M-AND-B 22948, A CGMP PHOSPHODIESTERASE INHIBITOR, IS A PULMONARY VASODILATOR IN LAMBS
M-AND-B 22948, A CGMP PHOSPHODIESTERASE INHIBITOR, IS A PULMONARY VASODILATOR IN LAMBS
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DOI：
10.1152/ajpheart.1993.264.1.h252
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发表时间：
1993-01-01
影响因子：
--
通讯作者：
SOIFER, SJ
中科院分区：
文献类型：
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作者：
BRANER, DAV;FINEMAN, JR;SOIFER, SJ
为了研究肺血管张力和内皮依赖性肺血管舒张是由血管平滑肌细胞cGMP浓度的变化介导的这一假设，我们研究了选择性鸟苷3 '，5'-环磷酸（cGMP）磷酸二酯酶抑制剂M&B 22948对8只完整新生羔羊的血流动力学效应。在休息时，M&B 22948（1.0-2.5 mg/kg）选择性降低肺动脉压（8.5 +/- 6.6至10.3 +/-4.5%，P < 0.05）。同样，M&B 22948（0.5-5.0 mg/kg）在由U46619诱导的肺动脉高压期间产生选择性剂量依赖性肺动脉压降低，（7.7 ± 4.2至44.2 ± 4.4%，P < 0.05）或肺泡缺氧（9.5 ± 6.2至29.0 ± 11.0%，P < 0.05）。此外，M&B 22948增强了乙酰胆碱和ATP（内皮依赖性和cAMP依赖性血管扩张剂）的肺血管扩张作用，但不增强异丙肾上腺素（内皮非依赖性和cAMP依赖性血管扩张剂）的肺血管扩张作用。由于M&B 22948抑制cGMP的分解，因此本研究支持体外数据，即cGMP的血管平滑肌细胞浓度的变化部分地可调节肺血管张力并介导肺循环中的内皮依赖性血管舒张反应。此外，N（ω）-硝基-L-精氨酸（一种内皮衍生的舒张因子合成抑制剂）阻断了M&B 22948的血管舒张作用，表明大部分内源性cGMP是由内皮衍生的舒张因子释放产生的。
To investigate the hypothesis that pulmonary vascular tone and endothelium-dependent pulmonary vasodilation are mediated by changes in the vascular smooth muscle cell concentration of cGMP, we studied the hemodynamic effects of M&B 22948, a selective guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor, in eight intact newborn lambs. At rest, M&B 22948 (1.0-2.5 mg/kg) selectively decreased pulmonary arterial pressure (by 8.5 +/- 6.6 to 10.3 +/- 4.5%, P < 0.05). Similarly, M&B 22948 (0.5-5.0 mg/kg) produced selective dose-dependent decreases in pulmonary arterial pressure during pulmonary hypertension induced either by U46619 (by 7.7 +/- 4.2 to 44.2 +/- 4.4%, P < 0.05) or by alveolar hypoxia (by 9.5 +/- 6.2 to 29.0 +/- 11.0%, P < 0.05). In addition, M&B 22948 augmented the pulmonary vasodilating effects of acetylcholine and ATP (both endothelium- and cGMP-dependent vasodilators) but not isoproterenol (an endothelium-independent and cAMP-dependent vasodilator). Because M&B 22948 inhibits the breakdown of cGMP, this study supports the in vitro data that changes in the vascular smooth muscle cell concentration of cGMP, in part, may regulate pulmonary vascular tone and mediate endothelium-dependent vasodilator responses in the pulmonary circulation. In addition, N(omega)-nitro-L-arginine (an inhibitor of endothelium-derived relaxing factor synthesis) blocked the vasodilating effects of M&B 22948, suggesting that the majority of endogenous cGMP is generated by the release of endothelium-derived relaxing factor.