Differential effects of vitamin D receptor activators on aortic calcification and pulse wave velocity in uraemic rats.
BACKGROUND
Vascular calcification is associated with an increase in cardiovascular mortality in stage 5 chronic kidney disease. To determine if vitamin D receptor activators (VDRAs) have differential effects in the pathogenesis of aortic calcification, we assessed the effects of paricalcitol and doxercalciferol in vivo using 5/6 nephrectomized (NX) rats. To quantify the functional consequences of vascular calcification, pulse wave velocity (PWV), an aortic compliance index, was measured.


METHODS
NX rats were fed a diet containing 0.9% phosphorous and 0.6% calcium 4 weeks prior to and throughout the study. On Day 0, rats received vehicle or VDRA (0.083, 0.167 and 0.333 microg/kg, i.p.) three times per week for 6 weeks. At Day 0 and Weeks 2 and 6, blood was drawn and PWV was measured by Doppler ultrasound.


RESULTS
VDRAs (0.167 and 0.333 microg/kg) consistently lowered PTH at Weeks 2 and 6. All doses of paricalcitol increased serum calcium at Week 6 but not at Week 2, while the two higher doses of doxercalciferol increased serum calcium at both Weeks 2 and 6. Treatment with paricalcitol (0.333 microg/kg) increased serum phosphorus at Weeks 2 and 6; these changes were not different from those observed in 5/6 NX rats. All doses of doxercalciferol increased serum phosphorus at Week 6. Paricalcitol had no effect on Ca x P; however, the two highest doses of doxercalciferol increased Ca x P at Weeks 2 and 6 above that observed in the 5/6 NX vehicle-treated group. There were no differences in aortic calcium and phosphorus contents at the end of 6 weeks among SHAM-, 5/6 NX- and paricalcitol-treated rats. However, treatment with the two higher doses of doxercalciferol caused a significant elevation in aortic calcium and phosphorus contents. Measurements of PWV demonstrated differential effects of VDRAs on vascular compliance. Paricalcitol produced no effects on PWV, while the two highest doses of doxercalciferol increased PWV at Week 6.


CONCLUSIONS
In uraemic rats with established secondary hyperparathyroidism, we demonstrate differential effects of paricalcitol and doxercalciferol on aortic calcification and PWV, independent of serum Ca, P and Ca x P, suggesting different mechanisms of action between VDRAs.
Noonan
William
W
Abbott Laboratories, GPRD, 1029 Sanderling Ct, Antioch, CA, USA. William.Noonan@abbott.com
Koch
Kristin
K
Nakane
Masaki
M
Ma
Junli
J
Dixon
Doug
D
Bolin
Antoinette
A
Reinhart
Glenn
G
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001783:Blood Flow Velocity / Q000187:drug effects; D002114:Calcinosis / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D004872:Ergocalciferols / Q000633:toxicity*; D006962:Hyperparathyroidism, Secondary / Q000188:drug therapy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009392:Nephrectomy; D010281:Parathyroid Hormone / Q000097:blood; D010758:Phosphorus / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000819:agonists*; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D014511:Uremia / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D014655:Vascular Resistance / Q000187:drug effects
D004872:Ergocalciferols; D010281:Parathyroid Hormone; D018167:Receptors, Calcitriol; D010758:Phosphorus; C042533:1 alpha-hydroxyergocalciferol; C084656:paricalcitol; D002118:Calcium