AJP - Heart Calcium Transients and Cell-Sarcomere
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 285: H1882-H1889, 2003; doi:10.1152/ajpheart.01148.2002
0363-6135/03 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via ISI Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jolma, P.
Right arrow Articles by Pörsti, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jolma, P.
Right arrow Articles by Pörsti, I.

Increased calcium intake reduces plasma cholesterol and improves vasorelaxation in experimental renal failure

Pasi Jolma,1 Peeter Kööbi,1 Jarkko Kalliovalkama,1,2 Mika Kähönen,1,3 Meng Fan,1 Heikki Saha,4 Heikki Helin,5 Terho Lehtimäki,6 and Ilkka Pörsti1,4,7

1Department of Pharmacological Sciences, University of Tampere, Tampere FIN-33014; Departments of 2Anesthesia and Intensive Care, 3Clinical Physiology, 4Internal Medicine, and 5Pathology, and 6Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Centre for Laboratory Medicine, Tampere University Hospital and Medical School, University of Tampere, Tampere FIN-33014; and 7Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, Helsinki FIN-00029, Finland

Submitted 2 January 2003 ; accepted in final form 1 July 2003


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
Chronic renal failure (CRF) is associated with abnormal lipid metabolism and high prevalence of vascular complications. Calcium salts are commonly used in CRF as phosphate binders. Increased calcium intake may also lower plasma cholesterol and beneficially influence vascular tone. Therefore, we investigated the influence of increasing dietary calcium from 0.3% to 3.0% for 8 wk after 5/6 nephrectomy (NTX) on plasma cholesterol and mesenteric resistance vessel tone in male Sprague-Dawley rats. The groups were Sham, Sham-Calcium, NTX, and NTX-Calcium (n = 10–11). Blood pressure was modestly elevated after NTX, whereas the plasma creatinine, urea nitrogen, phosphate, and parathyroid hormone levels were clearly increased. The high-calcium diet suppressed plasma phosphate and parathyroid hormone but was without effect on blood pressure. The NTX resulted in 1.6-fold elevation in plasma total cholesterol and 40% reduction in high density-to-low density lipoprotein ratio (HDL/LDL). However, the lipid profile in NTX rats on the high-calcium diet did not differ from sham-operated controls. The endothelium-mediated relaxations induced by acetylcholine were impaired in NTX rats, whereas the response was normalized by a high-calcium diet. No differences in vasorelaxations by the endothelium-independent vasodilator nitroprusside were detected. In conclusion, improved vasorelaxation after a high-calcium diet could be due to reduced plasma total cholesterol and ameliorated HDL/LDL ratio, although decreased plasma phosphate and parathyroid hormone may also play a significant role in the vascular effects of increased calcium intake.

endothelium; phosphate; resistance artery; smooth muscle

CHRONIC RENAL FAILURE (CRF) is associated with various vascular complications and abnormal lipid metabolism (2, 16). Among CRF patients, cardiovascular disease is a major cause of morbidity, leading to a 20-fold increased risk of cardiovascular death compared with healthy controls (1, 16). However, the pathophysiological mechanisms affecting the arteries and contributing to the development of the vasculopathic state are still poorly understood.

The present knowledge of the effects of uremia on the function of resistance arteries is also scarce, although small arteries are important regulators of peripheral vascular resistance, and high blood pressure often accompanies impaired renal function (4). Endothelial dysfunction is considered to play a significant role in the pathogenesis of CRF and its complications (23), and patients with impaired kidney function have often exhibited decreased endothelium-mediated vasodilatation (17, 23, 33).

CRF leads to decreased phosphate excretion, and elevated phosphate levels with reduced vitamin D synthesis result in the development of secondary hyperparathyroidism (28). The disturbed calcium-phosphate balance and high parathyroid hormone (PTH) levels are considered to significantly contribute to the cardiovascular pathology in CRF (28). Oral administration of calcium carbonate and other phosphate-binding agents, which reduce intestinal phosphate absorption, are used in CRF to lower the plasma levels of phosphate and PTH (11). Calcium supplementation has also been reported to reduce plasma cholesterol levels, probably because orally ingested calcium binds bile acids and saturated fatty acids in the intestine (14, 34, 37). Elevated plasma cholesterol level is known to be associated with impaired endothelial function in both humans (6) and in rats (10, 18, 21). However, the effects of high calcium intake on plasma lipid profile and resistance vessel function in renal failure are unknown.

