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R U Simpson

Publications and source records attributed to R U Simpson.

At least 37 records · Page 2Linked to original sources
PubMed1990

Involvement of vitamin D3 with cardiovascular function. III. Effects on physical and morphological properties.

We have previously shown that depletion of vitamin D3 in rats results in a large increase in the contractile function of isolated hearts (R. E. Weishaar, J. Clin. Invest. 79: 1706-1712, 1987). To characterize the mechanism responsible for this increase, the effect of vitamin D3 depletion on key physical and morphological properties of cardiac muscle was examined. Depletion of vitamin D3 increased the heart weight/body weight ratio. This increase could neither be blocked by limiting hypocalcemia nor reversed by restoring increasing serum calcium levels. The cardiomegaly observed 9 wk after vitamin D3 depletion was not accompanied by an increase in myocardial water content or leakage of myocardial creatine phosphokinase and was not caused by myocardial cell hypertrophy. Histological examination of ventricular muscle from vitamin D3-deficient rats revealed a significant decrease in myofibrillar area and a significant increase in extracellular space. The increase in extracellular space was accompanied by a significant increase in myocardial collagen. Prevention of hypocalcemia in the vitamin D3-deficient rats did not prevent the increase in myocardial collagen. Such alterations in the physical and morphological properties of myocardial tissue might represent the basis for the change in myocardial contractile function that accompanies lengthy periods of vitamin D3 deficiency.

Animals↗
PubMed1989

1,25-Dihydroxyvitamin D3 regulation of c-myc protooncogene transcription. Possible involvement of protein kinase C.

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) regulates the expression of c-myc protooncogene in HL-60 promyelocytic leukemia cells (Reitzma, P. H., Rothberg, P. G., Astrin, S. M., Trial, J., Barshavit, Z., Hall, A., Teitelbaum, S. U., and Kahn, A. J. (1983) Nature 306, 492-494). The regulation of c-myc expression occurs at least in part at the transcriptional level (Simpson, R. U., Hsu, T., Begley, D. A., Mitchell, B. S., and Alizadeh, B. N. (1987) J. Biol. Chem. 262, 4104-4108). Also, 1,25-(OH)2D3 stimulates an increase in protein kinase C (PKC) levels and inhibitors of PKC block 1,25-(OH)2D3-induced differentiation of HL-60 cells (Martell, R. E., Simpson, R. U., and Taylor, J. M. (1987) J. Biol. Chem. 262, 5570-5575). In this report we demonstrated that sphinganine, an inhibitor of PKC that is mechanistically and structurally distinct from 1-(5-isoquinoline sulfonyl)-2-methylpiperazine-HCl (H-7), also blocks 1,25-(OH)2D3 induction of HL-60 cell differentiation. The effect of inhibitors of PKC on 1,25-(OH)2D3 regulation of c-myc transcription was examined. H-7 (18 microM) and sphinganine (3 and 6 microM) blunted 1,25-(OH)2D3-induced reduction of c-myc transcription as assessed by nuclear run-off assays. We showed that c-myc/beta-actin ratios (cpm/cpm, % of control mean +/- S.E.) were as follows: ethanol control, 100 +/- 14%; 50 nM 1,25-(OH)2D3, 17 +/- 5%; 50 nM 1,25-(OH)2D3 and 6 microM H-7, 13 +/- 6%; 50 nM 1,25-(OH)2D3 and 18 microM H-7, 53 +/- 6% 50 nM 1,25-(OH)2D3 and 18 microM N-[2-guanidinoethyl]-5-isoquinoline sulfonamide (HA-1004), 10 +/- 8%; 50 nM 1,25-(OH)2D3 and 6 microM sphinganine, 49 +/- 8%. No significant differences in c-myc transcription between control, 18 microM H-7, 18 microM HA-1004, and 3 or 6 microM sphinganine-treated cells were observed. The block in c-myc transcription was beyond exon 1, and regulation of exon 1 transcription by 1,25-(OH)2D3 was not detected. Furthermore, we demonstrated that expression of markers for HL-60 cell differentiation was more rapidly induced by 25 nM 12-O-tetradecanoylphorbol-13-acetate than 50 nM 1,25-(OH)2D3, suggesting that direct activation of PKC by phorbol esters may make processes required for 1,25-(OH)2D3 induction of differentiation unnecessary. In summary, these data suggest that a primary effect of 1,25-(OH)2D3 on HL-60 cells is to regulate PKC levels, and regulation of c-myc transcription by 1,25-(OH)2D3 is a result of this action.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1989

Synthesis and evaluation of iodinated analogues of diacylglycerols as potential probes for protein kinase C.

