Unité Mixte de Recherche 5014, Centre National de la Recherche Scientifique, Institut Fédératif de Recherche Cardio-vasculaire 39, Faculté de Pharmacie, 69373 Lyon cedex 08, France
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ABSTRACT |
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The present study evaluated the acute
effects of ANG II (5-480 ng/kg iv) and phenylephrine (PE;
0.2-146 µg/kg iv) on total renal (RBF) and medullary blood flow
(MBF) in anesthetized Lyon hypertensive (LH) and low-blood-pressure
(LL) rats. ANG II and PE induced dose-dependent decreases in both RBF
and MBF, which were greater in LH than in LL rats. Interestingly, after
ANG II, but not after PE, the initial medullary vasoconstriction was
followed by a long-lasting and dose-dependent vasodilation that was
significantly blunted in LH compared with LL rats. The mechanisms of
the MBF effects of ANG II were studied in LL rats only. Blockade of
AT1 receptors with losartan (10 mg/kg) abolished all the
effects of ANG II, whereas AT2 receptor blockade with
PD-123319 (50 µg · kg1 · min
1
iv) did not change these effects. Indomethacin (5 mg/kg) decreased by
~90% the medullary vasodilation induced by the lowest doses of ANG
II (from 15 ng/kg). In contrast,
NG-nitro-L-arginine methyl ester (10 mg/kg and 0.1 mg · kg
1 · min
1
iv) and the bradykinin B2-receptor antagonist HOE-140 (20 µg/kg and 10 µg · kg
1 · min
1
iv) markedly lowered the medullary vasodilation at the highest doses of
ANG II only. In conclusion, this study shows that LH rats exhibit an
altered MBF response to ANG II compared with LL rats and indicates that
the AT1 receptor-mediated medullary vasodilator response to
low doses of ANG II is mainly due to the release of PGs, whereas the
dilator response to high doses of ANG II has additional nitric oxide-
and kinin-dependent components.
renin-angiotensin system; renal hemodynamics; hypertension; angiotensin II receptors, laser-Doppler flowmetry
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INTRODUCTION |
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RENAL MEDULLARY BLOOD FLOW (MBF) is thought to play an important role in maintaining body fluid homeostasis and in the long-term control of blood pressure (BP) by modulating the pressure-natriuresis relationship (4, 33). Interestingly, MBF has been shown to be sensitive to most of the vasoactive agents, but its response may differ from that of cortical blood flow (10, 25), thus suggesting that its regulation might be specific and independent of that of cortical blood flow.
It is well demonstrated that ANG II decreases cortical blood flow, enhances tubular sodium reabsorption, and shifts the pressure-natriuresis relationship toward a higher BP (21). However, its effects on MBF remain unclear. Indeed, a number of studies have demonstrated that the medullary vasculature was poorly sensitive to the vasoconstrictor effects of ANG II compared with the cortical circulation (5, 11, 21, 22). However, Pallone (28) has shown that ANG II induced a potent vasoconstriction of isolated medullary vasa recta in Sprague-Dawley rats, a response also observed in conscious rats (18). Conversely, other investigators have reported that the systemic infusion of ANG II increased papillary blood flow in young Sprague-Dawley and Wistar rats (25, 37) by increasing local medullary synthesis of vasodilator agents such as PGs, nitric oxide (NO), or kinins. Indeed, it has been shown that an inhibition of PG synthesis allowed ANG II to decrease papillary blood flow (30) and that the increase in papillary blood flow caused by ANG II was greatly dependent on the production of NO (27, 37). This was confirmed by Zou et al. (40), who demonstrated that ANG II increased the medullary release of NO. The involvement of kinins was raised by the findings that renal kinins increased papillary blood flow (25) through NO release (20).
Lyon hypertensive rats (LH) exhibit exaggerated renal vasoconstriction and blunted pressure-natriuresis (14) associated with enhanced MBF autoregulation in response to increases in renal perfusion pressure (34). Because their hypertension is fully dependent on an active renin-angiotensin system (12) and because their renal hemodynamics and tubular sodium reabsorption are hypersensitive to ANG II (16), we hypothesized that the MBF of LH rats could be hypersensitive to the effects of ANG II.
To test this hypothesis, MBF responses to graded doses of ANG II were studied in LH rats and compared with the MBF responses of their low-blood-pressure (LL) controls. In addition, we examined the possible mechanisms involved in the increase in MBF caused by ANG II. For that purpose, the specificity of the response was evaluated by comparing the MBF response after ANG II to that of another vasoconstrictor, phenylephrine (PE). The role of ANG II subtype 1 (AT1) and subtype 2 (AT2) receptors in this response was determined using specific antagonists. Finally, the effect of ANG II was evaluated after inhibition of PG synthesis by indomethacin, inhibition of NO production by NG-nitro-L-arginine methyl ester (L-NAME), and after bradykinin B2 receptor blockade by HOE-140.
