Department of Physiology & Membrane Biology, School of Medicine, University of California, Davis, CA 95616, USA.
J Physiol. 2011 Jan 15;589(Pt 2):341-53. doi: 10.1113/jphysiol.2010.199588. Epub 2010 Nov 22.
Inhibition of phosphodiesterase 4 (PDE4) to increase endothelial cAMP and stabilize the endothelial barrier attenuates acute inflammatory increases in vascular permeability.We extended this approach to attenuate physiological increases in vascular permeability in response to atrial natriuretic peptide (ANP), which acts with the kidney to regulate plasma volume. We measured blood-to-tissue albumin clearance and changes in plasma volume in isoflurane-anaesthetized mice (C57BL/6J) pre-treated with rolipram (8 mg kg(-1) I.P., 30 min). Rolipram significantly reduced albumin permeability, measured using a dual-label fluorescence method, in skin and skeletal muscle compared with ANP alone (500 ng kg(-1) min(-1)). Skin and muscle tissue accounted for 70% of the reduction in whole body albumin clearance taking into account albumin clearance in gastrointestinal (GI) tissue, heart and kidney. The action of ANP and rolipram to modify albumin clearances in duodenum and jejunum could be accounted for by local increases in vascular perfusion to increase surface area for exchange. ANP increased haematocrit from 40.6% to 46.8%, corresponding to an average loss of 22% plasma fluid volume (227 μl), and this was almost completely reversed with rolipram. Renal water excretion accounted for less than 30% of plasma fluid loss indicating that reduced albumin permeability and reduced filtration into vasodilated GI tissue were the predominant actions of PDE4 inhibition. Similar fluid retention was measured in mice with endothelial-restricted deletion of the guanylyl cyclase-A receptor for ANP. Stabilizing the endothelial barrier to offset ANP-induced increases in vascular permeability may be part of a strategy to maintain plasma volume.
抑制磷酸二酯酶 4（PDE4）以增加内皮细胞 cAMP 并稳定内皮屏障，可减轻急性炎症引起的血管通透性增加。我们将这种方法扩展到减轻心房利钠肽（ANP）引起的血管通透性的生理增加，ANP 与肾脏一起作用以调节血浆体积。我们在预先用罗利普兰（rolipram）（8mg/kg 腹腔注射，30 分钟）处理的异氟烷麻醉的小鼠（C57BL/6J）中测量了血液到组织的白蛋白清除率和血浆体积的变化。与单独的 ANP 相比，罗利普兰显著降低了皮肤和骨骼肌中使用双标记荧光法测量的白蛋白通透性（500ng/kg/min）。考虑到胃肠道（GI）组织、心脏和肾脏的白蛋白清除率，皮肤和肌肉组织占全身白蛋白清除率降低的 70%。ANP 和罗利普兰改变十二指肠和空肠中白蛋白清除率的作用可以通过局部增加血管灌注来增加交换表面积来解释。ANP 将红细胞压积从 40.6%增加到 46.8%，对应于平均损失 22%的血浆液体量（227μl），这几乎可以被罗利普兰完全逆转。肾脏水排泄仅占血浆液体丢失的 30%以下，表明降低的白蛋白通透性和减少滤过到血管扩张的 GI 组织是 PDE4 抑制的主要作用。在内皮细胞特异性缺失 ANP 受体的小鼠中也测量到了类似的液体保留。稳定内皮屏障以抵消 ANP 诱导的血管通透性增加可能是维持血浆体积的策略的一部分。
