(Hypertension. 1996;27:906-913.)
© 1996 American Heart Association, Inc.
Articles |
Differing Metabolism and Bioactivity of Atrial and Brain Natriuretic Peptides in Essential Hypertension
From the Department of Medicine, Christchurch (New Zealand) School of Medicine, Christchurch Hospital.
Correspondence to Dr A. Mark Richards, Department of Medicine, Christchurch School of Medicine, Christchurch Hospital, PO Box 4345, Christchurch, New Zealand.
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Abstract |
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Abstract Plasma concentrations of both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are elevated in severe hypertension, acute myocardial infarction, and heart failure. In the current study of individuals with essential hypertension, we have documented the hemodynamic, hormonal, and endocrine effects of infusions of these two peptides given alone or in combination in equimolar doses calculated to induce increments in plasma peptides to concentrations (30 to 60 pmol/L) observed in these disease states. The metabolic clearance rate of ANP (4.56±0.62 L/min) was greater than that for BNP (3.4±0.23 L/min, P<.001). Infusions of each cardiac hormone impaired the clearance of coinfused peptide. All peptide infusions enhanced natriuresis (17% to 70% above preinfusion levels versus placebo, 6%; P<.001), lowered blood pressure (10 to 18 mm Hg fall in mean arterial pressure below placebo levels; P<.001), increased hematocrit, suppressed the renin-angiotensin-aldosterone system, and enhanced plasma norepinephrine concentrations. The natriuretic and blood pressure–lowering effects of BNP were twofold to threefold those of ANP. In contrast, ANP-induced increments in plasma and urinary second messenger (cGMP) levels were greater than those for BNP. Both peptides suppressed the renin-angiotensin-aldosterone system (approximately one-third fall in renin activity and plasma aldosterone) and enhanced plasma norepinephrine concentrations (+30%) to a similar degree. Increments in plasma ANP and BNP that occur simultaneously in cardiovascular disease states appear capable of causing hemodynamic, endocrine, and renal effects that would tend to ameliorate conditions such as hypertension or heart failure.
Key Words: natriuretic peptides • renin-angiotensin system • hypertension, essential • catecholamines • cyclic GMP • natriuresis
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Introduction |
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The role of the cardiac hormone brain natriuretic peptide (BNP) in health and cardiovascular disorders such as hypertension is not well defined. A large body of data exists concerning the plasma levels of atrial natriuretic peptide (ANP) and its hormonal, renal, and endocrine effects in both experimental and human hypertension.1 2 3 4 5 6 7 8 In contrast, corresponding information concerning the more recently discovered9 BNP remains scant. To date, only a few reports describe the effects of exogenous BNP administered to humans,10 11 12 13 14 15 16 and only two concern subjects with essential hypertension.15 16
Existing data suggest that the effects of administered exogenous BNP (including natriuresis and suppression of renin-angiotensin-aldosterone system activity) are qualitatively similar to those of ANP.5 6 15 16 However, in humans the two peptides have different plasma half-life periods (approximately 3 and 20 minutes for ANP and BNP, respectively).11 17 In addition, there appears to be a different relationship between attained levels of plasma peptide and consequent elevation of plasma levels of the second messenger cGMP18 19 ; ie, ANP is a more potent stimulus to plasma cGMP than is BNP.
To date, no direct comparison of the effects of equimolar infusions of BNP and ANP in human hypertension has been reported. We have published data indicating that in normal volunteers relatively low-dose infusions of either ANP or BNP can reduce the metabolic clearance of coinfused BNP and ANP, presumably by way of competition in one or more of their shared degradative pathways.18 19 At present, it is unknown whether simultaneous increments in plasma ANP and BNP in hypertension have additive, synergistic, or complementary end-organ effects. Plasma concentrations of both peptides are elevated in severe hypertension, acute myocardial infarction, and heart failure.2 20 21 22 23 These observations suggest that we should seek information comparing the effects of ANP and BNP and the two peptides combined in health and in disease states. Therefore, we have documented the hemodynamic, hormonal, and endocrine effects of infusions of ANP and BNP given either alone or together in equimolar doses in subjects with essential hypertension.
