Atrial Natriuretic Peptide in Chronically Hypertensive Dogs
Abstract We determined the renal and depressor activities of 10, 50, and 100 pmol/kg per minute IV of human atrial natriuretic peptide-(99-126) in conscious one-kidney, one clip dogs with chronic hypertension and modest renal dysfunction, as indicated by mild proteinuria. Atrial natriuretic peptide increased fractional sodium excretion by 0.009±0.002, 0.042±0.005, and 0.049±0.007, respectively; urinary excretion of atrial natriuretic peptide by −0.4±0.8, 3.3±1.4, and 15.8±7.4 fmol/min; and cGMP excretion by 0.65±0.06, 1.65±0.08, and 4.88±0.85 nmol/min in one-kidney shams. The changes in fractional sodium excretion were significantly attenuated in the hypertensive dogs (0.005±0.002, 0.018±0.003, and 0.022±0.004, respectively) despite exaggerated increases in atrial natriuretic peptide excretion (3.3±1.6, 22.0±5.0, and 46.6±10.8 fmol/min) and cGMP excretion (0.96±0.47, 4.51±1.27, and 7.06±1.38 nmol/min). The slope of the line relating urinary atrial natriuretic peptide to cGMP was significantly suppressed in the hypertensive dogs, suggesting a downregulation of the guanylate cyclase–linked receptors. The slope of the relationship between cGMP excretion and the natriuretic response was also depressed in the hypertensive dogs, indicating possible impairment of cGMP signal transduction. The differences between sham and hypertensive dogs were diminished when urinary levels of atrial natriuretic peptide were maximized by prior treatment with SQ 28603, an inhibitor of neutral endopeptidase EC 184.108.40.206. Atrial natriuretic peptide caused comparable decreases in mean arterial pressure and increases in glomerular filtration rate in sham and hypertensive dogs, suggesting similar vascular reactivity. In conclusion, dogs with chronic one-kidney, one clip hypertension and mild proteinuria were hyporesponsive to the renal activity of atrial natriuretic peptide, presumably because of renal receptor downregulation and possible defects in cGMP signal transduction.
ANP produces vasodilation and natriuresis, actions that mediate its proven antihypertensive efficacy. These activities are mediated by guanylate cyclase–linked receptors that are located throughout the vasculature and kidney, especially the glomerulus and collecting duct.1 The antihypertensive potency of exogenous ANP depends on the experimental model studied, in that deoxycorticosterone acetate–salt hypertensive rats are more sensitive than renal or genetic hypertensive models.2 3 In a similar fashion, deoxycorticosterone acetate–salt hypertensive rats are more sensitive than spontaneously hypertensive rats (SHR) to NEP inhibitors,4 5 agents that enhance endogenous ANP by preventing its degradation. Therefore, ANP and NEP inhibitors lower blood pressure most effectively in low-renin, volume-dependent models of hypertension in which plasma ANP concentrations are elevated.4 5
The renal responses to exogenous ANP and to NEP inhibitors appear to be affected more by renal perfusion pressure, the prevailing levels of renin activity, and the sodium status of the animals than by the hypertensive model. Specifically, the natriuretic activity of exogenous ANP is diminished when renal perfusion pressure is lowered,2 3 6 the renin-angiotensin system is strongly activated,7 or sodium intake is restricted.8 9 In addition, diminished renal responsiveness has been reported in models of nephrotic syndrome10 11 12 characterized by heavy proteinuria and reduced GFR. The reason that ANP has less activity in renal failure has not yet been determined.
In the present study we examined the depressor and renal responses to exogenous hANP-(99-126) and the selective NEP inhibitor SQ 28603 (N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-β-alanine) in conscious dogs with chronic 1K1C hypertension. Our colony of 1K1C hypertensive dogs had been established 4 years earlier and had begun to exhibit early signs of renal impairment, that is, a modest increase in urinary protein excretion. The present results provide the first evidence of renal resistance to hANP-(99-126) in the presence of mild renal dysfunction resulting from chronic hypertension.
