title: Nitroxide derivatives for imaging of hypercholesterolemia-induced kidney dysfunction and assessing the effectiveness of antilipidemic drugs.
abstract: The present study was designed to clarify the possibility for application of nitroxide derivatives in magnetic resonance imaging (MRI) of hypercholesterolemia-mediated renal dysfunction in mice, as well as to assess the effectiveness of antilipidemic drugs (cholestyramine and ezetimibe). The mice were separated in four groups: (i) on a normal diet (ND) without medication (control); (ii) on a high cholesterol diet (CD) without medication; (iii) CD mice receiving cholestyramine; and (iv) CD mice receiving ezetimibe. In CD mice without medication, a hypercholesterolemia was developed, detected by the increasing of total plasma cholesterol and non-HDL cholesterol, and decreasing of HDL cholesterol. The hypercholesterolemia compromised renal function: blood urea nitrogen, creatine and uric acid increased significantly, accompanied with development of glomerulosclerosis, enhancement of the amount of neutrophils and overexpression of metalloproteinase-9. The mice were subjected to anesthesia and MR imaging was performed on 7 T magnet (T1-weighted incoherent gradient-echo sequence; fast low-angle shot). The region-of-interest was selected within the kidney. The images were obtained before and after injection of contrast probe [carbamoyl-PROXYL (CMP) or Gd-DTPA]. In the kidney of ND mice, the MRI signal intensity increased after injection of CMP, reached a maximum (very well-defined renal filtration peak) and decreased to the baseline level within 14 min. In kidney of CD mice, the CMP-mediated enhancement of MRI signal was not detected. Antilipidemic drugs patially abolished the effect of hypercholesterolemia on CMP-enhanced MRI in the kidney. The kinetic curves of Gd-enhanced MRI signal had also different profiles in the kidney of ND and CD mice. They were similar to the profiles of the kinetic curves, obtained from MR urography of healthy human and human with renal pathology, respectively. The present study suggests that CMP is a suitable MRI contrast probe for visualization of hypercholesterolemia-induced renal dysfunction in intact animals and the assessment of the efficacy of antilipidemic drugs. The probe was applied at a concentration that was 3 times lower than the LD50 for intravenous administration in mice. Since the probe is excreted by the kidney, it could be considered harmless for mammalians in the selected dose and appropriate candidate for translational research.
authors: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors: Atsuyuki
authors: A
authors: Tomizawa
authors: George
authors: G
authors: Hadjidekov
authors: Itsuko
authors: I
authors: Ishii
authors: Rumiana
authors: R
authors: Bakalova
authors: Zhivko
authors: Z
authors: Zhelev
authors: Ichio
authors: I
authors: Aoki
authors: Tsuneo
authors: T
authors: Saga
authors: Mitsukazu
authors: M
authors: Kitada
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001384:Azetidines / Q000627:therapeutic use; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000009:adverse effects; D002792:Cholestyramine Resin / Q000627:therapeutic use; D003287:Contrast Media / Q000009:adverse effects / Q000737:chemistry*; D003497:Cyclic N-Oxides / Q000009:adverse effects; D016903:Drug Monitoring / Q000379:methods*; D000069438:Ezetimibe; D019786:Gadolinium DTPA / Q000009:adverse effects; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007700:Kinetics; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009589:Nitrogen Oxides / Q000009:adverse effects / Q000737:chemistry*; D011759:Pyrrolidines / Q000009:adverse effects; D051437:Renal Insufficiency / Q000175:diagnosis* / Q000209:etiology / Q000473:pathology
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D002791:Cholesterol, Dietary; D003287:Contrast Media; D003497:Cyclic N-Oxides; D009589:Nitrogen Oxides; D011759:Pyrrolidines; D002792:Cholestyramine Resin; C077426:3-carbamoyl-2,2,5,5-tetramethyl-1-pyrrolidinyl-N-oxyl; D002784:Cholesterol; D000069438:Ezetimibe; C039900:nitroxyl; D019786:Gadolinium DTPA