Analogues of diacylglycerol containing a 3-(3-amino-2,4,6-triiodophenyl)-2-ethylpropanoyl or 3-(3-amino-2,4,6-triiodophenyl)propanoyl group in the 2-position (1a and 1b, respectively) were synthesized and shown to compete with [3H]phorbol dibutyrate [( 3H]PDBu) for binding in a crude rat brain preparation. Phorbol diesters have been shown to bind specifically to protein kinase C and the PDBu receptor has been copurified with protein kinase C activity. The four diastereomers of 1a (1c-f) were synthesized from chiral starting material and studied in the same assay. The affinities for the [3H]PDBu binding site of 1a, 1b, and two isomers of 1a with naturally occurring L configuration were comparable to that of 1-oleoyl-2-acetyl-rac-glycerol (OAG), but the D isomers of 1a were essentially inactive. The chirality of the side chain did not influence the binding affinity. Activation of protein kinase C by 1a, 1c, and 1e demonstrated the same stereochemical requirements, but none were as active as OAG. For the 1,3-isomers 2, 2a, and 2b, the competitive binding studies gave different results. The racemic mixture and the D isomer, 2b, were able to compete for binding, but the L isomer, 2a, did not compete. These studies demonstrate that diacylglycerol binding to and activation of protein kinase C is stereospecific for the glycerol backbone, but not the side chain. Furthermore, the D-1,3-isomer must exist in a conformation such that the acyl and hydroxyl oxygens assume a spatial relationship similar to that in the L-1,2-isomers.

Animals↗
PubMed1989

Iodoaryl analogues of dioctanoylglycerol and 1-oleoyl-2-acetylglycerol as probes for protein kinase C.

Analogues of dioctanoylglycerol (diC8) and 1-oleoyl-2-acetylglycerol (OAG) containing an iodoaryl group have been synthesized and shown to compete with [3H]phorbol dibutyrate [( ([3H]PDBu) for binding to protein kinase C in a crude rat brain preparation. Phorbol diesters have been shown to bind specifically to protein kinase C and the PDBu receptor has been copurified with protein kinase C activity. All three diacylglycerol analogues were comparable to OAG in binding affinity. In an assay of protein kinase C activation, the diC8 analogue was more active than the OAG analogues, thus demonstrating greater structural specificity under the conditions of this assay.

Animals↗
PubMed1989

Effect of vitamin D metabolites on calcitriol metabolism in experimental renal failure.

Previous studies from our laboratory have demonstrated that metabolic clearance rate (MCR) of calcitriol is decreased in experimental renal failure. In this experiment, we examined the effects of calcitriol, 25-hydroxyvitamin D3 (25(OH)D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) on the MCR of calcitriol in renal failure produced in rats by partial nephrectomy. The MCR of calcitriol in these rats with renal failure was significantly lower than in control rats with sham operations. Plasma concentrations of calcitriol did not differ between the rats with moderate renal failure and control rats (sham, 74.7 +/- 3.6 pg/ml, N = 7; renal failure, 67.7 +/- 6.0, N = 6; serum creatinine 0.56 +/- 0.02 mg/dl vs. 0.96 +/- 0.02); however, the levels were significantly lower in rats with severe renal failure (sham, 66.5 +/- 5.1 pg/ml, N = 7, severe renal failure, 49.6 +/- 2.1 pg/ml, N = 8; serum creatinine 0.53 +/- 0.01 mg/dl vs. 1.40 +/- 0.03). Subcutaneous infusion of calcitriol (10 ng/kg/day) in rats with severe renal failure for one week significantly increased the MCR of calcitriol (0.22 +/- .01 vs. 0.17 +/- .01 ml/min/kg, P less than 0.001). Infusion of 25(OH)D3 (600 ng/day) or 24,25(OH)2D3 (1 microgram/day) in rats with renal failure for one week also increased the MCR of calcitriol (25(OH)D3, 0.25 +/- 0.01 ml/min/kg; 24,25(OH)2D3, 0.25 +/- 0.01, both P less than 0.001) when compared to rats with renal failure infused with vehicle (0.21 +/- 0.01). Administration of 24,25(OH)2D3 significantly lowered the plasma levels of calcitriol in rats with renal failure (52.3 +/- 3.1 pg/ml, P less than 0.05) in comparison to the rats with renal failure infused with vehicle (67.7 +/- 6.0).(ABSTRACT TRUNCATED AT 250 WORDS)

