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(Hypertension. 1995;25:1053-1057.)
© 1995 American Heart Association, Inc.

Articles

Cardiovascular Effects of Brain Natriuretic Peptide in Essential Hypertension

Giorgio La Villa; Gianni Bisi; Chiara Lazzeri; Caterina Fronzaroli; Laura Stefani; Giuseppe Barletta; Riccarda Del Bene; Gianni Messeri; Gaetano Strazzulla; Franco Franchi

From the Cardiovascular Unit, Istituto di Medicina Interna (G. La V., C.L., C.F., L.S., G.S., F.F.); Nuclear Medicine Unit, Dipartimento di Fisiopatologia Clinica (G. Bisi); Cardiovascular Unit, Clinica Medica I (G. Barletta, R. Del B.), University of Florence School of Medicine; and Laboratorio di Endocrinologia, U.S.L. 10D (G.M.), Florence, Italy.

	Abstract

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Abstract We evaluated the cardiovascular effects of pathophysiological plasma levels of brain natriuretic peptide in seven patients with mild to moderate essential hypertension by performing equilibrium radionuclide angiocardiography at baseline and during brain natriuretic peptide infusion at increasing doses (4, 8, 10, and 12 pmol/kg per minute for 20 minutes each). Brain natriuretic peptide induced a progressive reduction of left ventricular end-diastolic volume (from 107.5±10.3 to 89.0±11.0 mL at the end of all infusion periods) and end-systolic volume, whereas stroke volume did not show any significant change (from 64.9±5.9 to 62.7±7.8 mL). Cardiac output, arterial pressure, and peripheral vascular resistance did not change significantly. The lack of effects on systemic hemodynamics was probably due to compensatory activation of the sympathetic nervous system, as indicated by the significant increase in plasma norepinephrine levels (from 1.75±0.18 to 2.19±0.21 nmol/L), heart rate (from 68±6 to 81±6 beats per minute), peak ejection rate, and peak filling rate. These results indicate that brain natriuretic peptide, at the pathophysiological plasma concentrations reached in this study, influences cardiovascular homeostasis mainly by reducing cardiac preload.

Key Words: natriuretic peptides, brain • hypertension, essential • radionuclide imaging • cardiac output • hemodynamics

	Introduction

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Brain natriuretic peptide (BNP), a recently discovered member of the natriuretic peptide family, is a cardiac hormone having a marked similarity to atrial natriuretic peptide with respect to both amino acid composition and biological activities.^{1 2 3} Patients with essential hypertension show high plasma BNP levels,^{4 5 6} which correlate with the degree of hypertension^{5 6} and, after the development of left ventricular hypertrophy, with left ventricular mass index.⁴ In these patients, administration of low-dose BNP induced marked diuretic and natriuretic responses, without affecting arterial pressure, cardiac output, and peripheral vascular resistance (PVR).⁷

To further assess the pathophysiological relevance of the increased cardiac release of BNP in hypertension, we administered synthetic human BNP in increasing amounts, to raise its plasma concentrations within the pathophysiological range, and evaluated whether and at what plasma level this hormone influences cardiovascular function, as estimated by a noninvasive, scintigraphic technique.

	Methods

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Study Protocol
Seven inpatients (four men and three women; aged 59 to 65 years; mean, 61±1 years) with mild to moderate essential hypertension according to World Health Organization criteria gave their informed consent to participate in the study, which was approved by the local Ethics Committee in April 1994. All patients had diastolic pressure of 90 mm Hg or higher, a history of hypertension lasting at least 1 year, abnormal 24-hour ambulatory blood pressure profile, and a hypertensive retinopathy. Secondary hypertension was excluded by clinical history, physical examination, laboratory tests, and excretory urogram or captopril scintigraphy. No patient was in the accelerated or malignant stage of hypertension, and none had complicated hypertension; diabetes; or pulmonary, cardiac, or renal disease. Previous medications, if any, were discontinued at least 1 month before the study in all but one patient, who consumed diltiazem (180 mg/d) until 24 hours before the study. All patients followed a controlled diet with 100 mmol sodium for a week before the study.

On the day before the study, echocardiographic examination was performed as recommended by the American Society of Echocardiography,⁸ and left ventricular mass index was calculated according to Devereux and Reichek.⁹ A 24-hour urine collection was also obtained for measurement of urinary sodium excretion.

On the day of the study, patients had breakfast at 7:30 AM; at 2 PM, they were referred to the study room. An antecubital vein in each arm was cannulated for BNP infusion and blood sampling. An electrocardiograph was continuously monitored in lead II. The cuff of an automated apparatus (Dinamap, Critikon) was positioned on the nondominant arm for blood pressure recording.