Establishment of the Hypertensive Colony
A colony of renal hypertensive dogs was established by constricting the renal artery of unilaterally nephrectomized mongrel dogs. Briefly, dogs of either sex were injected with atropine (0.02 mg/kg IM) and oxymorphone (0.08 mg/kg IM) before anesthesia was induced with intravenous thiopental. Anesthesia was maintained with 1% to 3% isoflurane/99% to 97% oxygen, and one kidney was excised. Ten to 14 days later each dog was anesthetized according to the procedures outlined above, and a permanent perivascular clamp was tightened around the renal artery until renal blood flow was reduced by approximately 55%. In sham-operated dogs a clamp was placed loosely around the renal artery so that renal blood flow was unrestricted. Within the year preceding the studies listed below, an indwelling catheter was inserted into a carotid artery in each dog. The free end of the catheter was attached to a vascular access port implanted subcutaneously in the midscapular region. All surgeries were performed under sterile conditions, and the dogs were treated prophylactically with antibiotics for 7 to 10 days. The studies described below were conducted in six 1K1C dogs that had been hypertensive for 3 to 4 years. All surgical procedures and experimental protocols were approved by the Bristol-Myers Squibb animal care and use committee.
Experimental Procedures and Measurements
All dogs were fasted overnight and lightly restrained in a standard canine sling. MAP was measured via a Huber point needle inserted into the vascular access port and connected to a Gould-Statham pressure transducer (Spectramed). Patency of the arterial catheter was ensured by continuous infusion of 50 μL/min sterile saline. MAP and heart rate were continuously recorded on a chart writer (Gould Electronics) and stored electronically with a Po-Ne-Mah data-acquisition system (Digital Acquisition Analysis).
A perivascular catheter was introduced into a cephalic vein, and a Foley catheter (8F for females and 7F for males) was inserted aseptically into the urinary bladder for timed urine collections. Creatinine (50 mg/kg plus 1 mg/kg per minute) and para-aminohippuric acid (8 mg/kg plus 0.3 mg/kg per minute) were administered intravenously at a rate of 1 mL/min. Forty-five to 60 minutes later the bladder was flushed with 20 mL sterile distilled water. Thereafter, urine was collected and the bladder was flushed at 20-minute intervals for the rest of the experiment.
Arterial blood samples were drawn in heparin at the midpoint of each 20-minute urine collection. Hematocrit was determined with microcapillary tubes, and the remaining blood was centrifuged to separate the plasma. The concentrations of creatinine and para-aminohippuric acid in urine and in each midpoint plasma sample were determined by spectrophotometric assays (Instrumentation Laboratories Phoenix Chemistry Analyzer). The renal clearances of creatinine and para-aminohippuric acid were calculated as estimates of GFR and effective renal plasma flow (ERPF), respectively. Filtration fraction was calculated by GFR/ERPF. Sodium and potassium concentrations in plasma and urine were measured by ion-selective electrodes (Instrumentation Laboratories Phoenix Chemistry Analyzer), and urinary electrolyte excretion rates (micromoles per minute) were calculated. Fractional sodium excretion was computed and expressed in decimal form. Protein concentrations were measured in each midpoint plasma sample by the Coomassie brilliant blue dye binding assay or by the Biuret technique (Bio-Rad Laboratories). Urinary protein concentrations were also determined and excretion rates calculated.
Additional arterial blood samples were drawn in chilled tubes containing EDTA at the end of the second control period and at 20-minute intervals thereafter (except as noted below) for determination of PRA and the plasma concentrations of ANP and cGMP. Plasma samples collected for measurement of PRA were stored at 0°C until analyzed with a radioimmunoassay kit (Biotecx). Aprotinin (1000 kallikrein inhibiting units/mL) and sodium azide (2 mg/mL) were added to the plasma and urine samples that were later analyzed for ANP and cGMP concentrations with the use of radioimmunoassay kits (Peninsula Laboratories and New England Nuclear Products, respectively). The procedures for storage, extraction, and assay of these samples were described previously.13
Sham and 1K1C hypertensive dogs were studied on four separate occasions for determination of the renal and depressor effects of vehicle, hANP-(99-126) (Peninsula Laboratories), the selective NEP inhibitor SQ 28603 (synthesized by Bristol-Myers Squibb), and hANP-(99-126) in the presence of SQ 28603. Saline (0.1 mL/min) was infused intravenously during two 20-minute control periods in each dog. The effects of vehicle were determined by continuing the saline infusion for an additional 3 hours in the sham (n=4) and 1K1C hypertensive (n=6) dogs. In a second test in the same dogs the saline infusion was replaced with solutions of hANP-(99-126) such that doses of 10, 50, and 100 pmol/kg per minute were infused sequentially at 0.1 mL/min during the three 20-minute periods following the baseline measurements. After the final dose of hANP-(99-126) the saline infusion was restored and urine collections were continued at 20-minute intervals for 2 more hours. A third experiment was conducted to evaluate the effects of 30 μmol/kg IV of SQ 28603 on the renal and depressor responses to 10, 50, and 100 pmol/kg per minute IV hANP-(99-126) in the four sham dogs and in five of the 1K1C hypertensive dogs. Finally, the activity of 30 μmol/kg IV of SQ 28603 alone was assessed in the sham (n=4) and 1K1C hypertensive (n=4) dogs. In the latter study plasma samples for hormonal determinations were collected at hourly intervals after administration of the NEP inhibitor in both sham and 1K1C hypertensive dogs. Each dog was allowed to recover for at least 3 weeks between studies.
