Angiotensin II and renal medullary blood flow in Lyonrats - 《American Journal of Physiology》美国生理学杂志干细胞之家



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发表于 2009-4-21 13:32 |只看该作者 |倒序浏览 |打印

作者：AlbertSarkis, Kiao LingLiu, MingLo,  DanielBenzoni作者单位：Unité Mixte de Recherche 501 Centre National de laRecherche Scientifique, Institut Fédératif de RechercheCardio-vasculaire Faculté de Pharmacie, 69373 Lyon cedex 0 France


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      【摘要】3 V) g0 j) ^4 g: R; o
   The present study evaluated the acuteeffects 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 RBFand MBF, which were greater in LH than in LL rats. Interestingly, afterANG II, but not after PE, the initial medullary vasoconstriction wasfollowed by a long-lasting and dose-dependent vasodilation that wassignificantly blunted in LH compared with LL rats. The mechanisms ofthe MBF effects of ANG II were studied in LL rats only. Blockade ofAT 1 receptors with losartan (10 mg/kg) abolished all theeffects of ANG II, whereas AT 2 receptor blockade withPD-123319 (50 µg · kg 1 · min 1 iv) did not change these effects. Indomethacin (5 mg/kg) decreased by~90% the medullary vasodilation induced by the lowest doses of ANGII (from 15 ng/kg). In contrast, N G -nitro- L -arginine methyl ester (10 mg/kg and 0.1 mg · kg 1 · min 1 iv) and the bradykinin B 2 -receptor antagonist HOE-140 (20 µg/kg and 10 µg · kg 1 · min 1 iv) markedly lowered the medullary vasodilation at the highest doses ofANG II only. In conclusion, this study shows that LH rats exhibit analtered MBF response to ANG II compared with LL rats and indicates thatthe AT 1 receptor-mediated medullary vasodilator response tolow doses of ANG II is mainly due to the release of PGs, whereas thedilator response to high doses of ANG II has additional nitric oxide-and kinin-dependent components.; [/ H) g7 Q* }& q# w
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renin-angiotensin system; renal hemodynamics; hypertension; angiotensin II receptors, laser-Doppler flowmetry 5 {, h/ A1 @6 [4 s; x5 H
      【关键词】 Angiotensin medullary Lyonrats
   INTRODUCTION; G$ O5 w/ B7 w" O( i- P

RENAL MEDULLARY BLOOD FLOW (MBF) is thought to play an important role in maintainingbody 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 mostof the vasoactive agents, but its response may differ from that ofcortical blood flow ( 10, 25 ), thus suggesting that itsregulation might be specific and independent of that of cortical blood flow.. w9 M9 d  a! O. T# ?' F3 e
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It is well demonstrated that ANG II decreases cortical blood flow,enhances tubular sodium reabsorption, and shifts thepressure-natriuresis relationship toward a higher BP( 21 ). However, its effects on MBF remain unclear. Indeed,a number of studies have demonstrated that the medullaryvasculature was poorly sensitive to the vasoconstrictor effects of ANGII compared with the cortical circulation ( 5, 11, 21, 22 ).However, Pallone ( 28 ) has shown that ANG II induced apotent vasoconstriction of isolated medullary vasa recta inSprague-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 youngSprague-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 ofPG synthesis allowed ANG II to decrease papillary blood flow ( 30 ) and that the increase in papillary blood flow causedby ANG II was greatly dependent on the production of NO ( 27, 37 ). This was confirmed by Zou et al. ( 40 ), whodemonstrated that ANG II increased the medullary release of NO. Theinvolvement of kinins was raised by the findings that renal kininsincreased papillary blood flow ( 25 ) through NO release( 20 ).