All patients remained in the supine position for at least 45 minutes. Then they received a 20-minute infusion of placebo (90 mL of 5% dextrose plus 10 mL haemaccel; infusion rate, 75 mL/h) followed by synthetic human BNP-32 (Novabiochem) at 4, 8, 10, and 12 pmol/kg per minute. Each dose was administered for 20 minutes. BNP solution was prepared by dissolving synthetic human BNP in 5% dextrose (90 mL) plus haemaccel (10 mL, Behring) and was administered at increasing rates (25, 50, 62.5, and 75 mL/h) with the use of a peristaltic pump. Haemaccel was added to BNP solution because it has been shown to minimize BNP adsorption onto the walls of the infusion set.^{7 10}

Equilibrium radionuclide angiocardiography was performed after in vivo labeling of red blood cells with 925 MBq (25 mCi) of ^99mTc. Patients were imaged supine in the "best septal" left anterior oblique projection. Acquisition and processing were made with the use of an Elscint SP4 scintillation camera equipped with a low-energy, all-purpose parallel hole collimator (Elscint), using 24 frames per cycle, 64x64 matrices, and a x2 zoom factor. Five-minute repeated acquisitions were obtained during the last 5 minutes of each 20-minute period of placebo or BNP infusion. For each acquisition, 5 to 7 million counts were acquired. Data were processed with the use of a conventional validated semiautomatic method¹¹ involving multiple regions of interest (ROI) and background subtraction. Absolute left ventricular end-diastolic volume (LVEDV) was calculated with a validated nongeometric method.¹¹ From the obtained left ventricular curve, the following parameters were calculated: left ventricular ejection fraction (LVEF), peak emptying rate (PER), and peak filling rate (PFR). Right ventricular ejection fraction (RVEF) was estimated with a two ROI method. The following parameters were also measured: arterial pressure (at minutes 1 and 4 of each 5-minute acquisition period), heart rate (mean of all values recorded during each 5-minute acquisition period), and plasma BNP levels (at the end of each infusion period). Finally, hematocrit, plasma renin activity (PRA), and plasma concentrations of proteins and norepinephrine were measured at baseline and at the end of the last infusion period.

Left ventricular end-systolic volume (LVESV), stroke volume, cardiac output, and PVR were subsequently calculated from LVEDV, LVEF, heart rate, and mean arterial pressure (diastolic pressure+1/3 pulse pressure).

Analytical Methods
Blood samples (7 mL) for human BNP-32 determinations were collected in ice-chilled tubes containing EDTA and aprotinin (Trasylol, Bayer; 3500 kallikrein inhibiting units). Samples were centrifuged at 3000 rpm at 4°C, and plasma was stored at -80°C until further processing. BNP was extracted with Sep-Pak C18 cartridges (Waters Associates) and assayed by radioimmunoassay (kit from Peninsula Laboratories), as previously described.^{5 12} Aliquots (100 µL) of the reconstituted BNP extracts were incubated in triplicate with 100 µL of anti-BNP antibody at 4°C overnight. Then ¹²⁵I-BNP (10 000 to 12 000 cpm) was added, mixed, and incubated at 4°C overnight. Standard curves were constructed with standard BNP over a concentration range of 0.33 to 128 pg per tube. Precipitation was obtained with 100 µL of diluted goat anti-rabbit IgG serum and 1000 µL of diluted normal rabbit serum. Precipitates were allowed to form for 2 hours at room temperature; radioimmunoassay buffer was then added, the pellet was separated by centrifugation at 1700g for 20 minutes, supernatant was removed, and radioactivity was counted in a gamma counter (Packard Instruments). Recovery of standard BNP added to buffer and human plasma to achieve concentrations of 0 to 300 pmol/L was always greater than 70% (buffer: 76.4±1.0%; variation coefficient, 7.9%; human plasma: 76.0±1.0%; variation coefficient, 7.4%). Within- and between-assay coefficients of variation for human BNP-32 assay were 5.4% and 14.3%, respectively, and the limit of detection was 0.3 pmol/L. A close parallelism was observed between dilution of extracted plasma and a standard curve.

PRA and norepinephrine were measured with the use of commercial kits (Angiotensina I ¹²⁵I kit, RADIM, and CAT-A-KIT, Amersham, respectively).

Statistical Analysis
Data were analyzed by Student's t test for paired data or ANOVA for repeated measurements, followed by multiple range testing, as appropriate. The two-variable regression analysis was used to assess correlations. Results are given as mean±SEM.

	Results

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All patients completed the study. According to the Penn Convention,⁹ all patients had left ventricular hypertrophy (left ventricular mass index, 168±13 g/m²; range, 134 to 214 g/m²). Urinary sodium excretion, evaluated on the day before the study, ranged from 93 to 106 mmol, confirming adherence to the diet.

