Enhancement of vasoconstrictor response by a noncalcemic analogue of vitamin D3.

To clarify the effects of active vitamin D3 on pressor and vascular responses to vasoconstrictor substances, we studied pressor responses to the intravenous injection of norepinephrine or angiotensin II (Ang II) and vasoconstrictor responses to norepinephrine. Sprague-Dawley rats were given 1,25-dihydroxyvitamin D3 subcutaneously (200 ng/kg per day) for 14 days. The administration of 1,25-dihydroxyvitamin D3 augmented the pressor responses to norepinephrine and Ang II in conscious rats and was associated with a significant increase in serum calcium concentration (11.0 +/- 0.2 mg/dl). To further clarify whether the increased pressor response to vasoconstrictors may be due to the calcemic or direct action of active vitamin D3, we studied the effect of its noncalcemic analogue, 22-oxacalcitriol, and its inactive analogue, 24,25-dihydroxyvitamin D3, on the pressor response to vasoconstrictors in rats. The pressor responses to norepinephrine and Ang II were apparently augmented in 22-oxacalcitriol-treated rats similarly to 1,25-dihydroxyvitamin D3-treated rats. In contrast, the pressor responses were not affected by either 24,25-dihydroxyvitamin D3 or the intravenous infusion of calcium chloride. In an ex vivo experiment using a mesenteric preparation, the vascular sensitivity to norepinephrine was moderately augmented in rats treated with both 22-oxacalcitriol and 1,25-dihydroxyvitamin D3 but was not affected in rats treated with 24,25-dihydroxyvitamin D3. The results suggest that the enhanced pressor responses to norepinephrine and Ang II could be attributed to the direct effect of active vitamin D3 on vasculature rather than to hypercalcemia.