(Hypertension. 1995;25:1238-1244.)
© 1995 American Heart Association, Inc.
Articles |
Association Between the Natriuretic Action of Angiotensin-(1-7) and Selective Stimulation of Renal Prostaglandin I2 Release
From the Department of Pharmacology, New York Medical College, Valhalla.
Correspondence to Caroline P. Bell-Quilley, PhD, Safety Pharmacology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Rd, PO Box 1539, King of Prussia, PA 19406-0939.
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Abstract |
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Abstract We previously reported that angiotensin-(1-7) [Ang-(1-7)], a heptapeptide derived from the metabolism of either Ang I or Ang II, was biologically active in the rat isolated kidney, producing a marked diuresis and natriuresis that could be dissociated from the modest increase in glomerular filtration rate. The natriuretic response was accompanied by an increase in sodium concentration and concomitant decrease in urinary potassium concentration. Ang-(1-7) has also been shown to stimulate arachidonic acid release from isolated proximal tubules and elicit prostaglandin release from a number of tissues. Therefore, in the present study we tested the hypothesis that prostaglandins participate in the renal actions of Ang-(1-7). Rat isolated kidneys were perfused at 37°C with gassed (95% O2/5% CO2) Krebs-Henseleit buffer containing oncotic agents and amino acids for six 10-minute clearance periods at a constant pressure of 90 mm Hg. Ang-(1-7) was infused at a rate that achieved a final concentration of 3 pmol/mL in the presence and absence of 10 µmol/L indomethacin. Prostaglandin E2 (PGE2) and PGI2 released into ureteral and venous effluents were measured by enzyme-linked immunoassay. During Ang-(1-7) infusion there was a selective increase in 6-keto-PGF1
, an index
of PGI2, appearing in both urine and perfusate;
PGE2 levels were unchanged. Inhibition of stimulated
6-keto-PGF1 release with indomethacin
halved the fourfold increase in urine flow and sevenfold increase in
sodium excretion rate without altering the increase in urinary sodium
concentration produced by Ang-(1-7). In contrast, the increased
potassium excretion rate was unchanged, despite the reduction in urine
flow, as indomethacin abolished the fall in urinary
potassium concentration caused by Ang-(1-7) infusion alone. Thus,
Ang-(1-7) is a specific stimulus for renal PGI2 versus
PGE2 release. This effect may mediate Ang-(1-7)–induced
natriuresis and diuresis and fall in urinary potassium concentration
but does not appear to be involved in the doubling of urinary sodium
concentration. It is possible that these observations have relevance to
the link between prostaglandins and converting enzyme inhibitors in
view of earlier reports that these antihypertensive agents
substantially increase Ang-(1-7).
Key Words: angiotensins • natriuresis • indomethacin • prostaglandins • immunoenzyme techniques • kidney • rats
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Introduction |
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It is becoming increasingly evident that metabolites of the renin-angiotensin system other than angiotensin II (Ang II) are biologically active. In particular, the spectrum of effects of des-[Phe8]Ang II, most commonly known as Ang-(1-7), has provoked special attention, as Ang-(1-7) is a major product of Ang I metabolism by several tissues,1 2 including the proximal tubule brush border.3 Relevant to the latter site of synthesis, we reported that Ang-(1-7) is a potent natriuretic agent in the rat isolated kidney in the absence of an effect on renal vascular resistance.4 This was in contrast to the potent vasoconstrictor action of Ang II over the same dose range. Moreover, the vascular response to Ang II was associated with a natriuresis only at the higher doses. A similar response of the anesthetized rat to renal arterial infusion of Ang-(1-7) has been reported.5
Additional properties of Ang-(1-7) include the ability to stimulate prostaglandin release from human astrocytes,6 glioma cells,7 and rabbit vas deferens8 with a potency similar to that of Ang II. On the other hand, Ang-(1-7) has been shown to be considerably more potent than Ang II in stimulating prostaglandin release from cultured endothelial cells.9 With respect to effects on renal eicosanoids, a recent study showed that Ang-(1-7) was as potent as Ang II as a stimulus for arachidonic acid release by isolated proximal tubule epithelial cells.10 However, no studies have addressed the effect of Ang-(1-7) on prostaglandin release by the intact kidney or have linked the changes in intrarenal prostaglandin release to the functional effects of Ang-(1-7).