Baseline plasma BNP levels were 4.23±0.78 pmol/L (range, 2.45 to 7.61 pmol/L). These values were significantly higher than those observed in our laboratory in healthy subjects (1.43±0.05 pmol/L; range, 0.72 to 2.00 pmol/L; n=38, P<.001). BNP infusion induced a progressive, significant increase in plasma BNP levels up to a maximum of 56.14±3.80 pmol/L (range, 46.15 to 70.57 pmol/L) (Fig 1).

View larger version (28K): [in this window] [in a new window]   Figure 1. Bar graph shows plasma brain natriuretic peptide (BNP) levels in seven patients with essential hypertension at baseline and during administration of synthetic human BNP at increasing infusion rates. Plasma BNP levels in each period were significantly different from the others.

Results of cardiovascular function observed at baseline conditions and during BNP infusion are given in Fig 2 and the Table. Administration of human BNP at 4 pmol/kg per minute for 20 minutes did not induce appreciable changes in any of the measured parameters. At higher BNP infusion rates (8 pmol/kg per minute or more), there was a progressive, significant reduction of both LVEDV and LVESV, whereas stroke volume showed a small, nonsignificant decrease (Fig 2). LVEF also increased during the infusion, but the difference reached statistical difference only at the highest infusion rate. At this last period, PER and PFR of the left ventricle significantly increased, whereas changes in heart rate were significant in the third and fourth infusion periods. RVEF, the only systolic index of the right ventricle we measured, was not affected by the infusion (Table).

View larger version (39K): [in this window] [in a new window]   Figure 2. Bar graph show left ventricular end-diastolic volume (LVEDV), stroke volume (SV), and left ventricular end-systolic volume (LVESV) at baseline and during administration of synthetic human brain natriuretic peptide (BNP) at increasing infusion rates. *P<.05 vs baseline; **P<.05 vs baseline and 4 pmol/kg per minute; #P<.05 vs baseline, 4, and 8 pmol/kg per minute.

View this table: [in this window] [in a new window]   Table 1. Cardiovascular Functional and Systemic Hemodynamic Parameters at Baseline and During Brain Natriuretic Peptide Infusion in Seven Patients With Essential Hypertension

Plasma BNP levels measured at baseline and at the end of each infusion period significantly correlated with LVESV (r=-.40, P<.05), LVEF (r=.44, P<.01), PER (r=.34, P<.05), and PFR (r=.53, P<.05).

The Table also shows the behavior of systemic hemodynamics at baseline and at the end of each infusion period. Cardiac output had a trend toward higher values at the highest infusion rate, but the differences were not significant. Systolic and diastolic arterial pressures and PVR were not affected by BNP administration.

BNP infusion induced a significant increase in plasma protein concentration (from 6.75±0.10 to 6.89±0.13 g/dL at baseline and the end of the fourth infusion period, respectively, P<.02). Hematocrit showed a trend toward higher values at the end of the infusion (from 0.35±0.01 to 0.37±0.01), but the difference was not significant because of the fact that hematocrit increased in five patients but decreased or was unchanged in two. PRA (from 0.38±0.11 to 0.33±0.07 ng/L per second) did not change during the study, whereas plasma norepinephrine concentration significantly increased (from 1.75±0.18 to 2.19±0.21 nmol/L, P<.05).

	Discussion

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As opposed to atrial natriuretic peptide, which is mainly produced by the atria,¹³ BNP is synthesized and released into the circulation by the ventricles.^{2 3} Circulating plasma levels of this hormone are lower than those of atrial natriuretic peptide in physiological conditions^{3 4 5 10 12} and show a marked increase in pathophysiological conditions characterized by alterations of cardiac function and systemic hemodynamics, such as congestive heart failure,³ myocardial infarction,^{14 15} end-stage renal failure,¹⁶ hypertension,^{4 5 6} and cirrhosis with ascites.¹⁷ Therefore, it is conceivable that BNP may be involved in the regulation of cardiovascular homeostasis. This hypothesis is consistent with the results of other studies showing that BNP has a remarkable relaxing activity on smooth muscle cells¹ and that the administration of pharmacological doses of BNP to humans¹⁸ and experimental animals^{19 20 21 22 23 24 25} markedly affects systemic hemodynamics and renal function, because it is followed by a reduction of arterial pressure and PVR and an increase in diuresis and natriuresis.