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MATERIALS AND METHODS |
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Animals
Fifteen-week-old male LH and LL rats were used. Animals were housed in controlled conditions (temperature, 21 ± 1°C; humidity, 60 ± 10%; 8:20-h light-dark cycle). They were fed a standard diet (Elevage, Villemoisson-sur-orge, France) containing 0.3% sodium and tap water ad libitum. Studies were conducted in agreement with our institutional guidelines for animal care.Surgical Preparation
On the day of the experiment, the rats were anesthetized with inactin (thiobutabarbital, 75 mg/kg body wt ip, Research Biochemicals, Natick, MA) and ketamine (25 mg/kg body wt ip, Merial, Lyon, France) and placed on a heating blanket (model 50-6980, Harvard Apparatus, Edinbrige, KY) to maintain the rectal temperature at 37 ± 0.5°C. A tracheotomy was performed to facilitate breathing. The left jugular and the two femoral veins were cannulated for bolus injections and infusions, respectively. The left carotid artery was cannulated to record the mean BP through a pressure transducer (model P23ID, Statham Instrument Division, Gould, Cleveland, OH). To replace fluids lost during surgery, a 5% bovine albumin (fraction V, Sigma, St. Louis, MO) in 0.9% NaCl solution was infused for 30 min at a rate of 33 µl · 100 g body wtAt the end of the experiment, the left kidney was removed, decapsulated, blotted dry, and weighed. The position of the laser probe into the medulla was checked macroscopically after injection of methylene blue in the hole made by the flow probe. RBF was normalized per gram of the kidney weight. Renal vascular resistance (RVR) was calculated as the ratio of mean BP to RBF. The values of MBF were expressed as arbitrary perfusion units (PU).
Experimental Protocols
Effects of ANG II and PE in control animals. After surgical preparation, 60 min were allowed for stabilization. Baseline values of mean BP, RBF, and MBF were recorded during the last 5 min of stabilization in LH (n = 13) and LL (n = 13) rats. Then, the animals were randomly distributed in two groups receiving either intravenous bolus injections of ANG II (Sigma) at doses of 5, 15, 30, 60, 120, 240, and 480 ng/kg [LH (n = 6) and LL (n = 7)] or intravenous bolus injections of PE (Sigma) at doses of 0.2, 0.6, 1.8, 5.4, 16.2, 48.6, and 145.8 µg/kg [LH (n = 7) and LL (n = 6)]. Consecutive administrations of ANG II or PE were separated by a period of 10 min to allow a full recovery of hemodynamic variables.
Effects of AT1 or AT2 receptor blockade
in LL rats.
Twenty-five minutes after surgical preparation, baseline values of mean
BP, RBF, and MBF were recorded for 5 min. Then, losartan (DuPont Merck
Pharmaceutical, Wilmington, DE), an AT1-receptor antagonist, was injected intravenously at the dose of 10 mg/kg in LL
rats (n = 7). In another group of LL rats (n =
8), PD-123319 (Sigma), a specific AT2-receptor antagonist,
was infused intravenously at the dose of 50 µg · kg1 · min
1
during the experiment. Twenty-five minutes after administration of
these antagonists, the above hemodynamic parameters were recorded once
again for 5 min, and then the injections of ANG II (5-480 ng/kg)
were performed as described above.
Effects of PGs, NO, or kinin blockade in LL rats.
This experiment was performed in three groups of LL rats.
Twenty-five minutes after surgical preparation, baseline values of mean
BP, RBF, and MBF were recorded for 5 min. Then, the rats received an
intravenous injection of indomethacin (Sigma) at a dose of 5 mg/kg
(n = 7), L-NAME at a dose of 10 mg/kg followed by an intravenous infusion at the rate of 0.1 mg · kg1 · min
1
(n = 7), or HOE-140 (Sigma) at a dose of 20 µg/kg
followed by an intravenous infusion at the rate of 10 µg · kg
1 · min
1
(n = 8). In each group, 25 min after pretreatment, mean BP,
RBF, and MBF were recorded once again for 5 min, and then the
injections of ANG II (5-480 ng/kg) were performed as described above.
Statistical Analysis
Values are means ± SE. The between-strain differences reported in Table 1 were analyzed using Student's t-test for unpaired data. The between-strain differences in the dose-response curves of ANG II and PE were analyzed using a two-way analysis of variance followed by a Fisher multiple-range test. The dose-related effects of ANG II and PE within groups and the effects of treatment were analyzed using one-way analysis of variance. A difference was considered to be statistically significant at P < 0.05.