It is well established that many of the actions of Ang II involve an eicosanoid component, such as participation of thromboxane A2 and products of the 12-lipoxygenase pathway in renal vasoconstriction.11 12 13 14 Importantly, the stimulation of arachidonic acid release from renal tubular epithelia has been linked to the inhibition of sodium reabsorption by high concentrations of Ang II.15
Based on these considerations we hypothesized that, as for Ang II, the ability of Ang-(1-7) to increase glomerular filtration rate (GFR) and water and electrolyte excretion rates might be mediated by vasodilator, natriuretic prostaglandins. Therefore, in the present study we examined the capacity of Ang-(1-7) to stimulate release of prostaglandin E2 (PGE2) and PGI2 into venous and ureteral effluents of the rat isolated kidney and their possible role in the renal response to Ang-(1-7) through the use of indomethacin to inhibit prostaglandin synthesis. We used the isolated kidney preparation so that we could exclude systemic influences, eg, stimulation of vasopressin release by Ang-(1-7)16 or changes in aldosterone release as a response to changes in extracellular fluid volume. Additionally, we eliminated the possible contribution of prostaglandins arising from extrarenal sources.
Ang-(1-7) increased the release of 6-keto-PGF1,
an index of PGI2 formation, without altering the release of
PGE2. As reported previously,4 Ang-(1-7)
increased the loss of salt and water, in contrast to the stable
excretion rates in the untreated time control group, in which initial
sodium reabsorption exceeded 98.5%. Indomethacin inhibition of
Ang-(1-7) stimulation of 6-keto-PGF1 was accompanied by
attenuation of the increase in water and sodium excretion rates,
whereas indomethacin alone did not alter basal renal
function.
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Methods |
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Male Sprague-Dawley rats weighing 300 to 400 g were anesthetized with pentobarbital (65 mg/kg IP, Butler Co), and 0.4 mL mannitol (10% wt/vol) and 0.1 mL heparin (1000 U/mL, Elkins-Sinn Inc) were injected intravenously. A midline incision was made and the right kidney surgically isolated and perfused with a modified Krebs-Henseleit solution, exactly as described previously,13 via a catheter in the renal artery. Bovine serum albumin (Bovimar CRG7, Intergen Co) and Ficoll 70 (Pharmacia) were used as oncotic agents, and a mixture of 20 amino acids was included to improve the functional characteristics of the kidney. Vitamin B12 was added at a concentration of 50 µg/mL for GFR determinations. Perfusate chloride concentration was adjusted to a normal concentration of 102 mmol/L by substitution of sodium acetate for NaCl. Concentrations of other electrolytes and organic constituents were as described previously.13 Urine was collected from a ureteral catheter, and the venous effluent, collected via a catheter placed in the lower abdominal vena cava, was recirculated through a humidified membrane lung and gassed with 95% O2/5% CO2. Perfusion pressure, monitored by a pressure transducer (Statham P23, Grass Instruments) placed proximal to the renal arterial catheter and recorded on a Grass polygraph, was maintained constant at 90 mm Hg by continual adjustments in perfusate flow rate. At the completion of surgery, rats were killed by a lethal intracardiac injection of KCl, and the kidneys were perfused in situ.
Experimental Protocol
After a 15-minute equilibration period, renal function was
examined during six 10-minute clearance periods. The first was used as
a pretreatment clearance period to establish the viability of the
preparation. Initial sodium reabsorption of less than 98.5% served as
a basis for termination of the experiment. Perfusate flow rate was
determined from collection of the venous outflow over 30 seconds at the
start and end of each period. Urine was collected over the entire
10-minute clearance period and the volume determined gravimetrically.
Aliquots of perfusate and urine were taken for measurement of
electrolytes and vitamin B12 and assays of prostanoids.
