Renal Angiotensin Type 2 Receptors Mediate Natriuresis Via Angiotensin III in the Angiotensin II Type 1 Receptor–Blocked Rat
Whereas angiotensin (Ang) II is the major effector peptide of the renin–angiotensin system, its metabolite, des-aspartyl1-Ang II (Ang III), may also have biologic activity. We investigated the effects of renal interstitial (RI) administration of candesartan (CAND), a specific Ang II type 1 receptor (AT1) blocker, with and without coinfusion of PD-123319 (PD), a specific Ang II type 2 receptor (AT2) blocker, on Na+ excretion (UNaV) in uninephrectomized rats. We also studied the effects of unilateral RI infusion of Ang II or Ang III on UNaV with and without systemic infusion of CAND with the noninfused kidney as control. In rats receiving normal Na+ intake, RI CAND increased UNaV from 0.07±0.08 to 0.82±0.17 μmol/min (P<0.01); this response was abolished by PD. During Na+ restriction, CAND increased UNaV from 0.06±0.02 to 0.1±0.02 μmol/min (P<0.05); this response also was blocked by PD. In rats with both kidneys intact, in the absence of CAND, unilateral RI infusion of Ang III did not significantly alter UNaV. However, with systemic CAND infusion, RI Ang III increased UNaV from 0.08±0.01 μmol/min to 0.18±0.04 μmol/min (P<0.01) at 3.5 nmol/kg per minute, and UNaV remained elevated throughout the infusion; this response was abolished by PD. However, RI infusion of Ang II did not significantly alter UNaV at any infusion rate (3.5 to 80 nmol/kg per minute) with or without systemic CAND infusion. These results suggest that intrarenal AT1 receptor blockade engenders natriuresis by activation of AT2 receptors. AT2 receptor activation via Ang III, but not via Ang II, mediates the natriuretic response in the presence of systemic AT1 receptor blockade.
Angiotensin (Ang) II, the primary transducer peptide of the renin–Ang system (RAS), acts at 2 major Ang II receptors, type 1 (AT1) and type 2 (AT2).1 The majority of Ang II actions are believed to occur via the AT1 receptor, including antinatriuresis.2 The role of the AT2 receptor is less clearly understood.3 Furthermore, whereas Ang II has been considered the major effector peptide of the RAS, its direct metabolite, des-aspartyl1-Ang II (Ang III) also has biologic activity.4 Indeed, some actions originally attributable to Ang II, such as vasopressin release, are mediated at least in part by Ang III.5 Recent reports suggest that Ang III could be involved in renal physiological processes as well.6–8
Studies involving AT2 receptors and the regulation of sodium (Na+) excretion have been limited. In vitro studies have demonstrated that the AT2 receptor may decrease renal proximal tubule bicarbonate reabsorption via phospholipase A2 and arachidonic acid release.9 In vivo studies in mice lacking the AT2 receptor (AT2-null), have demonstrated a shift to the right (less sensitive) in the pressure-natriuresis curve.10 In addition, antinatriuretic and pressor hypersensitivity to Ang II has been documented in AT2-null mice.11 However, the AT1 receptor is upregulated in AT2-null mice,12 which may account for at least part of the aforementioned effects on pressure-natriuresis and antinatriuresis, respectively.
Because previously published studies have provided evidence for inhibition of renal Na+ excretion (UNaV) in AT2-null animals,10,11 the present studies were designed to demonstrate the role of AT2 receptor stimulation in the regulation of UNaV in normal rats. A recent study by Crowley et al13 emphasized the unique and nonredundant contribution of renal AT1 receptors in blood pressure homeostasis that was virtually equivalent to and independent of the contribution of extrarenal AT1 receptors. We investigated the effects of specific intrarenal AT1 receptor blockade with the insurmountable AT1 receptor antagonist candesartan (CAND) and specific AT2 receptor blockade with PD-123319 (PD) on UNaV in rats during both normal and low Na+ intake. We also investigated the effects of direct unilateral renal interstitial (RI) administration of Ang II or Ang III on UNaV with and without systemic AT1 receptor blockade with CAND and direct RI coinfusion of PD. We selected Ang II and Ang III as effector peptides of the AT2 receptor in these experiments, because their respective roles in renal Na+ handling have not yet been elucidated.
