Sildenafil alters calcium signaling and vascular tone in pulmonary arteries from chronically hypoxic rats
Sildenafil alters calcium signaling and vascular tone in pulmonary arteries from chronically hypoxic rats
复制标题
DOI：
10.1152/ajplung.00449.2003
复制
发表时间：
2004-09-01
影响因子：
4.9
通讯作者：
Savineau, JP
中科院分区：
文献类型：
--
作者：
Pauvert, O;Bonnet, S;Savineau, JP
西地那非是一种有效的5型核苷酸依赖性磷酸二酯酶（PDE）抑制剂，最近被提议作为治疗或预防肺动脉高压（PAHT）的治疗工具。因此，我们研究了西地那非对肺动脉平滑肌细胞（PASMCs）的钙信号和肺动脉（PA）的反应性从慢性缺氧（CH）诱导的肺动脉高压大鼠与对照组（常氧）大鼠相比的影响。CH大鼠在低压舱（50.5 kPa）中维持3周，导致PAHT完全发展。在加载有钙荧光团indo 1的PASMC中测量细胞内钙浓度（[Ca 2 +]（i））。与对照大鼠不同，西地那非（10 - 100 nM）降低了CH大鼠PASMCs的静息[Ca 2 +]（i）值。在对照组和CH大鼠的PASMCs中，西地那非浓度依赖性地抑制G偶联膜受体激动剂（如血管紧张素II和苯肾上腺素）诱导的[Ca 2 +]（i）反应，但对咖啡因诱导的[Ca 2 +]（i）反应幅度无影响。西地那非（0.1 nM - 1 μ M）浓度依赖性地降低CH大鼠中存在的基础PA张力，并松弛对照和CH大鼠中苯肾上腺素预收缩的PA环。这些数据表明，西地那非是CH大鼠的有效肺动脉舒张剂，可使CH诱导的静息[Ca 2 +]（i）和基础张力升高正常化。因此，西地那非敏感性PDE 5的药理学抑制下调了该肺动脉高压模型中涉及的Ca 2+信号通路。
Sildenafil, a potent type 5 nucleotide-dependent phosphodiesterase (PDE) inhibitor, has been recently proposed as a therapeutic tool to treat or prevent pulmonary artery hypertension (PAHT). We thus studied the effect of sildenafil on both the calcium signaling of isolated pulmonary artery smooth muscle cells (PASMCs) and the reactivity of pulmonary artery (PA) obtained from chronic hypoxia (CH)-induced pulmonary hypertensive rats compared with control (normoxic) rats. CH rats were maintained in an hypobaric chamber (50.5 kPa) for 3 wk leading to full development of PAHT. Intracellular calcium concentration ([Ca2+](i)) was measured in PASMCs loaded with the calcium fluorophore indo 1. Unlike in control rats, sildenafil ( 10 - 100 nM) decreased the resting [Ca2+](i) value in PASMCs obtained from CH rats. In PASMCs from both control and CH rats, sildenafil concentration dependently inhibited the [Ca2+](i) response induced by G-coupled membrane receptor agonists such as angiotensin II and phenylephrine but had no effect on the amplitude of the [Ca2+](i) response induced by caffeine. Sildenafil (0.1 nM - 1 muM) concentration dependently reduced basal PA tone that is present in CH rats and relaxed PA rings precontracted with phenylephrine in both control and CH rats. These data show that sildenafil is a potent pulmonary artery relaxant in CH rats and that it normalizes CH-induced increases in resting [Ca2+](i) and basal tone. Consequently, pharmacological inhibition of sildenafil-sensitive PDE5 downregulates the Ca2+ signaling pathway involved in this model of pulmonary hypertension.