Four experimental groups of six to seven kidneys each were studied as follows: time control; 10 µmol/L indomethacin; 3 pmol/mL Ang-(1-7); and Ang-(1-7) plus indomethacin given in combination as for the single treatment groups. Indomethacin was prepared as a concentrated solution of 10 mmol/L dissolved in NaHCO3 (4.2% wt/vol) and added at the beginning of perfusion. Ang-(1-7) was infused from the beginning of the second clearance period. The peptide was dissolved in saline at a concentration of 1.5 mmol/L and administered at a rate of 3 µL/mL per minute according to the perfusate flow rate. NaHCO3 and saline vehicles were administered as appropriate.
Prostaglandin Assays
Prostaglandins were measured in unextracted samples with the use
of second-antibody, solid-phase, enzyme-linked immunoassay (ELISA)
according to Pradelles et al.17 Microtiter plates
(Immunoplate II, NUNC, Laboratory Disposable Products) were coated with
goat anti-rabbit IgG (200 µL per well, Boehringer Mannheim
Biochemicals) at a concentration of 10 µg/mL, diluted with 50 mmol/L
potassium phosphate buffer, pH 7.4. After an overnight incubation at
4°C, plates were washed three times with successive 300-µL volumes
of wash buffer composed of 0.05% Tween 20 in 10 mmol/L potassium
phosphate buffer, pH 7.4. Plates were then filled with enzyme
immunoassay buffer of the following composition: 0.1 mol/L potassium
buffer, 0.4 mmol/L NaCl, 85 mmol/L Na4EDTA, 0.01% wt/vol
NaN3, and 0.1% wt/vol bovine serum albumin. Plates
were then covered with microtest plastic film (Fisher) and stored at
4°C for a minimum of 18 hours before their use in the competitive
binding step. Coated plates could be stored in this manner for several
weeks. After buffer removal, 50-µL aliquots of enzymatic tracer,
antibody, and either prostaglandin standard (4 to 2000 pg/mL) or
samples, diluted as appropriate with buffer, were placed in duplicate
in the coated wells. Nonspecific binding was determined by replacement
of antibody with buffer and maximal binding by equilibration in the
absence of prostanoids. After overnight equilibration at 4°C, plates
were washed three times with 300 µL enzyme immunoassay buffer. Wells
were filled with 200 µL Ellman's reagent. The concentrated Ellman's
stock solution [69.16 mmol/L acetylthiocholine iodide and 54.24 mmol/L
5,5'-dithiobis(2-nitrobenzoic acid) in phosphate buffer] was stored at
-20°C and diluted 1:100 as required. After 1 to 2 hours of shaking,
absorbance was read at 405 nm with automated subtraction of readings at
630 nm to correct for nonspecific absorbance (Microplate EL309, Biotek
Instruments). Microtitration and washing steps were carried out with an
automatic dispenser (Pro/Pette, Perkin-Elmer). Curve fitting was done
with computerized mass action smoothed spline interpolation (Packard
Instrument Co), and sample prostaglandin concentrations were
automatically calculated by reference to the standard curve. The
validity of application of ELISA for assay of perfusate and urine
samples was established as described previously for radioimmunoassay of
rat urine.18 Limits of sensitivity were 7.8 pg/mL for both
prostanoids, this being the lowest standard for percent binding of
maximum bound (B/Bo) less than 90%.
Determination of Electrolytes and Vitamin B12 and
Calculations
Perfusion pressure and perfusate flow rate for each period were
calculated as the mean of measurements made at the beginning and end of
each period. Renal vascular resistance was calculated as the ratio of
perfusion pressure to perfusate flow rate. GFR was calculated from
colorimetric measurements of the vitamin B12 concentration
in perfusate and urine.19 Vitamin B12
absorbance of samples, diluted as appropriate into 96-microwell plates,
was measured at 550 nm, with subtraction of the blank at 630 nm, with
the use of the spectrophotometric plate reader. GFR was determined from
the product of urine flow and vitamin B12 concentration
divided by the perfusate vitamin B12 concentration.