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Methods |
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Eight male subjects with mild essential hypertension and no evidence of significant end-organ disease (other than left ventricular hypertrophy) aged 44 to 63 years (mean, 51 years) and weighing 66 to 104 kg (mean, 85 kg) were studied. The experimental proposal was approved by the Ethics Committee of the Southern Regional Health Authority (Canterbury), all participants gave informed consent, and all procedures were conducted in accordance with institutional guidelines. Entry criteria included systolic blood pressures consistently greater than 140 mm Hg but less than 180 mm Hg together with diastolic pressures consistently greater than 95 mm Hg but less than 115 mm Hg on multiple recordings over a period of at least 4 weeks after cessation of all antihypertensive medications. Subjects underwent baseline echocardiography, electrocardiography, chest radiography, plasma biochemistry, hematology, and fasting lipid profile analysis.
Subjects were studied on three or four separate occasions separated by at least 2 weeks in a balanced, single-blind, placebo-controlled, randomized, crossover fashion on the 4th day of constant sodium (150 mmol/d) and potassium (80 mmol/d) diet periods. On the morning of each study day, subjects ate breakfast and drank a fluid load of 500 mL at 7 AM. After subjects arrived at the study room at 8 AM, a 24-hour urine collection was completed. Subjects then remained seated throughout each study day (8 AM to 5 PM) except for standing to pass urine. Urine flow was maintained by having subjects drink 200 mL distilled water each hour. A light lunch was taken at 12:30 PM.
Between 10 AM and 3 PM, subjects received infusions of human ANP-(99-126) (2 pmol/kg per minute), human BNP-32 (2 pmol/kg per minute), a combination of human ANP and human BNP (ANP/BNP, 1 pmol/kg per minute of each peptide), or placebo (haemaccel). All eight subjects received all three "active" infusates. Six of the eight also received time-matched placebo infusions. The natriuretic peptides were administered in the same volume of haemaccel as that used in the placebo (vehicle) infusion, and the same infusion volume was used for all study phases. Metabolic clearance rate of peptides was calculated as infusion rate divided by steady-state concentration, subtracting baseline or time-matched placebo concentration of peptide. Intravenous inulin and para-aminohippurate infusions were given between 8:30 AM and 5 PM for serial measurements of glomerular filtration rate and effective renal plasma flow.24 Blood pressure and heart rate were measured every 15 minutes in duplicate with an automated sphygmomanometer (Electronic Services Ltd). Hourly urine samples were collected for measurement of volume, sodium, potassium, creatinine, para-aminohippurate, inulin, and cGMP. Venous blood samples were taken at 30- to 60-minute intervals between 9 AM and 5 PM via an indwelling forearm cannula in the arm contralateral to that used for peptide infusions. Plasma ANP, BNP, cGMP, plasma renin activity, aldosterone, cortisol, epinephrine, and norepinephrine were measured by established methods.25 26 27 28 29 30 For each subject, to minimize the potentially confounding effects of interassay variability, we performed measurements of individual hormones in single assays for all study days. Cross-reactivity of ANP antiserum with BNP was less than 0.2% and of BNP antiserum with ANP was less than 0.1%. The interassay coefficient of variation was highest for epinephrine at 18% and lowest for norepinephrine at 5%. Intra-assay coefficients of variation fell between 5% and 9%. Hematocrit was measured every 30 to 60 minutes in duplicate with the microhematocrit technique.
Data were analyzed by ANOVA,31 with treatment and time as repeated measures factors. Results are presented as mean±SE; a value of P<.05 was taken to indicate statistical significance.
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Results |
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Six subjects completed all four stages of the protocol. Because of technical and logistic reasons, two further subjects completed the three active peptide phases but not the placebo portion of the study. Results from these two subjects, when added to those from the other six participants for analysis of results during active peptide infusions, showed no significant effect on trends or mean results of these three phases. For the sake of clarity, the data are confined to those six subjects for whom data from all four study phases (ie, placebo-controlled) were available. The exception is calculated metabolic clearance of peptides, for which data from all eight subjects were available.
Mean seated blood pressure at the end of the drug withdrawal phase immediately before commencement of the first of the 4 detailed study days was 152±2/95±1.5 mm Hg and did not differ significantly before each study infusion. Two of eight subjects fulfilled electrocardiographic criteria for left ventricular hypertrophy. Echocardiography indicated a mean left ventricular mass of 281±32 g, mean posterior wall thickness of 10±0.05 mm, and interventricular septal thickness of 14±1.2 mm. Ejection fraction averaged 68±2%. Mean plasma creatinine was 0.08±0.005 mmol/L (0.9±0.006 mg/dL); hemoglobin, 154±3 g/L (15.4±0.3 g/dL); total cholesterol, 5.7±0.4 mmol/L (220±15 mg/dL); triglycerides, 2.1±0.3 mmol/L (186±27 mg/dL); and high-density lipoprotein cholesterol, 1.1±0.1 mmol/L (43±4 mg/dL). Mean 24-hour urinary sodium excretion (173±25, 186±21, 174±11, and 180±18 mmol/d for 24 hours preceding ANP, BNP, ANP/BNP, and placebo infusions, respectively) did not differ significantly. Similarly, 24-hour potassium excretions (66±9, 70±6, 70±10, and 77±17 mmol/d, respectively) were well matched between study days.