To minimize interanimal variability each data point was expressed as the change from the average control value. Significant differences among treatments were identified by ANOVA for repeated measures and contrasts. Results are given as mean±SEM. Significant correlations were determined with a simple regression model; differences between the slopes of the curves were determined by ANOVA.
Characteristics of the 1K1C Hypertensive Model
MAP (Table 1⇓) was significantly greater in the 1K1C hypertensive compared with sham dogs. Urinary protein excretion (Table 1⇓) was also significantly elevated in the hypertensive dogs, suggesting that renal permselectivity may be impaired in these dogs with long-standing hypertension. However, all measures of electrolyte excretion and renal hemodynamics were within normal ranges, so there was no other evidence of overt renal failure in these dogs.
Effects of Intravenous Human ANP-(99-126) in 1K1C Hypertensive and Sham Dogs
Infusion of hANP-(99-126) in 1K1C hypertensive dogs and sham controls produced comparable dose-related reductions in MAP (Fig 1⇓) without affecting heart rate (data not shown). SQ 28603 alone tended to increase MAP in both 1K1C hypertensive and normotensive sham dogs (Fig 1⇓). Furthermore, the NEP inhibitor did not significantly potentiate the depressor responses obtained during infusion of exogenous hANP-(99-126) in either group of dogs.
In contrast, the natriuretic (Fig 2⇓), diuretic, and kaliuretic (Table 2⇓) responses to exogenous hANP-(99-126) in the 1K1C hypertensive dogs were significantly less than those measured in the sham dogs. NEP inhibition by SQ 28603 significantly increased the magnitude of the natriuretic (Fig 2⇓) and diuretic (Table 2⇓) responses to lower doses of exogenous hANP-(99-126) and prolonged the recovery to baseline after the final dose of hANP-(99-126) in both normotensive and hypertensive dogs. After SQ 28603 the differences between the natriuretic (Fig 2⇓) and diuretic (Table 2⇓) responses to hANP-(99-126) in the sham and hypertensive dogs were no longer significant. Furthermore, the NEP inhibitor did not consistently enhance the kaliuretic activity of hANP-(99-126) in either sham or 1K1C hypertensive dogs (Table 2⇓).
Urinary ANP and cGMP (Fig 3⇓) excretion rates rose in dose-related fashions in the 1K1C hypertensive dogs infused with hANP-(99-126). Only the highest dose of hANP-(99-126) significantly increased urinary ANP or cGMP excretion rates in the sham dogs, so these responses were significantly less than those measured in the 1K1C hypertensive dogs. This pattern of larger urinary ANP and cGMP responses in the 1K1C hypertensive dogs was contrary to the weaker natriuretic activity of hANP-(99-126) in the hypertensive group. Accordingly, the slope of the line relating log urinary ANP excretion to the natriuretic responses to exogenous hANP-(99-126) in the 1K1C dogs was significantly reduced compared with that in sham dogs (Fig 4⇓). The relationship between urinary ANP and cGMP excretion was also more shallow for the 1K1C hypertensive than for the sham dogs (Fig 4⇓). Finally, the cGMP excretion rates were significantly correlated to the natriuretic responses during hANP-(99-126) infusion in both sham and 1K1C hypertensive dogs (data not shown); however, the slopes of those relationships for the sham and 1K1C hypertensive groups (536 and 147 μmol Na · min−1/pmol cGMP · min−1, respectively) differed significantly. These data suggested a possible downregulation of the renal guanylate cyclase–linked receptors in the 1K1C hypertensive dogs.
