VS‐105: a novel vitamin D receptor modulator with cardiovascular protective effects
| Autor: | Megumi Kawai, J. Ruth Wu-Wong, Masaki Nakane, Yung-wu Chen |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Male
Paricalcitol medicine.medical_specialty Cardiotonic Agents Calcitriol Heart Ventricles Parathyroid hormone HL-60 Cells Themed Section: Drug Discovery Left ventricular hypertrophy Nephrectomy Calcitriol receptor Phosphates Rats Sprague-Dawley Ventricular Dysfunction Left Internal medicine Tumor Cells Cultured medicine Animals Humans Myocytes Cardiac Endothelium Doxercalciferol Aorta Pharmacology Hyperparathyroidism business.industry Drug Administration Routes Cell Differentiation medicine.disease Rats Vasodilation Endocrinology Parathyroid Hormone Ergocalciferols Kidney Failure Chronic Receptors Calcitriol Calcium Hypertrophy Left Ventricular Kidney Diseases business medicine.drug Kidney disease |
| Zdroj: | British Journal of Pharmacology. 164:551-560 |
| ISSN: | 1476-5381 0007-1188 |
| DOI: | 10.1111/j.1476-5381.2011.01473.x |
| Popis: | 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 EC50 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. |
| Databáze: | OpenAIRE |
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