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(Hypertension. 1995;26:628-633.)
© 1995 American Heart Association, Inc.

Articles

Acute Effects of Physiological Increments of Brain Natriuretic Peptide in Humans

Giorgio La Villa; Laura Stefani; Chiara Lazzeri; Claudia Zurli; Cristina Tosti Guerra; Giuseppe Barletta; Renzo Bandinelli; Gaetano Strazzulla; Franco Franchi

From the Cardiovascular Unit, Istituto di Medicina Interna (G.L.V., L.S., C.L., C.T.G., G.S., F.F.), Endocrinology Unit, Dipartimento di Fisiopatologia Clinica (C.Z.), and Cardiovascular Unit, Clinica Medica I (G.B.), University of Florence School of Medicine; and Laboratorio Centrale di ANALISI, Azienda Ospedaliera di Careggi (R.B.), Florence, Italy.

	Abstract

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Abstract To investigate the effects of physiological increases in plasma brain natriuretic peptide concentration in humans, we studied six healthy volunteers who received incremental infusions (0.25 pmol/kg per minute in the first hour and 0.50 pmol/kg per minute in the second) of synthetic human brain natriuretic peptide-32 in a placebo-controlled, crossover study. Peptide plasma levels were 1.69±0.39 pmol/L at baseline and rose 1.5- and 3-fold with the lower and higher doses, respectively. These values were within the normal range and also comparable to those reported in patients with mild essential hypertension. The urinary excretion rate of cGMP also increased during brain natriuretic peptide infusion, indicating stimulation of natriuretic peptide receptors. Peptide administration induced a significant 1.7-fold increase in urinary sodium excretion without affecting renal plasma flow (para-aminohippurate clearance), glomerular filtration rate (creatinine clearance), and urine flow rate. Fractional proximal sodium reabsorption (lithium clearance method) was unchanged, and fractional distal sodium reabsorption significantly decreased. Brain natriuretic peptide caused no changes in arterial pressure, heart rate, hematocrit, and serum proteins, but it exerted an inhibitory effect on the renin-aldosterone axis, as indicated by the significant 50% or more decrease of plasma renin activity and urinary excretion rate of aldosterone. These results suggest that brain natriuretic peptide may be involved in the overall regulation of body fluid and cardiovascular homeostasis in humans, mainly through its natriuretic and endocrine effects.

Key Words: natriuretic peptides • kidney function tests • sodium • renin-angiotensin system • aldosterone

	Introduction

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The second member of the natriuretic peptide family, BNP, is a cardiac hormone^{1 2} that is thought to contribute, together with ANP, to the regulation of cardiovascular homeostasis and fluid volume.^{3 4 5} BNP is mainly produced and released into circulation by the ventricles^{1 2 6} in response to ventricular stretch.⁷ In healthy subjects plasma BNP levels increase with age⁸ and are influenced by volume-related stimuli, because they increase in response to a high sodium diet⁹ or passive leg raising¹⁰ and are reduced by the assumption of the sitting position.¹⁰ High plasma BNP levels have been observed in disease states characterized by fluid overload, such as congestive heart failure,^{2 6 8 11} end-stage renal failure,¹² and cirrhosis with ascites.¹³ Plasma BNP levels are also increased in patients with essential hypertension.^{10 14 15} In this latter condition they correlate with the degree of hypertension^{10 14} and are modified by changes in sodium intake.¹⁶

BNP has a spectrum of pharmacological activities similar to those of ANP, including diuretic, natriuretic, hypotensive, and smooth muscle relaxant activities and inhibition of the renin-aldosterone axis.^{4 5 17 18} These effects are due to the stimulation of guanylate cyclase–linked natriuretic peptide receptors, leading to an increase in cGMP concentration in target cells.^{3 4 5} Previous studies by us¹⁹ and others²⁰ have shown that administration of BNP to healthy volunteers to increase plasma BNP levels up to 40-fold over baseline values has evident effects on renal sodium handling but does not modify cardiac output and blood pressure.