SQ 28603 significantly increased urinary ANP excretion when given alone to either the 1K1C hypertensive or normotensive sham dogs (Fig 3⇑, left). The NEP inhibitor potentiated both the cGMP (Fig 3⇑, right) and urinary ANP (Fig 5⇓) responses to exogenous hANP-(99-126) in both normotensive and hypertensive dogs such that the differences between the two groups were obviated. [Note that it was necessary to display the urinary ANP responses obtained in the presence of SQ 28603 plus hANP-(99-126) in a separate figure because of the differences in scales.] SQ 28603 also reduced the slopes of the best-fit lines relating ANP excretion to the natriuretic and urinary cGMP responses in both the sham dogs (74 μmol Na · min−1/log [fmol ANP · min−1] and 0.0005 pmol cGMP · min−1/fmol ANP · min−1) and 1K1C hypertensive dogs (60 μmol Na · min−1/log [fmol ANP · min−1] and 0.0004 pmol cGMP · min−1/fmol ANP · min−1, respectively). Presumably, the NEP inhibitor raised urinary ANP concentrations to supermaximal levels for stimulation of the guanylate cyclase–linked receptors. Under these conditions the differences between the normotensive and hypertensive groups were eliminated.
In contrast to the changes in urinary ANP and cGMP excretions, plasma concentrations of ANP and cGMP (Fig 6⇓) rose to higher levels in the vehicle-treated sham dogs than in the 1K1C hypertensive dogs. Whereas SQ 28603 alone had no significant effect on plasma ANP or cGMP concentrations (Fig 6⇓), the NEP inhibitor significantly increased and prolonged the plasma ANP and cGMP responses to infused hANP-(99-126). In the presence of SQ 28603 the differences between the responses in normotensive sham and 1K1C hypertensive dogs were virtually obliterated. However, plasma ANP concentrations were only weakly correlated to the natriuretic responses (r2=.352 for sham dogs and r2=.0305 for 1K1C hypertensive dogs).
Human ANP-(99-126) significantly reduced PRA (Table 3⇓) in both the 1K1C hypertensive and normotensive sham dogs. As seen previously in normotensive dogs,14 there was a rebound increase in PRA once the hANP-(99-126) infusions were discontinued. SQ 28603 alone also suppressed PRA, especially in the sham dogs (Table 3⇓). When given before the hANP-(99-126) infusions, SQ 28603 prevented the rebound hyperreninemia during recovery.
GFR (Table 4⇓) increased significantly during hANP-(99-126) infusion in the 1K1C hypertensive dogs, whereas effective renal plasma flow (data not shown) was unaffected. Consequently, filtration fraction (Table 4⇓) increased significantly. These responses in the hypertensive dogs were not statistically different from the responses obtained in sham dogs. SQ 28603 significantly enhanced both the increase in GFR produced by the lowest hANP-(99-126) dose and the rise in filtration fraction stimulated by the highest hANP-(99-126) dose in the 1K1C hypertensive dogs. After treatment with SQ 28603 the increases in filtration fraction produced by all hANP-(99-126) doses were greater in the 1K1C hypertensive than sham control dogs.
Human ANP-(99-126) infusions increased both hematocrit (Fig 7⇓) and plasma protein concentrations (+0.14±0.08, +0.21±0.05, and +0.24±0.5 [P<.05] μg/mL for 10, 50, and 100 pmol/kg per minute, respectively) in the 1K1C hypertensive dogs. Hematocrit also rose during infusion of the highest hANP-(99-126) dose in the normotensive sham dogs (Fig 7⇓), whereas the changes in plasma protein concentrations (−0.03±0.16, +0.20±0.22, and +0.45±0.22 μg/mL, respectively) were not significant because of the variability of the responses. SQ 28603 increased hematocrit when given alone and potentiated the responses to exogenous hANP-(99-126) in the sham dogs. In both the normotensive and hypertensive dogs SQ 28603 sustained the increases in hematocrit throughout the 3-hour study.