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RESULTS |
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Effects of ANG II and PE in Control Animals
As shown in Table 1, LH rats differed from LL rats by a higher mean BP and a decreased RBF, leading to elevated RVR; baseline MBF did not differ between LH and LL rats.Typical recordings of mean BP, RBF, and MBF in response to the four
highest doses of ANG II and PE in one LL and one LH rat are depicted in
Figs. 1 and
2, respectively. In LH and LL rats, both drugs increased mean BP and decreased RBF. Interestingly, ANG II,
but not PE, elicited a biphasic response in MBF (Figs. 1 and
3A). In LL rats, the initial
rapid and short lasting (<1 min) decrease (vasoconstrictor component)
was followed by a marked and long-lasting (>2 min) increase
(vasodilator component). In LH rats, the decrease in MBF was more
pronounced than in LL controls, whereas the delayed
vasodilation was significantly blunted over the range of ANG II doses
(Figs. 1 and 3A).
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As shown in Fig. 3A, mean BP responses to the lowest doses
(5-30 ng/kg) of ANG II were significantly higher
(P < 0.05) in LH than in LL rats. RBF dose dependently
decreased after ANG II injections in both strains, and this decrease
was significantly greater (P < 0.001) in LH than in LL
rats (until the dose of 120 ng/kg). Finally, over the entire range of
ANG II doses and in both strains, the decreases in MBF were less marked
than those in RBF (8 ± 1% for MBF and
20 ± 2% for RBF
in LL rats;
17 ± 2% for MBF and
35 ± 5% for RBF in LH
rats for the ANG II dose of 30 ng/kg).
As shown in Fig. 3B, PE elicited similar mean BP and RBF responses to those for ANG II. RBF decreased nearly to zero flow with the highest doses, which is not meaningful. Concerning MBF, the decrease was more marked in LH than in LL rats. In contrast, no delayed vasodilation was observed after PE in both LL and LH rats (Figs. 2 and 3B).
Effects of AT1 or AT2 Receptor Blockade in LL Rats
As shown in Table 2, losartan significantly decreased mean BP and increased RBF in LL rats. Treatment with PD-123319 did not significantly modify mean BP or RBF. Finally, neither losartan nor PD-123319 altered baseline MBF.
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AT1 blockade by losartan abolished the effects of ANG II on
mean BP, RBF, and the vasoconstrictor and vasodilator components of the
MBF response in LL rats (Fig. 4). In
contrast, the hemodynamic responses to ANG II remained unchanged after
blockade of AT2 receptors by PD-123319 (Fig. 4).
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Effects of PGs, NO, or Kinin Blockade in LL Rats
As shown in Table 2, indomethacin did not significantly modify mean BP and RBF but significantly decreased baseline MBF. In response to subsequent administrations of ANG II, the decrease in RBF did not significantly differ between indomethacin-pretreated and control LL rats (Fig. 5). Interestingly, from the lowest ANG II dose (15 ng/kg), indomethacin significantly enhanced the ANG II-induced dose-dependant decrease in MBF (P < 0.001) and markedly attenuated (P < 0.001) the increase in MBF by ~90% (Fig. 5).
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L-NAME administration significantly increased baseline mean BP and decreased RBF and MBF (Table 2). The decrease in RBF elicited by increasing doses of ANG II was blunted and rapidly reached a maximal level in L-NAME-pretreated animals compared with controls (Fig. 5). The ANG II-induced medullary vasoconstriction (from 15 ng/kg) was significantly enhanced (P < 0.001) by L-NAME, whereas medullary vasodilation was lowered by ~80% only for the highest doses of ANG II (Fig. 5).
Treatment with HOE-140 had no effect on baseline values of mean BP, RBF, and MBF (Table 2). The decreases in RBF and MBF (Fig. 5) induced by ANG II were significantly enhanced by HOE-140 treatment (P < 0.001 for both parameters). Finally, HOE-140 attenuated the medullary vasodilation (by ~40%) for the highest doses of ANG II only (Fig. 5).
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DISCUSSION |
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The major findings of the present work are that 1) ANG II injection induces a dose-dependent biphasic MBF response characterized by a rapid decrease followed by a durable increase; this response is specific to ANG II, as it is not seen after PE; 2) in response to ANG II, LH rats exhibit an increased medullary vasoconstriction and a blunted medullary vasodilation compared with LL rats; 3) both the ANG II-induced medullary vasoconstriction and vasodilation are mediated by AT1 receptors; and 4) the medullary vasodilation is mainly due to a release of PGs and NO.