Lyon hypertensive rats (LH) exhibit exaggerated renal vasoconstrictionand blunted pressure-natriuresis ( 14 ) associated withenhanced MBF autoregulation in response to increases in renal perfusionpressure ( 34 ). Because their hypertension is fully dependent on an active renin-angiotensin system ( 12 ) andbecause their renal hemodynamics and tubular sodium reabsorption arehypersensitive to ANG II ( 16 ), we hypothesized that theMBF of LH rats could be hypersensitive to the effects of ANG II.0 M; H' d6 {; H4 ]& L2 q1 ]5 s( O- E
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To test this hypothesis, MBF responses to graded doses of ANG II werestudied in LH rats and compared with the MBF responses of theirlow-blood-pressure (LL) controls. In addition, we examined the possiblemechanisms involved in the increase in MBF caused by ANG II. For thatpurpose, the specificity of the response was evaluated by comparing theMBF response after ANG II to that of another vasoconstrictor,phenylephrine (PE). The role of ANG II subtype 1 (AT 1 ) andsubtype 2 (AT 2 ) receptors in this response was determinedusing specific antagonists. Finally, the effect of ANG II was evaluatedafter inhibition of PG synthesis by indomethacin, inhibition of NOproduction by N G -nitro- L -argininemethyl ester ( L -NAME), and after bradykinin B 2 receptor blockade by HOE-140.; A: V" Q) i8 L/ K# @
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MATERIALS AND METHODS0 s! K5 u9 J# y) U, f9 q
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Animals

Fifteen-week-old male LH and LL rats were used. Animals werehoused in controlled conditions (temperature, 21 ± 1°C;humidity, 60 ± 10%; 8:20-h light-dark cycle). They were fed astandard 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.: \; y  G$ I5 A$ M1 m/ W$ H# z

Surgical Preparation

On the day of the experiment, the rats were anesthetized withinactin (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 torecord the mean BP through a pressure transducer (model P23ID, StathamInstrument Division, Gould, Cleveland, OH). To replace fluids lostduring 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 bodywt 1 · min 1 and thenreplaced by 1% bovine albumin in 0.9% NaCl solution infused at thesame rate during the experiment ( 6, 7 ). Through a midlineabdominal incision, an ultrasonic transit-time flow probe (1RB,Transonic Systems, Ithaca, NY) was placed around the left renal arteryfor continuous recording of the total renal blood flow (RBF) using atransit-time flowmeter (model T106, Transonic Systems). The left kidneywas freed from its surrounding tissue and immobilized in a plastic cupto avoid respiration-induced movements. A needle laser-Doppler flowprobe (400-µm diameter, model 411, Perimed, Järfälla,Sweden) was inserted perpendicularly into the middle pole of the leftkidney through a hole made in the capsule using a 25-gauge needle andadvanced to a depth of 5 mm in the medulla ( 34 ). This wasmade using a stereotaxic apparatus (model 900, David Kopf Instruments,Tujunga, CA). The probe was connected to a flowmeter (Laser DopplerSystem, Periflux 4001 Master, Perimed) for continuous measurement ofMBF and was calibrated before the experiment using a motility standard(PF 1001, Perimed). During the experiment, pulsatile arterial pressure, RBF, and MBF were continuously monitored using a computerized recordingsystem (LabVIEW 5.0 software, National Instruments, Austin, TX). Datawere sampled every 2 ms and stored on a CD-ROM. Average mean BP, RBF,and MBF were computed off-line.' N: \* `% d, s, L/ p
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At the end of the experiment, the left kidney was removed,decapsulated, blotted dry, and weighed. The position of the laser probeinto the medulla was checked macroscopically after injection ofmethylene blue in the hole made by the flow probe. RBF was normalizedper gram of the kidney weight. Renal vascular resistance (RVR) wascalculated as the ratio of mean BP to RBF. The values of MBF wereexpressed as arbitrary perfusion units (PU).
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Experimental Protocols4 L7 Z+ u$ \+ c; N0 Q. U
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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 last5 min of stabilization in LH ( n = 13) and LL ( n =13) rats. Then, the animals were randomly distributed in two groupsreceiving either intravenous bolus injections of ANG II (Sigma) atdoses 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)]. Consecutiveadministrations of ANG II or PE were separated by a period of 10 min toallow a full recovery of hemodynamic variables.
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Effects of AT 1 or AT 2 receptor blockadein LL rats. Twenty-five minutes after surgical preparation, baseline values of meanBP, RBF, and MBF were recorded for 5 min. Then, losartan (DuPont MerckPharmaceutical, Wilmington, DE), an AT 1 -receptor antagonist, was injected intravenously at the dose of 10 mg/kg in LLrats ( n = 7). In another group of LL rats ( n =8), PD-123319 (Sigma), a specific AT 2 -receptor antagonist,was infused intravenously at the dose of 50 µg · kg 1 · min 1 during the experiment. Twenty-five minutes after administration ofthese antagonists, the above hemodynamic parameters were recorded onceagain for 5 min, and then the injections of ANG II (5-480 ng/kg)were performed as described above., ]. E% j* ?8 o1 h0 ?8 w9 V

