Edgley Amanda J, Tare Marianne, Evans Roger G, Skordilis Con, Parkington Helena C
Department of Physiology, Monash University, Clayton, Australia.
Am J Physiol Regul Integr Comp Physiol. 2008 Sep;295(3):R829-39. doi: 10.1152/ajpregu.00861.2007. Epub 2008 Jul 16.
We assessed the relative contributions of endothelium-derived relaxing factors to renal vasodilation in vivo and determined whether these are altered in established streptozotocin-induced diabetes. In nondiabetic rats, stimulation of the endothelium by locally administered ACh or bradykinin-induced transient renal hyperemia. Neither basal renal blood flow (RBF) nor renal hyperemic responses to ACh or bradykinin were altered by blockade of prostanoid production (indomethacin) or by administration of charybdotoxin (ChTx) plus apamin to block endothelium-derived hyperpolarizing factor (EDHF). In contrast, combined blockade of nitric oxide (NO) synthase, N(omega)-nitro-l-arginine methyl ester (l-NAME), and prostanoid production reduced basal RBF and the duration of the hyperemic responses to ACh and bradykinin and revealed a delayed ischemic response to ACh. Accordingly, l-NAME and indomethacin markedly reduced integrated (area under the curve) hyperemic responses to ACh and bradykinin. Peak increases in RBF in response to ACh and bradykinin were not reduced by l-NAME and indomethacin but were reduced by subsequent blockade of EDHF. l-NAME plus indomethacin and ChTx plus apamin altered RBF responses to endothelium stimulation in a qualitatively similar fashion in diabetic and nondiabetic rats. The integrated renal hyperemic responses to ACh and bradykinin were blunted in diabetes, due to a diminished contribution of the component abolished by l-NAME plus indomethacin. We conclude that NO dominates integrated hyperemic responses to ACh and bradykinin in the rat kidney in vivo. After prior inhibition of NO synthase, EDHF mediates transient renal vasodilation in vivo. Renal endothelium-dependent vasodilation is diminished in diabetes due to impaired NO function.
我们评估了内皮源性舒张因子对体内肾血管舒张的相对贡献，并确定在链脲佐菌素诱导的糖尿病模型中这些因子是否发生改变。在非糖尿病大鼠中，局部给予乙酰胆碱（ACh）或缓激肽刺激内皮可诱导短暂性肾充血。阻断前列腺素生成（吲哚美辛）或给予蝎毒素（ChTx）加蜂毒明肽以阻断内皮源性超极化因子（EDHF），均不会改变基础肾血流量（RBF）以及对ACh或缓激肽的肾充血反应。相比之下，联合阻断一氧化氮（NO）合酶、N（ω）-硝基-L-精氨酸甲酯（L-NAME）和前列腺素生成会降低基础RBF以及对ACh和缓激肽的充血反应持续时间，并揭示出对ACh的延迟缺血反应。因此，L-NAME和吲哚美辛显著降低了对ACh和缓激肽的综合（曲线下面积）充血反应。L-NAME和吲哚美辛并未降低对ACh和缓激肽的RBF峰值增加，但随后阻断EDHF可降低该峰值。L-NAME加吲哚美辛以及ChTx加蜂毒明肽在糖尿病和非糖尿病大鼠中以定性相似的方式改变了RBF对内皮刺激的反应。糖尿病时对ACh和缓激肽的综合肾充血反应减弱，这是由于L-NAME加吲哚美辛所消除的成分的贡献减少所致。我们得出结论，在大鼠体内肾脏中，NO主导了对ACh和缓激肽的综合充血反应。在预先抑制NO合酶后，EDHF介导体内短暂性肾血管舒张。由于NO功能受损，糖尿病时肾内皮依赖性血管舒张减弱。
