Reddy V M, Wong J, Liddicoat J R, Johengen M, Chang R, Fineman J R
Department of Cardiothoracic Surgery, University of California, San Francisco 94143-0106, USA.
Am J Physiol. 1996 Aug;271(2 Pt 2):H562-70. doi: 10.1152/ajpheart.1996.271.2.H562.
To investigate early endothelial function associated with increased pulmonary blood flow, vascular shunts were placed between the ascending aorta and main pulmonary artery in 18 late-gestation fetal sheep. Four weeks after delivery, the lambs were instrumented to measure vascular pressures and blood flows, and blood was collected to measure plasma concentrations of guanosine 3',5'-cyclic monophosphate [cGMP, the second messenger to nitric oxide (NO)-mediated vasodilation] and L-arginine (the precursor for NO synthesis). The responses to the endothelium-dependent vasodilators acetylcholine (ACh, 1.0 microgram/kg) and ATP (0.1 mg.kg-1.min-1), the endothelium-independent vasodilators M & B-22948 (a cGMP-specific phosphodiesterase inhibitor, 2.5 mg/kg) and inhaled NO (40 ppm), and N omega-nitro-L-arginine (an inhibitor of NO synthase, 5 mg/kg) were then compared with responses in 12 age-matched controls. Vasodilator responses in control lambs were determined during pulmonary hypertension induced by U-46619 (a thromboxane A2 mimic). Shunted lambs displayed a selective impairment of endothelium-dependent pulmonary vasodilation, an augmented pulmonary vasoconstricting response to NO synthase inhibition, increased plasma cGMP concentrations, and decreased L-arginine concentrations. Taken together, these data suggest that lambs with pulmonary hypertension and increased pulmonary blood flow have early aberrations in endothelial function, as manifested by increased basal NO activity, that cannot be further increased by agonist-induced endothelium-dependent vasodilators.
为了研究与肺血流量增加相关的早期内皮功能，在18只妊娠晚期胎羊的升主动脉和主肺动脉之间放置血管分流装置。分娩后4周，对羔羊进行仪器安装以测量血管压力和血流量，并采集血液以测量血浆中环磷酸鸟苷（cGMP，一氧化氮（NO）介导的血管舒张的第二信使）和L-精氨酸（NO合成的前体）的浓度。然后将对内皮依赖性血管舒张剂乙酰胆碱（ACh，1.0微克/千克）和ATP（0.1毫克·千克⁻¹·分钟⁻¹）、内皮非依赖性血管舒张剂M&B-22948（一种cGMP特异性磷酸二酯酶抑制剂，2.5毫克/千克）和吸入的NO（40 ppm）以及NO合酶抑制剂Nω-硝基-L-精氨酸（5毫克/千克）的反应与12只年龄匹配的对照羊的反应进行比较。在由U-46619（一种血栓素A2类似物）诱导的肺动脉高压期间测定对照羔羊的血管舒张反应。分流的羔羊表现出内皮依赖性肺血管舒张的选择性损害、对NO合酶抑制的肺血管收缩反应增强、血浆cGMP浓度升高和L-精氨酸浓度降低。综上所述，这些数据表明，患有肺动脉高压和肺血流量增加的羔羊在内皮功能方面存在早期异常，表现为基础NO活性增加，激动剂诱导的内皮依赖性血管舒张剂不能进一步增加这种活性。