Perfusate and urinary electrolytes were measured with an automatic
electrolyte analyzer (model 644, Ciba Corning). Electrolyte excretion
rate was the product of urine flow and electrolyte concentration.
Fractional excretion of water and electrolytes was calculated by
dividing the absolute excretion by the filtered load. Urinary
prostaglandin excretion rates were determined by multiplying
prostaglandin concentration by urine flow.
Statistical Analyses
Differences between groups were assessed by one-way ANOVA
conducted with the SAS/PC computer program (SAS Instruments). When the
F value indicated overall significance, specific comparisons were made
with the least significant difference test using an adjusted value
of 0.01, as only half the possible comparisons were of interest. A
value of P<.05 was considered statistically
significant.20
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Results |
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Urinary and Venous Prostaglandin Release
Table 1 gives the time course of changes in 6-keto-PGF1
and PGE2 in urine. Compared with
the time control, Ang-(1-7) infusion produced a considerably greater
increase in 6-keto-PGF1 excretion during the 60 minutes
of perfusion that, by the last clearance period, was more than
threefold the modest time-dependent increase in the control group
(Table 1). Indomethacin was highly effective in inhibiting this
Ang-(1-7)–stimulated 6-keto-PGF1 excretion. However,
the basal excretion of 6-keto-PGF1 was resistant to
indomethacin inhibition. PGE2 excretion
also increased as a function of time of perfusion. However, in contrast
to the stimulatory effect on
6-keto-PGF1, PGE2
excretion in kidneys infused with Ang-(1-7) was identical to that in
control, irrespective of the time point examined (Table 1).
Indomethacin substantially inhibited PGE2 excretion in both
vehicle control and Ang-(1-7) groups.
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In the venous compartment, 6-keto-PGF1 levels were below
the limits of detection before the 40-minute time point. Thereafter,
6-keto-PGF1 concentrations were higher in the
Ang-(1-7)–infused kidneys (Table 1) compared with control.
Indomethacin reduced 6-keto-PGF1 concentrations to below
the limits of detection throughout. Once again, in contrast to the
increase in 6-keto-PGF1, the venous levels of
PGE2 (Table 1) were not affected by Ang-(1-7) but were
inhibited by indomethacin. Thus, Ang-(1-7) produced a
selective increase in PGI2 in both vascular and tubular
compartments that was sensitive to inhibition by
indomethacin.
Renal Vascular Resistance, Perfusate Flow Rate, and GFR
There were no significant differences between the four treatment
groups for renal vascular resistance and renal perfusate flow, which
ranged between 2.3 and 2.8 mm Hg/(mL/min) and 30 and 39 mL/min,
respectively, throughout the course of perfusion. However, Ang-(1-7)
did cause a modest increase in GFR that was significantly different
from the control group for the last two clearance periods and showed
borderline significance (P<.08) for the other three
Ang-(1-7) infusion clearance periods (Table 2). GFR also
tended to be higher for the Ang-(1-7) plus indomethacin
group compared with the respective indomethacin
control group, but this effect did not reach statistical significance.
Indomethacin alone at this normal chloride concentration did not
influence GFR.
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Water and Electrolyte Excretion Rates
During the 60 minutes of perfusion in the control group, there was
a modest time-dependent increase in sodium and water excretion rates,
whereas potassium excretion declined slightly (Figure).
Ang-(1-7) caused an immediate increase in water and sodium excretion
rates that increased further to more than fourfold and sevenfold the
pretreatment levels, respectively. The potassium excretion rate was
less affected, as it increased only twofold. Although
indomethacin alone did not affect basal water and
electrolyte excretion rates, its ability to inhibit Ang-(1-7)
stimulation of PGI2 release was accompanied by a reversal
of the increased excretion of water and sodium (Figure). In contrast,
indomethacin did not change the Ang-(1-7) stimulation
of potassium excretion rate (Figure).
