contraction of plasma volume does not underlie the falls in arterial pressure. Taken together, the current data suggest a direct vasorelaxant effect by BNP.

In addition, changes in ventricular diastolic function in response to infused BNP, as has been observed in an altered hemodynamic response to exercise in a group of patients with isolated diastolic heart failure,⁴⁰ could account for some of the observed hemodynamic effects. However, we recorded no change in echocardiographic mitral valve diastolic flow parameters in the current study.

Pharmacokinetic Model
The model (two-compartment) and weighting function (1/y) used for the pharmacokinetic analysis gave good visual fits for the data points. The values estimated by the model for the primary parameters from which the mean pharmacokinetic values were obtained were associated with quite a large range, suggesting that caution should be applied when interpreting the values in absolute terms. A model-independent estimate of the t1/2 can also be made from the mean residence time (MRT), ie, t1/2=0.693xMRT, calculated; thus, the mean t1/2 for the group was 116 minutes, which is not markedly different from the mean value of 91 minutes estimated using the model. The values of Vss and clearance in this group were of the same order as those previously found in normal volunteers and patients with hypertension,^{7 27} although the value for clearance was perhaps slightly lower. Carefully matched studies will be required to rule out subtle effects of left ventricular dysfunction on BNP pharmacokinetics.

Significance of the Observed Changes in cGMP and ANP
The plasma cGMP response to increments of plasma BNP was also similar to that observed during BNP infusions in other subject groups, and is distinctly less than that seen with infusions of ANP.^{7 27} In view of the fact that the bioactivity of BNP observed in the current study and also in previous work conducted in normal volunteers and in hypertensive patients matches or exceeds that of ANP in terms of hemodynamic effect, it seems possible that the pool of natriuretic peptide receptors leading to cGMP release into plasma may be more accessible to ANP than to BNP. It is also possible that a specific BNP receptor exists with an alternative second messenger.

Plasma ANP was significantly increased by approximately one third above control levels within the first hour of BNP infusions. This finding is consistent with those from Yoshimura et al,¹⁴ who observed an approximately 20% increase in plasma ANP above baseline levels during their brief, high-dose BNP infusions in patients with heart failure. It is possible that the introduction of BNP displaces ANP from clearance pathways including the non-guanylate cyclase–linked "clearance" receptor. Furthermore, we have previously reported the ability of relatively low-dose infusions of ANP and BNP to significantly alter achieved levels of the other peptide during dual infusions in normal volunteers.^{8 41} In the current study the return of plasma ANP to matched placebo values after 1 hour of BNP infusions may reflect increased activity of alternate clearance pathways for ANP or perhaps, more plausibly, decreased endogenous secretion of ANP secondary to reduction in intracardiac pressures. In this regard the trend toward falls in plasma concentrations of N-terminal ANP would mitigate against enhanced ANP (and concomitant N-terminal ANP) secretion underlying the observed initial elevation of plasma ANP.

In summary, we have reported that sustained infusion of BNP, producing clinically relevant increments in plasma peptide concentrations, results in clear-cut falls in systemic arterial pressure, left ventricular filling pressure, and pulmonary artery pressures without changes in cardiac output and heart rate. In addition, there is no significant natriuresis or change in endogenous creatinine clearance over the 7 hours from commencement of BNP infusions. The renin-angiotensin system and the sympathetic nervous system appear to be relatively suppressed during the infusion period, and some evidence of a relative release of aldosterone is observed in the postinfusion phase. Plasma ANP is augmented in the early part of the BNP infusion before any major hemodynamic effect consistent with displacement of ANP by BNP from degradative pathways. The profile of effects by BNP in this group with cardiac impairment closely parallels those previously observed with ANP. The dose of BNP is less than that of ANP previously employed,^{11 12 13} and the full dose relationship of one peptide versus the other for renal, hemodynamic, and hormonal effects in heart failure remains to be defined. Overall, our findings suggest that increments in plasma BNP concentrations with heart failure have important compensatory effects on hemodynamic status and possibly other neurohumoral factors. Therapeutic manipulation of plasma/tissue BNP in heart failure warrants further investigation.

	Acknowledgments

 
This work was supported in part by the Health Research Council of New Zealand. We thank Dr Chris Frampton for statistical advice, Marilyn Cullens for dietetic assistance, and the Special Tests nursing staff. Barbara Griffin provided secretarial assistance. Help from the technical staff of the Departments of Cardiology and Endocrinology is gratefully acknowledged.

Received October 31, 1996; first decision December 16, 1996; accepted February 25, 1997.

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