Vitamin D derivatives acutely reduce endothelium-dependent contractions in the aorta of the spontaneously hypertensive rat

1 Department of Pharmacology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong; and 2 Hybrigenics, Paris, France Submitted 5 February 2008 ; accepted in final form 8 May 2008 The available evidence suggests that vitamin D has cardiovascular effects besides regulating calcium homeostasis. To examine the effect of 1,25-dihydroxyvitamin D 3 , the major metabolite of vitamin D, on endothelium-dependent contractions, aortic rings of spontaneously hypertensive rats (SHR) were suspended in organ chambers for isometric force measurements. Rings were incubated with N -nitro- L -arginine methyl ester ( L -NAME) and then exposed to increasing concentrations of acetylcholine, ATP, or the calcium ionophore to trigger contractions. This was done in the absence or presence of 1,25-dihydroxyvitamin D 3 . The release of prostacyclin after acetylcholine or A-23187 stimulation was also measured. The cytosolic-free calcium concentration was measured by confocal microscopy after incubation with the fluorescent dyes fluo-4 and fura red. The presence of vitamin D receptors was confirmed using immunohistochemistry. Acetylcholine- and ATP-induced endothelium-dependent contractions were significantly reduced compared with those obtained in the absence of the drug. This effect was not present if A-23187 was used as an agonist. The acetylcholine- but not the A-23187-induced release of prostacyclin was reduced by the acute administration of 1,25-dihydroxyvitamin D 3 . Exposure to 1,25-dihydroxyvitamin D 3 reduced the increase in cytosolic-free calcium concentration caused by acetylcholine but not by A-23187 in cells. Vitamin D receptors were densely distributed in the endothelium. Inecalcitol (19-nor-14-epi-23-yne-1,25-dihydroxyvitamin D 3 ), a synthetic analog of vitamin D, caused a comparable depression of endothelium-dependent contractions as 1,25-dihydroxyvitamin D 3 . These results demonstrate that vitamin D 3 modulates vascular tone by reducing calcium influx into the endothelial cells and hence decreasing the production of endothelium-derived contracting factors. calcium; endothelium-derived contracting factors; inecalcitol Address for reprint requests and other correspondence: P. M. Vanhoutte, Dept. of Pharmacology, Univ. of Hong Kong, 2/F, Laboratory Block, Li Ka Shing Faculty of Medicine, Faculty of Medicine Bldg., 21 Sassoon Rd., Pokfulam, Hong Kong (e-mail: vanhoutt{at}hkucc.hku.hk )