The present study was designed to test the phosphate-binding hypothesis and whether phosphate binding and prevention of the development of secondary hyperparathyroidism by a high-calcium diet can also reduce plasma cholesterol levels in experimental CRF, and whether these changes are reflected as alterations in the control of resistance artery tone.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
Animals and experimental design. Male Sprague-Dawley rats (n = 42; n = 18 in additional extended follow up) were housed two to a cage with access to water and food (AnalyCen; Lindköping, Sweden). Systolic blood pressures (rat age 8 wk) were measured at +28°C with a tail-cuff blood pressure meter (model 129; IITC; Woodland Hills, CA). Surgical procedures were performed under ketamine/diazepam anesthesia (75 and 2.5 mg/kg ip, respectively). In the 5/6 nephrectomized (NTX) groups, the upper and lower poles of the left kidney were cut off, and the right kidney was removed (38). In the sham groups, both kidneys were decapsulated. Antibiotics (60 mg/kg metronidazole and 225 mg/kg cefuroxim) were given postoperatively, and pain was relieved with buprenorphine (0.2 mg/kg subcutaneously) three times a day during the first 3 days. Four weeks after NTX (rat age 12 wk), the rats were divided into four groups (Sham, Sham-Calcium, NTX, and NTX-Calcium; n = 10–11) of equal mean systolic blood pressures and body weights. The Sham and NTX rats continued on chow containing 0.3% calcium, whereas the Sham-Calcium and NTX-Calcium rats were on 3% calcium. Extra calcium was supplied as the carbonate salt, and otherwise the chows were identical.

High calcium intake continued for 8 wk, and 24-h fluid consumption and urine output were measure at study week 20. The rats were weighed and anesthetized (1.3 g/kg urethane), and blood samples from cannulated carotid artery for plasma electrolyte, creatinine, urea nitrogen, phosphate, PTH, 1,25-dihydroxyvitamin D [1,25(OH)2D3], cholesterol, and hemoglobin measurements were drawn into chilled tubes, and for ionized Ca2+ into glass capillaries, with heparin as anticoagulant. The hearts and kidneys were removed and weighed, and third-order branches from the mesenteric arterial bed were excised under a dissecting microscope (Nikon).

Eighteen more rats in three groups (Sham, NTX, and NTX-Calcium; n = 6 in all) were followed for a further 8 wk, so that the follow up after subtotal nephrectomy or sham operation was altogether 20 wk. Then plasma creatinine and aortic tissue calcification were examined.

The Mulvany multimyograph (model 610A, J.P. Trading; Aarhus, Denmark) was employed for vascular studies. In this isometric system the force transducer is directly linked to a computer with Myodaq software (J.P. Trading). Vessels were mounted as ring preparations (length 1.9 mm) on two 40-µm stainless steel wires, each of which was attached to a myograph jaw. The physiological salt solution (PSS; pH 7.4) contained (in mM) 119.0 NaCl, 25.0 NaHCO3, 11.1 glucose, 1.6 CaCl2, 4.7 KCl, 1.2 KH2PO4, and 1.2 MgSO4, and aerated with 95% O2-5% CO2. Normalization of the vascular preparations was then performed so that the internal diameter of the vessel was set at 90% of that obtained when exposed to an intraluminal pressure of 100 mmHg in the relaxed state (19).

The experimental design of the study was approved by the Animal Experimentation Committee of the University of Tampere, Finland, and the Provincial Government of Western Finland Department of Social Affairs and Health, Finland. Moreover, the investigation conforms to theAmerican Physiological Society's "Guiding Principles for Research Involving Animals."

Morphological analyses of small arteries and thoracic aorta. Morphology of small arteries was examined with a pressure myograph (Living Systems Instrumentation; Burlington, VT) as previously reported, and the development of myogenic tone was inhibited by Ca2+-free solution containing 30 mmol/l EDTA (30). Three 5-µm aortic cross sections from the 18 rats that were followed for another 8 wk were stained with von Kossa stain and processed for light microscopic evaluation. An expert who was blinded to the treatment of the rats quantified aortic calcification from three aortic cross sections from each animal. The calcification was expressed as the percentage of the aortic cross section.