The experiments, which were approved by the University of Virginia Animal Research Committee, were conducted in 250-g Sprague-Dawley rats (Harlan, Teklad; n=73 total). Rats were placed under general anesthesia with pentobarbital (50 mg/mL) or nembutal (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 blood pressure (BP).
Renal Cortical Interstitial Infusion
Through a midline laparotomy, the right and left kidneys were exposed. A polyethylene (PE-10) 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 space. When dual substances were infused, they were combined immediately before the experimental periods.
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 RI AT1 Receptor Blockade and AT1 Plus AT2 Receptor Blockade on UNaV in Uninephrectomized Rats on Normal and Low Na+ Intake
Rats (n=8 in each group) were studied on normal (0.28% dietary NaCl) or low (0.04% NaCl) Na+ intake. Rats were anesthetized with an intraperitoneal injection of pentobarbital (5 mg/100 g body weight). Uninephrectomy was performed on each rat, and an open-bore microcatheter was inserted directly into the superficial cortical RI space of the remaining kidney. MAPs were monitored during a 1-hour control period (vehicle infusion with 5% dextrose in water; D5W) followed by 4 consecutive 1-hour experimental periods (periods 1 to 4), during which pharmacological agents were infused. In group 1, vehicle was infused directly into the renal cortical interstitial space at a rate of 2.5 μL/min during the control and all of the experimental periods (time control). In another group, CAND (0.01 mg/ kg per minute) alone was infused during periods 1 to 4. In a third group, CAND and PD (10 μg/kg per minute) were combined and infused during periods 1 to 4. UNaV was quantified hourly via urethral catheter.
Effects on UNaV of Unilateral RI Ang III in the Presence and Absence of Systemic AT1 Receptor Blockade With and Without RI AT2 Receptor Blockade
Rats (n=8 in each group) were studied on normal Na+ intake with both kidneys intact. There were a total of 3 groups in this experiment. In all of the rats, the right kidney served as the control kidney and was infused with D5W vehicle (2.5 μL/min) directly into the RI space during both control (1 hour) and experimental collection periods (30 minutes each). In the first group, Ang III (3.5, 7, and 14 nmol/kg per minute) was infused cumulatively into the RI space of the left (experimental) kidney after a 1-hour control infusion of D5W (2.5 μL/min). In the second group, 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 systemic CAND (0.01 mg/kg per minute) infusion 24 hours before and during the experiment. RI infusion of Ang III in escalating doses (3.5, 7, and 14 nmol/ kg per minute) was infused into the left kidney during each 30-minute experimental period. In the third group, systemic CAND infusion was achieved in the same manner as in the second group, but Ang III and PD (10 μg/kg per minute) were coinfused into the RI space of the left kidney. In all 3 of the groups, both ureters were cannulated individually to collect urine for quantification of UNaV for the control and 3 experimental periods from both the right (control) and left (experimental) kidneys.
Effects of RI Ang II on UNaV in the Absence or Presence of Systemic AT1 Receptor Blockade
Rats (n=6 per group) were studied in an identical manner as in the previously described experiment except that Ang II was substituted for Ang III. In the first group, Ang II (3.5, 7, and 14 nmol/kg per minute) was infused into the RI space of the left kidney after a 1-hour control period. In the second group, this study was repeated in the presence of a systemic CAND (0.01 mg/kg per minute) infusion 24 hours before and during the experiment. Lastly, the entire experiment was repeated (n=17) using higher infusion rates of Ang II (20, 40, 80 nmol/kg per minute) in the presence of systemic CAND.
