Chronic treatment with vitamin D lowers arterial blood pressure and reduces endothelium-dependent contractions in the aorta of the spontaneously hypertensive rat

Abstract

Vitamin D has cardiovascular protective effects besides regulating calcium homeostasis. To examine the chronic in vivo effect of a physiological dose of 1,25-dihydroxyvitamin D(3) on the occurrence of endothelium-dependent contractions, spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were treated with the vitamin D derivative for 6 wk. The serum 1,25-dihydroxyvitamin D(3) level of both treated WKY and SHR was significantly higher than in untreated rats while the mean arterial blood pressure of the treated SHR was significantly lower than that of control SHR. Aortic rings with or without endothelium were studied in conventional organ chambers for isometric force measurement. Confocal microscopy was used to measure the cytosolic free calcium concentration (with the fluorescent dye fluo 4) and reactive oxygen species (ROS; with dichlorodihydrofluorescein diacetate). Reverse transcription PCR and Western blotting were used to determine the mRNA and protein expression level of cyclooxygenase-1 (COX-1), prostacyclin synthase, and thromboxane synthase. The endothelium-dependent concentration-contraction curves to both acetylcholine- and A-23187-induced contractions were shifted to the right in aortas from treated SHR but not from treated WKY. The chronic treatment normalized the relaxations of contracted preparations to acetylcholine. There were no significant differences in the increases in cytosolic free calcium concentration evoked by acetylcholine and A-23187 between control and treated groups. The endothelial ROS level was higher in SHR than WKY aortas and reduced by the chronic treatment. The gene and protein expression studies indicated that the overexpression of COX-1 observed in SHR aorta was reduced by the chronic treatment. These results demonstrate that chronic treatment with 1,25-dihydroxyvitamin D(3) modulates vascular tone and this modulation is accompanied by a lowered blood pressure, reduced expression of COX-1 mRNA and protein, and reduced ROS level in SHR. The reduction in endothelium-dependent contractions does not involve the surge in endothelial cytosolic calcium concentration that initiates the contractions.