Mesenteric arterial responses in vitro. Presence of intact endothelium in vascular preparations was confirmed by a clear relaxation to 1 µM ACh in 5 µM norepinephrine (NE)-precontracted rings and the absence of endothelium by the lack of this response. The endothelium was removed by perfusing air through the lumen.

Arterial contractions to NE and endothelium-mediated relaxations in endothelium-intact small arteries. Contractions to NE (0.1–10 µM) were first cumulatively determined. Thereafter relaxations to ACh (1 nM-10 µM) were examined in arteries precontracted with 5 µM NE, which resulted in ~80% of the maximal contractile response attained in both groups. The rings were allowed a 30-min equilibration period in PSS between each cumulative response.

Arterial contractions to KCl and endothelium-independent relaxations to exogenous nitric oxide (endothelium-denuded small arteries). Contractions to increasing concentrations of KCl were determined, and in solutions containing high concentrations of K+ (20–125 mM) NaCl was replaced with KCl on an equimolar basis. Relaxations to 1 nM-100 µM nitroprusside [nitric oxide (NO) donor] were examined in rings precontracted with 5 µM NE. The preparations were allowed a 30-min equilibration period in PSS between each relaxation.

Plasma electrolytes, urea nitrogen, phosphate, PTH, 1,25(OH)2D3, cholesterol, creatinine, protein, pH, and hemoglobin measurements. Plasma potassium and sodium concentrations were measured by potentiometric direct dry chemistry, urea nitrogen by colorimetric enzymatic dry chemistry, and phosphate by colorimetric end-point dry chemistry analyzer (Vitros 950, Johnson & Johnson Clinical Diagnostics; Rochester, NY). Plasma PTH was measured by immunometric assay (IRMA, Immutopics; San Clemente, CA). 1,25(OH)2D3 was quantified by radioreceptor assay (24). Total fasting plasma triglycerides, and total and high-density lipoprotein (HDL) cholesterol concentrations were analyzed with the use of an automatic analyzer (Cobas Integra 700, Hoffman-La-Roche; Basel, Switzerland). LDL cholesterol concentration was calculated with the use of Friedewald's formula. Plasma creatinine was determined by the kinetic colorimetric assay according to Jaffe and plasma protein by colorimetric end-point measurement according to Biuret (Cobas Integra analyzer). Plasma-ionized Ca2+ and pH were measured with the use of an ion-selective electrode (model 634 Ca2+/pH Analyzer, Ciba Corning Diagnostics; Sudbury, UK). Hemoglobin was determined by photometric analysis with the use of a cyanide-free hemoglobin reagent (H* 2, Technicon Instruments; Tarrytown, NY).

Data presentation and analysis of results. The maximal wall tensions to NE and KCl were expressed in milli-Newtons per millimeter. The EC50 for NE and KCl in each ring was calculated as a percentage of maximal response and presented as the negative logarithm (pD2), which was used in the statistical analysis. The relaxations in response to ACh and nitroprusside were presented as a percentage of preexisting contractile force. The EC50 for ACh in each ring was also presented as the negative logarithm (pD2), and scatterplots were generated to emphasize the possible relationships between plasma levels of cholesterol, LDL, HDL-to-LDL (HDL/LDL ratio), PTH, phosphate, ionized calcium, and the pD2 values for ACh in subtotally nephrectomized rats. The results from sham-operated animals were excluded from the scatterplots because increased calcium intake had no effect on arterial tone in these animals.

Statistical analysis was carried out by one- and two-way ANOVA supported by the Bonferroni test when carrying out pairwise comparisons between the test groups. ANOVA for repeated measurements was applied for data consisting of repeated observations at successive time points. Results are expressed as means ± SE, and the differences were considered significant when P < 0.05. Unless otherwise indicated, the P values in the text refer to ANOVA for repeated measurements. In the subtotally nephrectomized rats, correlation analyses were also performed between plasma levels of creatinine, urea, and the pD2 values for ACh. Spearman's correlation coefficient (r; two tailed) was calculated, which was considered significant when P < 0.05.