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 meanBP, RBF, and MBF were recorded for 5 min. Then, the rats received anintravenous 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 · kg 1 · min 1 ( n = 7), or HOE-140 (Sigma) at a dose of 20 µg/kgfollowed 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 theinjections of ANG II (5-480 ng/kg) were performed as described above./ x9 o5 M2 Z) j% J
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Statistical Analysis5 x( f  ~! b! b0 d: ?8 o0 G& ]

Values are means ± SE. The between-strain differencesreported in Table 1 were analyzed usingStudent's t -test for unpaired data. The between-straindifferences in the dose-response curves of ANG II and PE were analyzedusing a two-way analysis of variance followed by a Fishermultiple-range test. The dose-related effects of ANG II and PE withingroups and the effects of treatment were analyzed using one-wayanalysis of variance. A difference was considered to be statisticallysignificant at P  R" S9 j6 l% P4 V

Table 1. Baseline blood pressure and renal hemodynamics in 15-wk-oldanesthetized rats0 r$ t( L" W) z
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RESULTS

Effects of ANG II and PE in Control Animals1 ?3 F5 A4 E# I4 h7 q2 J. {
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As shown in Table 1, LH rats differed from LL rats by a highermean BP and a decreased RBF, leading to elevated RVR; baseline MBF didnot differ between LH and LL rats.

Typical recordings of mean BP, RBF, and MBF in response to the fourhighest doses of ANG II and PE in one LL and one LH rat are depicted inFigs. 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 3 A ). In LL rats, the initialrapid and short lasting ( min) decrease (vasoconstrictor component)was followed by a marked 2 min) increase(vasodilator component). In LH rats, the decrease in MBF was morepronounced than in LL controls, whereas the delayedvasodilation was significantly blunted over the range of ANG II doses(Figs. 1 and 3 A ).

Fig. 1. Typical recordings of mean blood pressure (BP), total renal (RBF),and medullary blood flow (MBF) in response to intravenous injections ofANG II in 1 Lyon low-blood-pressure (LL; A ) and 1 Lyonhypertensive (LH; B ) rat. PU, perfusion units.# |6 o1 n" G" {) O) D% Z! @8 M; p

Fig. 2. Typical recordings of mean BP, total RBF and MBF in response tointravenous injections of phenylephrine (PE) in 1 LL ( A ) and1 LH rat ( B ).) a2 Q: x, O& c/ Y

Fig. 3. Peak changes in mean BP ( mean BP), RBF ( RBF), and MBF( MBF) after ANG II ( A ) or PE ( B ) injections in15-wk-old LH and LL rats. Values are means ± SE.** P P

As shown in Fig. 3 A, mean BP responses to the lowest doses(5-30 ng/kg) of ANG II were significantly higher( P LH than in LL rats. RBF dose dependentlydecreased after ANG II injections in both strains, and this decreasewas significantly greater ( P ng/kg). Finally, over the entire range ofANG II doses and in both strains, the decreases in MBF were less markedthan those in RBF ( 8 ± 1% for MBF and 20 ± 2% for RBFin LL rats; 17 ± 2% for MBF and 35 ± 5% for RBF in LHrats for the ANG II dose of 30 ng/kg).3 Z8 W3 t0 T) s' V. a" m2 N
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As shown in Fig. 3 B, PE elicited similar mean BP and RBFresponses to those for ANG II. RBF decreased nearly to zero flow withthe highest doses, which is not meaningful. Concerning MBF, thedecrease was more marked in LH than in LL rats. In contrast, no delayedvasodilation was observed after PE in both LL and LH rats (Figs. 2 and 3 B ).