We undertook the present study to investigate whether BNP has biological actions at physiological plasma levels. Therefore, we evaluated the effects of incremental dose infusion of synthetic human BNP-32 (calculated to increase plasma BNP concentrations within the physiological range) on renal function, the renin-aldosterone axis, and blood pressure in a group of healthy subjects in a randomized, placebo-controlled, crossover study.

	Methods

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Study Protocol
Six healthy volunteers (three men and three women; age, 25 to 39 years; mean [±SD], 31±6 years) gave informed consent to participate in this single-blind, placebo-controlled, random-order, crossover study, which was approved by the local Ethics Committee. No subject had any history of hypertension or cardiovascular, renal, respiratory, hepatic, or metabolic diseases, nor were they taking any drugs. Physical examination, blood pressure, urinalysis, blood cell count, fasting serum glucose, blood urea nitrogen, creatinine, electrolytes, electrophoresis of serum proteins, enzymes, and electrocardiographic and echocardiographic findings were also normal. All subjects consumed a controlled 100 mmol sodium diet for a week before and throughout the study.

On the first day of the study at 5 PM lithium carbonate (600 mg, 16.2 mmol lithium) was given orally for measurement of lithium clearance. The next day subjects had breakfast at about 7:30 AM. At about 1:30 PM they received an oral water load (10 mL/kg body weight). Half an hour later an antecubital vein in each arm was cannulated for infusion of substances and blood sampling. The cuff of an automated apparatus (Dinamap, Critikon), validated against standard sphygmomanometry before each experiment, was positioned in the nondominant arm for blood pressure and heart rate recordings. Thereafter, all subjects were given an intravenous priming dose of PAH, followed by a continuous infusion throughout the study. To obtain adequate urine flow rates and increase the accuracy of urine collections, we also infused 5% dextrose (5 mL/kg body weight per hour) throughout the study. At 3 PM after 1 hour of equilibration blood was withdrawn for measurement of ANP and BNP, and urine was obtained by spontaneous voiding and discarded. Immediately afterward, three 1-hour clearance periods were performed in baseline conditions and during the administration of synthetic human BNP-32 (Clinalfa; 0.25 pmol/kg per minute in the second and 0.50 pmol/kg per minute in the third clearance period) or placebo. BNP solution was prepared by dissolving the calculated amount of synthetic human BNP in 5% dextrose (90 mL) plus haemaccel (Behring, 10 mL) and was administered in increasing rates (25 and 50 mL/h) with a peristaltic pump. Haemaccel was used to minimize BNP adsorption onto the walls of the infusion set.²⁰ Placebo consisted of the same solution (5% dextrose [90 mL] plus haemaccel [10 mL]) without BNP and was infused at the same rates. Blood samples were obtained in the middle and urine was collected at the end of each clearance period for the determination of urine flow rate, PAH, creatinine, lithium, sodium, and urinary concentrations of aldosterone and cGMP. The following parameters were also measured: blood pressure and heart rate (every 10 minutes), plasma BNP (every 30 minutes), hematocrit, serum proteins, PRA, and plasma ANP (at the end of each clearance period). All subjects remained supine throughout the study except when voiding. Hemodynamic measurements were always followed by blood sampling and then urine collection. The above protocol was repeated after 4 days, crossing over the treatments.

To establish the physiological range of plasma BNP, we obtained a blood sample from 57 consecutive healthy subjects (30 men and 27 women; mean age, 41±14 years; range 22 to 64 years) on uncontrolled sodium intake who gave informed consent to be submitted to this procedure. A plastic cannula was inserted into an antecubital vein of all subjects in the morning after overnight fasting, and blood was withdrawn after 45 minutes of bed rest.

Evaluation of Renal Function
Plasma and urinary PAH concentrations were measured by a fluorometric technique.¹⁹ Lithium was measured in diluted (1:10) serum and urine samples by atomic absorption spectrophotometry.¹⁹ Creatinine and lithium clearances were calculated as estimations of RPF, GFR, and distal sodium delivery,²¹ respectively. Segmental sodium handling was assessed by calculation of fractional sodium excretion, fractional proximal sodium reabsorption, fractional distal sodium delivery, and fractional distal sodium reabsorption according to Koomans et al.²¹

