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

1 Renal vasoconstriction in response to angiotensin II (ANGII) is known to be modulated by nitric oxide (NO). Since sheer stress stimulates the releas e of a variety of vasoactive compounds from endothelial cells, we studied t he impact of shear stress on the haemodynamic effect of ANGII in isolated p erfused kidneys of rats under control conditions and during NO synthase inh ibition with L-NAME (100 mu M). 2 Kidneys were perfused in the presence of cyclo-oxygenase inhibitor (10 mu M indomethacin) with Tyrode's solution of relative viscosity eta = 1 (low viscosity perfusate, LVP) or, in order to augment shear stress, with Tyrode 's solution containing 7% Ficoll 70 of relative viscosity eta = 2 (high vis cosity 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 b y 37 +/- 5%. During NO inhibition, vascular conductance was only 2.5 +/- 0. 2 fold elevated in HVP Is LVP kidneys, demonstrating shear stress-induced v asodilatation by NO and non-NO/non-prostanoid compound(s). 4 ANGII (10-100 pM) constricted the vasculature in LVP kidneys, but was wit hout effect in HVP kidneys. During NO inhibition, in contrast, ANGII vasoco nstriction 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 sens itive to AT(2) receptor blockade in our earlier studies. Accordingly, in HV P kidneys, increasing concentrations of the AT(2) receptor antagonist PD123 319 (5 and 500 nM) gradually abolished the potentiation of ANGII vasoconstr iction during NO inhibition, but did not affect vasoconstriction in respons e 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 part ially 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.