Effects of AT 1 or AT 2 Receptor Blockade inLL Rats

As shown in Table 2, losartansignificantly decreased mean BP and increased RBF in LL rats. Treatmentwith PD-123319 did not significantly modify mean BP or RBF. Finally,neither losartan nor PD-123319 altered baseline MBF.
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Table 2. Effects of different treatments in 15-wk-old anesthetized LL rats" q$ h1 G; x& v/ D

AT 1 blockade by losartan abolished the effects of ANG II onmean BP, RBF, and the vasoconstrictor and vasodilator components of theMBF response in LL rats (Fig. 4 ). Incontrast, the hemodynamic responses to ANG II remained unchanged afterblockade of AT 2 receptors by PD-123319 (Fig. 4 ).( X" b! a4 `: ?6 H" }

Fig. 4. Peak mean BP, RBF, and MBF in response to ANG IIinjections in 15-wk-old LL rats pretreated with losartan or PD-123319.Values are means ± SE.) Z- M' @% T9 C" Q4 ?! p2 j

Effects of PGs, NO, or Kinin Blockade in LL Rats* v/ W4 W0 x: T+ ~/ ~
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As shown in Table 2, indomethacin did not significantly modifymean BP and RBF but significantly decreased baseline MBF. In responseto subsequent administrations of ANG II, the decrease in RBF did notsignificantly differ between indomethacin-pretreated and control LLrats (Fig. 5 ). Interestingly, from thelowest ANG II dose (15 ng/kg), indomethacin significantly enhanced theANG II-induced dose-dependant decrease in MBF ( P attenuated ( P 5 ).3 D% {7 ]' X  ]% D2 y
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Fig. 5. Peak RBF and MBF in response to ANG II injectionsin 15-wk-old LL rats pretreated with indomethacin, N G -nitro- L -arginine methylester (L -NAME), or HOE-140. Values are means ± SE.* P P" {& B3 V3 y. \* y0 Y
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L -NAME administration significantly increasedbaseline mean BP and decreased RBF and MBF (Table 2 ). Thedecrease in RBF elicited by increasing doses of ANG II was blunted andrapidly reached a maximal level in L -NAME-pretreatedanimals compared with controls (Fig. 5 ). The ANG II-induced medullaryvasoconstriction (from 15 ng/kg) was significantly enhanced( P L -NAME, whereas medullaryvasodilation was lowered by ~80% only for the highest doses of ANGII (Fig. 5 ).* h9 @/ V: v& q: t: _
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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 ) inducedby ANG II were significantly enhanced by HOE-140 treatment( P the medullary vasodilation (by ~40%) for the highestdoses of ANG II only (Fig. 5 ).- \" e. Q! m4 t- @# J

DISCUSSION4 |* ~5 H; l* n6 E
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The major findings of the present work are that 1 ) ANGII injection induces a dose-dependent biphasic MBF responsecharacterized by a rapid decrease followed by a durable increase; thisresponse is specific to ANG II, as it is not seen after PE; 2 ) in response to ANG II, LH rats exhibit an increasedmedullary vasoconstriction and a blunted medullary vasodilationcompared with LL rats; 3 ) both the ANG II-induced medullaryvasoconstriction and vasodilation are mediated by AT 1 receptors; and 4 ) the medullary vasodilation is mainly dueto a release of PGs and NO.
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The importance of MBF in the long-term control of BP has beendemonstrated by experiments showing that a primary reduction in MBFallowed the development of hypertension ( 24 ), whereas anincrease in MBF can lower hypertension ( 17 ). Previousstudies suggested that LH rats are prone to retain sodium, becausetheir pressure-natriuresis is blunted ( 14 ) and they aresalt sensitive ( 8 ). The mechanisms involved in this sodiumretention are unknown but may involve altered MBF regulation( 34 ). Because hypertension in LH rats is dependent on anactive renin-angiotensin system ( 12 ), we examined theresponse of MBF to ANG II in LH compared with LL rats. For thatpurpose, MBF was measured using a laser-Doppler flow probe aspreviously described ( 34 ).

