Angiotensin II-induced renal responses in anesthetized rabbits: effects of Nω-nitro-l-arginine methyl ester and losartan

Helwig

1998

1 We showed earlier that NO inhibition caused a left-shift and augmented E max of the concentrationresponse curve of AT 1 -mediated (angiotensin II)-induced vasoconstrictions (AII-VC) in the rat kidney. The 0.01 ± 0.1 nM AII-VC unmasked by the potentiating e ect of NO inhibition, were sensitive not only to AT 1 (L158809), but also to AT 2 receptor (PD123319) antagonists. We now demonstrate the role of endothelium and eicosanoids in the NO-masked AT 1 /AT 2 -mediated component of the AII-VC in isolated indomethacin-perfused kidneys of the rat. 2 L-NAME increased 0.1 nM AII-VC 7.2 fold. Pretreatment of the kidneys with factor VIII antibody/ complement or with the detergent CHAPS to damage endothelium, decreased carbachol-induced vasodilatation and blunted by 60 and 30% respectively, the enhancement of AII-VC during NO inhibition. 3 L-NAME also increased 3 mM noradrenaline (NA)-induced vasoconstriction (NA-VC) 8.1 fold. In contrast to AII-VC, endothelium damage was without e ect on the enhancement of NA-VC by L-NAME, suggesting a dominant role of endothelium-derived NO in the enhancement of NA-VC. 4 During NO inhibition, ETYA (2 mM; an inhibitor of all arachidonic acid derived pathways) and anaphto¯avone (10 mM; an inhibitor of the cytochrome P450 isozymes), decreased by 85% the 0.1 nM AII-VC. 5 In conclusion, during NO inhibition, the AT 1 -mediated constriction to low concentrations of AII, which is sensitive to AT 2 antagonists, depends on intact endothelium, and can be blocked by inhibition of eicosanoid synthesis. The results suggest that the AII-mediated vasoconstriction through AT 1 receptors is potentiated in the absence of NO, by the release of eicosanoids from the endothelium through AT 2 receptors.

Section: Introductionmentioning

confidence: 99%

AT₂ antagonist‐sensitive potentiation of angiotensin II‐induced constriction by NO blockade and its dependence on endothelium and P450 eicosanoids in rat renal vasculature

Helwig

1998

“…While tonic release of NO in the basal relaxed state exerts a direct vasodilatory eect, it has often been stated that suppression of endogenous NO ampli®es any vasoconstrictor that is active in the renovascular system (Baylis et al, 1990;Adachi et al, 1996;Baylis & Qiu, 1996;Parekh et al, 1996). The present in vitro results were in excellent agreement with this concept: both Ang II-and NE-induced vasoconstrictions were found to be markedly increased during perfusion in the presence of 0.1 mM L-NAME as compared to the vasoconstrictions induced in control-perfused kidneys.…”

Section: Blockade Of the No/cgmp Pathway Enhances Vasoconstrictor Resmentioning

confidence: 99%

“…Tonic constitutive release of endothelial NO plays a major modulatory role in maintaining blood pressure and renal hemodynamics in the baseline state (Baylis et al, 1990) and many studies have shown that NO attenuates the renal eects of vasoconstrictor drugs (Adachi et al, 1996;Parekh et al, 1996). Thus, it has currently been reported (for a review see Navar et al, 1996) that blocking NO synthesis potentiates the eect of Ang II in vitro as well as in vivo as long as endogenous Ang II is acutely activated or exogenous Ang II levels are raised by infusion.…”

Section: Introductionmentioning

confidence: 99%

AT₂‐antagonist sensitive potentiation of angiotensin II‐induced vasoconstrictions by blockade of nitric oxide synthesis in rat renal vasculature

Barthelmebs

et al. 1997

1 Although the actions of angiotensin II (Ang II) on renal haemodynamics appear to be mediated by activation of the AT 1 receptor subtype, AT 2 binding sites have also been evidenced in the adult kidney vasculature. As NO is known to mask part of the renal eects of vasoconstrictor drugs, we queried whether the Ang II-induced vasoconstrictions could occur via multiple receptor subtypes during inhibition of NO synthesis. We explored the eect of AT 1 and AT 2 receptor (AT-R) antagonists on Ang II-induced pressure increases during NO synthase or soluble guanylyl cyclase inhibition in rat isolated kidneys perfused in the presence of indomethacin at constant¯ow in a single-pass circuit. 2 In the absence of NO blockade, the AT 1 -R antagonist L-158809 (500 nM) antagonized the Ang IIinduced vasoconstrictions, while the AT 2 -R antagonist PD-123319 (500 nM) had no eect. 3 Perfusing kidneys in the presence of either NO synthase inhibitors, L-NAME (100 mM) or L-NOARG (1 mM), or soluble guanylyl cyclase inhibitor, LY-83583 (10 mM), signi®cantly increased both molar pD 2 (from 9.40+0.25 to 10.36+0.11) and E max values (from 24.9+3.1 to 79.9+4.9 mmHg) of the concentration ± response curve for Ang II-induced vasoconstriction. 4 In the presence of L-NAME, 500 nM L158809 abolished the Ang II-induced vasoconstrictions whatever the concentration tested. On the other hand, 500 nM PD-123319 reversed the left shift of the concentration ± response curve for Ang II (molar pD 2 value 9.72+0.13) leaving E max value unaected (91.3+7.6 mmHg). 5 In the presence of L-NAME, the potentiated vasoconstriction induced by 0.1 nM and the augmented vasoconstriction induced by 10 nM Ang II were fully inhibited in a concentration-dependent manner by L-158809 (0.05 ± 500 nM). By contrast, PD-123319 (0.5 ± 500 nM) did not aect the 10 nM Ang II-induced vasoconstriction and concentration-dependently decreased the 0.1 nM Ang II-induced vasoconstriction plateauing at 65% inhibition above 5 nM antagonist. 6 Similar to PD-123319, during NO blockade the AT 2 -R antagonist CGP-42112A at 5 nM decreased by 50% the 0.1 nM Ang II-induced vasoconstriction and at 500 nM had no eect on 10 nM Ang II-induced vasoconstriction. 7 In conclusion, the renal Ang II-induced vasoconstriction, which is antagonized only by AT 1 -R antagonist in the presence of endogenous NO, becomes sensitive to both AT 1 -and AT 2 -R antagonists during NO synthesis inhibition. While AT 1 -R antagonist inhibited both L-NAME-potentiated and -augmented components of Ang II-induced vasoconstriction, AT 2 -R antagonists inhibited only the L-NAME-potentiated component.

“…ANGII‐induced vasoconstriction is importantly modulated by NO, as it has been demonstrated by means of NO donors and blockade of endogenous NO ( Adachi et al ., 1996 ; Madrid et al ., 1997 ; Parekh et al ., 1996 ). Our present results extend these findings, showing that vasoconstriction in response to ANGII can be strongly attenuated by shear stress‐induced NO production.…”

Section: Discussionmentioning

confidence: 98%

“…This is particularly true for the action of angiotensin II (ANGII) on the renal microcirculation, which is modulated by endothelium‐derived nitric oxide (NO), prostaglandins, and other eicosanoids ( Arima et al ., 1994 ; 1997 ; Ito et al ., 1991 ; 1993 ; Navar et al ., 1996 ; Oyekan et al ., 1997 ; Sigmon et al ., 1992 ). Among these compounds, NO importantly counter‐balances the renal AT 1 receptor‐mediated vasoconstriction ( Adachi et al ., 1996 ; Madrid et al ., 1997 ; Parekh et al ., 1996 ). Interestingly, suppression of ANGII‐induced renal vasoconstriction by NO involves further endothelial autacoids, as we have recently demonstrated that, during NO synthase inhibition, renal vasoconstriction in response to subnanomolar concentrations of ANGII is potentiated by an AT 2 receptor antagonist‐sensitive mechanism, which depends on intact endothelium and constrictory P450 metabolites ( Muller et al ., 1997 ; 1998 ).…”

Section: Introductionmentioning

confidence: 99%

Role of shear stress in nitric oxide‐dependent modulation of renal angiotensin II vasoconstriction

Barthelmebs

et al. 1999

1 Renal vasoconstriction in response to angiotensin II (ANGII) is known to be modulated by nitric oxide (NO). Since shear stress stimulates the release of a variety of vasoactive compounds from endothelial cells, we studied the impact of shear stress on the haemodynamic e ect of ANGII in isolated perfused kidneys of rats under control conditions and during NO synthase inhibition with L-NAME (100 mM). 2 Kidneys were perfused in the presence of cyclo-oxygenase inhibitor (10 mM indomethacin) with Tyrode's solution of relative viscosity Z=1 (low viscosity perfusate, LVP) or, in order to augment shear stress, with Tyrode's solution containing 7% Ficoll 70 of relative viscosity Z=2 (high viscosity perfusate, HVP). 3 Vascular conductance was 3.5+0.4 fold larger in HVP as compared with LVP kidneys, associated with an augmentation of overall wall shear stress by 37+5%. During NO inhibition, vascular conductance was only 2.5+0.2 fold elevated in HVP vs LVP kidneys, demonstrating shear stress-induced vasodilatation by NO and non-NO/non-prostanoid compound(s). 4 ANGII (10 ± 100 pM) constricted the vasculature in LVP kidneys, but was without e ect in HVP kidneys. During NO inhibition, in contrast, ANGII vasoconstriction was potentiated in HVP as compared with LVP kidneys. 5 The potentiation of ANGII vasoconstriction during NO inhibition has been shown to be mediated by endothelium-derived P450 metabolites and to be sensitive to AT 2 receptor blockade in our earlier studies. Accordingly, in HVP kidneys, increasing concentrations of the AT 2 receptor antagonist PD123319 (5 and 500 nM) gradually abolished the potentiation of ANGII vasoconstriction during NO inhibition, but did not a ect vasoconstriction in response to ANGII in LVP kidneys. 6 Our results demonstrate, that augmentation of shear stress by increasing perfusate viscosity induces vasodilatation in the rat kidney, which is partially mediated by NO. Elevated levels of shear stress attenuate renal ANGII vasoconstriction through enhanced NO production and are required for AT 2 sensitive potentiation during NO inhibition.