(Hypertension. 1995;26:1167-1172.)
© 1995 American Heart Association, Inc.
Articles |
Inhibition of Atrial Natriuretic Peptide Excretory Action by Bradykinin
From the Unidad de Regulación Neurohumoral, Departamento de Ciencias Fisiológicas, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile.
Correspondence to Mauricio P. Boric, PhD, Departamento Ciencias Fisiológicas, FCCBB, Pontificia Universidad Católica de Chile, Casilla 114-D, Santiago, Chile. E-mail mboric@genes.bio.puc.cl.
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Abstract We examined whether the excretory effect of atrial natriuretic peptide could be antagonized by intravenously administered bradykinin or by elevated endogenous kinin levels attained during converting enzyme inhibition. Urinary volume and sodium and potassium excretion were determined every 20 minutes in female, anesthetized Sprague-Dawley rats (weight, 0.19 to 0.22 kg) infused with 10 µL/min isotonic glucose. In some experiments, urinary cGMP content was measured by radioimmunoassay. Two intravenous boluses of 209 pmol (0.5 µg) atrial natriuretic peptide were given before and after the injection of test substances, and the response ratio was used to quantify inhibition. Single injections of 94.3 or 142 pmol (100 or 150 ng) bradykinin, 3 minutes prior to atrial natriuretic peptide, inhibited the excretion of water, sodium, and potassium by 70%, 75%, and 50%, respectively. Larger (236 to 472 pmol) or smaller (23.6 to 47.2 pmol) bradykinin doses were ineffective. None of the bradykinin doses tested affected basal urinary output, systemic pressure, or the modest depressor effect of atrial natriuretic peptide. The anti–atrial natriuretic peptide effect of bradykinin was completely prevented by the kinin receptor antagonist Hoe 140. Converting enzyme inhibition with ramipril (96 nmol IV) also blunted atrial natriuretic peptide diuresis and natriuresis by 70% and reduced urinary cGMP excretion by 50%. These effects of ramipril were mediated by endogenous kinin accumulation, since they were abolished by pretreatment with Hoe 140. It is concluded that intrarenal kinins modulate the renal actions of atrial natriuretic peptide, and at a precise concentration bradykinin strongly antagonizes atrial natriuretic peptide by preventing its transduction mechanism.
Key Words: atrial natriuretic factor • ramipril • ACE • kinins • cyclic GMP
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Introduction |
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Atrial natriuretic peptide exerts potent vascular and renal actions that enable this hormone to play a pivotal role in short- and long-term regulation of vascular volume and blood pressure (for review, see Reference 1). In anesthetized rats the excretory action of ANP is antagonized by pepsin hydrolysates of fresh human or rat plasma or plasma globulins when introduced in the peritoneal cavity2 or the duodenal lumen.3 This inhibition occurs in the absence of any detectable change in arterial pressure. The peptidic fraction responsible for the antidiuretic effect was initially named PU.4 5 While attempting to isolate and characterize the putative active agent and its substrate, we found that plasma free of kininogens was unable to yield PU upon pepsin digestion and also that the BK antagonist Hoe 140 completely prevented the anti-ANP effects of PU.6 More recently we demonstrated the anti-ANP effect of intraperitoneal or intraduodenal injections of two prokinin peptides of 16 and 18 amino acids, which were synthesized according to the sequences of peptides found after pepsin hydrolysis of bovine kininogen.7 Both peptides contained the BK sequence. Similarly, intraperitoneal injection of BK, in the range of 0.47 to 1.89 nmol (0.5 to 2 µg) per rat, was able to counteract the sodium, potassium, and water excretion induced by an IV bolus of 209 pmol (0.5 µg) ANP, given 40 minutes after BK (Boric et al, unpublished results, 1995). All these findings indicate that BK or other kinins present in PU are responsible for inhibiting ANP excretory actions. It has been reported that inhibition of ACE blunted the response to ANP in humans.8 9 Although decreased angiotensin II and lowered blood pressure were indicated as the likely cause for the diminished response to ANP, increased kinin concentration after ACE inhibition should be considered, since this enzyme, also named kininase II, is a major protease in kinin metabolism.10 11
In this report, we explored whether small IV BK doses injected shortly before ANP can reproduce the anti-ANP effect of intraperitoneal injections. Second, to confirm whether endogenous kinins can modulate the ANP action, we inhibited ACE–kininase II with ramipril12 and used the specific BK antagonist Hoe 14013 to differentiate effects mediated by enhanced kinin concentration from those due to decreased angiotensin II. Finally, to gain insight into the mechanism of ANP inhibition by PU or kinins, we measured the urinary output of cGMP, the second messenger to ANP.1
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Methods |
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Animals and Reagents
Female Sprague-Dawley rats weighing 0.19 to 0.22 kg were bred and kept at the university animal facilities. All experimental procedures were in accordance with institutional and international guidelines for the welfare of animals. BK, ANP (5-28, atriopeptin II, rat form), cGMP, S-cGMP-TME, and bovine immunoglobulins were purchased from Sigma Chemical Co. Hoe 140 was a gift from Hoescht. Ramipril, pure powder, was a gift of Hoescht Chile. A rabbit specific anti-cGMP antibody was generously provided by Dr Mark Currie from Medical University of South Carolina. All other reagents of analytical grade were purchased from E. Merck.
Diuresis Bioassay
The previously described experimental setup2 3 was
slightly modified. Fasted rats with free access to water were then
anesthetized with sodium pentobarbital 40 mg/kg IP and were
heparinized. Polyethylene catheters were inserted in the trachea,
veins, and arteries as indicated. A constant infusion of 10 µL/min
isotonic glucose was started through the jugular vein (0.6 mL/h), and
MAP was monitored by connecting a femoral artery to a transducer and a
Grass polygraph. The bladder was cannulated with a silicone elastomer
(Silastic) tubing through the urethra and, after a brief equilibration
period, urine was collected during 10 periods of 20 minutes each. All
drugs were freshly prepared from frozen aliquots, dissolved in isotonic
glucose, and injected at room temperature through a femoral vein. Two
boluses of 209 pmol (0.5 µg) of ANP in 100 µL, termed S1 and S2,
were injected at the start of the fourth and ninth periods,
respectively. The S2-to-S1 response ratio was used to evaluate the
inhibitory effect of test substances that were injected
before S2, as indicated. Six to eight rats were used per group.
Experimental Protocols
The first protocol was designed to assess the effects of BK on
the response to ANP. The animals received a single dose of 23.6, 47.2,
94.3, 142, 236, or 472 pmol BK (25, 50, 100, 150, 250, or 500 ng,
respectively) in 50 µL 3 minutes before S2, while a control group
received just the vehicle. To test for possible priming interactions
between ANP and BK, another group of rats received 94.3 pmol BK 3
minutes before S1 instead of before S2. A ninth group received 3.83
nmol (5 µg) Hoe 140 in the middle of period six, 5 minutes before the
injection of 142 pmol (150 ng) BK, chosen as the most effective BK
dose. An additional control group received only 3.83 nmol Hoe 140, 8
minutes prior to S2.
In the second protocol, the effect of ACE inhibition upon ANP excretory action was assessed in four groups. The first group received 96 nmol (40 µg) ramipril (R) at the beginning of period seven, 40 minutes prior to S2; the second group received 3.83 nmol (5 µg) Hoe 140 by the end of period six, 5 minutes prior to the injection of 96 nmol ramipril (R+H). The other two groups did not receive injections of ANP but received the same amounts of ramipril or ramipril plus Hoe 140 as did groups one and two; these groups were used to establish the effect of these drugs on baseline urinary output and MAP.
Determinations
Urinary volume was measured gravimetrically, and sodium and
potassium levels were measured in a Eppendorf flame spectrophotometer.
When cGMP was determined, urine samples were collected on ice; they
were quickly frozen after they were weighed and aliquots for
Na+ and K+ measurements were taken. cGMP was
determined in an RIA as described,14 using S-cGMP-TME
iodinated by the method of Oehlenshlager et
al15 as tracer. Briefly, after urine aliquots were diluted
with RIA buffer (0.05 mol/L sodium acetate, pH 6.2), the samples were
acetylated by adding 10 µL triethylamine:acetic anhydride
(2:1) and stirring. Then the samples were incubated overnight
at 5°C, in 500 µL final volume, containing anti-cGMP antibody
diluted 1:40 000 and 13 000 CPM of 125I–S-cGMP-TME.