24,25-Dihydroxyvitamin D 3↗
PubMed1988

Effects of protein kinase inhibitors 1(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) and N-[2-guanidinoethyl]-5-isoquinolinesulfonamide hydrochloride (HA1004) on calcitriol-induced differentiation of HL-60 cells.

HL-60 promyelocytic leukemia cells were induced to differentiate by 1,25-dihydroxyvitamin D3 (calcitriol) into mature monocytes. Differentiation was assessed by nitro blue tetrazolium dye reduction, nonspecific esterase activity, and DNA synthesis. Terminal differentiation of cultures induced by calcitriol (10 nM) was inhibited by 80% when cells were treated simultaneously with protein kinase inhibitors 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) (32 microM) and N-[2-guanidinoethyl]-5-isoquinolinesulfonamide hydrochloride (HA1004) (320 microM). The IC50 for inhibition of calcitriol-induced differentiation was approximately 15 microM for H-7 and 170 microM for HA1004. The IC50 values for H-7 and HA1004 antagonism of calcitriol-induced differentiation are quantitatively and relatively correlated to their known action to inhibit protein kinase C activity. Treatment of cells with concentrations of 0-32 microM H-7 or 0-320 microM HA1004 alone did not affect cell growth, differentiation, or trypan blue exclusion. However, higher concentrations of H7 (greater than 32 microM) and HA1004 (greater than 320 microM) were found to be cytotoxic. The data presented suggest that calcitriol-induced differentiation is antagonized by inhibitors of protein kinase and are consistent with the hypothesis that kinase C activity is required for HL-60 cell differentiation.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1988

Involvement of 1,25-dihydroxyvitamin D3 in regulating myocardial calcium metabolism: physiological and pathological actions.

The role of the prohormone vitamin D3 in regulating calcium and phosphate metabolism in the intestine, kidney, and bone has been known for several decades. Recent studies have provided evidence that vitamin D3, may also play an important role in regulating metabolism in other organs, including heart. This role has been suggested by the identification of a specific receptor for 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin D3, in these tissues, as well as the presence of a 1,25(OH)2D3-dependent calcium binding protein. Although administration of excessive quantities of vitamin D3 has been shown in many studies to produce myocardial calcinosis and heart failure, the importance of vitamin D3 in regulating myocardial metabolism under normal conditions has only recently been demonstrated. The purpose of the present review is to assess the current status of research regarding the pathological and physiological actions of vitamin D3 on the heart. The initial section of this report will focus on the pathological effects of excessive vitamin D3 on cardiovascular function, while the latter sections will describe recent studies related to the involvement of 1,25(OH)2D3 in regulating calcium homeostasis in ventricular cells and the relationship between vitamin D3 and myocardial contractility.

Animals↗
PubMed1988

Calcitriol synthesis is decreased in spontaneously hypertensive rats.

To investigate the mechanisms of abnormal calcium metabolism, such as hypocalcemia, decreased intestinal calcium absorption and hypercalciuria in spontaneously hypertensive rats (SHR), we have measured the plasma concentration of calcitriol and its synthesis in 5-, 8-, 12-, 16-, and 20-week-old normotensive Wistar Kyoto rats (WKY) and SHR. Metabolic clearance rate (MCR) and production rate (PR) of calcitriol were measured by the constant isotope infusion method. Plasma concentration of calcitriol and PR of calcitriol were decreased in SHR after 12 weeks of age. MCR of calcitriol, however, was not different between WKY and SHR in any age group. Therefore, the decreased synthesis of calcitriol accounts for the lower plasma level of calcitriol in SHR after 12 weeks of age. Metabolic acidosis or decreased renal function could not account for the decreased synthesis of calcitriol, since the blood pH and pCO2 and creatinine clearance were similar between WKY and SHR at times when the calcitriol synthesis was reduced in SHR. Plasma concentration of ionized calcium was also lower in SHR after 12 weeks of age. Plasma concentration of calcitonin was significantly higher in 16-week-old SHR (41.6 +/- 1.5 pg/ml) than in age-matched WKY (30.5 +/- 1.7, P less than 0.001). The values, however, were not different between 8- and 12-week-old WKY and SHR. We believe that the decreased synthesis of calcitriol could be the pathogenetic factor for the development of abnormal calcium metabolism in SHR. Age of animals should be considered when studying the calcium metabolism in SHR.