Few studies have been published on the effects of pathophysiological rather than pharmacological plasma BNP levels in humans. McGregor et al²⁶ first administered low-dose BNP to healthy subjects and observed a significant inhibition of the renin-aldosterone axis but no effects on blood pressure, renal hemodynamics, or sodium excretion. This previous study, however, was performed with porcine rather than human BNP and did not take into account the species-specificity of this substance.²⁰ More recently, similar studies were performed in healthy subjects¹⁰ and patients with essential hypertension⁷ with the use of human BNP. In these studies, BNP was infused at a rate of 2 pmol/kg per minute for 2 hours, leading to plasma levels up to a maximum of approximately 25 pmol/L. BNP infusion had an evident natriuretic activity but did not affect arterial pressure and PRA. In another study from our laboratory,¹² BNP administration (4 pmol/kg per minute for 1 hour) raised plasma BNP up to approximately 35 pmol/L, but it did not modify cardiac output, arterial pressure, or PVR in a group of healthy subjects. It is important to note that in all of these studies, plasma BNP levels, although in the pathophysiological range, were fivefold to eightfold higher than those previously reported in hypertension.^{4 5 6}

In the present study, BNP infusion induced a progressive increase in plasma BNP concentrations, which were about 3-, 6-, 9-, and 13-fold the baseline values at the infusion rates of 4, 8, 10, and 12 pmol/kg per minute, respectively. These levels are in the "pathophysiological" range, being comparable with those observed in disease states such as congestive heart failure,³ myocardial infarction,^{14 15} and renal failure,¹⁶ all of which are well-recognized complications of essential hypertension. However, they are higher than those usually reported in patients with essential hypertension.^{4 5 6}

Evaluation of cardiovascular function by equilibrium radionuclide angiocardiography showed that BNP infusion exerted marked effects on cardiovascular function but only at plasma levels higher than those observed in hypertension. In fact, there was a progressive reduction in LVEDV, which reached statistical significance in the second, third, and fourth periods (that is, at infusion rates of 8, 10, and 12 pmol/kg per minute). The mechanism or mechanisms responsible for this phenomenon were not specifically investigated in the present study. The most likely possibility, however, is that this reduction of LVEDV was due to a reduction of cardiac preload, which in turn may be the consequence of BNP-induced vasodilation, perhaps mostly occurring in the venous compartment, since PVR, as estimated by the angioscintigraphic method used in this study, did not change. The possibility that there was a shift of fluid from the intravascular to the extravascular space also may be considered, but available data on this point are somewhat conflicting. In fact, plasma protein concentration significantly increased, and hematocrit also increased in five of seven patients, but this latter difference was not significant. Similar results (that is, a significant increase in protein concentration without any significant change in hematocrit) were also obtained in previous studies in healthy subjects¹⁰ and patients with essential hypertension⁷ with infusion of pathophysiological doses of BNP, leading to plasma BNP concentrations comparable to those achieved in the present investigation.

Changes in LVESV, LVEF, PER, PFR, and heart rate observed during BNP infusion were probably compensatory mechanisms to avoid a fall in stroke volume and cardiac output despite the reduced left ventricular preload. This interpretation is supported by the increase in plasma norepinephrine levels observed at the end of BNP infusion. Indeed, activation of the sympathetic nervous system might account in large part for these latter changes. Previous data by Yoshimura et al,¹⁸ who showed that BNP in the pharmacological range reduced right atrial and pulmonary capillary wedge pressures, together with arterial pressure and PVR, are also consistent with this interpretation. On the other hand, the possibility that direct effects of BNP on the heart might have contributed at least partially to the observed changes of cardiovascular function cannot be definitively ruled out, since natriuretic peptide receptor (NPR) genes are expressed in the human heart.²⁷ However, the administration of atrial natriuretic peptide, which activates the same NPRs as BNP, has recently been found to have no effect on myocardial contractility, despite the fact that the doses used were in the pharmacological range.²⁸

In the present study, there were no appreciable modifications in cardiac output, arterial pressure, or PVR during BNP infusion. These results are in agreement with those obtained with pathophysiological doses of BNP in previous studies in healthy subjects^{10 12} and hypertensive patients.⁷ The lack of changes in PVR during BNP infusion are probably due to baroreceptor-mediated, compensatory activation of the sympathetic nervous system, which maintained the arteriolar tone despite the vasodepressor activity of BNP. However, it is also possible that BNP, at the plasma concentrations achieved in this study, has no relaxing activity on arteriolar smooth muscle cells. The lack of changes in PRA was probably due to the opposite effects of BNP, which inhibits renin release, and the sympathetic nervous system, which has a well-known stimulatory activity. Indeed, PRA was also unchanged in the study by Yoshimura et al,¹⁸ despite the reduction of arterial pressure induced by pharmacological doses of BNP.

In conclusion, pathophysiological plasma concentrations of BNP reduced LVESV and LVEDV and increased LVEF, PER, PFR, and heart rate without modifying stroke volume, cardiac output, arterial pressure, and PVR in a group of patients with essential hypertension. These results, together with those of previous investigations showing that BNP also has remarkable diuretic and natriuretic activities,^{7 10 12} suggest that this hormone may be involved in the overall regulation of cardiovascular homeostasis. Whether BNP also has direct cardiac effects remains to be established.

	Acknowledgments

 
Supported by grants from the Italian Ministero dell'Università e della 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 October 27, 1994; first decision December 16, 1994; accepted January 27, 1995.

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