Similar tubes containing 10 to 1000 fmol cGMP were used for the
standard curve. After the incubation, 200 µg immunoglobulin was
added, and the antibody was precipitated in 50% ammonium sulfate and
centrifuged. Bound counts were detected in a gamma counter
(LKB-Wallac 1270) equipped with an automatic RIA program to determine
cGMP content of unknown samples by interpolation.
Analysis
Experiments in which arterial pressure differed more
than 15 mm Hg between S1 and S2 were discarded. Animals having sodium
or volume excretions larger than the mean+2 SDs and those whose first
response lay within percentile 5 were not considered. In this way, of
82 successfully completed experiments, results from 76 rats that
presented a similar baseline excretion and a
homogeneous first response to ANP were available for
analysis. In each series, a paired t test was
performed to compare the response to S1 versus S2. In addition,
differences between experimental groups were performed by unpaired
t test, with correction for multiple comparisons with a
single control when appropriate.16
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Results |
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Effects of BK
Baseline excretion was fairly stable during periods one to three. After the first ANP bolus, there was a rapid rise in urinary output, with increases of about 7 times in volume, 50 times in sodium, and 3 times in potassium excretion, while arterial pressure decreased significantly by
5 mm Hg (P<.01, paired
t test) (Figs 1 and 2). cGMP excretion also increased by 6
to 10 times during period four (Fig 2). All these
parameters returned toward baseline in periods five to six
and remained stable until the second ANP bolus. In control animals
receiving just vehicle, the second ANP bolus produced a larger
excretory response, about 1.5 times the first one (Fig 1), confirming previous observations in this
experimental model.2 3 In contrast, after the injection of
BK the response to S2 was significantly reduced depending on the dose
used. After 142 pmol (150 ng) BK, the S2-to-S1 response ratio was
0.47±0.07 for diuresis, 0.37±0.08 for natriuresis, and
0.88±0.23 for potassium, in the absence of arterial
pressure changes (Fig 1). All these anti-ANP effects of BK were
completely prevented by the administration of 3.8 pmol Hoe 140 prior to
BK (Fig 1). Hoe 140 alone did not modify any of the excretory responses
induced by ANP; the values coincided with the BK+Hoe 140 data
presented in Fig 1 and for simplicity are not shown. Neither
BK, Hoe 140, nor their combination produced detectable changes in
systemic arterial pressure.
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Out of six different doses of BK tested, only 94.3 and 142 pmol (100 and 150 ng) per rat were able to inhibit the natriuretic-diuretic effect of ANP (Fig 3). In contrast, smaller (23.6 and 47.2 pmol per rat) or larger (236 and 472 pmol per rat) BK doses failed to alter the response to ANP. In no case was there a potentiating effect of BK on ANP-induced natriuresis or diuresis. As a norm, changes in potassium excretion were less conspicuous and followed changes in diuresis, with one exception. With 472 pmol BK, sodium or water output was not affected but the potassium response to ANP was slightly reduced. Injection of 236 and 472 pmol (200 to 500 ng) BK induced a pressure drop of about 10 to 25 mm Hg for 12 to 20 seconds, an effect that vanished well before the second ANP bolus. None of the BK doses modified the vasodepressor effect of ANP (Fig 3).
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The injection of 93.2 pmol BK prior to S1 reduced ANP diuresis and natriuresis to a similar extent to when this dose of BK was given before S2, again without changes in systemic pressure. The diuretic response to S1 was blunted to 0.545±0.055 mL/kg and natriuresis to 59±13 µmol/kg sodium in 20 minutes (n=6). These values were significantly smaller (P<.01) than the response to S1 in all the other series, which ranged between 1.070±0.049 and 1.640±0.327 mL/kg for volume and between 117±11 and 234±59 µmol/kg for sodium. Potassium excretion was not significantly blunted, to 48.3±6.8 µmol/kg compared with the other series (range, 58.1±11.8 to 96.3±9.3). Excretory S2-to-S1 ratios in the group that received BK before S1 were 1.83±0.28 for volume, 2.37±0.40 for sodium, and 1.05±0.18 for potassium.
Effects of Converting Enzyme Inhibition
In control experiments, without ANP injections, application of
ramipril in period seven significantly reduced arterial
pressure accompanied by a modest but significant increase in sodium,
water, and potassium excretion, which steadily rose from period seven
to period ten (Table). These vasoactive and
diuretic effects of ramipril were not associated with changes
in cGMP urinary excretion (Table). Furthermore, they were not blocked
by pretreatment with Hoe 140, indicating that they probably were not
caused by kinin accumulation but depended on blockade of
angiotensin II formation (Table).