Aging↗
PubMed1988

Production and metabolic clearance of calcitriol in acute renal failure.

Metabolic clearance rate (MCR) and production rate (PR) of calcitriol were studied three and seven days after ischemic acute tubular necrosis (ATN). Creatinine clearance was decreased three days after clamping the renal arteries (0.42 +/- 0.03 ml/min/100 g, N = 6 in ATN vs. 0.68 +/- 0.09, N = 7 in sham controls; P less than 0.001). Plasma concentrations (24.1 +/- 1.9 pg/ml) and PR of calcitriol (9.8 +/- 0.91 ng/kg/day) were significantly lower in ATN rats three days after ischemic insult when compared to sham control rats, respectively (76.6 +/- 7.3 pg/ml, and 29.6 +/- 3.3 ng/kg/day; both P less than 0.01). The MCRs of calcitriol were not different between ATN (0.28 +/- 0.02 ml/min/kg) and sham control rats (0.27 +/- 0.01). By the seventh day after ischemic injury, when creatinine clearance of ATN rats returned to normal, both the PR and plasma concentrations of calcitriol also returned to normal values in these animals. In order to assess the effect of uremia on calcitriol metabolism, MCR and PR of calcitriol were measured in rats with reinfusion of their urines for 24 hours. The PR of calcitriol was significantly decreased (9.42 +/- 1.21; vs. controls, 20.5 +/- 2.9 ng/kg/day, P less than 0.001) in uremic animals. Since decreased PR of calcitriol was also accompanied by decreased MCR of calcitriol, plasma concentrations of calcitriol of the uremic rats with intact kidneys remained within normal values. We conclude that the PR of calcitriol is decreased early in ATN rats. Although the MCR was not decreased in mild ATN rats, it may decrease in severe acute renal failure.

Acute Kidney Injury↗
PubMed1987

1,25-Dihydroxyvitamin D3 regulation of phorbol ester receptors in HL-60 leukemia cells.

In this study the relationship between cell binding of phorbol 12,13-dibutyrate (PDBu) and induction of differentiation by 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) was examined. Binding of [3H]PDBu increased within 12 h of 1,25-(OH)2D3 treatment, and a 60-130% increase in [3H]PDBu receptor levels was observed within 24 h. By 48 h, however, [3H]PDBu binding was not different from control. Scatchard analysis of [3H]PDBu binding showed no statistical differences in Kd value (Kd approximately equal to 30 nM) between 1,25-(OH)2D3-treated and control cells 22 h post-treatment; however, a 2-fold increase in Bmax was observed in treated (338 +/- 24 pmol/10(9) cells) compared to control cultures (170 +/- 14 pmol/10(9) cells). Stimulation of [3H]PDBu binding was dependent on 1,25-(OH)2D3 concentrations over a range of 1-100 nM. Homogenates from 1,25-(OH)2D3-treated HL-60 cells also demonstrated an increase (70%) in [3H]PDBu binding to the Ca2+/phospholipid-dependent enzyme protein kinase C as assessed by incubation of cell homogenates with [3H]PDBu in the presence of saturating phosphatidylserine and calcium concentrations. This suggests that the increase in [3H]PDBu binding cannot be entirely explained by modulation of the latter two agents. Cycloheximide (5 microM), an inhibitor of protein synthesis, ablated the 1,25-(OH)2D3-stimulated increase in [3H]PDBu binding to intact HL-60 cells. These data demonstrate that an increase in [3H]PDBu binding occurs early in the course of 1,25-(OH)2D3-induced differentiation, results from an increased number of [3H]PDBu-binding site, and is dependent on protein synthesis.