Baseline plasma concentrations of BNP and ANP averaged over the preinfusion period were well matched for each of the study days (8.9±1, 9.2±0.8, 9.7±1, and 8.7±0.8 pmol/L for plasma BNP before infusions of ANP, BNP, ANP/BNP, and placebo, respectively, P=NS; 11.6±1, 11.1±0.9, 12.3±1, and 12.4±1.1 pmol/L for the corresponding ANP levels, P=NS). Peptide infusates were assayed and indicated a close match between calculated and actually administered peptide load. For infusions of BNP alone or ANP alone, rates of 1.94±0.07 and 2.14±0.09 pmol/kg per minute were achieved (P=NS). For the combined infusion (theoretically, 1 pmol/kg per minute of both ANP and BNP), achieved infusion rates were 1.0±0.05 and 0.9±0.02 pmol/kg per minute for ANP and BNP, respectively. Thus, with addition of the two lower-dose infusates (for the combined infusion phase), the total cardiac peptide infusion rate was 1.9 pmol/kg per minute. This figure was not statistically different from the total peptide infusion rates achieved for infusions of BNP or ANP alone.
As expected, plasma concentrations of BNP increased significantly above
baseline and matched placebo levels during both BNP and ANP/BNP
infusions (P>.001) but were unchanged during ANP and
placebo infusions (Fig 1
). Similarly, plasma
concentrations of ANP increased significantly during both ANP and
ANP/BNP infusions (P<.001) but were unchanged during BNP
and placebo infusions. Despite well-matched infusion rates,
steady-state increments in plasma BNP concentrations exceeded those
observed for plasma ANP during equimolar infusions. During infusion of
BNP alone, the mean increment in plasma BNP (averaged over the final
three sampling points of peptide infusions) above baseline and
time-matched placebo levels was 47±2.6 pmol/L. The corresponding
mean increment in plasma ANP during infusions of ANP alone was 40±4
pmol/L (P<.001). Accordingly, calculated
metabolic clearance rates for BNP were consistently
less than those for equimolar infusions of ANP in all eight subjects
(BNP, 3.4±0.23 versus ANP, 4.56±0.62 L/min; ie, BNP clearance was
23% less than ANP clearance; P<.001).
Metabolic clearance rates for BNP and ANP during combined
infusions were consistent with this initial result in that the
metabolic clearance rate for BNP remained lower than that
for ANP (2.46±0.13 versus 3.69±0.24 L/min, ie, 33% lesser rate for
BNP clearance compared with ANP; P<.001). Furthermore,
metabolic clearance rates at the lower dose of both ANP and
BNP given together were less than the corresponding rates for the
higher dose of peptide given alone (BNP alone, 3.49±0.23 versus
half-dose BNP [given together with half-dose ANP], 2.46±1.3
L/min; ie, -29%, P<.001; ANP alone, 4.56±0.62
versus lower-dose ANP [given together with half-dose BNP],
3.69±0.24 L/min; ie, -19%, P<.001). When increments
in plasma ANP and BNP during the combined infusions were summed, the
result (55±3.4 pmol/L) was 17% greater than that observed for
infusions of BNP alone (47±2.6 pmol/L, P<.001) and 38%
greater than that observed for infusions of ANP alone (40±4 pmol/L,
P<.001). This corresponded to a calculated mean plasma
clearance of ANP/BNP of 2.86±0.14 L/min, a figure that falls below
clearance rates for either peptide administered alone. In summary,
metabolic clearance of BNP was consistently less
than that for equimolar infusions (both 2 and 1 pmol/kg per minute) of
ANP, and for both peptides metabolic clearance was less at
the lower-dose infusion in the presence of the coinfused
peptide.
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), BNP (2 pmol/kg per
minute) (
), combined ANP/BNP (1 pmol/kg per minute of each)
(
), or placebo (
). For all panels, all phases differ
significantly from all others (P<.001) except for plasma
ANP (top), which did not differ (P=NS) between placebo and
BNP infusions. Conversely, plasma BNP (middle) did not differ
(P=NS) between placebo and ANP infusions. Mean±SE is
shown.
