title: Vitamin D receptor agonist VS-105 improves cardiac function in the presence of enalapril in 5/6 nephrectomized rats.
abstract: Vitamin D receptor (VDR) agonists (VDRAs) are commonly used to manage hyperparathyroidism secondary to chronic kidney disease (CKD). Patients with CKD experience extremely high risks of cardiovascular morbidity and mortality. Clinical observations show that VDRA therapy may be associated with cardio-renal protective and survival benefits in patients with CKD. The 5/6 nephrectomized (NX) Sprague-Dawley rat with established uremia exhibits elevated serum parathyroid hormone (PTH), hypertension, and abnormal cardiac function. Treatment of 5/6 NX rats with VS-105, a novel VDRA (0.05 and 0.5 μg/kg po by gavage), once daily for 8 wk in the presence or absence of enalapril (30 mg/kg po via drinking water) effectively suppressed serum PTH without raising serum calcium. VS-105 alone reduced systolic blood pressure (from 174 ± 6 to 145 ± 9 mmHg, P < 0.05) as effectively as enalapril (from 174 ± 6 to 144 ± 7 mmHg, P < 0.05). VS-105 improved cardiac functional parameters such as E/A ratio, ejection fraction, and fractional shortening with or without enalapril. Enalapril or VS-105 alone significantly reduced left ventricular hypertrophy (LVH); VS-105 plus enalapril did not further reduce LVH. VS-105 significantly reduced both cardiac and renal fibrosis. The lack of hypercalcemic toxicity of VS-105 is due to its lack of effects on stimulating intestinal calcium transport and inducing the expression of intestinal calcium transporter genes such as Calb3 and TRPV6. These studies demonstrate that VS-105 is a novel VDRA that may provide cardiovascular benefits via VDR activation. Clinical studies are required to confirm the cardiovascular benefits of VS-105 in CKD.
authors.affiliation: Vidasym, Chicago, Illinois ruth.wuwong@prodigy.net.
authors.forename: J Ruth
authors.initials: JR
authors.lastname: Wu-Wong
authors.affiliation: Vidasym, Chicago, Illinois.
authors.forename: Yung-Wu
authors.initials: YW
authors.lastname: Chen
authors.affiliation: Vidasym, Chicago, Illinois.
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Wessale
mesh_terms: D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000494:pharmacology*; D005355:Fibrosis; D006961:Hyperparathyroidism / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009392:Nephrectomy / Q000379:methods*; D010281:Parathyroid Hormone / Q000097:blood; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000378:metabolism; D020127:Recovery of Function; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: C570781:5-(2-(1-(1-(3-hydroxy-2,3-dimethylbutoxy)ethyl)-7alpha-methyldihydro-1H-inden-4(2H,5H,6H,7H,7alphaH)-ylidene)ethylidene)-2-methylenecyclohexane-1,3-diol; D000806:Angiotensin-Converting Enzyme Inhibitors; D002316:Cardiotonic Agents; D010281:Parathyroid Hormone; D018167:Receptors, Calcitriol; D004656:Enalapril; D002117:Calcitriol
keywords: PTH; cardiac function; chronic kidney disease; vitamin D analog; vitamin D receptor