Paricalcitol Treatment and Arterial Tone in Experimental Renal Insufficiency

Abstract

Aim: To examine whether treatment of secondary hyperparathyroidism with paricalcitol provides benefits to arteries in uremic rats. Methods: 5/6-nephrectomized rats were treated (NX+Pari) or not treated (NX) with paricalcitol (200 ng/kg, thrice weekly) for 12 weeks. Aortic histology and isolated segments of the main and 2nd-order mesenteric arterial branches were studied. Results: Creatinine clearance was reduced by 54–61%, plasma phosphate increased 2.1- to 2.5-fold, and blood pressure by 40 mm Hg in both NX groups. PTH increased 13-fold in NX and 5-fold in NX+Pari rats. Calcification in aortic cross-sections increased from 2.1 to 7.1% after paricalcitol. In the large mesenteric artery, vasoconstriction to noradrenaline was reduced in NX+Pari rats. In the large and small arteries, vasorelaxation to acetylcholine was impaired in NX rats and unaffected by paricalcitol. In the small artery, paricalcitol increased nitric oxide synthase inhibition-resistant relaxation to acetylcholine, and maximal relaxation to levcromakalim. The small arteries of NX rats featured increased wall cross-sectional area, while paricalcitol further increased wall thickness and the wall:lumen ratio. Conclusion: Paricalcitol treatment showed both benefits and harmful effects in uremic rats: in the large artery vasoconstriction was reduced but calcification increased, while in the small artery vasorelaxation via potassium channels was moderately improved but hypertrophic remodeling was aggravated.

Vitamin D and the Cardiovascular System

“…The effect of vitamin D on K þ channels is not limited to SHR. Similar findings have also been reported in 5/6-nephrectomized rats treated with paricalcitol, in this case leading to improved vasorelaxation in small mesenteric arteries [19].…”

“…The improved relaxation was abolished by an eNOS inhibitor suggesting that paricalcitol affects nitric oxide production [18]. However, this result is not supported by another study using the same animal model [19], a discrepancy which could be related to different levels and duration of disease progression. In the study showing a positive effect of paricalcitol [16], animals were treated with the drug immediately following nephrectomy for a total of 6 weeks.…”

“…Paricalcitol reduced maximal contraction elicited by norepinephrine in mesenteric artery from rats with renal insufficiency. Similarly, this was attributed to calcium deposition in the vascular wall [19]. A negative correlation between maximal contraction and calcium content was also found in aorta from vitamin-D-treated rats fed with a normal or high-cholesterol diet [38].…”

Effect of paricalcitol on renin and albuminuria in non-diabetic stage III-IV chronic kidney disease: a randomized placebo-controlled trial

“…In 5/6 nephrectomized rats, Freundlich et al documented a significant suppression of renin-angiotensin genes when paricalcitol was initiated a few days after surgery [5]. On the contrary, instituting paricalcitol treatment 15 weeks after 5/6 nephrectomy did not cause any changes in RAS components [22,23]. The latter animal model of CKD may more accurately resemble the state of chronic renal insufficiency in man.…”

Vitamin D Receptor Activation Mitigates the Impact of Uremia on Endothelial Function in the 5/6 Nephrectomized Rats

“…Wong et al [27] have also shown that calcitriol acutely reduced endothelium-dependent contractions in the aorta of the spontaneously hypertensive rat. Karavalakis et al [28] reported that, in the 5/6 nephrectomized rats fed a special diet that induced severe hyperphosphatemia, paricalcitol at 0.2  μ g/kg reduced vasoconstriction but increased calcification in the large artery. As a comparison, our results show that paricalcitol improves endothelial function in the 5/6 NX rats with normal serum phosphate levels.…”