The present study is the first to examine the renal and depressor effects of hANP-(99-126) in dogs with long-standing 1K1C hypertension. This is a unique model in that the dogs were hypertensive for several years and had developed proteinuria, an indicator of incipient renal failure. Even though urinary ANP excretion was enhanced in the 1K1C hypertensive dogs, the natriuretic responses to exogenous hANP-(99-126) were attenuated compared with one-kidney sham dogs. Differences in glomerular perfusion pressure were unlikely to explain the diminished renal responsiveness in the 1K1C hypertensive dogs because the depressor responses to hANP-(99-126), and presumably the changes in renal perfusion pressure, were similar in the two groups. Furthermore, hANP-(99-126) did not significantly affect effective renal plasma flow in either the normotensive or hypertensive dogs, indicating that the autoregulatory responses were intact in both groups of dogs. Therefore, the present data suggest that renal handling of ANP is abnormal and the renal guanylate cyclase–linked ANP receptors are downregulated in 1K1C hypertensive dogs.
The present results differ from those of previous studies in which the natriuretic responses to exogenous ANP in conscious2 or anesthetized15 1K1C hypertensive rats were comparable to those stimulated in normotensive control rats. However, our findings resemble the renal resistance reported in normotensive rats with experimental nephrotic syndrome induced by aminonucleosides10 12 or adriamycin.11 Specifically, the increases in sodium excretion10 11 12 and GFR10 stimulated by exogenous ANP were greatly attenuated in rats with severe reductions in GFR and heavy proteinuria. The natriuretic response to a nondepressor dose of ANP was larger in animals with milder renal failure but remained less than that measured in normal rats.12 Therefore, the mild renal dysfunction in our hypertensive dogs may have diminished the renal activity of hANP-(99-126).
The reduced natriuretic activity of hANP-(99-126) in the 1K1C hypertensive dogs is somewhat surprising given the exaggerated urinary ANP responses observed in these animals. In our previous studies in conscious dogs with pacing-induced heart failure in which basal plasma ANP was elevated, SQ 28603 stimulated natriuresis accompanied by significant increases in urinary ANP and cGMP but no change in plasma ANP concentrations.13 16 Therefore, it appeared that the increase in urinary ANP was a predictor of changes in sodium excretion. In the 1K1C hypertensive dogs the reduction of the slope of the line relating urinary ANP excretion to cGMP excretion suggests that the renal resistance to hANP-(99-126) may be in part due to downregulation of the guanylate cyclase–linked receptors, presumably by increased tubular delivery of ANP. This conclusion would be consistent with previous studies showing that the density of ANP renal receptors decreased during long-term infusion of ANP at doses that did not increase plasma peptide concentrations in SHR.17 Furthermore, the decrease in the slope of the relationship between urinary cGMP and sodium excretion in the 1K1C hypertensive dogs indicates a possible defect in the transduction of the cGMP signal. Although the possibilities listed above require additional experimental verification, the present data suggest that changes in renal receptor sensitivity and signal transduction may explain in part the renal resistance in our 1K1C hypertensive dogs with mild renal dysfunction.
The unexpectedly large increases in urinary ANP excretion in the 1K1C hypertensive dogs indicate that under certain pathological conditions renal handling of ANP may be deranged. Under normal conditions the fractional excretion of ANP was less than 1% of the filtered load in the sham and 1K1C hypertensive dogs in the present study, indicating extremely effective elimination of the filtered peptide. Even when the plasma concentrations of the peptide were increased 5- to 10-fold during hANP-(99-126) infusions, calculated fractional excretion of ANP was not increased in the sham dogs and rose from approximately 1% to 3% in the 1K1C hypertensive dogs. Therefore, the renal removal of ANP is highly efficient even during large plasma loads. This process may be mediated by two independent pathways, namely, degradation of ANP by NEP and internalization of the peptide by specific clearance receptors.
NEP appears to play an important role in the renal metabolism of ANP. In the present study SQ 28603 alone increased the calculated fractional ANP excretion from less than 1% to 3% and 13% in the sham and 1K1C hypertensive dogs, respectively. The fact that a greater percentage of the calculated filtered ANP load was protected by an NEP inhibitor in the 1K1C hypertensive dogs at normal plasma levels suggests that the increased ANP excretion cannot be explained by NEP downregulation.
The ANP clearance receptors are located primarily in the glomerulus1 and therefore may limit the amount of ANP available for filtration into the tubules. Downregulation of these receptors in the 1K1C hypertensive dogs could potentially have increased ANP excretion by permitting greater amounts of the peptide to be filtered. Alternatively, the increased glomerular permselectivity that allowed proteinuria in the 1K1C hypertensive dogs may also have enhanced glomerular filtration of ANP. These last two possibilities remain to be examined directly.