Ang II amide (ASN-Val5)-Ang II (Sigma) and Ang III (des-Asp1)-Ang II (Sigma), both AT1 receptor and AT2 receptor agonists, were used for these studies (Ang II inhibition constant 1.0×10−9 mol/L and 0.6×10−9 mol/L for AT1 and AT2 receptors, respectively, and Ang III inhibition constant 10.5×10−9 mol/L and 2.2×10−9 mol/L for AT1 and AT2 receptors, respectively, in brain14). CAND (CV-11974), a specific, potent insurmountable inhibitor of AT1 receptors (IC50 >1×10−5 mol/L and 2.9×10−8 mol/L for AT2 and AT1 receptors, respectively), was used either interstitially in the kidney or systemically for AT1 receptor blockade in anesthetized animals. PD (Parke-Davis), a specific AT2 receptor antagonist (IC50 2×10−8 mol/L and >1×10−4 mol/L for AT2 and AT1 receptors, respectively), was used interstitially to block the AT2 receptor.
Comparisons among vehicle, AT1 receptor blocker (CAND), AT2 receptor blocker (PD), and AT1 and AT2 receptor agonists (Ang II and Ang III) 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.
Effects of RI AT1 Receptor Blockade and AT1 Plus AT2 Receptor Blockade on UNaV in Uninephrectomized Rats on Normal and Low Na+ Intake
As demonstrated in Figure 1, during normal Na+ intake, RI CAND infusion increased UNaV from a precontrol value of 0.07±0.08 to 0.45±0.17 μmol/min (P<0.05) in period 2 to 0.70±0.17 μmol/min (P<0.05) during period 3 and to 0.82±0.17 (P<0.01) μmol/min during period 4. PD coinfusion abolished the natriuretic response to CAND (P<0.05 from CAND alone and P value was not significant from precontrol and vehicle time control) during each experimental period. Infusion of vehicle (time control) resulted in no change in UNaV from precontrol during periods 1 to 4.
As illustrated in Figure 2, during normal Na+ intake, RI CAND infusion decreased MAP from a precontrol value of 119±5 mm Hg to 102±3 mm Hg (P<0.01) during period 1 and to 101±6 mm Hg (P<0.05) during period 2, after which MAP rose to levels not significantly different from precontrol values. The addition of PD reversed the reduction of MAP engendered by CAND in periods 1 and 2. Vehicle infusion did not alter MAP from a precontrol value of 99±21 mm Hg through all 4 of the experimental periods.
During dietary Na+ restriction (Figure 3A), a 1-hour RI CAND infusion increased UNaV from a precontrol value of 0.057±0.012 to 0.1±0.017 μmol/min (P<0.05). The addition of RI PD blocked the natriuretic response to RI CAND. There was no significant difference in UNaV from precontrol during the time-control vehicle infusion. As demonstrated in Figure 3B, RI CAND infusion decreased MAP from a precontrol value of 128±5 mm Hg to 106±6 mm Hg (P<0.01), and the addition of PD to CAND did not alter the hypotensive response (MAP 99±7 mm Hg; P<0.01). There was no significant change in MAP during vehicle infusion (time control).
Effects of RI Ang III in the Presence or Absence of Systemic AT1 Receptor Blockade on UNaV With or Without RI AT2 Receptor Blockade
As illustrated in Figure 4A, in the absence of systemic CAND administration, RI infusion of Ang III at cumulative infusion rates of 3.5, 7, and 14 nmol/kg per minute into the left kidney did not significantly alter UNaV from a control value of 0.10±0.02 μmol/min. UNaV was also unchanged from precontrol values in the contralateral (right) control kidney in response to Ang III infusion into the experimental (infused) kidney.
However, as shown in Figure 4B, in the presence of systemic CAND administration, RI Ang III infusion increased UNaV from 0.08±0.01 to 0.18±0.04 μmol/min (P<0.01) at 3.5 nmol/kg per minute, to 0.17±0.03 μmol/min (P<0.01) at 7 nmol/kg per minute, and to 0.14±0.03 μmol/min (P<0.05) at 14 nmol/kg per minute. UNaV was unchanged in the contralateral control kidney in response to Ang III infusion into the experimental kidney. Coinfusion of PD with Ang III (in the presence of systemic CAND administration; Figure 4C) eliminated the natriuretic response seen with Ang III infusion (Figure 4B). There was no significant increase in UNaV from the infused or contralateral kidney at any infusion rate of Ang III in the presence of RI PD.
