Published online before print December 26, 2006, doi: 10.1161/01.HYP.0000254833.85106.4d
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(Hypertension. 2007;49:625.)
© 2007 American Heart Association, Inc.
Original Articles, Part 2 |
Intrarenal Aminopeptidase N Inhibition Augments Natriuretic Responses to Angiotensin III in Angiotensin Type 1 Receptor–Blocked Rats
From the Division of Endocrinology and Metabolism (S.H.P., B.A.K., N.L.H., H.M.S., R.M.C.), Department of Internal Medicine, University of Virginia Health System, Charlottesville; and Institut National de la Sante et de la Recherche Medicale U36 (M.-C.F.-Z., B.P.R.), UFR des Sciences Pharmaceutiques et Biologigues, Universite Rene Descartes, Paris, France.
Correspondence to Robert M. Carey, PO Box 801414, University of Virginia Health System, Charlottesville, VA 22908-1414. E-mail rmc4c{at}virginia.edu
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Abstract |
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The renal angiotensin angiotensin type 2 receptor has been shown to mediate natriuresis, and angiotensin III, not angiotensin II, may be the preferential angiotensin type 2 receptor activator of this response. Angiotensin III is metabolized to angiotensin IV by aminopeptidase N. The present study hypothesizes that inhibition of aminopeptidase N will augment natriuretic responses to intrarenal angiotensin III in angiotension type 1 receptor–blocked rats. Rats received systemic candesartan for 24 hours before the experiment. After a 1-hour control, cumulative renal interstitial infusion of angiotensin III at 3.5, 7, 14, and 28 nmol/kg per minute (each dose for 30 minutes) or angiotensin III combined with aminopeptidase N inhibitor PC-18 was administered into 1 kidney. The contralateral control kidney received renal interstitial infusion of vehicle. In kidneys infused with angiotensin III alone, renal sodium excretion rate increased from 0.05±0.01 µmol/min in stepwise fashion to 0.11±0.01 µmol/min at 28 nmol/kg per minute of angiotensin III (overall ANOVA F=3.68; P<0.01). In angiotensin III combined with PC-18, the renal sodium excretion rate increased from 0.05±0.01 to 0.32±0.08 µmol/min at 28 nmol/kg per minute of angiotensin III (overall ANOVA F=6.2; P<0.001). The addition of intrarenal PD-123319, an angiotensin type 2 receptor antagonist, to renal interstitial angiotensin III plus PC-18 inhibited the natriuretic response. Mean arterial blood pressure and renal sodium excretion rate from control kidneys were unchanged by angiotensin III ± PC-18 + PD-123319. Angiotensin III plus PC-18 induced a greater natriuretic response than Ang III alone (overall ANOVA F=16.9; P=0.0001). Aminopeptidase N inhibition augmented the natriuretic response to angiotensin III, suggesting that angiotensin III is a major agonist of angiotensin type 2 receptor–induced natriuresis.
