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

Abstract

To clarify the effects of active vitamin D 3 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 D 3 subcutaneously (200 ng/kg per day) for 14 days. The administration of 1,25-dihydroxyvitamin D, 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 D 3 , we studied the effect of its noncalcemic analogue, 22-oxacalcitriol, and its inactive analogue, 24,25-dihydroxy vitamin D } , 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 D 3 -treated rats. In contrast, the pressor responses were not affected by either 24,25-dihydroxy vitamin D 3 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 D 3 but was not affected in rats treated with 24,25-dihydroxyvitamin D 3 . The results suggest that the enhanced pressor responses to norepinephrine and Ang II could be attributed to the direct effect of active vitamin D, on vasculature rather than to hypercalcemia. the calcemic effect of 1,25(OH) 2 D 3 might in some way contribute to the increased pressor action of the active vitamin D 3 . Elevation of serum calcium concentration in forearm blood flow with intrabrachial infusion of calcium not only increased basal forearm vascular resistance but also augmented the forearm vascular responses to vasoactive substances in humans.10 In addition to its calcemic effect, 1,25(OH) 2 D 3 has noncalcemic effects, such as stimulating cell differentiation," depressing parathyroid hormone, 12 and enhancing the immune response. 13 We therefore should consider both noncalcemic and calcemic effects as contributing to the vasoconstrictive action of 1,25(OH) 2 D 3 .There have been no previous studies on the noncalcemic action of 1,25(OH) 2 D 3 on vasculature. To evaluate whether noncalcemic effects of 1,25(OH) 2 D 3 may be involved in increased vasoconstrictor responses, we studied the effect of chronically administered 1,25-(OH) 2 D 3 , its noncalcemic analogue 22-oxacalcitriol (OCT), or its nonactive analogue 24,25 -dihydroxyvitamin D 3 [24,25(OH) 2 D 3 ] on the in vivo and ex vivo vascular responses to norepinephrine or angiotensin II (Ang II) in Sprague-Dawley rats. Methods Protocol 1Forty 8-week-old male Sprague-Dawley rats (body weight, 200-250 g; Charles River Japan, Atsugi, Japan) were subjected to continuous infusion of 200

Blood Pressure Is Correlated with Vitamin D₃ Serum Levels in Dialysis Patients

“…It has been demonstrated that vitamin D 3 supplementation, when given at pharmacological doses, increases the vascular tonus in rats [18][19][20] and that this effect may be independent of the increase in the vascular calcium content [21,22]. These observations also hold true in humans.…”

Vitamin D and the Cardiovascular System

“…In SHR, 1,25(OH) 2 D 3 treatment increased the active stress response of resistance arteries to norepinephrine and arginine vasopressin, without changing sensitivity [41]. Moreover, the perfusion pressure induced by norepinephrine was significantly elevated in mesenteric vascular bed from 1,25(OH) 2 D 3 -treated, as well as nonhypercalcemic vitamin D analog (22-oxacalcitriol)-treated rats compared to controls [42].…”

Parathyroid Hormone and Calcitriol in Hypertension Caused by Dietary Calcium Deficiency in Rats

“…The receptor of calcitriol has been shown in vascular smooth muscle cells [64, 65], and calcitriol also stimulates the capture of calcium from the extracellular space [66, 67, 68, 69, 70]. Moreover, treatment with calcitriol increases the force-generating capacity of isolated resistance arteries [66, 69]and enhances the pressor response to norepinephrine and angiotensin II in vivo [71]. …”