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(Hypertension. 1996;27:1259-1266.)
© 1996 American Heart Association, Inc.
Articles |
Acute and Chronic Neutral Endopeptidase Inhibition in Rats With Aortocaval Shunt
From the Franz Volhard Klinik, Virchow Klinikum, and the Max Delbrück Center for Molecular Medicine, Humboldt University of Berlin (Germany).
Correspondence to Dr Roland Willenbrock, Laboratory for Experimental Heart Failure LEH, Franz-Volhard-Klinik/Max-Delbrück-Centrum, Wiltbergstr. 50, 13125 Berlin, FRG.
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Abstract |
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Abstract In heart failure, sodium and water retention develop despite elevated plasma levels of atrial natriuretic peptide. Atrial natriuretic peptide is degraded in part by a neutral endopeptidase. Whether neutral endopeptidase inhibition improves sodium and water excretion in heart failure is unknown. We determined the effect of neutral endopeptidase inhibition on plasma levels of atrial natriuretic peptide and the renal response to acute volume expansion in rats with aortocaval shunts and in sham-operated controls. Acute endopeptidase inhibition with SQ 28,603 (30 mg/kg) elevated atrial natriuretic peptide plasma levels in both shunted rats (523±54 to 1258±330 pmol/L, P<.05) and controls (184±28 to 514±107 pmol/L, P<.05). Urinary cGMP excretion, which reflects renal action, increased in parallel. However, the diuretic and natriuretic responses to acute volume expansion were enhanced only in control rats and not in shunted rats. In contrast to the acute effects, chronic neutral endopeptidase inhibition with SCH 34826 (30 mg/kg twice daily) in shunted rats did not change atrial natriuretic peptide plasma levels or cGMP excretion. Nevertheless, the diuretic and natriuretic responses to acute volume load were increased by chronic endopeptidase inhibition in shunted rats (1789±154 to 2674±577 µL/80 min and 99±31 to 352±96 µmol/80 min, respectively; P<.05). Chronic endopeptidase inhibition attenuated the cardiac hypertrophic response to aortocaval shunt without changing arterial blood pressure. Our data show that the renal effects of neutral endopeptidase inhibition are not necessarily dependent on changes in atrial natriuretic peptide plasma levels but instead may be mediated by local inhibition of the neutral endopeptidase in the kidney. In addition, chronic endopeptidase inhibition may attenuate heart failure–induced cardiac hypertrophy independent of hemodynamic effects.
Key Words: heart failure, congestive • atrial natriuretic peptide • endopeptidase, neutral • heart hypertrophy • natriuresis • diuresis
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Introduction |
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The cardiac hormone ANP influences volume regulation and vascular tone (for review, see References 1 through 41 2 3 4 ). In heart failure, volume and sodium retention occur despite an activated ANP system. ANP production in heart failure is particularly increased in the ventricles.5 6 7 8 Despite markedly elevated ANP plasma levels, volume homeostasis and electrolyte homeostasis are impaired in heart failure, and the renal response to an acute volume load is diminished. The increased ANP levels may not be sufficient to evoke a response because of counterregulation by the renin-angiotensin-aldosterone and sympathetic nervous systems. Whether even higher ANP levels could create a new balance between the vasoconstricting and vasodilating and natriuretic systems in heart failure is not known.
The action of ANP is mainly mediated by its second messenger, cGMP.9 10 Two ANP receptors, ANP-A and ANP-B, contain the particulate guanylate cyclase as part of their structure.11 12 A third ANP receptor, ANP-C, is believed to have a clearance function.13 Stimulation of the particulate guanylate cyclase by ANP results in elevated cGMP levels in plasma and increased urinary cGMP excretion, both of which correlate with the biological activity of ANP.14 ANP is rapidly removed from the plasma by ANP-C receptors and by a specific NEP.13 15 16 17 NEPI leads to decreased ANP clearance.18 In most studies, NEPI alone did not elevate ANP plasma levels. However, when exogenous ANP and C-ANP were coadministered, the increase in ANP plasma levels was potentiated by NEPI,18 and the biological responses were enhanced.19 20 Furthermore, the volume-induced increase in ANP plasma levels in normal rats was enhanced by acute NEPI.21 22 Whether further activation of the ANP system might be able to improve the depressed renal response to acute volume load in experimental heart failure is unknown. We therefore investigated the renal response to acute volume expansion in rats with aortocaval shunt–induced experimental heart failure.
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Methods |
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Animals
Male Wistar rats (Moellegaard Animal Farms, Schoenwalde, Germany) weighing 230 to 250 g were used in all studies. They were fed normal rat chow and allowed free access to tap water. The rats were kept on a 12-hour light/dark cycle. All experiments were performed between 7 AM and noon. The studies were approved by the Council of Animal Care and performed according to the guidelines of the American Physiological Society.