Key Words: angiotensin • sodium • natriuresis • angiotensin III • AT2 receptor • AT1 receptor
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Introduction |
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The renin–angiotensin system (RAS) is a coordinated hormonal cascade that governs fluid and electrolyte balance and blood pressure (BP). In recent years, a major emphasis has been placed on distinguishing the roles of the systemic circulating RAS from local tissue RAS. Studies have demonstrated the importance of a tissue RAS in the brain, peripheral blood vessels, adrenal glands, and kidneys.1–7 An essential requirement for a tissue RAS is that all of the components necessary for the biosynthesis of active peptide products reside within the tissue. In the kidney, renin, angiotensinogen, and angiotensin-converting enzyme mRNA have been localized in a site-specific manner.8–11 Renal interstitial (RI) fluid has been shown to contain nanomolar levels of angiotensin II (Ang II) and des-aspartyl1-Ang II (Ang III), which are
1000-fold higher than in the plasma.12 These observations, together with the findings that the angiotensin type 1 (AT1) and angiotensin type 2 (AT2) receptors have been found in glomerular epithelial cells, cortical tubules, and interstitial cells,13–15 have resulted in attempts to define the distinctive roles of the intrarenal RAS. Although Ang II has been considered the major effector peptide of the RAS, Ang III also demonstrates biologic activity. Ang II is converted to Ang III by aminopeptidase A, which is further converted to des-arginine2-Ang III (Ang IV) by aminopeptidase N ([APN] Figure 1). Some actions originally attributed to Ang II in the brain, such as vasopressin release, have now been found to be attributable to Ang III.16 In the kidney, RI administration of Ang III, but not Ang II, engenders natriuresis in AT1 receptor–blocked rats.17 In addition, Ang III–induced natriuresis seems to be mediated by the AT2 receptor, because the natriuretic response is abolished by the addition of PD-123319 (PD), a specific AT2 receptor antagonist.17
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The metabolism of Ang III to Ang IV is mediated by APN, a homodimeric, membrane-bound, zinc-dependent aminopeptidase that preferentially releases neutral amino acids from the N-terminal end of oligopeptides.18,19 A specific APN inhibitor (inhibition constant [Ki]=8.0±1.7 nM), 2-amino-4-methylsulfonyl-butane-thiol ([PC-18] Figure 1), has been shown to increase the half-life of endogenous Ang III in vivo.20 In the present study, we evaluated the renal sodium (Na+) excretion rate (UNaV) in response to selective intrarenal infusion of Ang III with and without PC-18, in the presence of candesartan (CAND), an insurmountable nonpeptide AT1 receptor antagonist. In addition, we evaluated the natriuretic response to Ang III plus PC-18 in the presence of PD to confirm the role of the AT2 receptor in natriuresis.
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Methods |
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Animal Preparation
The experiments, which were approved by the University of Virginia Animal Research Committee, were conducted in 250-g Sprague–Dawley rats (Harlan, Teklad; N=21 total). All of the studies were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Rats were placed under general anesthesia with pentobarbital (50 mg/mL) given 5 mg/100 g body weight IP, which resulted in deep anesthesia for control (60 minutes) and 3 (30 minutes each) experimental periods. A tracheostomy was performed in all of the rats, and arterial access was achieved by direct cannulation of the right carotid artery. Intravenous access was obtained via cannulation of the right internal jugular vein in each rat. Rats were housed under controlled conditions (temperature: 21±1°C; humidity: 60±10%; and light: 8 to 20 hours). Experiments were initiated at the same time each day to prevent any diurnal variation in BP.
Renal Cortical Interstitial Infusion
Through a midline laparotomy, the right and left kidneys were exposed. A polyethylene interstitial infusion tube was inserted inside a 15-cm long PE-60 tube, and a gauze mesh was glued to the junction. Through a 30-gauge needle, the PE-10 tube was inserted into the kidney at 0.2 cm to access the cortical interstitial space. To prevent dislodging, the gauze mesh was glued to the surface of the kidney using Vetabond glue (3 mol/L Animal Care Products). The infusion catheters were connected to a Harvard pump 5522, and substances were infused directly into the renal cortical interstitial compartment. When dual substances were infused, they were combined immediately before the experimental periods.
BP Measurements
Mean arterial BP (MAP) was measured by the direct intracarotid method with the use of a BP analyzer (Micromed Inc). MAPs were recorded every 5 minutes and averaged for each of the control and experimental periods.
Effects of Unilateral RI Ang III and Systemic AT1 Receptor Blockade on UNaV in Rats on Normal Na+ Intake
Rats (N=8 per group) were studied on normal Na+ intake, with both kidneys intact. Using a sterile technique, osmotic micropumps (Alzet 8.0 µL/h per day) were implanted into the interscapular region with the animals under short-term anesthesia with ketamine (100 mg/mL) and xylazine (20 mg/mL) for CAND (0.01 mg/kg per minute) infusion 24 hours before and during the experiment. The right kidney was infused with 5% dextrose in water (2.5 µL/min) vehicle directly into the RI space during both control (1 hour) and experimental collection periods (30 minutes each) and served as the control kidney. Ang III (3.5, 7, 14, and 28 nmol/kg per minute) was infused cumulatively into the RI space of the left (experimental) kidney after a 1-hour control infusion of vehicle. Both ureters were cannulated individually to collect urine for quantification of UNaV for the control and 4 experimental periods from both the right (control) and left (experimental) kidneys.
