title: Endothelin receptor antagonist reverses decreased NO system in the kidney in vivo during exercise.
abstract: 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.
authors.affiliation: Center for Tsukuba Advanced Research Alliance, Institute of Health and Sport Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan. smaeda@tara.tsukuba.ac.jp
authors.forename: Seiji
authors.initials: S
authors.lastname: Maeda
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyauchi
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Iemitsu
authors.forename: Takumi
authors.initials: T
authors.lastname: Tanabe
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Goto
authors.forename: Iwao
authors.initials: I
authors.lastname: Yamaguchi
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D065130:Endothelin A Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology / Q000502:physiology*; D008297:Male; D009392:Nephrectomy; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D009929:Organ Size / Q000187:drug effects; D005082:Physical Exertion / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020239:Receptor Cross-Talk / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D065130:Endothelin A Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C113972:T 0201; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat