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

Abstract

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.

High concentrations of oxytocin cause vasoconstriction by activating vasopressin V 1A receptors in the isolated perfused rat kidney

“…These results differ from the full agonist activity reported on other arteries of the rat (Katusic et al 1986;Stam et al 1998;Chen et al 1999), although partial agonist activity was also observed in human uterine arteries (Jovanovic et al 1997). Apparent reduction in agonist potency and efficacy might be linked to the modulation of agonist-induced vasoconstriction by a vasodilator component via the release of endothelium-derived relaxing factors (Millette and Lamontagne 1996;Muller et al 1997) or the activation of relaxing mechanisms directly on vascular smooth muscle cells. In our hands however, oxytocin evoked no renal vasodilation after blockade of V 1A receptors and its renal vasoconstrictor response was not potentiated after blockade of oxytocin receptors.…”

Effects of AT1 Receptor Blockade on Plasma Thromboxane A₂ (TXA₂) Level and Skin Microcirculation in Young Healthy Women on Low Salt Diet

“…In addition to their effect on blood pressure, long-term administration of AT1 receptor blockers results in a several-fold increase in plasma ANG II and thus a possible overstimulation of AT2 receptors [40,41,42,43]. Therefore, the effect of AT2 receptor stimulation is becoming increasingly important in both physiological and pathological situations, for example, hypertension.…”

“…Therefore, the effect of AT2 receptor stimulation is becoming increasingly important in both physiological and pathological situations, for example, hypertension. Furthermore, a cross-talk between the two receptor subtypes (AT1 and AT2) has been described [42,43], and AT1 receptor blockade might also unmask potential effects of AT2 receptors that were overridden by AT1 receptor stimulation. This potential activation of AT2 receptors during AT1 receptor blockade may have an important role in maintaining vascular relaxation mechanisms, as previous studies have demonstrated that AT2 receptors play a vasodilator role and that selective stimulation of AT2 receptors in the presence of AT1 receptor antagonists is predicted to have a beneficial clinical effect in controlling blood pressure [44,45,46].…”

Physiological and Pathophysiological Functions of the AT 2 Subtype Receptor of Angiotensin II

“…2 Therefore, the effect of the stimulation of the AT 2 R is becoming increasingly important in both physiological and pathological situations. Furthermore, a cross-talk between the 2 receptor subtypes (AT 1 R and AT 2 R) has been described, 3,4 and AT 1 R blockade might also unmask potential effects of AT 2 Rs that were inhibited by AT 1 R stimulation.…”