Chong Terry J, Victorino Gregory P
Department of Surgery, UCSF-East Bay, Alameda County Medical Center, Oakland, California 94602, USA.
J Surg Res. 2006 Mar;131(1):105-10. doi: 10.1016/j.jss.2005.09.010. Epub 2005 Oct 26.
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.
血管紧张素II受体亚型（AT1和AT2）已被证明可调节微血管液体渗漏。然而，它们的细胞内信号转导途径尚未阐明。我们推测，AT1激活通过激发cGMP合成和诱导cAMP降解发挥其增加通透性的作用，而AT2激活通过刺激cAMP合成和增强cGMP降解来减少液体渗漏。
采用微插管技术，测量大鼠肠系膜小静脉的水力传导率（Lp）。在持续灌注AT1激动剂Sar1加以下两种物质之一时研究AT1的信使信号转导：1）一种cGMP合成抑制剂LY83583，或2）一种cAMP降解抑制剂咯利普兰。同样，用AT2激动剂CGP42112A加以下两种物质之一研究AT2信号转导：1）一种cAMP合成抑制剂双脱氧腺苷，或2）一种cGMP降解抑制剂扎普司特。Lp值表示为平均值±标准误×10（-7）cm/s/cm H2O。每组n = 6。
抑制cGMP合成减弱了AT1激动作用的通透性增加效应，使Lp峰值从4.91±0.25降至2.30±0.10（P < 0.001）。抑制cAMP降解也降低了AT1激动作用对峰值L（p）的影响，从2.25±0.22降至1.30±0.13（P < 0.001）。同时，抑制cAMP合成完全阻断了AT2激动作用的通透性降低效应，在此期间Lp从基线的0.92±0.08增加到峰值4.