The importance of MBF in the long-term control of BP has been demonstrated by experiments showing that a primary reduction in MBF allowed the development of hypertension (24), whereas an increase in MBF can lower hypertension (17). Previous studies suggested that LH rats are prone to retain sodium, because their pressure-natriuresis is blunted (14) and they are salt sensitive (8). The mechanisms involved in this sodium retention are unknown but may involve altered MBF regulation (34). Because hypertension in LH rats is dependent on an active renin-angiotensin system (12), we examined the response of MBF to ANG II in LH compared with LL rats. For that purpose, MBF was measured using a laser-Doppler flow probe as previously described (34).
In LL rats, ANG II induced a brief decrease in MBF that was less marked than that for total RBF. This result is in good agreement with the experiments showing that, in normotensive rats, MBF is less sensitive to the vasoconstrictor effect of ANG II than the cortical circulation (5, 6, 11, 21). This initial response was followed by a marked and long-lasting vasodilation, thus leading to a biphasic response that does not appear related to the manner in which ANG II was administered. Indeed, 1) MBF did not change after injection of an equivalent volume of saline; 2) the responses to ANG II were dose dependent, although the increasing bolus doses of ANG II were injected at a constant volume; and 3) in rats pretreated with losartan, ANG II, given in the same manner to untreated rats, did not modify MBF. In addition, although such a biphasic response to ANG II is at variance with studies demonstrating that ANG II infusion induces only medullary vasodilation (2, 25, 37), a similar response to ANG II injection was recently reported by Rajapakse et al. (31) in anesthetized rabbits. Interestingly, the long-lasting and dose-dependent increase in MBF induced by ANG II was not observed with PE, despite a similar systemic and renal vasoconstriction. Although the arterial pressure was not controlled in our study, the ANG II-induced increase in MBF has been shown to occur even if the increase in arterial pressure was prevented by an aortic clamp (2, 25). Taken together, these observations show that the biphasic MBF response is specific to ANG II and demonstrate that the increase in MBF induced by ANG II is not related to an increase in renal perfusion pressure. It has been shown that ANG II, but not PE, is able to increase Ca2+-dependent NO synthase activity in renal medulla (23). This observation presumably explains why PE did not induce renal medullary vasodilation as did ANG II in LL rats.
No baseline differences in MBF could be observed between LH and LL rats. In contrast, MBF responses to ANG II differed between the two strains. LH rats exhibited a more marked decrease in MBF. These results are in accordance with previous studies demonstrating that the medullary circulation of the spontaneously hypertensive rat (SHR) is more sensitive to the vasoconstrictor effect of ANG II compared with that of normotensive Wistar-Kyoto rats (6). Similar results have been also observed in Dahl salt-sensitive rats (36). The increased medullary sensitivity to ANG II seen in these hypertensive rats was partly explained by a deficit in NO (13, 36). However, our results differ from those observed in spontaneously hypertensive and Wistar-Kyoto rats in which a medullary vasodilation was not observed after the vasoconstriction induced by ANG II (6). LH rats also differed from LL rats by a blunted increase in MBF after ANG II. The contribution of this abnormality to the hypertension of LH rats remains to be clarified. However, it might be of pathophysiological importance, because 1) the blunted medullary vasodilation favors the vasoconstrictor and antinatriuretic effects of ANG II within the kidney and thus may contribute to the ANG II-induced decrease in sodium excretion; and 2) in LH rats, the decreased renal sodium excretion was found to be sensitive to ANG II (16).
The nature of the receptor subtypes and the mechanisms involved in ANG II-induced MBF response were examined in LL rats only because these animals exhibit marked vasodilation. It is evident that the mechanisms involved in LL rats could differ from those in LH rats. Most of the biological actions of ANG II are known to be mediated through AT1 receptors. However, recent evidence suggests that AT2 receptors may be important in the regulation of BP and renal function by counterbalancing the vasoconstrictor and antinatriuretic actions of AT1 receptors (3). The role of AT1 receptors was examined using their specific antagonist losartan at the dose usually used (38). We observed that losartan not only suppressed the ANG II-induced medullary vasoconstriction but also the secondary vasodilation, thus demonstrating that the increase in MBF is AT1 receptor mediated. Moreover, this response is likely related to a secondary release of vasodilators, because 1) it occurred subsequent to and durably after ANG II administration; 2) AT1 receptors are localized not only in renal cortical vasculature but also in the vasa recta of the outer and inner medulla (1, 39); and 3) the activation of AT1 receptors increases the release of local vasodilators (23, 35). The role of AT2 receptors in ANG II effects was examined using PD-123319 infused at a dose demonstrated to be highly specific for AT2 receptors (15, 19). The lack of influence of PD-123319 on the systemic and renal effects of ANG II showed that the involvement of AT2 receptors was negligible in our experimental conditions. Similar results have been recently reported by Badzynska et al. (2) in normotensive rats, in which no change in ANG II-induced cortical and MBF was observed after treatment with PD-123319.
In the present work, only baseline MBF decreased markedly after treatment with indomethacin. The effect of endogenous PGs on medullary blood perfusion was also observed by other investigators (25, 26, 32) and is in good agreement with the fact that the rate of synthesis and tissue concentration of PGs is higher in the renal medulla than in the cortex (35). Indomethacin did not significantly modify the decrease in total RBF induced by ANG II but enhanced the vasoconstrictor effects of ANG II on MBF. These results are in good agreement with those of Parekh and colleagues (29, 30), who demonstrated an active participation of PGs in buffering the vasoconstrictor effects of ANG II in medullary circulation. Moreover, our results clearly demonstrated that the inhibition of PGs by indomethacin markedly reduced ANG II-mediated medullary vasodilation. In addition to its vascular effects, indomethacin increases sodium reabsorption from renal tubules by inhibiting prostaglandin synthesis. However, an early study showed that the increasing indomethacin-induced sodium concentrations in the renal medulla did not decrease papillary plasma flow (9).
Inhibition of NO production with L-NAME dramatically changed blood perfusion in cortical and medullary regions in LL rats and significantly increased their mean BP. L-NAME also markedly increased medullary vasoconstriction induced by ANG II to a similar extent as did indomethacin, whereas it blunted medullary vasodilation to a lesser extent. However, it is noteworthy that these effects were probably underestimated because of the marked hemodynamic changes induced by L-NAME before ANG II administration. Therefore, it is likely that RBF and MBF rapidly reached their minimal levels because they cannot decrease further. These results provide evidence that the medullary vasodilation evoked by ANG II injections not only depends on PGs but also on the release of NO. Indeed, the AT1 receptor activation is known to increase NO production in the medulla by increasing the Ca2+-dependent NO synthase activity (23). In this regard, it has been shown that a decrease in the release of NO into the medulla lowered papillary blood flow whereas an increase by ANG II elevated papillary blood flow (26, 28).
To determine whether kinin formation participated in ANG II-induced medullary vasodilation, the animals were pretreated with HOE-140, a specific bradykinin B2 receptor antagonist (7). This treatment did not modify the baseline systemic and renal hemodynamics in LL rats nor change their mean BP response to ANG II injections. However, HOE-140 enhanced the vasoconstrictor effects of ANG II on RBF as well as on MBF. The contribution of kinins to ANG II-induced medullary vasodilation was observed only at the highest doses of ANG II. This suggests that in LL rats, kinins were more involved in buffering renal vasoconstriction. In the present work, the AT1 receptor-mediated medullary vasodilator response to low doses of ANG II is mainly due to the release of PGs, whereas the vasodilator response to high doses of ANG II has additional NO- and kinin-dependent components.
In conclusion, the present work shows that intravenous ANG II injection in LL rats induces a biphasic medullary response characterized by an initial vasoconstriction followed by a vasodilation. Both responses are AT1 receptor mediated. The medullary vasodilation is unlikely due to systemic or renal vasoconstriction, as it was not seen in response to PE. At low ANG II doses, the medullary vasodilation appears to involve the release of PGs, while the response to higher ANG II doses also involves NO and kinins. LH rats differ from LL rats by an exaggerated medullary vasoconstriction response to ANG II and a blunted medullary vasodilation. As the renal medullary circulation appears to be an integral component of the long-term regulation of arterial pressure, the functional consequences of the altered MBF response to ANG II might contribute to the impaired pressure-natriuresis and hypertension in LH rats.
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ACKNOWLEDGEMENTS |
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We are indebted to Prof. Jean Sassard for help and useful comments.
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FOOTNOTES |
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A. Sarkis is the recipient of a fellowship from the Société Française d'Hypertension Artérielle.
Address for reprint requests and other correspondence: A. Sarkis, Département de Physiologie et Pharmacologie Clinique, CNRS UMR 5014, Faculté de Pharmacie, 8 Ave. Rockefeller, 69373 Lyon cedex 08 France (E-mail: sarkisalbert{at}hotmail.com).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published October 22, 2002;10.1152/ajprenal.00248.2002
Received 8 July 2002; accepted in final form 16 October 2002.
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