Angiotensin II Subtype AT1 and AT2 Receptors Regulate Microvascular Hydraulic Permeability via cAMP and cGMP

Abstract

Angiotensin II receptor subtypes (AT1 and AT2) have been shown to modulate microvascular fluid leak. However, their intracellular signal transduction pathways have not been elucidated. We hypothesized that AT1 activation exerts its permeability-increasing effect by provoking cGMP synthesis and inducing cAMP degradation and that AT2 activation decreases fluid leak by stimulating cAMP synthesis and enhancing cGMP degradation. Using a microcannulation technique, hydraulic permeability (Lp) was measured in rat mesenteric venules. The messenger signal transduction of ATI was studied during continuous perfusion with the AT1 agonist, Sar1 plus either 1) a cGMP synthesis inhibitor, LY83583, or 2) an inhibitor of cAMP degradation, Rolipram. Likewise, AT2 signal transduction was studied with the AT2 agonist, CGP42112A, plus either 1) a cAMP synthesis inhibitor, dideoxyadenosine, or 2) an inhibitor of cGMP degradation, Zaprinast. Lp values are represented as mean +/- SEM x 10(-7) cm/s/cm H2O. For each group n = 6. Inhibition of cGMP synthesis blunted the permeability-increasing effect of AT1 agonism and decreased the peak Lp from 4.91 +/- 0.25 to 2.30 +/- 0.10 (P < 0.001). Inhibition of cAMP degradation also reduced the effect of AT1 agonism on peak L(p) from 2.25 +/- 0.22 to 1.30 +/- 0.13 (P < 0.001). Meanwhile, cAMP synthesis inhibition completely blocked the permeability-decreasing effect of AT2 agonism during which Lp increased from a baseline of 0.92 +/- 0.08 to a peak of 4.38 +/- 0.20 (P < 0.001). During inhibition of cGMP degradation, AT2 activation was able to decrease peak Lp from 2.26 +/- 0.15 to 1.46 +/- 0.05 (P < 0.001). When cGMP synthesis and cAMP degradation were inhibited, the effect on fluid leak by AT1 activation was blunted. Inhibition of cAMP synthesis completely blocked the effect of AT2 activation on fluid leak, while AT2 activation continued to decrease fluid leak despite inhibition of cGMP degradation. The AT1 receptor appears to increase fluid leak by stimulating both cGMP synthesis and cAMP degradation, while the AT2 receptor decreases fluid leak by stimulating cAMP synthesis, but not cGMP degradation.