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P<.05
between angiotensin-(1-7) groups.Ang-(1-7) had opposite effects on urinary electrolyte concentrations, as sodium concentration doubled and potassium concentration was halved by the last clearance period (Table 3). Indomethacin did not alter this increase in sodium concentration. In contrast, indomethacin prevented the fall in potassium concentration produced by Ang-(1-7) (Table 3).
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As Ang-(1-7) had a positive effect on GFR, we also evaluated the data in terms of fractional excretion rates to discern those effects primarily attributable to a tubular site of action. Essentially the same results were obtained irrespective of whether the results were expressed in absolute or fractional terms. Ang-(1-7) infusion significantly increased fractional water and electrolyte excretion rates, and indomethacin attenuated these effects (Table 4). Thus, the diuretic and natriuretic effects of Ang-(1-7) and their modification by indomethacin appear to result primarily from a tubular site of action as opposed to an effect on filtered load.
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Discussion |
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The renal functional responses of the rat isolated kidney to Ang-(1-7) were accompanied by increases in the release of 6-keto-PGF1
, and only
6-keto-PGF1, an index of PGI2,
into both ureteral and venous compartments. Indomethacin inhibition of
this enhanced PGI2 release was associated with a diminution
of the natriuretic and diuretic actions of the heptapeptide and
prevention of the fall in urinary potassium concentration. Thus, the
results of this study support our original hypothesis that the renal
actions of Ang-(1-7) depend, at least in part, on prostaglandins. This
is consistent with evidence that the depressor effect of Ang-(1-7) in
the pithed rat also has a prostaglandin-dependent
component.21 In addition, the
indomethacin-sensitive effects of Ang-(1-7) in the
kidney may be specifically mediated by a selective increase in the
release of PGI2. However, the absence of a significant
effect of indomethacin on the ability of Ang-(1-7) to
increase urinary sodium concentration or GFR indicates that these two
effects are independent of an increase in cyclooxygenase-derived
arachidonic acid metabolites. With respect to the vascular compartment, Ang-(1-7) did not affect renal vascular resistance. However, infusion of the kidney with Ang-(1-7) was not entirely devoid of hemodynamic consequences, as GFR increased. Although this effect was modest, it was consistent with the small increases in GFR described earlier,4 which we suggested were indicative of an effect on microvascular resistances or mesangial cell contraction, as renal perfusate flow was not affected by Ang-(1-7). The ability of Ang-(1-7) to increase PGI2 could explain this effect in view of its potency as an agent that causes relaxation of vascular smooth muscle and the mesangium.22 23 24 However, when the increased PGI2 was blocked by indomethacin, the Ang-(1-7)–induced increase in GFR was not markedly affected, suggesting that PGI2 may not be solely responsible for the ability of Ang-(1-7) to slightly increase GFR.
In contrast to its modest vascular action, Ang-(1-7) had substantial effects on water and electrolyte excretion rates. These diuretic and natriuretic responses of the rat isolated kidney were consistent with our earlier observations4 and with the recent report that Ang-(1-7) is also natriuretic when infused into the renal artery of the rat.5 On the other hand, intraperitoneal injection of Ang-(1-7) in water-loaded rats was shown to be antinatriuretic and antidiuretic.25 Whether Ang-(1-7) administered by this route escapes metabolism before reaching the kidney is uncertain given the rapidity with which peptides are broken down. Moreover, although there is no direct evidence, it is possible that the reduction in excretion rates after intraperitoneal administration reflects direct effects of Ang-(1-7) on the gastrointestinal tract, as angiotensin receptors are abundant at this visceral site, and their stimulation affects electrolyte transport.26
Indomethacin effectively reduced Ang-(1-7)–stimulated increases in PGI2. However, basal PGI2 excretion was not affected despite the fact that indomethacin inhibited basal levels of PGE2. Previously, Terragno et al27 showed that the susceptibility of PGE2 to inhibition by indomethacin depended on the experimental conditions. The results of the present study provide an example of differences in the sensitivity of basal release of specific prostaglandins to indomethacin. It is well established that different tissues exhibit differential sensitivity to inhibitors of cyclooxygenase,28 and recent studies have described cyclooxygenase isozymes that vary in their susceptibility to blockade by indomethacin.29 30 These differential sensitivities, coupled with the multiple cell types in the kidney and compartmentalization of synthesis of individual prostaglandins,31 provide a possible explanation for the resistance of basal PGI2 release to indomethacin. Pharmacokinetic influences on the accessibility of indomethacin to discrete intrarenal sites of PGI2 release32 may also be important.