Plasma cGMP concentrations were significantly enhanced above placebo
values during all active peptide infusions (P<.001, Fig 1
).
However, the increment in plasma cGMP induced by ANP was more than
twofold the response to equimolar infusions of BNP (Fig 1). The plasma
cGMP response to the combined peptide infusion fell between those
observed with BNP alone and ANP alone. Each of these three responses
differed significantly from the other two (P<.001 for all
comparisons). Hence, despite clearly greater sustained increments in
plasma concentration, BNP induced smaller increments in plasma levels
of cardiac peptide second messenger (cGMP) than ANP. The intermediate
effect of combined peptide infusions remained consistent, with
a lesser effect of BNP compared with ANP. Similarly, urinary cGMP
excretion was enhanced by all three active peptide infusions and showed
the same pattern as that observed with plasma cGMP responses (Fig 2).
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Renal Response
Natriuresis and urinary excretion of cGMP are illustrated in Fig 2. All peptide infusions were natriuretic compared with
placebo. However, BNP administered alone was significantly more
natriuretic than ANP. The mean peak intrainfusion
increments in sodium excretion above immediate preinfusion levels were
7, 28, 98, and 112 µmol/min for infusion of placebo, ANP, BNP, and
ANP/BNP, respectively (P<.01 for all active infusions
versus placebo and P<.001 for BNP versus ANP). Urine volume
rose significantly with each peptide infusion (peaking at 33% to
68% above baseline values in contrast to placebo, 20%;
P<.01 to .001, Table 1). Urinary, potassium,
and creatinine excretions (Table 1) and calculated
creatinine clearance (data not shown) did not differ
significantly between study phases. Trends toward sustained or enhanced
inulin clearance and reduced para-aminohippurate clearance,
though not statistically significant when considered in isolation,
resulted in a significant enhancement of renal filtration fraction
above placebo values (Table 1) for infusions of BNP (+32%,
P<.05) and ANP/BNP (+32%, P<.01) but not ANP
(+23%, P=NS).
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Hemodynamic Response
Systolic, mean, and diastolic
arterial pressures remained well matched for all four study
phases until the midpoint of the infusion period. At this point
(approximately 12:30 PM, ie, after 2.5 hours of peptide
infusion), a clear decline in systolic, diastolic
(data not shown), and mean arterial pressures was seen on
all 4 study days. This coincided with the timed ingestion of a light
meal. After this point, peptide infusions produced a significant
(P<.01 to .001) sustained effect on arterial
pressure that remained below time-matched placebo levels for the
remainder of the infusion period. The peak hypotensive effect (mean
arterial pressure, 10 to 18 mm Hg below placebo values)
was observed 90 minutes after infusions were halted (Fig 3). The hypotensive effects of BNP or ANP/BNP were
greater than that of ANP alone (P<.01 and
P<.05, respectively). Heart rate was similarly increased
(by approximately 8 beats per minute) relative to matched placebo
values from 2 hours of any active infusion through to completion of the
follow-up period (Fig 3, P<.05 for all
comparisons).
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Hematocrit rose during all peptide infusions but fell during
administration of vehicle (Table 2 and Fig 4; P<.05, P<.001, and
P<.01 for comparisons between placebo and BNP, placebo and
ANP, and placebo and ANP/BNP, respectively). The increment in
hematocrit observed during ANP infusion exceeded that with BNP infusion
(P<.01). Once again, the combined infusion yielded an
intermediate result (Fig 4).
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Hormones
Plasma renin activity and plasma aldosterone
concentration were similarly suppressed below time-matched placebo
values (approximately -33% and -38%, respectively) by all
three peptide infusions (P<.05 to .01, Fig 5). Plasma norepinephrine rose significantly
(approximately 30%) above placebo values during each peptide infusion
(P<.05 to .01, Fig 5). No statistically significant
difference in the response of renin, aldosterone, or
norepinephrine was observed among peptide infusions. Plasma
cortisol and epinephrine levels were not significantly affected
(Table 2).
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Discussion |
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Our data document the first direct comparison of the hormonal, endocrine, and hemodynamic effects of equimolar doses of ANP, BNP, and the two peptides combined in a controlled study in subjects with essential hypertension. The three active infusions had directionally similar effects, including enhanced natriuresis, reduced blood pressure, increased heart rate, increased plasma norepinephrine concentrations, and suppressed plasma renin activity and plasma aldosterone concentrations. However, the magnitude of natriuretic and blood pressure–lowering effects differed significantly among peptide infusions, as did calculated metabolic clearance rates for the natriuretic peptides and increments in plasma and urinary levels of the second messenger cGMP.