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Ramipril markedly blunted the response to ANP (Fig 2). S2-to-S1 response ratio was 0.45±0.03 for volume and 0.42±0.05 for sodium excretion. Although ANP did not induce any further increase in potassium excretion, S2-to-S1 response ratio for this electrolyte was 1.02±0.14 owing to the elevated baseline, still a value much smaller than the control ratio of 1.76±0.16 (Fig 3). Interestingly, the reduced diuresis and natriuresis observed after ramipril were matched by a parallel reduction in cGMP urinary output (Fig 2). All the anti-ANP effects of ramipril were abolished by previous treatment with the BK antagonist (Fig 2). In fact, Na, K, and volume S2-to-S1 response ratios of rats treated with ramipril+Hoe 140 were not different from those of controls (compare Figs 1 and 2). On the other hand, S2-to-S1 response ratio for cGMP excretion was close to one in the ramipril+Hoe 140 group. It should be noted that, except for the responses to S1 and S2, the baseline urinary output in the experimental groups treated with ramipril or ramipril+Hoe 140 (Fig 2) closely matched the respective control data reported in the Table.
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Discussion |
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The present results demonstrate a strong inhibitory effect of BK on the natriuretic and diuretic effect of exogenous ANP. BK was able to inhibit ANP only in a narrow range of nondepressor IV doses. Interestingly, we found that the same conditions are reproduced by enhanced endogenous kinin levels attained after kininase II is inhibited with ramipril. These findings extend our previous reports on ANP inhibition by IP and intraduodenal administration of prokinin peptides,7 or PU.2 3
Since about 90% to 95% of IV injected BK is destroyed in a single
passage through the lungs,17 it can be estimated that with
the effective anti-ANP doses, only 5 to 15 pmol (5 to 15 ng) BK reached
the arterial tree; probably 1 to 2 pmol dissolved in 1
to 2 mL plasma reached the kidneys during the first passage, and only
negligible amounts could be found thereafter. This represents a
concentration in the low nanomole per liter range, close to the
reported endogenous kinin levels in the rat
kidney.11 In view of these findings, it is tempting to
conclude that the previously reported injections of larger amounts of
prokinins (ranging between 0.5 and 2.5 nmol/rat), or PU into the
peritoneum or intestinal lumen2 3 7 resulted in a slow
absorption and/or transformation of prokinins that reached the precise
intrarenal BK concentrations required to elicit the anti-ANP effect
through stimulation of BK receptors.
The BK doses found effective against ANP do not affect baseline urinary output and had only a marginal, transient hypotensive effect that did not influence systemic pressure during the ANP response. On the other hand, inhibition of ACE–kininase II induced a modest but sustained diuretic-natriuretic effect associated with an arterial pressure drop. These effects of ramipril were not modified by Hoe 140, indicating that they were independent of BK receptor activation. Yet in these conditions, the response to a bolus ANP was markedly decreased, confirming previous reports with ACE inhibitors.8 9 We found now that the ANP blockade was due to endogenous kinin, as demonstrated by the lack of effect of the combined application of ramipril+Hoe 140. Taken together, these results rule out the possibility that the blunted ANP response observed after ramipril was influenced by the increased basal sodium excretion or by decreased angiotensin II.
On the basis of the observation that ramipril reduced ANP-induced cGMP urinary excretion and that this effect was reversed by Hoe 140, we can postulate a link between activation of kinin receptors and disruption of the ANP transduction mechanism. We have extended this observation in our laboratory, finding that IP injection of PU or BK also reduced ANP-induced cGMP excretion in parallel with inhibition of sodium and volume excretion (unpublished results). At the present time we cannot provide a suitable explanation of the mechanism involved in ANP inhibition at the cellular level. Several possibilities include changes in the number or affinity of guanylate cyclase ANP-R1 receptors or clearance type ANP-R2 receptors, enhanced cGMP specific phosphodiesterase activity, or interference with ANP-induced guanylate cyclase activity of the R1 receptor.1 An alternative pathway for interaction between BK and ANP would be the modulation of intrarenal activity levels of NEP 24.11, an enzyme that degrades both kinins and ANP.1 10 18 Finally, we cannot disregard the possible contribution of subtle intrarenal hemodynamic changes induced by these low BK doses, provided that these changes alter cGMP production by ANP.