The absence of any functional effect of indomethacin given alone is consistent with our recent observation that the renal response to indomethacin depends on chloride concentration33 such that opposite effects are observed at high and low concentrations of the anion. For example, during perfusion with high chloride, a marked natriuresis is observed, whereas at low chloride concentrations, indomethacin is antinatriuretic. At the normal concentration of chloride used in the present study, the opposing responses to indomethacin would be expected to result in no overall change in renal function.
The magnitude of the increases in excretion rates suggests that multiple sites are involved in the action of Ang-(1-7). The large increases in PGI2 that accompanied the increases in sodium and water excretion rates support an involvement of this prostanoid in this tubular response, a possibility that is further supported by the observation that PGI2 inhibition was associated with a considerable reduction in salt and water excretion without significant changes in GFR, pointing to a tubular site of action. Notwithstanding the evidence for the participation of PGI2, the incomplete reversal of the effect of Ang-(1-7) by indomethacin, despite the return of PGI2 to basal levels, lends support to the involvement of additional mechanisms. Moreover, the observation that indomethacin reversed the fall in potassium concentration, without affecting Ang-(1-7)–induced increases in urinary sodium concentration, is further evidence for multiple sites of action involving multiple mechanisms. These may include Ang-(1-7) stimulation of endothelium-derived relaxing factor,34 which is natriuretic in the isolated kidney,35 or enhanced release of cytochrome P-450–dependent metabolites of arachidonic acid in the proximal tubule. Ang-(1-7) is equipotent to Ang II as a stimulus for arachidonic acid release by isolated proximal epithelial cells, and Ang II inhibition of sodium transport at this site has been associated with stimulation of epoxide metabolites.10
The association between the stimulation of excretion and an increase in PGI2 is consistent with earlier reports demonstrating that PGI2 infusion into the renal artery of the dog, at a concentration that was devoid of an effect on GFR, was natriuretic and diuretic.36 On the other hand, PGE2 had a greater natriuretic potency than PGI2 at concentrations producing a renal vasodilator response.22 24 It has been suggested that increases in prostaglandin excretion simply reflect a flow-dependent stimulation of prostaglandin release.37 38 39 However, this seems an unlikely explanation for the increase in PGI2 for two reasons. First, the effect of Ang-(1-7) was selective for PGI2. Second, the tubular actions of Ang-(1-7) were blunted by cyclooxygenase inhibition, supporting the idea that increased release of PGI2 is a prerequisite for the enhanced water and electrolyte excretion rates. On the other hand, the mechanism for the increased urinary sodium concentration can be separated from an increase in PGI2, as indomethacin was without effect. In this regard, a mineralocorticoid effect cannot account for the reciprocal changes in urinary concentrations of potassium and sodium produced by Ang-(1-7), as aldosterone is not present in the isolated kidney preparation. In fact, this study clearly demonstrates that the fall in potassium concentration and increase in sodium concentration are dissociated events, the former being linked to a cyclooxygenase-dependent mechanism.
The lack of effect of Ang-(1-7) on PGE2 was unexpected in view of both the diuretic and natriuretic activities of PGE222 37 and the frequent association between increased flow rate and enhanced PGE2 excretion.38 39 However, a number of studies do not support a relationship between urine flow rate and renal PGE2 production.40 41 The results of the present study provide yet another example.