Effects of Unilateral RI Ang III Plus PC-18 on UNaV in Rats on Normal Na+ Intake in the Presence of Systemic AT1 Receptor Blockade
Rats (N=7) were studied on normal Na+ intake with both kidneys intact. Using a sterile technique, osmotic micropumps were implanted into the interscapular region with the animals under short-term anesthesia with ketamine (100 mg/mL) and xylazine (20 mg/mL) for CAND (0.01 mg/kg per minute) infusion 24 hours before and during the experiment. The right kidney was infused with vehicle directly into the RI space during both control (1 hour) and experimental collection periods (30 minutes each) and served as the control kidney. Ang III (3.5, 7, 14, and 28 nmol/kg per minute) plus PC-18 (25 µg/min) was infused cumulatively into the RI space of the left (experimental) kidney after a 1-hour control infusion of 5% dextrose in water (2.5 µL/min). Both ureters were cannulated individually to collect urine for quantification of UNaV for the control (1 hour) and 4 experimental (30 minutes each) periods from both the right (control) and left (experimental) kidneys.
Effects of RI Ang III Plus PC-18 Combined With PD in the Presence of Systemic AT1R Blockade
Rats (N=6) were studied on normal Na+ intake with both kidneys intact. Osmotic micropumps were implanted into the interscapular region with the animals under short-term anesthesia with ketamine (100 mg/mL) and xylazine (20 mg/mL) for CAND (0.01 mg/kg per minute) infusion 24 hours before and during the experiment. Ang III (3.5, 7, 14, and 28 nmol/kg per minute) plus PC-18 (25 µg/min) plus PD (10 µg/kg per minute) were infused cumulatively into the RI space of the left kidney after a 1-hour control infusion of vehicle. The right kidney was infused with vehicle directly into the RI space during both control (1 hour) and experimental collection periods (30 minutes each) and served as the control kidney. Both ureters were cannulated individually to collect urine for quantification of UNaV for the control (1 hour) and 4 experimental (30 minutes each) periods from both the right and left kidneys.
Pharmacological Agents
Ang III ([des-Asp1]-Ang II; Bachem), an AT1 and AT2 receptor agonist, was used for these studies (Ki 10.5x10–9 mol/L and 2.2x10–9 mol/L for AT1 and AT2 receptors, respectively, in the brain21). CAND, a specific, potent insurmountable inhibitor of AT1 receptors (IC50 >1x10–5 mol/L and 2.9x10–8 mol/L for AT2 and AT1 receptors, respectively), was used systemically for AT1 receptor blockade in anesthetized animals. PD (Parke-Davis), a specific AT2 receptor antagonist (IC50 2x10–8 mol/L and >1x10–4 mol/L for AT2 and AT1 receptors, respectively), was used interstitially to block the AT2 receptor. PC-18 (provided by Dr Bernard P. Roques), a specific APN inhibitor (Ki=8.0±1.7 nM),20,22 was infused interstitially to block the metabolism of Ang III to Ang IV.
Statistical Analysis
Comparisons among vehicle, AT1 receptor blocker (CAND), AT2 receptor blocker (PD), Ang III, and PC-18 (APN inhibitor) were estimated by ANOVA, including a repeated-measures term, by using the general linear models procedure of the Statistical Analysis System. Multiple comparisons of individual pairs of effect means were conducted by the use of least-square means pooled variance. Data are expressed as mean±1 SE. Statistical significance was identified at a level of P
0.05.