Hormonal Measurements
Blood samples (7 mL) for human BNP-32 and ANP determinations were collected in ice-chilled tubes containing EDTA and aprotinin (Trasylol, Bayer; 3500 kallikrein inhibiting units). Samples were centrifuged at 3000 rpm and 4°C, and plasma was stored at -80°C until further processing. Human BNP-32 and human ANP-28 were measured by radioimmunoassay after extraction with the use of kits from Peninsula Laboratories as reported elsewhere.^{19 22} PRA was measured by radioimmunoassay of generated angiotensin I after plasma incubation at 37°C, pH 6.0, for 90 minutes with the use of a commercial kit (Angiotensina I ¹²⁵I kit, RADIM). Urinary aldosterone and cGMP were assayed with commercial kits (Aldosterone kit, RADIM, and cGMP radioimmunoassay kit, Amersham, respectively). Results were corrected for the corresponding urine flow rates and expressed as U_ALDOV and U_cGMPV.

Statistical Analysis
Data are reported as mean±SD. Comparison between data obtained during placebo infusion and the BNP phase was performed with ANOVA for repeated measures with the use of a two-factor design (treatment and dose). Contrasts for the dose were performed with the use of the t test with Bonferroni correction to adjust the probability value for multiple comparisons. A value of P<.05 was taken to indicate statistical significance. Statistical analysis was performed with SPSS for Windows 6.0 (SPSS Inc).

	Results

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Plasma BNP levels measured in 57 healthy subjects on uncontrolled sodium intake were 1.54±0.38 (range, 0.86 to 2.91) pmol/L. All six healthy subjects submitted to BNP administration completed the study. U_NaV measured on the days before BNP and placebo infusions ranged between 90 and 115 mmol/d, confirming adherence to the diet.

Plasma BNP levels averaged 1.69±0.39 pmol/L at baseline and rose 1.5- and 3-fold during the lower (0.25 pmol/kg per minute) and higher (0.50 pmol/kg per minute) infusion rates, respectively (Fig 1). U_cGMPV also increased significantly during BNP infusion (placebo: 9.16±2.56, 9.61±2.53, and 9.80±2.51 pmol/s; BNP: baseline, 9.52±2.44 pmol/s; 0.25 pmol/kg per minute, 11.88±3.24 pmol/s, P<.01 versus placebo; 0.50 pmol/kg per minute, 15.11±4.25 pmol/s, P<.01 versus placebo; Fig 2).

View larger version (10K): [in this window] [in a new window]   Figure 1. Line graph shows plasma BNP levels during administration of BNP (solid line) or placebo (dashed line). ANOVA for repeated measures: F=23.82, P<.0001; *P<.01 vs placebo.

View larger version (15K): [in this window] [in a new window]   Figure 2. Line graphs show mean (solid line) and individual (dashed lines) values of UcGMPV in the three clearance periods performed during administration of placebo and BNP (1=baseline, 2=0.25 pmol/kg per minute, 3=0.50 pmol/kg per minute). Each subject is indicated with a different symbol. ANOVA for repeated measures: F=14.84, P<.001; *P<.01 vs placebo.

Data of arterial pressure and heart rate observed in the six healthy subjects during BNP or placebo administration are shown in Fig 3. No significant differences were found between the two treatments.

View larger version (26K): [in this window] [in a new window]   Figure 3. Line graphs show systolic, diastolic, and mean arterial pressures and heart rate during administration of BNP (squares) or placebo (triangles).

Results of renal function observed during BNP and placebo administration are reported in Table 1 and Fig 4. BNP infusion did not affect RPF and GFR (and thus filtration fraction) to any appreciable extent, whereas it had an evident natriuretic effect. In fact, U_NaV showed an approximate 52% increase during the lower BNP dose (0.25 pmol/kg per minute) and a further 12% increment during the higher dose (0.50 pmol/kg per minute). The cumulative increase in U_NaV induced by BNP infusion was therefore 70%. Individual values of U_NaV observed during placebo infusion were quite different from one subject to another, but the natriuretic effect of BNP was observed in all subjects, though to a different extent (Fig 4). Lithium clearance, proximal sodium reabsorption, and distal sodium delivery were not modified by BNP infusion. On the contrary, fractional distal sodium reabsorption decreased significantly. Finally, peptide administration did not modify urine flow rate.