The study design allowed direct comparison of metabolic clearance rates of the two peptides in strictly controlled circumstances. Infused alone or in combination with ANP, metabolic clearance of BNP is significantly less than that of its sister peptide, and the metabolic clearance of each peptide is less when it is coinfused (albeit at a lower dose) with the other peptide than when infused alone. Previous reports have suggested that the metabolic clearance rates of ANP and BNP (infused alone) are comparable in normal humans.11 32 However, comparative studies using equimolar infusion rates in the same subjects (as undertaken here) have not previously been done.
If confirmed, the lesser clearance of BNP may be explained by the known lesser affinity of human BNP for the natriuretic peptide clearance receptor compared with ANP33 and also the apparent lesser avidity of neutral endopeptidase (EC 3.4.24.11) for human BNP.34 The current data suggest that when coinfused, these peptides reduce one another's clearance. The ability of infused ANP to interfere with BNP clearance may exceed that of BNP to alter ANP clearance. Again, this fits with reports suggesting that ANP is a more able competitor than BNP for paths of cardiac peptide metabolic clearance.33 34 The dose of each peptide during coinfusion was halved from that during solo infusions; therefore, possible dose-related changes in clearance should be considered as an alternative explanation to peptide interaction. Our data cannot definitively rule out some influence of the dose change, but (in our experience of measured clearance at several doses of infused natriuretic peptide) clearance would be expected to rise rather than fall with a reduced dose. Therefore, the study design is more likely to minimize rather than exaggerate any interaction. In any case, we have previously demonstrated18 19 clear falls in peptide clearance of ANP and BNP, in which steady state is first achieved with a single peptide infusion and the second is added later at the same dose.
Infusions of ANP produce greater increments in cGMP than equimolar infusions of BNP. These distinctions are all the more intriguing when one considers that achieved increments in plasma ANP were less than for BNP and the effects of BNP on blood pressure and natriuresis exceeded those of the equimolar dose of ANP. Presumably, at least part of the greater biological effect of BNP is attributable to its greater mean steady-state level increment from baseline (BNP, 47 versus ANP, 40 pmol/L; P<.001). To dissect this factor from other possible mechanisms underlying the greater natriuretic and hypotensive effects of BNP will require further studies in which closely matched increments in plasma peptide concentrations are achieved; in addition, more complete dose-response curves should be constructed for each peptide. However, the greater vasodepressor effect of BNP than ANP/BNP despite the greater increment in plasma peptide (sum of increments in ANP and BNP) with the combined infusion (55±3.4 versus 47±2.6 pmol/L for BNP alone, P<.001) does suggest that BNP is intrinsically more active.
Obviously, greater increments in plasma BNP do not explain the lesser cGMP response to BNP. Conceivably, a proportion of guanylyl cyclase–linked receptors more successfully competed for by ANP than BNP occurs at tissue sites that preferentially favor spillover of the second messenger from intracellular to intravascular space. Hence, a population of "A" receptors on endothelial cells (the tissue most likely to immediately determine plasma cGMP) better stimulated by ANP than BNP could determine the plasma cGMP response quite independently of biological effects in other tissues. The urinary cGMP pattern reflects that seen in plasma, suggesting that the difference in second messenger generation is a prerenal phenomenon.
Possible explanations for the greater bioactivity of BNP include onset/offset kinetics from biological receptors (differing from ANP), allowing higher actions despite lower initial affinity for receptors. Second, BNP may have an as yet unidentified specific receptor and second messenger system.
