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      Differential Inhibition of Renin mRNA Expression by Paricalcitol and Calcitriol in C57/BL6 Mice

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          Background/Aims: Vitamin D receptor activators (VDRAs) may suppress renin expression and VDR-mediated renin inhibitors may offer a novel mechanism to control the RAS. Methods: We delineated the effects of paricalcitol and calcitriol on PTH, renin, and iCa<sup>2+</sup> in C57/BL6 mice administered vehicle, paricalcitol, or calcitriol (0.01, 0.03, 0.10, 0.33, 1.0 µg/kg s.c.) 3 days/week for 9 days. Results: Paricalcitol produced PTH suppression from 0.03 to 1.0 µg/kg (values between 9.7 ± 3.3 and 20.7 ± 4.7 pg/ml; vehicle = 88.0 ± 16.9) and elicited dose-dependent reductions in renin/GAPDH expression at 0.33 and 1.0 µg/kg (0.037 ± 0.002, 0.027 ± 0.003; vehicle = 0.054 ± 0.003) but produced no increases iCa<sup>2+</sup> at any dose tested. Calcitrol produced PTH suppression at all doses tested (between 6.4 ± 1.2 and 29.5 ± 17.2 pg/ml) and renin suppression at 0.10, 0.33, and 1.0 µg/kg (0.029 ± 0.002, 0.031 ± 0.003, and 0.038 ± 0.02). However, at 0.33 and 1.0 mg/kg, calcitriol produced increases iCa<sup>2+</sup> (1.31 ± 0.03 and 1.48 ± 0.02 mmol/l; vehicle = 1.23 ± 0.02 mmol/l). Conclusions: Paricalcitol produces significant, dose-dependent suppression of renin expression in the absence of hypercalcemia at doses 10-fold above those necessary for PTH suppression. Calcitriol also produced suppression of renin at doses at least 10-fold above those required for PTH suppression, but increases in iCa<sup>2+</sup> were observed at doses only 3-fold above those necessary to elicit renin suppression.

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          Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy.

          Elevated calcium and phosphorus levels after therapy with injectable vitamin D for secondary hyperparathyroidism may accelerate vascular disease and hasten death in patients undergoing long-term hemodialysis. Paricalcitol, a new vitamin D analogue, appears to lessen the elevations in serum calcium and phosphorus levels, as compared with calcitriol, the standard form of injectable vitamin D. We conducted a historical cohort study to compare the 36-month survival rate among patients undergoing long-term hemodialysis who started to receive treatment with paricalcitol (29,021 patients) or calcitriol (38,378 patients) between 1999 and 2001. Crude and adjusted survival rates were calculated and stratified analyses were performed. A subgroup of 16,483 patients who switched regimens was also evaluated. The mortality rate among patients receiving paricalcitol was 3417 per 19,031 person-years (0.180 per person-year), as compared with 6805 per 30,471 person-years (0.223 per person-year) among those receiving calcitriol (P<0.001). The difference in survival was significant at 12 months and increased with time (P<0.001). In the adjusted analysis, the mortality rate was 16 percent lower (95 percent confidence interval, 10 to 21 percent) among paricalcitol-treated patients than among calcitriol-treated patients. A significant survival benefit was evident in 28 of 42 strata examined, and in no stratum was calcitriol favored. At 12 months, calcium and phosphorus levels had increased by 6.7 and 11.9 percent, respectively, in the paricalcitol group, as compared with 8.2 and 13.9 percent, respectively, in the calcitriol group (P<0.001). The two-year survival rate among patients who switched from calcitriol to paricalcitol was 73 percent, as compared with 64 percent among those who switched from paricalcitol to calcitriol (P=0.04). Patients who receive paricalcitol while undergoing long-term hemodialysis appear to have a significant survival advantage over those who receive calcitriol. A prospective, randomized study is critical to confirm these findings. Copyright 2003 Massachusetts Medical Society
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            Essential hypertension: renin and aldosterone, heart attack and stroke.

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              1,25(OH)2 vitamin D3, and retinoic acid antagonize endothelin-stimulated hypertrophy of neonatal rat cardiac myocytes.

              1,25(OH)2 Vitamin D3 (VD3) and retinoic acid (RA) function as ligands for nuclear receptors which regulate transcription. Though the cardiovascular system is not thought to represent a classical target for these ligands, it is clear that both cardiac myocytes and vascular smooth muscle cells respond to these agents with changes in growth characteristics and gene expression. In this study we demonstrate that each of these ligands suppresses many of the phenotypic correlates of endothelin-induced hypertrophy in a cultured neonatal rat cardiac ventriculocyte model. Each of these agents reduced endothelin-stimulated ANP secretion in a dose-dependent fashion and the two in combination proved to be more effective than either agent used alone (VD3: 49%; RA:52%; VD3 + RA:80% inhibition). RA, at concentrations known to activate the retinoid X receptor, and, to a lesser extent, VD3 effected a reduction in atrial natriuretic peptide, brain natriuretic peptide, and alpha-skeletal actin mRNA levels. Similar inhibition (VD3:30%; RA:33%; VD3 + RA:59% inhibition) was demonstrated when cells transfected with reporter constructs harboring the relevant promoter sequences were treated with VD3 and/or RA for 48 h. These effects were not accompanied by alterations in endothelin-induced c-fos, c-jun, or c-myc gene expression, suggesting either that the inhibitory locus responsible for the reduction in the mRNA levels lies distal to the activation of the immediate early gene response or that the two are not mechanistically coupled. Both VD3 and RA also reduced [3H]leucine incorporation (VD3:30%; RA:33%; VD3 + RA:45% inhibition) in endothelin-stimulated ventriculocytes and, once again, the combination of the two was more effective than either agent used in isolation. Finally, 1,25(OH)2 vitamin D3 abrogated the increase in cell size seen after endothelin treatment. These findings suggest that the liganded vitamin D and retinoid receptors are capable of modulating the hypertrophic process in vitro and that agents acting through these or similar signaling pathways may be of value in probing the molecular mechanisms underlying hypertrophy.

                Author and article information

                Nephron Physiol
                Nephron Physiology
                S. Karger AG
                July 2007
                02 July 2007
                : 106
                : 4
                : p76-p81
                aIntegrative Pharmacology, bMetabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Ill., USA
                104875 Nephron Physiol 2007;106:p76–p81
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 3, References: 33, Pages: 1
                Original Paper

                Cardiovascular Medicine, Nephrology

                Calcitriol, Renin, PTH, Blood-ionized calcium, Paricalcitol


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