View this table: [in this window] [in a new window]   Table 1. Renal Function During BNP and Placebo Administration

View larger version (15K): [in this window] [in a new window]   Figure 4. Line graphs show mean (solid line) and individual (dashed lines) values of UNaV in the three clearance periods performed during administration of placebo and BNP (1=baseline, 2=0.25 pmol/kg per minute, 3=0.50 pmol/kg per minute). Each subject is indicated with a different symbol. ANOVA for repeated measures: F=10.24, P<.004; *P=.05 vs placebo; #P<.05 vs placebo, P<.05 vs 0.25 pmol/kg per minute BNP.

Data of hematocrit, serum proteins, PRA, plasma ANP, and U_ALDOV measurements are reported in Table 2 and Figs 5 and 6. BNP infusion induced a progressive reduction in PRA (Fig 5) and U_ALDOV (Fig 6), whereas it did not modify plasma ANP levels and blood volume, as indirectly assessed by hematocrit and serum protein measurements.

View this table: [in this window] [in a new window]   Table 2. Hematocrit, Serum Proteins, PRA, Plasma ANP, and UALDOV During BNP and Placebo Administration

View larger version (15K): [in this window] [in a new window]   Figure 5. Line graphs show mean (solid line) and individual (dashed lines) values of PRA in the three clearance periods performed during administration of placebo and BNP (1=baseline, 2=0.25 pmol/kg per minute, 3=0.50 pmol/kg per minute). Each subject is indicated with a different symbol. ANOVA for repeated measures: F=8.16, P=.008; *P<.05 vs placebo, P<.01 vs 0.25 pmol/kg per minute BNP.

View larger version (14K): [in this window] [in a new window]   Figure 6. Line graphs show mean (solid line) and individual (dashed lines) values of UALDOV in the three clearance periods performed during administration of placebo and BNP (1=baseline, 2=0.25 pmol/kg per minute, 3=0.50 pmol/kg per minute). Individual cases are indicated with different symbols. ANOVA for repeated measures: F=6.06, P=.019; *P<.05 vs placebo.

	Discussion

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The six healthy volunteers included in the present study had baseline plasma BNP levels similar to those observed in resting healthy subjects in most previous studies by us and others (see References 3, 5, and 23^{3 5 23} for review), as well as to levels found in the 57 healthy subjects on uncontrolled sodium intake included in the present study.

Plasma BNP levels increased approximately 1.5- and 3-fold with the lower and higher infusion rates, respectively. The first value is within the normal range in our laboratory, and it is similar to the mean increase in plasma BNP observed in healthy subjects in response to leg raising,¹⁰ high sodium intake,⁹ and retrograde ventriculoatrial conduction induced by ventricular pacing.²⁴ Plasma BNP levels observed at the end of BNP infusion at 0.50 pmol/kg per minute, though greater than the upper limit of the normal range in our laboratory, are similar to those reported by Naruse et al⁸ in aging subjects. Values achieved with the latter dose are also comparable to those observed in patients with mild essential hypertension^{10 15} and cirrhosis with ascites¹³ and are much lower than those reported in other disease states, such as heart failure, myocardial infarction, and chronic renal failure.^{2 5 6 8 11 12}

BNP infusion induced a progressive increase in U_cGMPV, suggesting stimulation of guanylate cyclase–linked natriuretic peptide receptors by BNP.

The results of the present study add further evidence to the hypothesis that BNP is involved in the regulation of body fluid and cardiovascular homeostasis in humans by demonstrating that increments in plasma BNP levels within the physiological range have clear renal and endocrine effects in healthy subjects. In fact, BNP infusion led to an approximate 1.7-fold increase in U_NaV when compared with time-matched placebo data. This natriuretic effect was observed in the absence of changes in RPF and GFR, pointing to a reduced tubular sodium reabsorption as the likely mechanism. The lack of effects on renal hemodynamics is in agreement with previous infusion studies^{19 20 25} in which changes in RPF and GFR only occurred when plasma BNP levels increased to at least 20-fold the normal range.^{19 20 25}