Shunt Operation
The aortocaval shunt was induced under ether
anesthesia by a modified method developed by Garcia and
Diebold.23 Briefly, a laparotomy was performed and the
aorta was punctured with a 1.2-mm disposable needle (Braun Melsungen)
distal to the renal arteries. The needle was advanced into the adjacent
inferior vena cava. After the vessels had been temporarily
clamped, the needle was withdrawn and the aortic puncture site was
sealed with a drop of cyanoacrylate glue (Instant Krazy Glue, Borden
Co). The persistence of the shunt was verified by visual inspection
(swelling of the vena cava and color change caused by mixture with
arterial blood) and by oximetry at the end of the
experiments. The perioperative mortality was less than
5%. Sham-operated control rats were treated identically, except
that no puncture of the vessels was performed.
Neutral Endopeptidase Inhibition
Thirty days after shunt initiation, acute NEPI was induced with
intravenous administration of SQ 28,603 (30 mg/kg)
immediately before the beginning of the baseline period. Chronic NEPI
was achieved by gavage with SCH 34826 (30 mg/kg twice daily) for 30
days beginning the day after shunt surgery. The pharmacology of SQ
28,603 and SCH 34826 is detailed elsewhere.19 24 The doses
of both compounds do not influence blood pressure or diuresis
when ANP plasma levels are not elevated.25 26 However,
when the ANP system is activated, both compounds increase ANP
levels further and elicit diuretic or hypotensive
effects.19 27
Hemodynamic Measurements
Hemodynamic studies were performed with rats
under chloral hydrate anesthesia (400 mg/kg) 30 days after
shunt production. A PE-50 catheter was inserted through the
right jugular vein into the superior vena cava. Arterial
blood pressure was measured by cannulation of the right carotid artery
and registered with a Statham P23XL pressure transducer and Gould AMP
4600 amplifier.
Acute Volume Load Protocol
Diuresis, natriuresis, and cGMP excretion were measured
with rats under chloral hydrate anesthesia. For
measurements of diuresis, cGMP, and sodium excretion, a PE-50
catheter was inserted into the bladder, and urine was collected in
20-minute periods. NaCl (0.9%) was infused at a flow rate of 1.5 mL/h
throughout the experiment. Surgery was followed by a 20-minute
equilibration period before baseline values were obtained during the
following 20 minutes. Acute volume load was then performed with 5 mL
hyperoncotic hydroxyethylpolysaccharide solution (HAES
10%, Braun Melsungen) infused within 5 minutes. Urine for this period
(t1) was collected during the 5-minute volume infusion and the
following 15 minutes. The experiment was continued for two additional
20-minute collection periods (t2 and t3).
Determination of ANP, cGMP, PRA, and Ang II
Blood samples for ANP (800 µL) were withdrawn from the carotid
artery at the end of each observation period in NaEDTA-preloaded (final
concentration, 7 mmol/L) and prechilled tubes. ANP degradation was
prevented with phenylmethylsulfonyl fluoride (final
concentration, 10 µmol/L) and pepstatin (3 µmol/L). The blood was
centrifuged at 4°C and 2000g for 10 minutes
immediately after withdrawal, and the plasma was kept at -80°C
until extraction. The blood was replaced with the same amount of blood
from donor shunted or sham-operated rats. ANP plasma samples were
extracted with C18 Sep-Pak columns that had been activated with
acetonitrile and ammonium acetate (0.2%, pH 4.0). After the addition
of plasma, the columns were washed again with ammonium acetate, and ANP
was eluted with acetonitrile (60%) and ammonium acetate (40%)
following a previously described protocol.28 Samples were
then measured by radioimmunoassay28 performed with ANP
antibodies kindly provided by Dr J. Gutkowska, Montreal, Canada.
Urinary cGMP was determined with a specific
radioimmunoassay.29 Antibodies were donated by Dr P.
Hamet, Montreal, Canada. For PRA and Ang II measurements, blood was
collected in prechilled NaEDTA tubes (final concentration, 7 mmol/L).
A-phenantrolin (Merck; final concentration, 1.25 mmol/L) and captopril
(final concentration, 1 mg/L) were added. PRA was determined by
measurement of Ang I formed per 60 minutes30 and Ang II by
radioimmunoassay as described previously.31
Statistical Analysis
The responses to volume load were compared by two-way ANOVA.
Differences between groups were evaluated with the corrected unpaired
Student's t test and Wilcoxon rank sum test as
appropriate. The significance level was accepted at a value of
P<.05. All data are expressed as mean±SE.