The percentage of increase in UNaV from Ang III (in the presence of CAND) was significantly greater than the percentage of decrease in UNaV that resulted from Ang III and PD administration (in the presence of CAND) when normalized for UNaV from CAND alone (P<0.001; Figure 5). In addition, the percentage of increase in UNaV from Ang III at 7.0 nmol/kg per minute and Ang III at 14 nmol/kg per minute in the presence of CAND was 39.2% and 41.9%, respectively, significantly higher than the 27.2% increase in UNaV induced by Ang III at 3.5 nmol/kg per minute (P<0.05; Figure 5).
As illustrated in Figure 6, systemic CAND administration decreased MAP from a control of 112+4 (precontrol for Ang III alone) to 89+6 mm Hg (P<0.01). Unilateral RI Ang III infusion did not alter MAP at any dose level either in the absence or presence of systemic CAND administration. Similarly, coinfusion of Ang III and PD did not alter MAP.
Effects of RI Ang II on UNaV With or Without Systemic AT1 Receptor Blockade
As demonstrated in Figure 7A, in the absence of CAND, Ang II did not significantly alter UNaV from a precontrol value of 0.10±0.02 μmol/min at any infusion rate. UNaV was also unchanged in the contralateral control kidney from a precontrol value of 0.127±0.019 μmol/min during the experiment. In addition, as shown in Figure 7B, in the presence of systemic CAND, intrarenal Ang II infusion did not significantly alter UNaV from a precontrol value of 0.07±0.03 μmol/min at any infusion rate of Ang II (3.5, 7, and 14 nmol/kg per minute). As illustrated in Figure 7C, systemic CAND infusion resulted in a lower MAP compared with values during the precontrol period (91.3±3.1 mm Hg versus 142.6±2.9 mm Hg; P<0.001), and this reduction in MAP was not significantly influenced by RI infusion of Ang II.
At higher infusion rates of RI Ang II in the presence of systemic CAND, UNaV also failed to change significantly from precontrol values. As shown in Figure 8A, in the absence of CAND, RI Ang II infusion resulted in UNaV values of 0.15±0.05 μmol/min during the precontrol period, 0.11±0.03 μmol/min during Ang II 20 nmol/kg per minute infusion, 0.14±0.05 μmol/min during Ang II 40 nmol/kg per minute infusion, and 0.25±0.05 μmol/min during Ang II 80 nmol/kg per minute infusion (all P values were not significant from control kidney). As shown in Figure 8B, in the presence of systemic CAND RI, Ang II infusion resulted in UNaV values of 0.08±0.02 μmol/min during the precontrol period, 0.15±0.03 μmol/min during 20 nmol/kg per minute infusion, 0.20±0.06 μmol/min during 40 nmol/kg per minute infusion, and 0.13±0.03 μmol/min during 80 nmol/kg per minute infusion (all P values were not significant from control kidney).
As illustrated in Figure 8C, systemic CAND infusion resulted in lower MAP compared with RI Ang II infusion alone during the precontrol period (79±5 mm Hg versus 114±4 mm Hg; P<0.0001), during the 20 nmol/kg per minute infusion period (79±4 mm Hg versus 115±4 mm Hg; P<0.0001), during the 40 nmol/kg per minute infusion period (80±5 mm Hg versus 112±5 mm Hg; P<0.0001), and during the 80 nmol/kg per minute infusion period (80±4 mm Hg versus 106±5 mm Hg; P<0.0001).