Human ANP-(99-126) increased GFR and filtration fraction equally in the sham and 1K1C hypertensive dogs. These findings are consistent with the observation that ANP causes afferent arteriolar dilation and potentiates efferent arteriolar constriction in isolated perfused rat kidneys.18 Because the changes in GFR in the shams were not statistically distinct from the responses in 1K1C hypertensive dogs, the hyporesponsiveness of the latter group cannot be attributed to differences in the renal vascular reactivity. In addition, the natriuretic responses were expressed as fractional sodium excretion, a measurement that is normalized for GFR. Therefore, the weaker natriuretic activity of hANP-(99-126) in the 1K1C hypertensive dogs is most consistent with an abnormality in tubular receptors.
The effects of reduced renal mass were assessed by comparison of the renal and depressor activities of hANP-(99-126) in our one-kidney sham dogs with the responses obtained in normal two-kidney dogs in a previous study.14 The depressor, natriuretic, diuretic, and GFR responses to equimolar doses of hANP-(99-126) were nearly identical in the two models. Therefore, it is unlikely that decreasing total nephron number is sufficient to alter the in vivo activity of exogenous hANP-(99-126).
The increases in plasma ANP during infusion of the exogenous peptide were less in the 1K1C hypertensive than in the sham dogs. This finding may suggest that there was greater systemic clearance or degradation of ANP in the 1K1C hypertensive dogs. Because SQ 28603 negated the differences between the sham and hypertensive dogs during ANP infusion, it is possible that NEP was upregulated. The present data do not allow speculation on the status of the C receptors in the 1K1C dogs, a second route by which ANP may be cleared.
In the present study hANP-(99-126) simultaneously increased both hematocrit and plasma protein concentrations in a reversible fashion. ANP is known to promote the translocation of fluid to the extravascular space by enhancing vascular permeability in normal rats and nephrectomized, splenectomized rats,19 indicating that the response does not depend on the renal excretion of water or the release of red blood cells caused by splenic contraction. The present data showing simultaneous rises are consistent with the proposal that ANP increases movement of fluid from the vascular system to the extravascular space as a consequence of increased capillary permeability.
Human ANP-(99-126) decreased PRA in both sham and 1K1C hypertensive dogs despite low basal levels. A rebound increase in PRA occurred in both groups of dogs when hANP-(99-126) infusions were discontinued. This pattern of inhibition and hyperreninemia is similar to that observed previously in two-kidney normotensive dogs.14 SQ 28603 prolonged the decreases in renin activity caused by hANP-(99-126) and prevented the postinfusion increases in PRA. Therefore, the rebound phenomena may be experienced only when ANP levels are rapidly returned to normal.
As seen in previous studies using related NEP inhibitors in conscious SHR20 and in normal monkeys,21 SQ 28603 significantly potentiated and prolonged the urinary ANP, cGMP, and natriuretic responses to hANP-(99-126) in 1K1C hypertensive dogs. These findings suggest that an NEP inhibitor may overcome the renal resistance to ANP if the levels of the peptide are sufficiently enhanced. Therefore, NEP inhibitors may offer novel therapy for patients with renal failure.
In summary, infusions of 10, 50, and 100 pmol/kg per minute of exogenous hANP-(99-126) increased immunoreactive ANP and its second messenger cGMP in the plasma and urine of conscious dogs with chronic 1K1C hypertension. Exogenous hANP-(99-126) also stimulated dose-related natriuresis, diuresis, and kaliuresis, presumably by increasing glomerular filtration and inhibiting tubular sodium reabsorption. The natriuretic responses in 1K1C hypertensive dogs were less than those measured in sham dogs, indicating decreased renal responsiveness that may be attributed to downregulation of the guanylate cyclase–linked receptors and a possible defect in the transduction of the cGMP signal. In conclusion, the renal activity of hANP-(99-126) is diminished in 1K1C dogs with long-standing hypertension and mild proteinuria.
Selected Abbreviations and Acronyms
|1K1C||=||one-kidney, one clip|
|ANP||=||atrial natriuretic peptide|
|GFR||=||glomerular filtration rate|
|hANP||=||human atrial natriuretic peptide|
|MAP||=||mean arterial pressure|
|NEP||=||neutral endopeptidase (EC 220.127.116.11)|
|PRA||=||plasma renin activity|
|SHR||=||spontaneously hypertensive rat(s)<\/.>|
- Received March 31, 1995.
- Revision received May 10, 1995.
- Accepted June 22, 1995.
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