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Results |
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Effects of Unilateral RI Ang III and Systemic AT1 Receptor Blockade on UNaV in Rats on Normal Na+ Intake
As demonstrated in Figure 2, in the presence of systemic CAND administration, RI Ang III infusion increased UNaV from a baseline of 0.05±0.01 to 0.07±0.01 µmol/min (P=NS) at 3.5 nmol/kg per minute, 0.07±0.01 µmol/min (P<0.05) at 7 nmol/kg per minute, 0.14±0.01 µmol/min (P<0.0001) at 14 nmol/kg per minute, and 0.11±0.01 µmol/min (P<0.01) at 28 nmol/kg per minute of Ang III (overall ANOVA F=3.68; P<0.01). UNaV was unchanged (P not significant) from vehicle-infused kidneys.
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, UNaV responses to 4 cumulative RI Ang III infusions (3.5, 7, 14, and 28 nmol/kg per minute) after a 1-hour precontrol period during which only vehicle was infused. 
, UNaV when only 5% dextrose in water was infused into the RI space of the control kidney for the duration of the experiment. Data represent mean±1 SE; *P<0.05, **P<0.01, ***P<0.0001 from time control.
Effects of Unilateral RI Ang III Plus PC-18 on UNaV in Rats on Normal Na+ Intake in the Presence of Systemic AT1 Receptor Blockade
Figure 3 demonstrates that, in the presence of systemic CAND administration, RI Ang III combined with PC-18 infusion increased UNaV from a baseline of 0.05±0.01 to 0.15±0.04 µmol/min (P<0.05) at 3.5 nmol/kg per minute, 0.16±0.03 µmol/min (P<0.05) at 7 nmol/kg per minute, 0.25±0.08 µmol/min (P<0.01) at 14 nmol/kg per minute, and 0.32±0.08 µmol/min (P<0.0001) at 28 nmol/kg per minute of Ang III (overall ANOVA F=6.2; P<0.001). Vehicle-infused kidneys did not show a significant change in UNaV across the duration of the experiment. When normalized for their respective vehicle-infused kidneys, RI Ang III plus PC-18 infusion resulted in a greater percentage increase in UNaV compared with RI Ang III alone, at 3.5 nmol/kg per minute (60.7±3.5% versus 36.2±1.0%; P0.05), at 7 nmol/kg per minute (71.3±2.5% versus 40.5±1.0%; P0.01), at 14 nmol/kg per minute (89.1±4.2% versus 57.2±1.0%; P0.05), and at 28 nmol/kg per minute (94.6±4.3% versus 44.7±2.0%; P0.01; Figure 4).
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, UNaV in response to 4 cumulative RI Ang III infusions (3.5, 7, 14, and 28 nmol/kg per minute) plus PC-18 (25 µg/min) after a 1-hour precontrol period during which only vehicle was infused.
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Effects of Unilateral RI Ang III Plus PC-18 and PD on UNaV in Rats on Normal Na+ Intake in the Presence of Systemic AT1 Receptor Blockade
In the presence of systemic AT1 receptor blockade, the addition of PD to intrarenal infusion of Ang III plus PC-18 inhibited the natriuretic response. Compared with time control, RI Ang III plus PC-18 plus PD significantly decreased UNaV from a control value of 0.044±0.02 to 0.01±0.01 µmol/min (P<0.05) at 28 nmol/kg per minute of Ang III infusion (Figure 5). When normalized for their respective vehicle-infused kidneys, the percentage of change in UNaV in response to RI Ang III plus PC-18 infusion compared with RI Ang III plus PC-18 plus PD was 2.12% versus 0.02% (P<0.05) at 3.5 nmol/kg per minute, 3.14% versus 0.84% (P<0.05) at 7 nmol/kg per minute, 6.21% versus 0.31% (P0.01) at 14 nmol/kg/ per minute, and 14.7% versus 0.82% (P0.01) at 28 nmol/kg per minute, respectively (Figure 6). Thus, the addition of PD prevented the natriuretic response to RI Ang III plus PC-18 administration at each Ang III infusion rate.
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, UNaV in response to 4 cumulative RI Ang III infusions (3.5, 7, 14, and 28 nmol/kg per minute) plus PC-18 (25 µg/min) plus PD (10 µg/min) after a 1-hour precontrol period during which only vehicle was infused.