Caenorhabditis elegans Proteins↗
PubMed1987

Transcriptional regulation of the c-myc protooncogene by 1,25-dihydroxyvitamin D3 in HL-60 promyelocytic leukemia cells.

Exposure of HL-60 promyelocytic leukemia cells to calcitriol results in a decrease in steady-state levels of c-myc mRNA and induces cellular differentiation. We have asked whether calcitriol has a direct effect on the transcription of the c-myc gene. 1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) decreased RNA elongation in a nuclear run-off transcription assay by 4 h after treatment. In the continuous presence of 1,25-(OH)2D3, HL-60 cell transcription of c-myc was decreased by 38% at 4 h and was abolished by 48 h. In contrast, the transcription of beta-actin was not affected by 1,25-(OH)2D3 treatment. The rate of transcription of c-myc and beta-actin was proportional to the number of nuclei and to time. Furthermore, specific hybridization of c-myc and beta-actin RNA was a linear function of RNA input. After a 48-h treatment, the c-myc/beta-actin ratio was decreased by 80-100% at [32P]RNA inputs ranging from 2 to 20 X 10(6) cpm/ml. These data temporally correlate inhibition of c-myc transcription with decreases in the steady-state levels of c-myc mRNA as assessed by Northern blot analysis. We conclude that the effect of 1,25-(OH)2D3 on c-myc expression occurs at the transcriptional level.

Actins↗
PubMed1987

Induction of differentiation of human promyelocytic leukemia cell line HL-60 by retinoyl glucuronide, a biologically active metabolite of vitamin A.

We examined the differentiation activity of retinoyl beta-D-glucuronide, a biologically active physiological metabolite of vitamin A, using the human promyelocytic leukemic cell line HL-60, which can be induced to differentiate with retinoic acid. Retinoyl beta-D-glucuronide (1 microM) inhibited HL-60 cell proliferation by 55-75%, inhibited tritiated thymidine incorporation into DNA by 63-80%, and induced 38-50% of the cells to differentiate into mature granulocytes. The potency of growth inhibition and induction of differentiation by retinoyl beta-D-glucuronide was similar to that of all-trans-retinoic acid. The continuous presence of either retinoyl beta-D-glucuronide or all-trans-retinoic acid was not required to obtain maximum growth arrest and differentiation: a 1-hr exposure of HL-60 cells to the retinoids gave the same response (measured after a total incubation time of 48 hr) as a 24-hr or 48-hr continuous treatment. Retinoyl beta-D-glucuronide (0.1-0.2 mM) was 50% less cytotoxic to HL-60 cells than all-trans-retinoic acid at an equimolar concentration. Retinoyl beta-D-glucuronide was not significantly metabolized to other retinoids; retinoic acid was not formed during incubation. We conclude that retinoyl beta-D-glucuronide can arrest HL-60 cell proliferation and induce their differentiation into mature granulocytes; it may act by itself or by being hydrolyzed to retinoic acid, which could be immediately utilized and metabolized. The therapeutic use of this retinoid as an antineoplastic agent is suggested.

Cell Differentiation↗
PubMed1987

Metabolic degradation and synthesis of calcitriol in spontaneously hypertensive rat.

Plasma calcitriol concentration is unexpectedly low in spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto rats (WKY) in view of previous findings of low plasma ionized calcium, hypophosphatemia, and hyperparathyroidism in SHR. Also, parathyroid hormone (PTH) and other exogenous stimuli cause a smaller increment in plasma calcitriol in SHR than in WKY. We investigated whether these differences in plasma calcitriol levels were due to decreased production rate (PR) or increased metabolic clearance rate (MCR) in SHR using the continuous infusion-isotope equilibration technique. In the basal state, MCR was 0.306 +/- 0.048 ml X min-1 X kg-1 in SHR and 0.284 +/- 0.026 ml X min-1 X kg-1 in WKY (P = NS). Estimated PR was lower in SHR (22.7 vs. 33.7 ng X day-1 X kg-1). With PTH infusion (3 U X h-1 X 100 g-1 for 20 h), MCR was 0.220 +/- 0.011 ml X min-1 X kg-1 in SHR and 0.256 +/- 0.017 ml X min-1 X kg-1 in WKY (P = NS). Measured PR was markedly lower in SHR (154 +/- 24 vs. 262 +/- 27 ng X day-1 X kg-1; P less than 0.02). Basal plasma PTH, total plasma calcium, and plasma inorganic phosphate were not different between SHR and WKY. Thus, SHR show diminished calcitriol production under basal condition and with PTH stimulation. MCR is not increased in SHR and does not appear to be influenced by PTH or the accompanying elevation in plasma calcium and calcitriol.