The current study is the first in which a clear lowering of blood
pressure has been observed with relatively low dose or
"pathophysiological" levels of BNP in
individuals with hypertension. The reduction in blood pressure was not
observed until at least halfway through the 5-hour infusion period and
may have been unmasked by the additional hypotensive effect of
ingestion of a light meal. The effect on heart rate, together with
raised plasma norepinephrine levels, suggests a
baroreflex-mediated sympathetic nervous system response. The
hypotensive effect of the infusion may have been adequately compensated
by increased sympathetic activity early in infusions, but after food,
the blood pressure–lowering effects of the peptide become
sufficient to be revealed in the latter part of the infusion and during
follow-up postinfusion observations. BNP was more hypotensive than
ANP in this experimental setting. The late increase in mean
arterial pressure observed in the latter part of the
experiment with administration of placebo was only partly attenuated by
ANP but abolished by BNP. The fact that the combined peptide infusion
gives an intermediate result is again consistent with a greater
response to BNP than ANP. Maximal reduction in blood pressure was
observed 90 minutes after infusions were halted (Fig 3), at a time when
plasma renin activity and plasma aldosterone had
"rebounded" to exceed placebo values and when plasma
norepinephrine remained elevated (Fig 5). Hence, the
reduction in blood pressure was not primarily mediated by suppression
of the renin-angiotensin-aldosterone or
sympathetic nervous systems but presumably reflects contraction of
plasma volume (as suggested by persistent changes in hematocrit, Fig 4)
with or without additional direct relaxant actions of cardiac peptides
on vascular smooth muscle. The effects of peptide infusions on
hematocrit are consistent with the known ability of ANP to
promote transfer of fluid volume from the intravascular to the
extravascular space and suggest that BNP has a similar action. The
apparently lesser potency of BNP (compared with ANP, Fig 4) is of
interest in view of the greater depressor and natriuretic
effects of BNP. The observation requires confirmation, but if
reproducible it indicates that the greater fall in blood pressure
observed with BNP is not due to a greater contraction in plasma
volume.
Enhanced natriuresis and a rise in renal filtration fraction are well-established actions of ANP and BNP.12 32 Our current data indicate that BNP is more natriuretic and has a greater effect on renal filtration fraction than ANP. This is the more impressive in view of the simultaneously greater hypotensive action of BNP, as the natriuretic response to ANP is very sensitive to renal perfusion pressure.4 35 36 This indicates that the pressure-natriuresis relationship for BNP lies to the left of that for ANP.
Suppression of renin activity and plasma aldosterone concentrations was clear-cut and very similar for all three peptide infusions. This would suggest that the threshold of these responses to both natriuretic peptides is relatively low and the current experimental design therefore does not permit distinction between ANP and BNP. However, the greater hypotensive and natriuretic effects of BNP exceed those of ANP, and yet similar suppression of renin and aldosterone is achieved. Thus, it remains possible that the peptides do differ in their ability to suppress the renin-angiotensin-aldosterone system.
We gave the peptides in combination to achieve the same total delivered dose of peptide as in each solo infusion. Despite achieving greater total increments in plasma peptide concentrations, the biological effects of the combined infusions did not exceed those of solo infusions. Hence, our data give no support for biological synergy between ANP and BNP. However, because biological dose-response relationships are generally sigmoid in character and the change in position on the curve resulting from halving the dose of each peptide is uncertain, it is only possible to suggest that gross synergism has not occurred. To further test for synergism, infusions of fixed doses of ANP and BNP alone and in combination could be given to check for greater than additive effect.
In summary, in essential hypertension relatively low-dose infusions of ANP, BNP, and the two peptides combined (calculated to induce increments in plasma concentrations of ANP, BNP, or both to levels observed in severe and complicated hypertension or in mild to moderate congestive heart failure) have readily measurable effects on renal function (particularly natriuresis), blood pressure, heart rate, and the activity of both the renin-angiotensin-aldosterone and sympathetic nervous systems. In addition, for the first time, equimolar doses of ANP and BNP have been compared in individuals with essential hypertension and indicate that the metabolic clearance rate of BNP is less than that of ANP and biological responses (particularly natriuresis and reduction in blood pressure) to BNP are greater than those to ANP. Given together, the two peptides are not synergistic. Conversely, increments in plasma and urinary second messenger levels (cGMP) are greater for ANP than BNP. Our data suggest that the two peptides interfere with one another's metabolic clearance, and in this respect the effect of ANP on BNP clearance is greater than vice versa.
Hence, increments in plasma ANP and BNP, which occur simultaneously after myocardial infarction, in severe and complicated hypertension, and in congestive heart failure, appear capable of inducing important hemodynamic, endocrine, and renal effects that would tend to ameliorate these pathological cardiovascular states. In view of the greater biological effect of BNP on blood pressure and sodium excretion, this may represent a beneficial mechanism in conditions such as congestive heart failure in which plasma concentrations of BNP come to equal or exceed those of ANP, in contrast to the situation in health in which the reverse is true.26
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Acknowledgments |
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This study was supported by the Health Research Council and the National Heart Foundation of New Zealand. Expert secretarial assistance was provided by Barbara Griffin.
Received October 5, 1995; first decision October 31, 1995; accepted December 21, 1995.
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