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Results |
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Heart and body weights, blood pressure, and heart rate are shown in Table 1
. After 30 days, shunted rats increased their
total heart weight, as well as atrial and ventricular
weights, compared with sham-operated controls. Acute NEPI had no
effect on these variables. Chronic NEPI, on the other hand,
resulted in a significant decrease in total heart weight and
ventricular weight in shunted rats compared with shunted
rats without chronic NEPI. These effects seemed to be independent of
hemodynamic changes because chronic inhibition led to
no significant change in blood pressure. Acute administration of NEP
inhibitor increased heart rate compared with vehicle in
shunted rats. On the other hand, chronic administration of NEP
inhibitor decreased heart rate in shunted rats compared
with vehicle.
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Natriuresis and diuresis in control rats are shown in Fig 1. Acute NEPI induced an elevated baseline
diuresis (269±38 to 716±93 µL/20 min, P<.001)
and natriuresis (11±3 to 92±36 µmol/20 min, P<.05).
When the ANP system was challenged with an acute volume load, acute
NEPI led to enhanced natriuretic and diuretic
responses (2896±214 to 4685±278 µL/80 min, P<.001).
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ANP plasma concentrations in response to volume expansion are shown in
Fig 2a. ANP in control rats showed higher values after
acute NEPI than after vehicle during the baseline period
(P<.05). After acute volume load, acute NEPI potentiated
this increase in ANP plasma levels (184±28 to 514±107 pmol/L,
P<.05). cGMP levels in these rats are shown in Fig 2b. Even
before acute volume load was performed, acute NEPI induced a fourfold
higher cGMP excretion (325±97 to 1382±317 µmol/20 min,
P<.01). Similar to baseline values, acute NEPI potentiated
the urinary cGMP response to acute volume load (762±136 to 3780±562
µmol/20 min, P<.001).
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Fig 3 shows the diuretic and
natriuretic responses to acute volume expansion in rats
with aortocaval shunt compared with controls. The diuretic
response (Fig 3a) to acute volume load was markedly blunted
(P<.001) in rats with aortocaval shunt compared with
controls. The natriuretic response (Fig 3b) was similarly
perturbed in shunted compared with control rats.
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Since the renin-angiotensin system is activated
in chronic heart failure and also influences natriuresis and
diuresis, we measured PRA and Ang II values. After 30 days of
shunt, PRA and Ang II concentrations were significantly elevated
compared with control rats (Table 2). Acute NEPI did not
significantly change Ang II concentrations in either control or shunted
rats.
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ANP concentrations after volume expansion in shunted rats receiving
vehicle or acute or chronic NEP inhibitor are shown in Fig 4a. Rats receiving NEP inhibitor acutely
showed a brisk increase in plasma ANP, which decreased progressively
during the last two collection periods. Shunted rats receiving either
vehicle or NEP inhibitor chronically showed no increase in
plasma ANP concentrations after volume expansion. We measured cGMP
excretion to assess second messenger function, as shown in Fig 4b.
Acute NEPI, which elevated ANP plasma levels, also led to an increased
cGMP excretion in shunted rats (from 1142±116 to 4649±651 µmol/20
min, P<.001). In contrast, chronic NEPI did not induce any
change in cGMP excretion.
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We also investigated whether the increase in ANP plasma levels induced
by acute NEPI would result in an improved diuretic response in
shunted rats. Surprisingly, neither baseline diuresis nor the
response to acute volume load was significantly changed after acute
treatment (Fig 5a) despite increased ANP plasma
concentrations. The natriuresis induced by acute NEPI showed a tendency
toward higher values (P=.06). In contrast to acute
treatment, chronic NEPI (which did not influence plasma ANP
concentrations) was able to induce an elevated diuretic
response to acute volume load (from 1789±154 to 2674±577 µL/80 min,
P<.05). Moreover, chronic NEPI led to a significantly
enhanced baseline sodium excretion (from 3±1 to 10±3 µmol/20 min,
P<.05) as well as to a more pronounced
natriuretic response to acute volume load (from 99±31 to
352±96 µmol/80 min, P<.05, Fig 5b). These data suggest
that chronic NEPI may be able to improve the renal response to acute
volume expansion independently of plasma ANP levels.
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Discussion |
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We tested the hypothesis that inhibition of the enzymatic degradation of ANP could improve the effectiveness of ANP in promoting diuresis and natriuresis during acute volume expansion in rats with heart failure. We found that acute NEPI did not enhance the diuretic and natriuretic responses to acute volume expansion in rats with heart failure; however, when given chronically, NEP inhibitor promoted natriuresis by an action that is not entirely clear. When NEP inhibitor was given chronically, acute volume expansion did not achieve higher ANP plasma levels than in vehicle-treated rats with heart failure.