These studies demonstrate that RI AT1 receptor blockade induced natriuresis in rats during both normal and low Na+ intake. The natriuresis due to AT1 receptor blockade was eliminated by concomitant RI AT2 receptor blockade. RI AT2 receptor blockade reversed the hypotensive effect of RI AT1 receptor blockade in rats on normal but not low Na+ diets. In addition, unilateral renal administration of Ang III, an AT2 receptor ligand,4 did not alter UNaV during normal Na+ intake. However, in the presence of systemic AT1 receptor blockade, RI Ang III administration induced a natriuretic response that was abrogated by concurrent RI AT2 receptor blockade. Finally, unlike Ang III, unilateral RI administration of Ang II, also an AT2 receptor ligand, did not alter UNaV in the presence of systemic AT1 receptor blockade. Increased concentrations of RI Ang II in the presence of AT1 receptor blockade also failed to alter the UNaV. Taken together, these findings strongly suggest that the renal AT2 receptor mediates natriuresis in normal rats, counterbalancing the antinatriuretic action of Ang II via the AT1 receptor. The natriuresis engendered by renal AT1 receptor blockade is mediated, at least in part, by AT2 receptor stimulation. RI Ang III is the preferential agonist of this response via the AT2 receptor.
Historically, the observation that marked antinatriuresis resulted from the systemic infusion of low doses of Ang II emphasized the importance of the RAS as a powerful Na+-conserving hormone system.15 However, Ang II has also been shown to cause natriuresis and diuresis when plasma concentrations are elevated to very high levels by infusion of Ang II or by extreme stimulation of endogenous Ang II formation, such as in malignant hypertension.16 The natriuretic effect of high rates of Ang II infusion is because of increased renal perfusion pressure, which may elevate the filtered Na+ load slightly and markedly reduces fractional Na+ reabsorption in proximal tubules and in sites distal to the proximal tubule.17 This concept of pressure natriuresis is not new, but the specific ligand-receptor interactions that mediate this response have yet to be determined.
Studies on the role of the AT1 receptor in Na+ homeostasis reveal that AT1A receptor knockout mice have reduced BP and, during Na+ restriction, develop a negative Na+ balance.18 These animals show normal increases in plasma aldosterone levels during Na+ depletion, consistent with the abundance of AT1B receptors in the adrenal zona glomerulosa. The findings suggest that the hypotension observed in the AT1A receptor knockout mice results from Na+ deficiency and blood volume depletion and are consistent with the major role of AT1A receptors in renal Na+ reabsorption. Furthermore, AT1A receptor knockout mice have a significant defect in urinary Na+ concentration and develop marked serum hypotonicity during water deprivation, resulting from an inability to maintain a maximal Na+ gradient in the kidney as opposed to an abnormality in vasopressin action.17
Few studies have examined the role of the AT2 receptors in Na+ homeostasis. Gross et al10 demonstrated a decreased sensitivity of the pressure-natriuresis curve in AT2-null mice, and both sustained antinatriuretic hypersensitivity and hypertension to Ang II in these mice.11 However, as demonstrated by Tanaka et al,12 the vascular response to Ang II is exaggerated through an upregulation of AT1 receptors in AT2-null mice. As a result, altered renal Na+ handling in AT2-null mice could be the result of AT1 receptor upregulation and not a specific AT2 receptor–mediated effect. Hakam and Hussain19 showed that intravenous infusion of PD, a specific AT2 receptor antagonist, abolished the CAND-induced natriuresis/diuresis in obese Zucker rats (a genetic model of obesity and hyperinsulinemia) to a greater degree than in lean rats. In their studies, direct stimulation of AT2 receptors with CGP-42112A produced a more significant natriuresis/diuresis in obese compared with lean rats.
Our studies employed pharmacological RI AT1 receptor blockade in normal rats to demonstrate that the resulting natriuresis was abrogated by a RI AT2 receptor blockade. These findings provide more direct evidence that renal stimulation of the AT2 receptor is, indeed, responsible for the natriuretic response in normal rats blocked intrarenally with CAND. Interestingly, systemic blockade of the AT1 receptor alone did not result in natriuresis in our studies. In this case, intrarenal AT2 receptor stimulation with Ang III was required to induce the natriuretic response, once again highlighting the unique and nonredundant contribution of the intrarenal RAS in Na+ homeostasis.