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, Percentage change in UNaV responses after the addition of RI PD (10 µg/kg per minute) to Ang III (3.5, 7, 14, and 28 nmol/kg per minute) plus PC-18 (25 µg/min) infusions, also normalized for vehicle-infused kidneys. Data represent mean±1 SE; *P<0.05, **P
MAP Responses to Intrarenal Ang III, Ang III Plus PC-18, and Ang III Plus PC-18 Plus PD Infusions in Rats on Normal Na+ Intake in the Presence of Systemic AT1 Receptor Blockade
As shown in Figure 7, compared with time control during which only vehicle was infused, RI administration of Ang III, Ang III plus PC-18, or Ang III plus PC-18 plus PD did not result in a significant change in systemic MAP. Compared with Ang III–infused rats, MAP was significantly greater in Ang III plus PC-18 and Ang III plus PC-18 plus PD-infused animals, during both control and experimental periods (P<0.05 and P<0.01, respectively).
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Discussion |
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The present studies demonstrate that RI Ang III, an AT2 receptor ligand, induces a natriuretic response in the presence of systemic AT1 receptor blockade. The natriuretic response was augmented by the intrarenal addition of PC-18 to Ang III and was blocked by the addition of PD, a specific AT2 receptor antagonist. Because the metabolism of Ang III to Ang IV by APN is inhibited by PC-18, these data demonstrate that Ang III is a significant mediator of AT2 receptor-induced natriuresis.
Ang III (Arg-Val-Tyr-Ile-His-Pro-Phe) is classically generated from the metabolism of Ang II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) by aminopeptidase A. In turn, APN metabolizes Ang III to Ang IV (Val-Tyr- Ile-His-Pro-Phe; Figure 1). Ang III is thought to possess biologic activity, both in renal and extrarenal tissues. In the brain, Ang III has been shown to cause vasoconstriction and mediate vasopressin release via the AT1 receptor.23,24 In the adrenal gland, aldosterone production is stimulated by Ang III.25 Ang III has also been reported to increase angiotensinogen levels and transforming growth factor-ß, fibronectin, and monocyte chemoattractant protein-1 gene expression in the kidney.26,27 Thus, whereas Ang II has traditionally been considered the major effector peptide of the systemic RAS, both Ang II and Ang III seem to exert biological activity in local tissue RAS.
Some authors argue that Ang III binds mainly to AT2 receptors and exhibits a lower affinity for AT1 receptors compared with that of Ang II.28 In the myometrial cells of the pig uterus, the Ki for Ang III at the AT2 receptor is 2.2±0.2 nM, and in rat liver membranes, the Ki for Ang III at the AT1 receptor is 10.5±0.3 nM, corroborating this observation. However, in the brain, Ang II and Ang III have been noted to display similar affinities for AT1 and AT2 receptors.29,30 The relative affinities for Ang II and Ang III for AT1 and AT2 receptors in the kidney have not been studied systematically. However, previous studies from our laboratory have demonstrated that RI infusion of Ang III, unlike Ang II, caused a significant natriuresis in the presence of systemic AT1 receptor blockade.17 The use of higher nanomolar concentrations of RI Ang II failed to induce a significant natriuretic response in that study.17 The addition of PD (a specific AT2 receptor antagonist) to intrarenal Ang III infusion abolished the Ang III–induced increase in natriuresis, providing pharmacological evidence that this effect is mediated by the AT2 receptor.17 Thus, it seems that within the intrarenal RAS, Ang III exerts a significant action at AT2 receptors, at least in the presence of AT1 receptor blockade.