NEP is widely distributed in brain, lung, intestine, and smooth muscle32 and is also found in blood and urine.33 34 Several organs, including the liver and lung, contribute to ANP clearance.35 However, the highest NEP concentrations have been found in the kidneys, where the enzyme is most abundant in the brush border proximal tubular epithelium and glomeruli.16 17 32 33 36 The enzyme accounts for the early observations that ANP has an extremely short half-life in rats with kidneys in place and a much longer half-life in anephric rats.37 NEP inhibitors have been developed in the hope that the effect of ANP could thereby be potentiated. Other researchers have shown that NEPI enhances the effect of a concomitant ANP infusion.38 39 40 Similarly, NEPI increases natriuresis in sodium-loaded normotensive subjects26 41 and hypertensive men42 as well as in hypervolemic rats.21 The effects of NEPI in normovolemic, normotensive subjects and experimental animals are contradictory.20 21 43
In the present study, acute NEPI in control rats increased ANP plasma levels after volume expansion compared with vehicle-treated rats. This effect led to an enhanced urinary cGMP excretion, diuresis, and natriuresis, both at baseline and after acute volume load. These data indicate that acute NEPI can effectively enhance the action of ANP on the kidney in normal rats. In contrast to our results, an acute effect of NEPI on baseline diuresis could not be observed in earlier studies.20 21 43 Differences in study design, such as continuous baseline volume infusion rates, NEP inhibitor doses, rat strain differences, and varying numbers of rats studied per group, are important factors in whether significant diuretic and natriuretic effects are observed. The potentiation of the renal responses of ANP to acute volume load is in agreement with previous data showing an increased renal response in hypervolemic rats after NEPI, with an elevation of both ANP and cGMP plasma concentrations.21
We used an aortocaval shunt model to study heart failure in rats. We showed that the model is characterized by cardiac enlargement, increased PRA, and high circulating Ang II levels and thus is analogous to high-output heart failure in humans. Plasma ANP levels were elevated approximately ninefold in rats with heart failure compared with levels in normal rats. Nevertheless, acute volume expansion resulted in a blunted natriuresis and diuresis, with no further increase in plasma ANP levels. In shunted rats given NEP inhibitor acutely before volume expansion, plasma ANP levels increased further even though they were already elevated. However, ANP resistance was such that this response resulted in no greater natriuresis or diuresis than observed in shunted rats receiving vehicle acutely. Acute NEPI did not appear to influence the renin-angiotensin system in this model further. Thus, additional acute counterregulation by the renin-angiotensin system is probably not responsible for the lack of a natriuretic response.
These results differ from those of a previous report describing an enhanced natriuretic effect with acute administration of the NEP inhibitor thiorphan.40 However, thiorphan is less specific for NEP than the NEP inhibitor we used, SQ 28,603, which is 30 000 times more specific for NEP than for the angiotensin-converting enzyme,20 the product of which also has an effect on natriuresis and diuresis. Thus, confounding effects are less likely in our study. Other studies demonstrated an effect of acute NEPI in dogs with cardiac pacemakers27 43 and in rats with experimental myocardial infarction.24 44 In congestive heart failure patients, no significant hemodynamic improvement could be observed despite increased ANP plasma levels,45 which is similar to the responses we observed.
The failure of an acute, almost 50% increase in plasma ANP (induced by acute NEPI) to cause an effect in shunted rats is curious. The lack of effect of acute NEPI in shunted rats could be due to the great capacity of ANP clearance receptors,18 which may buffer the elevated ANP concentrations and thus prevent the activation of the biologically active and cGMP-coupled receptors. However, measurement of second messenger production showed that cGMP production increased in parallel with ANP levels. These data indicate that the failure of acute NEPI to improve the renal response is likely due to a defect situated at the postreceptor level. Thus, the defect of the ANP system in heart failure may at least partially be located distal to the ANP receptors.
The importance of cGMP/ANP coupling has been discussed with regard to the natriuretic response to NEPI in hypertension.46 Since urinary cGMP excretion is a marker for the renal action of ANP,9 10 an estimation of the ratio of urinary cGMP to plasma ANP might be an indicator of the responsiveness of the ANP effector system. Although local ANP concentrations as well as other factors such as the bradykinins will influence renal cGMP generation, it is interesting that in shunted rats, much less cGMP per ANP is produced than in control rats. Acute NEPI increased plasma ANP and urinary cGMP in parallel and did not change their ratio. Moreover, acute NEPI did not improve the renal response. In contrast, chronic NEPI led to numerically slightly lower (not significant) ANP plasma concentrations and to a minor increase (not significant) in urinary cGMP, resulting in more cGMP production per ANP. Although this ratio is not an established parameter for the receptor responsiveness, it is interesting that the ratio, and not ANP concentrations nor cGMP values alone, correlates with improved diuretic and natriuretic responses to acute volume expansion.
The major finding in the present study was the significant improvement in natriuresis and diuresis at baseline and after acute volume expansion with chronic NEPI in shunted rats. This improvement in natriuresis and diuresis was independent of changes in circulating ANP levels. Few long-term NEPI studies have been performed. In hypertensive men, treatment with an NEP inhibitor for 8 weeks decreased blood pressure, which correlated with an increase in plasma ANP and cGMP.47 In a similar human study, the effect of NEPI dissipated after 5 days.48 NEPI for 4 weeks in spontaneously hypertensive rats changed neither renal excretory function nor hemodynamic parameters.25 In a recent study, NEPI for 9 weeks in hypertensive rats reduced both blood pressure and cardiac hypertrophy.49 Fewer data on the chronic effect of NEPI are available in heart failure. An oral NEP inhibitor was given for 10 days in a small group of heart failure patients, but no significant renal or hemodynamic improvement was observed.50 Six days of NEPI in experimental myocardial infarction did not induce any renal effects.44 To the best of our knowledge, the present investigation is the longest animal study of NEPI in heart failure.
We were surprised to observe no effect on baseline ANP levels with chronic NEPI in our shunted rats. On the basis of previous reports, we were confident that the oral availability of the compound was assured.19 Similar to our findings, a 4-day study in healthy men reported an increase in urinary and plasma cGMP levels without changes in circulating ANP levels.51 The lack of increased ANP levels could be related to activated compensatory mechanisms that counteract pharmacologically elevated ANP levels. The endopeptidase activity could be upregulated in response to chronic inhibition, or possibly a compensatory decreased ANP synthesis could account for the unchanged ANP plasma levels. A recent study on experimental heart failure reported unchanged endopeptidase concentrations in renal tissue and a decreased amount in pulmonary tissue.52 No data on the regulation of ANP synthesis or NEP production during NEPI are available thus far.
We showed that chronic NEPI restored the blunted diuretic and natriuretic responses to acute volume expansion in shunted rats without increasing ANP plasma levels. The NEP has its highest concentrations in the brush border membranes of the kidneys, and a local inhibition of the renal endopeptidase need not necessarily be reflected in increased ANP plasma levels. Our data indicate that local rather than circulating ANP levels are relevant for the biological effect. This hypothesis is supported by previous data in dogs with heart failure27 showing that acute NEPI could induce more diuresis than caused by a similar elevation in ANP plasma levels by ANP infusion. We did not study the possibility that other peptides, such as brain natriuretic peptide, urodilatin, or bradykinin, may have played a role in the responses we observed. Brain natriuretic peptide is degraded by NEP as well but has a lesser renal effect than ANP.53 54 55 Urodilatin is said to be relatively resistant to NEP,56 although a more recent work indicated that in vitro, this enzyme might be important for the degradation of urodilatin.57
Even though chronic NEPI significantly improved the diuretic and natriuretic responses to acute volume load in shunted rats, the renal response was still attenuated compared with that in control rats. This observation is most likely due to activated counterbalancing systems.58 Interestingly, chronic NEPI did not decrease blood pressure in shunted rats. However, we observed a significantly decreased heart weight in these rats. A reduction of cardiac hypertrophy in spontaneously hypertensive rats without a hemodynamic effect has previously been described by another group.25 59 These observations suggest that ANP may have a growth-inhibitory effect similar to the antiproliferative effect described in endothelial cells.60 An alternative explanation could be a subtle improvement in heart failure severity in shunted rats receiving NEP inhibitor chronically.
In conclusion, our results suggest that local renal concentrations of ANP rather than circulating levels of ANP are important for the effect of chronic NEPI. Chronic rather than acute inhibition of the ANP degrading NEP may be useful for improving the diuretic and natriuretic responses in heart failure.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The authors thank A. Schiche and J. Mothes for excellent technical assistance. We are grateful to P. Hamet and J. Tremblay, Montreal, Canada, for their encouragement and for donating antibodies for cGMP measurements. We thank J. Bohlender, Berlin, Germany, for Ang II measurements and E. Hackenthal, Heidelberg, Germany, for PRA determination.
Received August 15, 1995; first decision October 3, 1995; accepted February 15, 1996.
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