Considering the possible intrarenal sites at which increased PGI2 mediates the renal responses to the heptapeptide, it has been shown that Ang-(1-7) inhibits sodium transport and is a potent stimulus for arachidonic acid release by proximal tubule epithelial cells via activation of phospholipase A2.10 The magnitude of the natriuretic effect of Ang-(1-7) also points to a proximal site of action. However, an examination of the distribution of cyclooxygenase along the nephron with the use of immunohistochemical localization techniques has shown that the enzyme levels in proximal tissue are extremely low.42 43 Accordingly, the capacity of this nephron segment to generate prostaglandins is minimal. It therefore seems unlikely that the increase in PGI2 or the indomethacin-sensitive natriuresis results from an effect of Ang-(1-7) at a proximal tubular site. On the other hand, the collecting duct has a high prostaglandin synthesizing capacity, and PGI2 inhibits sodium reabsorption at this site.44 45 In this instance, this effect cannot be attributed to antagonism of antidiuretic hormone by PGI2,44 which is absent in the isolated kidney, and may be due to a direct effect of PGI2, as has been shown in studies with isolated collecting tubule preparations.45 However, in proportion to the entire nephron, the contribution of the collecting tubule to salt and water reabsorption is small. It is likely, therefore, that additional cyclooxygenase-mediated effects of intrarenally generated PGI2 are involved, such as redistribution of intrarenal blood flow and associated changes in peritubular pressures leading to decreases in reabsorption.
This is the first evidence that Ang-(1-7) affects renal prostaglandin
release, in contrast to an earlier study with cultured rabbit
renomedullary interstitial cells in which Ang-(1-7) had no
effect.46 This increased PGI2 release is
consistent with previous work showing that Ang-(1-7) elicits
prostaglandin release from a variety of other cell types, including
vascular smooth muscle47 and endothelial9
cells. However, PGI2 stimulation alone is peculiar to the
whole kidney, as these previous studies demonstrated that Ang-(1-7)
also increased PGE2. This selective increase in
PGI2 also distinguishes the effect of Ang-(1-7) on renal
prostaglandin synthesis from the reported effect of Ang II. Thus, Ang
II is a potent stimulus of PGE2 and thromboxane
B2 as well as 6-keto-PGF1 in both in vitro
and in vivo kidney preparations from several
species.11 12 14 Possible mechanisms for the selective
action of Ang-(1-7) include stimulation of renal cells that
preferentially generate PGI2; redirection of endoperoxide
to PGI2 synthesis as a result of diminished release of
12-hydroperoxyeicosatetraenoic acid, which has been shown to inhibit
prostacyclin synthetase48 ; or activation of an angiotensin
receptor specifically linked to prostacyclin synthase. With regard to
the latter, Ang-(1-7) stimulation of prostaglandin release from
endothelial cells shows differential sensitivity to angiotensin type 1
and type 2 receptor antagonists.9 47 Within the kidney,
there is evidence for angiotensin receptor
heterogeneity linked to different intracellular
messengers and differences in Ang II versus Ang-(1-7)
binding.49 This ability of Ang-(1-7) to selectively affect
PGI2 release provides a unique example of specific
regulation of renal PGI2 release as well as a paradigm in
which the responses to increases in PGI2 intrarenally are
manifest, as opposed to those experimental designs in which
PGI2 is infused into the renal artery, often with attendant
renal vasodilator effects.
In conclusion, the potent natriuretic action of Ang-(1-7) can be linked to selective stimulation of renal PGI2 release into both vascular and tubular compartments. As this heptapeptide metabolite of Ang I and Ang II is substantially increased by inhibitors of converting enzyme,50 it is possible that a selective increase in PGI2 as a result of increased Ang-(1-7) formation may have importance for the mechanisms underlying the action of these antihypertensive drugs.
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Acknowledgments |
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This work was supported by American Heart Association grants 91-014G and 94-318 and National Institutes of Health research grant RO1-HL-25394. We thank Dr M. Khosla for generous supplies of Arg-(1-7) and Dr J.C. McGiff for his helpful comments on the manuscript.
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Footnotes |
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This work was presented in preliminary form at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8-11, 1993.
Received September 23, 1994; first decision November 9, 1994; accepted February 16, 1995.
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