Further studies are needed to establish a complete time course and dose-response relations for this antagonistic interaction between BK and ANP. A few comments regarding this interaction are in order, however, since kinins are considered strong diuretic, natriuretic agents.10 19 Multiple intrarenal sites of actions are described to contribute to the diuretic effect of both the atrial hormone and kinins, namely, increased medullary blood flow and interstitial pressure,1 19 20 and inhibition of distal tubule and collector tubule sodium transport.21 In addition, both ANP and kinins are known to antagonize the renin-angiotensin system.1 19 20
First, in our experimental setting and with the doses used, BK does not enhance ANP-induced sodium excretion. Furthermore, ANP excretory response is clearly not mediated by kinins, since it was not affected by blockade of BK receptors with Hoe 140. This finding confirms previous reports in rats with compensated heart failure induced by an aortocaval fistula, in which Hoe 140 did not modify ANP excretion.22 Also, a recent work demonstrated that ACE inhibition by enalapril blunts the diuresis and natriuresis response and increased cGMP urinary excretion induced by NEP inhibition in humans.23 In contrast, it has been reported that in anesthetized rats the potentiation of ANP diuretic/natriuretic response induced by inhibition of NEP is blocked by infusion of BK antagonists.24 25 Several experimental differences can account for these apparently conflicting results. As we show here, the inhibitory effect of BK is obtained only in a very narrow dose range. We cannot know whether intrarenal kinin concentrations attained during NEP inhibition in rats were above the inhibitory range reported by us, given the high NEP activity in the rat kidney.26 Also, we used a single injection of the very stable and specific BK antagonist Hoe 140,13 whereas in those previous reports, very large doses of short-lasting BK antagonists were infused.24 25 The possibility exists that these high levels of BK analogues may have caused a certain degree of activation of BK receptors, comparable to that attained with the rather low single-dose amount of BK needed to elicit the anti-ANP effect. A partial agonist effect could explain, for instance, the finding by Sybertz et al25 that infusion of Thi5,8-D-Phe7-BK, at 20 µg · kg-1 · min-1, blunted diuresis and natriuresis induced by exogenous ANP in normal rats, with the same efficiency as ramipril did in our study. In addition, we should consider the natriuretic status of the animals; we infused 10 µL/min of isotonic glucose whereas the other authors have used 33 to 50 µL/min of isotonic NaCl,24 25 which may have set a different tubular response.
From the point of view of volume and pressure regulation, the negative interaction between BK and ANP may be quite important, particularly in sodium-retaining disorders. Sodium metabolic balance is one of the major factors leading to hypertension, in which an association between salt sensitivity and a greater propensity for renal failure has been described.27 In this connection, it has been reported that ANP levels are normal or elevated in most sodium-retaining disorders, such as cirrhosis28 or hypertension,1 but somehow the kidney is refractory to this hormone. The possibility that two physiological agents, such as kinins and ANP, assumed to be synergistic, can actually exert agonistic or antagonistic effects according to their relative molecular concentrations may have escaped consideration, perhaps because such negative interaction can be found only when BK is assayed at very low concentrations. It has to be mentioned that most previous reports showing a natriuretic-diuretic effect of kinins have used much larger, vasodilating kinin concentrations, infused for longer periods than those used here.29 30 The same holds true when additive natriuretic effects between BK and ANP were reported in dogs.31 A recent report shows that intrarenal kinin production is strongly reduced by high sodium diet and enhanced during low sodium intake in the rat.32 This finding may be related to the ability of kinin to block ANP natriuresis. We can speculate that suppressed kinin levels may facilitate a full ANP action during high sodium intake and, on the other hand, higher BK levels may inhibit ANP during low sodium. The findings here reported offer great potential to explore the role of kinins in clinical conditions associated with ANP refractoriness and altered sodium metabolism.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by grants FONDECYT 662/92 and 1930582. Thanks to José Cornejo who carried out most of the diuresis experiments, to Cristián Hernández, MsSc, who performed most of the cGMP RIA determinations, to Judith Gengler and Claudio Gómez, MsSc, for data handling and technical help, and to Dr H.A. Croxatto for reviewing this manuscript.
Received June 19, 1995; first decision August 18, 1995; accepted September 8, 1995.
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