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VS‐105: a novel vitamin D receptor modulator with cardiovascular protective effects
Author(s) -
WuWong J Ruth,
Kawai Megumi,
Chen Yungwu,
Nakane Masaki
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01473.x
Subject(s) - medicine , parathyroid hormone , endocrinology , hypercalcaemia , vitamin d and neurology , calcitriol receptor , kidney disease , calcitriol , hyperparathyroidism , secondary hyperparathyroidism , left ventricular hypertrophy , blood pressure , calcium
BACKGROUND AND PURPOSE Vitamin D receptor (VDR) modulators (VDRMs) such as calcitriol, paricalcitol and doxercalciferol are commonly used to manage hyperparathyroidism secondary to chronic kidney disease (CKD). CKD patients experience extremely high risks of cardiovascular morbidity and mortality. Clinical observations show that VDRM therapy may be associated with cardio‐renal protective and survival benefits for CKD patients. However, hypercalcaemia remains a serious side effect for current VDRMs, which leads to the need for frequent dose titration and serum Ca (calcium) monitoring. Significant clinical benefits can be derived from a VDRM with cardiovascular protective effects without the hypercalcaemic liability. EXPERIMENTAL APPROACH Male Sprague–Dawley rats were 5/6 nephrectomized and 6 weeks later, after they had established uraemia, elevated parathyroid hormone levels, endothelial dysfunction and left ventricular hypertrophy, the rats were treated with VS‐105, a novel VDRM. The effects of VS‐105 were also tested in cultured HL‐60 cells. KEY RESULTS VS‐105 induced HL‐60 cell differentiation with an EC 50 value at 11.8 nM. Treatment (i.p., 3× a week over a period of 2 weeks) of the 5/6 nephrectomized rats by VS‐105 (0.004–0.64 µg·kg −1 ) effectively suppressed serum parathyroid hormone without raising serum Ca or phosphate levels. Furthermore, 2 weeks of treatment with VS‐105 improved endothelium‐dependent aortic relaxation and attenuated left ventricular abnormalities in a dose range that did not affect serum Ca levels. Similar results were obtained when VS‐105 was administered i.p. or by oral gavage. CONCLUSIONS AND IMPLICATIONS VS‐105 exhibits an overall therapeutic product profile that supports expanded use in CKD to realize the cardiovascular protective effects of VDR activation.