title: Inhibition of Nitric Oxide Synthase 1 Induces Salt-Sensitive Hypertension in Nitric Oxide Synthase 1α Knockout and Wild-Type Mice.
abstract: We recently showed that α, β, and γ splice variants of neuronal nitric oxide synthase (NOS1) expressed in the macula densa and NOS1β accounts for most of the NO generation. We have also demonstrated that the mice with deletion of NOS1 specifically from the macula densa developed salt-sensitive hypertension. However, the global NOS1 knockout (NOS1KO) strain is neither hypertensive nor salt sensitive. This global NOS1KO strain is actually an NOS1αKO model. Consequently, we hypothesized that inhibition of NOS1β in NOS1αKO mice induces salt-sensitive hypertension. NOS1αKO and C57BL/6 wild-type (WT) mice were implanted with telemetry transmitters and divided into 7-nitroindazole (10 mg/kg/d)-treated and nontreated groups. All of the mice were fed a normal salt (0.4% NaCl) diet for 5 days, followed by a high-salt diet (4% NaCl). NO generation by the macula densa was inhibited by >90% in WT and NOS1αKO mice treated with 7-nitroindazole. Glomerular filtration rate in conscious mice was increased by ≈ 40% after a high-salt diet in both NOS1αKO and WT mice. In response to acute volume expansion, glomerular filtration rate, diuretic and natriuretic response were significantly blunted in the WT and knockout mice treated with 7-nitroindazole. Mean arterial pressure had no significant changes in mice fed a high-salt diet, but increased ≈ 15 mm Hg similarly in NOS1αKO and WT mice treated with 7-nitroindazole. We conclude that NOS1β, but not NOS1α, plays an important role in control of sodium excretion and hemodynamics in response to either an acute or a chronic salt loading.
authors.affiliation: From the Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa (X.W., L.W., J.W., G.Z., S.W., J.Z., R.L.); Shandong Medical Imaging Research Institute, Shandong Provincial Key Laboratory of Diagnosis and Treatment of Cardio-Cerebral Vascular Disease, Shandong University, Jinan, Shandong, China (X.W.); Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson (K.C., L.A.J.); and Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China (E.Y.L., G.Z.).
authors.forename: Ximing
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa (X.W., L.W., J.W., G.Z., S.W., J.Z., R.L.); Shandong Medical Imaging Research Institute, Shandong Provincial Key Laboratory of Diagnosis and Treatment of Cardio-Cerebral Vascular Disease, Shandong University, Jinan, Shandong, China (X.W.); Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson (K.C., L.A.J.); and Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China (E.Y.L., G.Z.).
authors.forename: Kiran
authors.initials: K
authors.lastname: Chandrashekar
authors.affiliation: From the Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa (X.W., L.W., J.W., G.Z., S.W., J.Z., R.L.); Shandong Medical Imaging Research Institute, Shandong Provincial Key Laboratory of Diagnosis and Treatment of Cardio-Cerebral Vascular Disease, Shandong University, Jinan, Shandong, China (X.W.); Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson (K.C., L.A.J.); and Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China (E.Y.L., G.Z.).
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: From the Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa (X.W., L.W., J.W., G.Z., S.W., J.Z., R.L.); Shandong Medical Imaging Research Institute, Shandong Provincial Key Laboratory of Diagnosis and Treatment of Cardio-Cerebral Vascular Disease, Shandong University, Jinan, Shandong, China (X.W.); Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson (K.C., L.A.J.); and Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China (E.Y.L., G.Z.).
authors.forename: En Yin
authors.initials: EY
authors.lastname: Lai
authors.affiliation: From the Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa (X.W., L.W., J.W., G.Z., S.W., J.Z., R.L.); Shandong Medical Imaging Research Institute, Shandong Provincial Key Laboratory of Diagnosis and Treatment of Cardio-Cerebral Vascular Disease, Shandong University, Jinan, Shandong, China (X.W.); Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson (K.C., L.A.J.); and Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China (E.Y.L., G.Z.).
authors.forename: Jin
authors.initials: J
authors.lastname: Wei
authors.affiliation: From the Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa (X.W., L.W., J.W., G.Z., S.W., J.Z., R.L.); Shandong Medical Imaging Research Institute, Shandong Provincial Key Laboratory of Diagnosis and Treatment of Cardio-Cerebral Vascular Disease, Shandong University, Jinan, Shandong, China (X.W.); Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson (K.C., L.A.J.); and Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China (E.Y.L., G.Z.).
authors.forename: Gensheng
authors.initials: G
authors.lastname: Zhang
authors.affiliation: From the Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa (X.W., L.W., J.W., G.Z., S.W., J.Z., R.L.); Shandong Medical Imaging Research Institute, Shandong Provincial Key Laboratory of Diagnosis and Treatment of Cardio-Cerebral Vascular Disease, Shandong University, Jinan, Shandong, China (X.W.); Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson (K.C., L.A.J.); and Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China (E.Y.L., G.Z.).
authors.forename: Shaohui
authors.initials: S
authors.lastname: Wang
authors.affiliation: From the Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa (X.W., L.W., J.W., G.Z., S.W., J.Z., R.L.); Shandong Medical Imaging Research Institute, Shandong Provincial Key Laboratory of Diagnosis and Treatment of Cardio-Cerebral Vascular Disease, Shandong University, Jinan, Shandong, China (X.W.); Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson (K.C., L.A.J.); and Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China (E.Y.L., G.Z.).
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa (X.W., L.W., J.W., G.Z., S.W., J.Z., R.L.); Shandong Medical Imaging Research Institute, Shandong Provincial Key Laboratory of Diagnosis and Treatment of Cardio-Cerebral Vascular Disease, Shandong University, Jinan, Shandong, China (X.W.); Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson (K.C., L.A.J.); and Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China (E.Y.L., G.Z.).
authors.forename: Luis A
authors.initials: LA
authors.lastname: Juncos
authors.affiliation: From the Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa (X.W., L.W., J.W., G.Z., S.W., J.Z., R.L.); Shandong Medical Imaging Research Institute, Shandong Provincial Key Laboratory of Diagnosis and Treatment of Cardio-Cerebral Vascular Disease, Shandong University, Jinan, Shandong, China (X.W.); Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson (K.C., L.A.J.); and Department of Physiology, Zhejiang University School of Medicine, Hangzhou, China (E.Y.L., G.Z.). ruisheng@health.usf.edu.
authors.forename: Ruisheng
authors.initials: R
authors.lastname: Liu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate / Q000502:physiology; D006973:Hypertension / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage*
chemical_list: D017673:Sodium Chloride, Dietary; D052248:Nitric Oxide Synthase Type I
keywords: 7-nitroindazole; arterial pressure; hypertension; sodium; telemetry