In LL rats, ANG II induced a brief decrease in MBF that was less markedthan that for total RBF. This result is in good agreement with theexperiments showing that, in normotensive rats, MBF is less sensitiveto the vasoconstrictor effect of ANG II than the cortical circulation( 5, 6, 11, 21 ). This initial response was followed by amarked and long-lasting vasodilation, thus leading to a biphasicresponse that does not appear related to the manner in which ANG II wasadministered. Indeed, 1 ) MBF did not change after injectionof an equivalent volume of saline; 2 ) the responses to ANGII were dose dependent, although the increasing bolus doses of ANG IIwere injected at a constant volume; and 3 ) in ratspretreated with losartan, ANG II, given in the same manner to untreatedrats, did not modify MBF. In addition, although such a biphasicresponse to ANG II is at variance with studies demonstrating that ANGII infusion induces only medullary vasodilation ( 2, 25, 37 ), a similar response to ANG II injection was recentlyreported by Rajapakse et al. ( 31 ) in anesthetized rabbits.Interestingly, the long-lasting and dose-dependent increase in MBFinduced by ANG II was not observed with PE, despite a similar systemicand renal vasoconstriction. Although the arterial pressure was not controlled in our study, the ANG II-induced increase in MBF has beenshown to occur even if the increase in arterial pressure was preventedby an aortic clamp ( 2, 25 ). Taken together, theseobservations show that the biphasic MBF response is specific to ANG IIand demonstrate that the increase in MBF induced by ANG II is notrelated to an increase in renal perfusion pressure. It has been shownthat ANG II, but not PE, is able to increase Ca 2  -dependentNO 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.6 b1 B. J: b0 M& |. C+ |: m/ W2 r
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No baseline differences in MBF could be observed between LH and LLrats. In contrast, MBF responses to ANG II differed between the twostrains. LH rats exhibited a more marked decrease in MBF. These resultsare in accordance with previous studies demonstrating that themedullary circulation of the spontaneously hypertensive rat (SHR) ismore sensitive to the vasoconstrictor effect of ANG II compared withthat of normotensive Wistar-Kyoto rats ( 6 ). Similarresults 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 ratsby 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 thevasoconstrictor and antinatriuretic effects of ANG II within the kidneyand thus may contribute to the ANG II-induced decrease in sodiumexcretion; and 2 ) in LH rats, the decreased renal sodiumexcretion was found to be sensitive to ANG II ( 16 ).
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The nature of the receptor subtypes and the mechanisms involved in ANGII-induced MBF response were examined in LL rats only because theseanimals exhibit marked vasodilation. It is evident that the mechanismsinvolved in LL rats could differ from those in LH rats. Most of thebiological actions of ANG II are known to be mediated throughAT 1 receptors. However, recent evidence suggests thatAT 2 receptors may be important in the regulation of BP andrenal function by counterbalancing the vasoconstrictor andantinatriuretic actions of AT 1 receptors ( 3 ).The role of AT 1 receptors was examined using their specificantagonist losartan at the dose usually used ( 38 ). Weobserved that losartan not only suppressed the ANG II-induced medullaryvasoconstriction but also the secondary vasodilation, thusdemonstrating that the increase in MBF is AT 1 receptormediated. Moreover, this response is likely related to a secondaryrelease of vasodilators, because 1 ) it occurred subsequentto and durably after ANG II administration; 2 )AT 1 receptors are localized not only in renal corticalvasculature but also in the vasa recta of the outer and inner medulla( 1, 39 ); and 3 ) the activation ofAT 1 receptors increases the release of local vasodilators( 23, 35 ). The role of AT 2 receptors inANG II effects was examined using PD-123319 infused at a dose demonstrated to be highly specific for AT 2 receptors( 15, 19 ). The lack of influence of PD-123319 on thesystemic and renal effects of ANG II showed that the involvement ofAT 2 receptors was negligible in our experimentalconditions. Similar results have been recently reported by Badzynska etal. ( 2 ) in normotensive rats, in which no change in ANGII-induced cortical and MBF was observed after treatment withPD-123319.