In the systemic circulation, Ang III is metabolized 2 to 4 times faster than Ang II in both dogs and humans.25,31 APN is a major enzyme responsible for the metabolism of Ang III in the kidney.23 APN is expressed on the brush border (apical) membranes of renal proximal tubule cells and enterocytes.31 One of the first in vivo studies using PC-18 to inhibit the activity of APN was conducted in mice,20 during which intracerebroventricular administration of PC-18 resulted in a 3.9-fold increase in the half-life of Ang III compared with control. The in vitro specificity of PC-18 toward APN, aminopeptidase A, and aminopeptidase B (APB), 3 zinc metalloproteases with significant identity between their amino acid sequences, was also tested in the study.20 The Ki values of this compound on APN were in the nanomolar range (Ki=8.0±1.7 nM), but PC-18 was 2150 and 125 times less active on aminopeptidase A and aminopeptidase B, respectively.20 Thus, the infusion of PC-18 into the RI compartment in the present study allowed for examination of the effects mediated by Ang III within the intrarenal RAS, with the advantage of permitting the normally rapidly degraded peptide to remain available for a longer period of time. It should be mentioned, however, that PC-18 inhibition of APN, although quite specific, may have effects on other intrarenal peptides that are metabolized by APN (eg, kallidin). It is, therefore, possible that some of our results could be explained by increases in biologically active peptides metabolized by APN, other than Ang III. However, if this is the case, the effects of the other substrates of APN would also have to be mediated by the renal AT2 receptor, given that the augmentation in natriuresis engendered by Ang III plus PC-18 was abolished by the coinfusion of PD, a specific AT2 receptor antagonist.
Our data indicate that addition of RI PC-18 to Ang III infusion causes a 1.8- to 2.8-fold increase in Na+ excretion compared with RI Ang III infusion alone. Because the augmentation of the natriuretic response imparted by PC-18 was reduced by 73% to 95% with the coadministration of PD, the AT2 receptor is largely responsible for this response. It should be noted, however, that PD infusion did not completely eliminate natriuresis in this study, suggesting that higher doses of the compound may be necessary for this effect or that other mechanisms resulting in continued natriuresis remain in play. Nonetheless, inhibition of the metabolism of Ang III by APN resulted in augmented natriuresis in AT1 receptor–blocked rats, confirming our previous observations that Ang III is an important mediator of the natriuretic response in the kidney.
MAP was not altered by the RI infusion of Ang III, Ang III plus PC-18, or Ang III plus PC-18 plus PD in this study, indicating that the distribution of these peptides was almost certainly confined to the kidney during the experimental periods. Thus, systemic hemodynamic factors that might have played a role in the natriuresis were eliminated. It should be noted that MAP, during both control and experimental periods, was higher in the combined Ang III and PC-18 and Ang III, PC-18, and PD-infused animals compared with the animals infused with Ang III alone. Because the MAP before any RI infusion of pharmacological agents was higher in these groups, we interpret our data to mean that variability in baseline response to anesthesia between rats, rather than differences because of infused pharmacological agents, accounted for this effect.
In summary, the present studies demonstrate in AT1 receptor–blocked rats that Ang III–induced natriuresis is augmented by infusion of PC-18, a compound that specifically inhibits APN, the enzyme primarily responsible for the Ang III degradation. The increase in natriuresis was blocked by the addition of a specific AT2 receptor antagonist, PD, elucidating a role for the renal AT2 receptor in natriuresis.
Perspectives
This study demonstrates that intrarenal pharmacological inhibition of the enzyme that metabolizes Ang III in the kidney (APN) results in an augmentation of Ang III–induced natriuresis mediated by the renal AT2 receptor in the presence of systemic AT1 receptor blockade. The regulation of APN at the renal level has not been studied systematically and remains open for future investigation. Additionally, the mechanisms by which Ang III induces AT2 receptor–mediated natriuresis have yet to be elucidated. Our results suggest that APN and the AT2 receptor are potentially important therapeutic targets in disorders characterized by Na+ and fluid retention, such as hypertension and congestive heart failure. Finally, because Ang II (and, thereby, its metabolites) is increased after chronic AT1 receptor blocker therapy, some of the beneficial effects of this class of agents may be mediated by actions of Ang III at the AT2 receptor.
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Acknowledgments |
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Sources of Funding
This study was supported by grants DK-07646 and HL-65659 to R.M.C. from the National Institutes of Health.
Disclosures
None.
Received October 16, 2006; first decision November 2, 2006; accepted November 29, 2006.
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