Wilson P S, Thompson W J, Moore T M, Khimenko P L, Taylor A E
Department of Physiology, University of South Alabama College of Medicine, Mobile 36688, USA.
J Surg Res. 1997 Jun;70(1):75-83. doi: 10.1006/jsre.1997.5095.
Vascular shear stress increases when blood flow or blood viscosity increases or when vessel diameter decreases. In the systemic circulation, shear stress is a potent stimulus for endothelial nitric oxide synthesis. We studied isolated rat lungs to determine whether increasing shear stress increases nitric oxide synthesis in the pulmonary circulation. Lungs were given the vasoconstrictor, U46619 (a thromboxane analogue), and perfused at constant flow rates or at constant pressure, since constant pressure perfusion minimizes changes in shear stress with vasoconstriction. The subsequent effect of the NOS inhibitor, N omega-methyl-L-arginine (LMA), or the soluble guanylyl cyclase inhibitor, 6-anilino-5,8-quinolinodione (LY83583) was assessed. Changes in pulmonary vascular resistance (PVR), pulmonary vascular compliance, and perfusate cyclic GMP concentration were measured as indicators of nitric oxide synthesis. The effect of the cyclic GMP-specific (type V) phosphodiesterase inhibitor, zaprinast, on perfusate cyclic GMP concentrations was also examined. An infusion of U46619 consistently increased PVR and decreased compliance. LMA and LY83583 also increased PVR in U46619-treated lungs perfused at constant flow rates, primarily by increasing precapillary resistance. LMA had no effect in U46619-treated lungs perfused at constant pressure. Perfusate cyclic GMP concentrations increased significantly after U46619 in lungs perfused at constant flow rates, but cyclic GMP levels did not change after U46619 in lungs perfused at constant pressure. Zaprinast also increased perfusate cyclic GMP, demonstrating that increases in intracellular cyclic GMP are reflected in circulating cyclic GMP concentrations. We conclude that vasoconstriction with U46619 increases nitric oxide synthesis in isolated rat lungs. Lungs perfused at constant pressure respond differently to NOS inhibitors compared to those perfused at constant flow, suggesting that shear stress may increase nitric oxide synthesis in the lung. Perfusate concentrations of cyclic GMP reflect activation of soluble guanylyl cyclase in this model.
当血流或血液黏度增加，或血管直径减小时，血管切应力会增大。在体循环中，切应力是内皮一氧化氮合成的有力刺激因素。我们研究了离体大鼠肺，以确定增加切应力是否会增加肺循环中一氧化氮的合成。给肺给予血管收缩剂U46619（一种血栓素类似物），并以恒定流速或恒压灌注，因为恒压灌注可使血管收缩时切应力的变化最小化。随后评估一氧化氮合酶抑制剂Nω-甲基-L-精氨酸（LMA）或可溶性鸟苷酸环化酶抑制剂6-苯胺基-5,8-喹啉二酮（LY83583）的作用。测量肺血管阻力（PVR）、肺血管顺应性和灌注液环磷酸鸟苷（cGMP）浓度的变化，作为一氧化氮合成的指标。还研究了环磷酸鸟苷特异性（V型）磷酸二酯酶抑制剂扎普司特对灌注液环磷酸鸟苷浓度的影响。输注U46619持续增加PVR并降低顺应性。在以恒定流速灌注的经U46619处理的肺中，LMA和LY83583也增加PVR，主要是通过增加毛细血管前阻力。LMA对以恒压灌注的经U46619处理的肺没有影响。在以恒定流速灌注的肺中，U46619后灌注液环磷酸鸟苷浓度显著增加，但在以恒压灌注的肺中，U46619后环磷酸鸟苷水平没有变化。扎普司特也增加灌注液环磷酸鸟苷，表明细胞内环磷酸鸟苷的增加反映在循环环磷酸鸟苷浓度中。我们得出结论，U46619引起的血管收缩增加了离体大鼠肺中一氧化氮的合成。与以恒定流速灌注的肺相比，以恒压灌注的肺对一氧化氮合酶抑制剂的反应不同，这表明切应力可能增加肺中一氧化氮的合成。在该模型中，灌注液中环磷酸鸟苷的浓度反映了可溶性鸟苷酸环化酶的激活。