Evaluation of intrarenal sodium handling with the lithium clearance technique suggests that the natriuretic effect of BNP was probably due to a reduced sodium reabsorption in the distal tubule. This result is in agreement with recent data from our laboratory obtained with pathophysiological doses of BNP in humans,¹⁹ and it is also consistent with previous experimental studies showing that BNP binds with high affinity to inner medullary collecting duct cells, where it inhibits conductive ²²Na⁺ uptake in vitro²⁶ and reduces sodium reabsorption in the medullary collecting ducts, as shown by an in vivo microcatheterization technique.²⁷

Lithium clearance is considered the best currently available method for evaluation of intrarenal sodium handling in humans^{21 28} and the tubular response to hormones and autacoids, such as ANP.^{29 30 31} Results obtained with this technique, however, should be taken with caution, because the possibility that lithium might be reabsorbed in the distal tubule cannot be definitively ruled out. Lithium per se may also have a small natriuretic effect, especially when given in high amounts.^{32 33} It should be noted, however, that the present study was performed with a placebo-controlled, crossover protocol, so that the same amount of lithium was also taken in the placebo phase. Furthermore, lithium was given at the commonly used dose of 16.2 mmol, but the infusion was started 22 hours after drug administration, resulting in serum lithium concentrations always lower than 0.17 mmol/L. At these plasma levels lithium was shown to have no appreciable effects on renal function and U_NaV in healthy subjects.³⁴

Unlike previous studies performed by administering pharmacological²⁵ or pathophysiological^{19 20} doses of BNP, we did not observe any diuretic response to BNP infusion. The healthy subjects included in this study, however, received a water load and had very high urine flow rates in both the BNP and placebo phases, making any diuretic effect of BNP very difficult to detect.

Another relevant finding of the current study is that BNP at physiological plasma levels induced a 50% or more decrease of PRA and U_ALDOV, indicating that this hormone exerts suppressor activity on the renin-aldosterone axis, which could have contributed to the natriuretic effect. The reduced U_ALDOV observed at physiological plasma levels in this study is in agreement with previous investigations showing that BNP is a powerful inhibitor of aldosterone secretion from cultured human adrenal cells¹⁷ and that the administration of pharmacological²⁵ or pathophysiological²⁰ doses of BNP reduced plasma aldosterone concentration in humans. On the other hand, no significant changes in PRA were observed in other infusion studies in humans.^{5 20 22 25} This apparent discrepancy is probably due to the fact that BNP, when administered in pharmacological or pathophysiological amounts, had more or less evident hemodynamic effects,^{20 22 25} which might have offset the inhibitory activity of the peptide on renin release. On the contrary, the physiological increase in plasma BNP levels achieved in the present study was not associated with any appreciable changes in heart rate and blood pressure, suggesting that the peptide, at the plasma levels reached in the present study, has no direct effects on systemic hemodynamics. The reduction in PRA observed during BNP administration in the present investigation further confirms this contention. Thus, BNP at physiological plasma levels contributes to the long-term regulation of body fluid homeostasis and blood pressure through its renal and endocrine effects.

In conclusion, low-dose BNP infusion to increase plasma BNP levels within the normal range was natriuretic and inhibited the renin-aldosterone axis in a group of healthy subjects. These results suggest that BNP is a hormone of physiological importance in the overall regulation of body fluid and cardiovascular homeostasis in humans.

	Selected Abbreviations and Acronyms

 

ANP = artrial natriuretic peptide BNP = brain natriuretic peptide GFR = glomerular filtration rate PAH = para-aminohippurate PRA = plasma renin activity RPF = renal plasma flow UALDOV = urinary excretion rate of aldosterone UcGMPV = urinary excretion rate of cGMP UNaV = urinary sodium excretion

	Acknowledgments

 
This work was supported by grants from the Italian Ministero per l'Università e la Ricerca Scientifica e Tecnologica (1994).

	Footnotes

 
Reprint requests to Giorgio La Villa, MD, Cardiovascular Unit, Istituto di Medicina Interna, University of Florence School of Medicine, viale Morgagni 85, I-50134 Florence, Italy.

Received March 20, 1995; first decision May 19, 1995; accepted June 30, 1995.

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