Animals↗
PubMed1987

Involvement of vitamin D3 with cardiovascular function. II. Direct and indirect effects.

To determine whether the changes in cardiovascular function that accompany vitamin D3 deficiency are the direct result of hypovitaminosis D3 or a response to the hypocalcemia that accompanies vitamin D3 deficiency, rats were maintained for 9 wk on a vitamin D3-deficient diet containing either low (0.4%) calcium or high (2.5%) calcium to prevent hypocalcemia. Rats were also maintained on the low-calcium, vitamin D3-deficient diet for 9 wk and then transferred to diets designed to reverse hypocalcemia or vitamin D3 deficiency. The results demonstrate that the changes in in vitro cardiac contractile function that accompany vitamin D3 deficiency 1) could not be prevented by preventing the hypocalcemia that normally accompanies vitamin D3 depletion or 2) could not be reversed by restoration of serum calcium to normal levels after the initial period of vitamin D3 depletion. In contrast, the change in in vitro vascular muscle contractile function observed in vitamin D3-deficient, hypocalcemic rats could be prevented by maintaining serum calcium at normal levels and also reversed by restoration of serum calcium to normal after an initial period of vitamin D3 deficiency. These observations indicate that hypocalcemia does not account for the changes in cardiac contractile function that result from vitamin D3 depletion and suggest a direct role for vitamin D3 or its metabolite 1,25-dihydroxyvitamin D3 in regulating cardiac contractility. Possible mechanisms underlying this direct effect were also explored.

Animals↗
PubMed1987

Production and degradation of calcitriol in renal failure rats.

We studied the metabolism of calcitriol in renal failure achieved by nephrectomy in three groups of rats. Group 1 (n = 7) had sham operation of nephrectomy. Group 2 (n = 8) had unilateral nephrectomy. Group 3 (n = 7) had 5/6 nephrectomy. Metabolic clearance rate (MCR) and production rate (PR) of calcitriol were studied 3 wk after the surgery. Serum creatinine concentrations were increased after nephrectomy for groups 2 and 3. Endogenous plasma levels of calcitriol were not different between the rats with renal failure and the controls. MCR of calcitriol were decreased in renal failure rats compared with controls (group 1, 0.24 +/- 0.01; group 2, 0.20 +/- 0.01, P less than 0.01; group 3, 0.16 +/- 0.01 ml.min-1.kg-1, P less than 0.001). The MCR of calcitriol was correlated with the endogenous creatinine clearance by linear regression analysis (r = 0.72, P less than 0.001). The PR of calcitriol were also decreased in renal failure; however, the decreases were much less than the amount of renal tissue removed. We concluded that production of calcitriol is decreased in the remnant kidney. The decreased synthesis is associated with decreased degradation of calcitriol resulting in normal concentrations of calcitriol in mild to moderately severe renal failure.

Animals↗
PubMed1987

Vitamin D3 and cardiovascular function in rats.

We have previously identified a receptor for 1,25-dihydroxyvitamin D3 in myocardial cells (Simpson, R.U. 1983. Circulation. 68:239.). To establish the relevance of this observation, we evaluated the role of the prohormone vitamin D3 in regulating cardiovascular function. In rats maintained on a vitamin D3-deficient diet for nine weeks, increases in systolic blood pressure (BP) and serum creatine phosphokinase (CPK) were observed. These increases coincided with a reduction of serum calcium from 10.3 to 5.6 mg/dl. However, while serum calcium remained depressed throughout the study, increases in BP and serum CPK were transient. After nine weeks of vitamin D3-depletion, but not after six weeks, ventricular and vascular muscle contractile function were also markedly enhanced. The increase in ventricular contractile function could not be prevented by maintaining serum calcium at 9.0 mg/dl during the period of D3-depletion. These observations suggest a primary role for the vitamin D3-endocrine system in regulating cardiovascular function.

Animals↗