Maeda Seiji, Miyauchi Takashi, Iemitsu Motoyuki, Tanabe Takumi, Goto Katsutoshi, Yamaguchi Iwao, Matsuda Mitsuo
Center for Tsukuba Advanced Research Alliance, Institute of Health and Sport Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
Am J Physiol Endocrinol Metab. 2004 Apr;286(4):E609-14. doi: 10.1152/ajpendo.00373.2003. Epub 2003 Dec 9.
Vascular endothelial cells produce endothelin (ET)-1, a potent vasoconstrictor peptide, and nitric oxide (NO), a potent vasodilator substance. There are interactions between ET-1 and NO. Exercise results in a marked decrease in renal blood flow. We previously reported that exercise causes an increase of ET-1 production in the kidney, whereas production of NO in the kidney is decreased. Furthermore, we recently revealed that the magnitude of decrease in blood flow to the kidney during exercise was significantly attenuated by the administration of the endothelin-A (ET(A)) receptor antagonist, strongly suggesting that endogenously increased ET-1 participates in the decrease of blood flow in the kidney during exercise. Because it was demonstrated that ET-1 depresses NO synthase (NOS) activity of cultured cells in vitro, we hypothesized that an increase of ET-1 production in kidney during exercise contributes to a decrease of NO production in kidney in vivo. We studied whether administration of the ET(A) receptor antagonist attenuates the decreases of NOS activity and NO production in the kidney during exercise. Rats performed treadmill running for 30 min after pretreatment with an ET(A) receptor antagonist (TA-0201, 0.5 mg/kg; TA-0201-treated exercise group) or vehicle (vehicle-treated exercise group). Control rats remained at rest (vehicle-treated sedentary group). Blood flow in the kidney was decreased by this exercise, but the magnitude of the decrease after pretreatment with TA-0201 was significantly smaller than that after pretreatment with vehicle. NOS activity in kidney was significantly lower in the vehicle-treated exercise group than in the vehicle-treated sedentary group, whereas that in the TA-0201-treated exercise group was significantly higher than that in the vehicle-treated exercise group. Expressions of endothelial NOS protein and NOx, the stable end product of NO, i.e., nitrite/nitrate, concentration in the kidney were significantly lower in the vehicle-treated exercise group than in the vehicle-treated sedentary group, whereas those in the TA-0201-treated exercise group were significantly higher than those in the vehicle-treated exercise group. The data suggest that increased ET-1 production in the kidney during exercise contributes to the decreases of NOS activity and NO production. Therefore, the present study provides a possibility that the exercise-induced increase in production of ET-1 in the kidney causes a decrease in blood flow in the kidney through two pathways, i.e., vasoconstrictive action and the action of attenuating NO production.
血管内皮细胞产生内皮素（ET）-1，一种强效的血管收缩肽，以及一氧化氮（NO），一种强效的血管舒张物质。ET-1和NO之间存在相互作用。运动导致肾血流量显著减少。我们之前报道过运动可使肾脏中ET-1的产生增加，而肾脏中NO的产生减少。此外，我们最近发现，给予内皮素A（ET(A)）受体拮抗剂可显著减轻运动期间肾脏血流减少的程度，这强烈表明内源性增加的ET-1参与了运动期间肾脏血流的减少。因为已证实在体外ET-1可抑制培养细胞的一氧化氮合酶（NOS）活性，我们推测运动期间肾脏中ET-1产生的增加导致体内肾脏中NO产生的减少。我们研究了给予ET(A)受体拮抗剂是否能减轻运动期间肾脏中NOS活性和NO产生的减少。大鼠在预先用ET(A)受体拮抗剂（TA-0201，0.5mg/kg；TA-0201处理的运动组）或溶剂（溶剂处理的运动组）预处理后进行30分钟的跑步机跑步。对照大鼠保持静止（溶剂处理的久坐组）。运动使肾脏血流减少，但用TA-0201预处理后的减少幅度明显小于用溶剂预处理后的减少幅度。溶剂处理的运动组肾脏中的NOS活性显著低于溶剂处理的久坐组，而TA-0201处理的运动组中的NOS活性显著高于溶剂处理的运动组。溶剂处理的运动组肾脏中内皮型NOS蛋白的表达以及NO的稳定终产物NOx（即亚硝酸盐/硝酸盐）的浓度显著低于溶剂处理的久坐组，而TA-0201处理的运动组中的这些指标显著高于溶剂处理的运动组。数据表明运动期间肾脏中ET-1产生的增加导致NOS活性和NO产生的减少。因此，本研究提供了一种可能性，即运动诱导的肾脏中ET-1产生的增加通过两种途径导致肾脏血流减少，即血管收缩作用和减弱NO产生的作用。