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In the present work, only baseline MBF decreased markedly aftertreatment with indomethacin. The effect of endogenous PGs on medullaryblood perfusion was also observed by other investigators ( 25, 26, 32 ) and is in good agreement with the fact that the rate ofsynthesis and tissue concentration of PGs is higher in the renalmedulla than in the cortex ( 35 ). Indomethacin did notsignificantly modify the decrease in total RBF induced by ANG II butenhanced the vasoconstrictor effects of ANG II on MBF. These resultsare in good agreement with those of Parekh and colleagues ( 29, 30 ), who demonstrated an active participation of PGs inbuffering 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 byinhibiting prostaglandin synthesis. However, an early study showed thatthe increasing indomethacin-induced sodium concentrations in the renal medulla did not decrease papillary plasma flow ( 9 ).! K+ t2 @2 i3 P& v" I
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Inhibition of NO production with L -NAME dramaticallychanged blood perfusion in cortical and medullary regions in LL rats and significantly increased their mean BP. L -NAME alsomarkedly increased medullary vasoconstriction induced by ANG II to asimilar extent as did indomethacin, whereas it blunted medullaryvasodilation to a lesser extent. However, it is noteworthy that theseeffects 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 minimallevels because they cannot decrease further. These resultsprovide evidence that the medullary vasodilation evoked by ANG IIinjections not only depends on PGs but also on the release of NO.Indeed, the AT 1 receptor activation is known to increase NOproduction in the medulla by increasing the Ca 2  -dependentNO synthase activity ( 23 ). In this regard, it has beenshown that a decrease in the release of NO into the medulla loweredpapillary blood flow whereas an increase by ANG II elevated papillaryblood flow ( 26, 28 )./ q& [4 |$ }+ _' m" q& f: p
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To determine whether kinin formation participated in ANG II-inducedmedullary vasodilation, the animals were pretreated with HOE-140, aspecific bradykinin B 2 receptor antagonist( 7 ). This treatment did not modify the baseline systemicand renal hemodynamics in LL rats nor change their mean BP response toANG II injections. However, HOE-140 enhanced the vasoconstrictoreffects of ANG II on RBF as well as on MBF. The contribution of kinins to ANG II-induced medullary vasodilation was observed only at thehighest doses of ANG II. This suggests that in LL rats, kinins weremore involved in buffering renal vasoconstriction. In the present work,the AT 1 receptor-mediated medullary vasodilator response tolow doses of ANG II is mainly due to the release of PGs, whereas thevasodilator response to high doses of ANG II has additional NO- andkinin-dependent components.+ j+ s4 U$ W, l' f6 `: n# e( o; F

In conclusion, the present work shows that intravenous ANG II injectionin LL rats induces a biphasic medullary response characterized by aninitial vasoconstriction followed by a vasodilation. Both responses areAT 1 receptor mediated. The medullary vasodilation isunlikely due to systemic or renal vasoconstriction, as it was not seenin response to PE. At low ANG II doses, the medullary vasodilationappears to involve the release of PGs, while the response to higher ANGII doses also involves NO and kinins. LH rats differ from LL rats by anexaggerated medullary vasoconstriction response to ANG II and a bluntedmedullary vasodilation. As the renal medullary circulation appears tobe an integral component of the long-term regulation of arterialpressure, the functional consequences of the altered MBF response toANG II might contribute to the impaired pressure-natriuresis andhypertension in LH rats., d: X0 H3 Z6 P% m; L3 N5 o
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ACKNOWLEDGEMENTS8 f" }9 B7 R% g9 `0 y0 i

We are indebted to Prof. Jean Sassard for help and useful comments.: ?% H4 T4 Z+ Q4 }: e
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