High lung PDE5: A strong basis for treating pulmonary hypertension with PDE5 inhibitors
High lung PDE5: A strong basis for treating pulmonary hypertension with PDE5 inhibitors
复制标题
DOI：
10.1016/j.bbrc.2005.06.183
复制
发表时间：
2005-09-02
影响因子：
3.1
通讯作者：
Francis, SH
中科院分区：
文献类型：
--
作者：
Corbin, JD;Beasley, A;Francis, SH
[H-3]伐地那非（Levitra）或[H-3]他达拉非（Cialis）结合用于定量大鼠肺和心脏组织中的PDE 5。每个放射性配体结合纯化的重组磷酸二酯酶-5（PDE 5）或粗提物中的PDE 5，具有强亲和力、高特异性、缓慢解离和良好的化学计量。PDE 5是提取物中检测到的唯一3 H受体结合蛋白，在肺中比在心脏提取物中高15倍，并且通过PDE 5催化活性测定的水平与通过3 H抑制剂结合测定的水平一致。肺中的高水平PDE 5接近于阴茎海绵体中的高水平，阴茎海绵体是PDE 5抑制剂靶向的组织。PDE 5是肺中主要的cGMP-PDE，按摩尔计算，比在体内磷酸化PDE 5的cGMP-dependent蛋白激酶（PKG）高五倍。心脏中PDE 5水平为PKG水平的一半。因此，肺血管平滑肌中PDE 5的丰度为PDE 5抑制剂治疗肺动脉高压提供了强有力的分子基础。爱思唯尔公司出版
[H-3]Vardenafil (Levitra) or [H-3]tadalafil (Cialis) binding was used to quantify PDE5 in rat lung and heart tissue. Each radioligand bound to purified recombinant phosphodiesterase-5 (PDE5) or to PDE5 in crude extracts with strong affinity, high specificity, slow dissociation, and good stoichiometry. PDE5, the only 3H inhibitor-binding protein detected in extracts, was 15 times higher in lung than in heart extracts, and the level measured by PDE5 catalytic activity agreed with that determined by 3H inhibitor binding. High level of PDE5 in lung approximated that in penile corpus cavernosum, the tissue targeted by PDE5 inhibitors. PDE5 was the predominant cGMP-PDE in lung, and on a molar basis was five times higher than cGMP-dependent protein kinase (PKG), which phosphorylates PDE5 in vivo. The PDE5 level was one-half that of PKG in heart. Thus, abundance of PDE5 in lung vascular smooth muscle provides a strong molecular basis for PDE5 inhibitor treatment of pulmonary hypertension. Published by Elsevier Inc.