The specific effector ligand of the AT2 receptor, which mediated the natriuretic response in the presence of systemic AT1 receptor blockade, was Ang III and not Ang II. Whereas the natriuretic response to Ang III in the presence of CAND was not observed as a dose-response relationship, the response was indeed sustained. The inability of RI Ang III to exert a natriuretic response in the absence of systemic AT1 receptor blockade is likely because of its agonist activity at the AT1 receptor. Alternatively, although less likely, the higher baseline UNaV values during the control period (Figure 4A) could have accounted for the lack of natriuretic response observed with RI Ang III infusion alone. Nonetheless, evidence has been mounting that Ang III, instead of Ang II, is the effector peptide of several responses in different local tissue RASs. For example, in the brain RAS, Ang III, instead of Ang II, was shown to mediate the pressor response by AT1 receptors, because selective blockade of the formation of brain Ang III resulted in a decrease in BP.20 In the kidney, we know that Ang II is converted to Ang III in vivo via aminopeptidase A, which is present in both glomeruli and renal tubules.4 Ang III is converted to Ang IV via aminopeptidase N. In the lumen of proximal tubule cells, the concentration of Ang II is 1000-fold higher than in plasma, but, because of the high density of peptidases, Ang II only represents &5% to 15% of total renal Angs.21 Terui et al6 found that the proteinuric effects of intravenous Ang II administration were greater than that of Ang III, but both increased the fractional excretion of albumin in a dose-dependent manner. However, the effects of RI administration of Ang II and Ang III at equimolar levels show that Ang III, rather than Ang II, mediates the natriuretic effect via the AT2 receptor in AT1 receptor–blocked rats.
The RI administration route in the present investigations deserves comment. This route of administration was used to eliminate systemic hemodynamic factors that may play a role in the natriuretic response. The lack of MAP changes during RI infusion of Ang II or Ang III indicated that the distribution of these peptides was almost certainly confined to the kidney during the experimental period. The decrease in MAP observed during intrarenal CAND administration was likely because of the long half-life of the agent with escape from the kidney into the systemic circulation (Figure 2). It should also be noted that RI PD infusion may have exerted systemic effects in that it appeared to reverse systemic CAND-induced hypotension (Figure 6). The reversal of CAND-induced hypotension with RI PD was more significant when CAND was infused systemically rather than intrarenally. In addition, intrarenal PD infusion blocked systemic CAND-induced hypotension in rats on normal Na+ intake compared with rats on a low Na+ diet. One possible explanation for this discrepancy may be that the balance of intrarenal AT1 and AT2 receptors may be shifted in favor of AT1 receptors in animals on low Na+ intake to enhance Na+ reabsorption. In this case, PD, a selective AT2 receptor antagonist, may not have been able to exert a significant effect because of the relative reduction of renal AT2 receptor expression. Additional studies are required to determine whether AT2 receptor–mediated natriuresis is due to hemodynamic, direct tubular actions, or both. The cell signaling mechanisms by which the AT2 receptor mediates natriuresis also need to be determined.
In summary, the present studies suggest that (1) RI AT1 receptor blockade engenders a natriuretic response that is blocked by renal AT2 receptor blockade, and (2) RI AT2 receptor stimulation via Ang III, and not Ang II, is responsible for mediating this natriuretic response in the presence of AT1 receptor blockade. These studies elucidate a role for Ang III in AT2 receptor–mediated natriuresis.
This study demonstrates for the first time that the angiotensin AT2 receptor mediates natriuresis in a normal animal model. The natriuretic effect of intrarenal AT1 receptor blockade was abolished by intrarenal AT2 receptor blockade, indicating that this beneficial action of AT1 receptor blockade is mediated, at least acutely, by AT2 receptor activation. We also demonstrated for the first time that the heptapeptide metabolite of Ang II, Ang III, is the preferential agonist stimulating natriureses via the renal AT2 receptor. The mechanisms by which Ang III activation of the renal AT2 receptor leads to natriuresis remain open to future investigation. Our results suggest that the AT2 receptor is a potentially important therapeutic target for disorders characterized by Na+ and fluid retention, such as hypertension and congestive heart failure.
- Received September 20, 2005.
- Revision received October 21, 2005.
- Accepted November 10, 2005.
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