Drugs. The following drugs were used: ketamine (Parke-Davis Scandinavia; Solna, Sweden), cefuroxim, diazepam (Orion Pharma; Espoo, Finland), metronidazole (Braun; Melsungen, Germany), buprenorphine (Reckitt and Colman; Hull, UK), acetylcholine chloride, norepinephrine bitartrate (Sigma; St. Louis, MO), and sodium nitroprusside (Fluka Chemie; Buchs, Switzerland). Stock solutions were created by dissolving the compounds in distilled water. All solutions were freshly prepared before use and protected from light.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 DISCLOSURES
 REFERENCES
 
Blood pressure, body and heart weights, total renal mass, drinking fluid, and urine volumes. Systolic blood pressures and body weights in individual study groups did not differ during the 12-wk follow up. However, when analyzed by two-way ANOVA, a modest but significant increase in blood pressure was observed in subtotally nephrectomized rats versus sham-operated controls: the mean systolic blood pressure values were 150.3 ± 2.7 mmHg in the two NTX groups, and 140.4 ± 2.9 mmHg in the two Sham groups (P = 0.018). The outcome of two-way ANOVA was also that increased calcium intake did not significantly influence blood pressure in this study (P = 0.12). Renal mass was ~30% lower in both NTX groups than the weight of the two kidneys in sham-operated rats. At the end of the study, the intake of drinking fluid and the output of urine were higher in the NTX rats when compared with the Sham rats (Table 1).


View this table:
[in this window]
[in a new window]
  		Table 1. Experimental group data at close of study

 

Laboratory findings. Plasma total cholesterol and HDL and LDL cholesterol levels were elevated in the NTX group but normalized by calcium supplementation (Fig. 1). Plasma concentrations of creatinine, urea nitrogen, PTH, and phosphate values were increased, whereas hemoglobin, ionized Ca2+, and protein concentrations were decreased in the NTX group when compared with the Sham group (Table 1 and Fig. 2). A high-calcium diet elevated plasma ionized Ca2+ and suppressed plasma phosphate and PTH in both NTX and Sham rats (Fig. 2). No changes were detected in plasma potassium or sodium concentrations (Table 1). Although plasma levels of active vitamin D in individual study groups did not significantly differ, analyses by two-way ANOVA showed that plasma 1,25(OH)2D3 was slightly but significantly lower in the NTX groups than the Sham groups (34.8 ± 1.8 vs. 40.4 ± 2.0 pg/ml, respectively, P = 0.049).



View larger version (19K):
[in this window]
[in a new window]
  		Fig. 1. Plasma total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, triglycerides, HDL/LDL ratio, and HDL/total cholesterol ratio at the end of the study. *P < 0.05 compared with the Sham group; {dagger}P < 0.05 compared with the nephrectomized (NTX) group.

 


View larger version (23K):
[in this window]
[in a new window]
  		Fig. 2. Plasma urea nitrogen, ionized calcium, phosphate, and parathyroid hormone (PTH) at the end of the study. *P < 0.05 compared with the Sham group; {dagger}P < 0.05 compared with the NTX group.

 

Morphology of small arteries and thoracic aorta. The resistance arteries showed no significant differences in lumen diameter or wall thickness between the study groups (Table 2). The cross sections of thoracic aortas from rats that were followed for another 8 wk showed increased calcification in the NTX group, whereas aortic calcification in the NTX-Calcium group did not differ from that in the Sham group (Table 2). The plasma levels of creatinine continued to rise in the NTX groups during the extended follow up (Table 2).


View this table:
[in this window]
[in a new window]
  		Table 2. Parameters of contractile responses and lumen diameters of isolated mesenteric arterial rings in experimental groups, and data from extended followup in 12 NTX and 6 sham rats that were followed for further 8 wk (altogether for 20 wk)

 

Responses of small mesenteric arterial preparations. The relaxations induced by ACh in endothelium-intact NE (5 µM)-precontracted preparations were impaired in the NTX group, whereas the NTX-Calcium and Sham-Calcium groups did not differ from the Sham group (Fig. 3A). The relaxations induced by nitroprusside, a vasodilator acting via formation of exogenous NO, were similar in all study groups (Fig. 3B). The vascular rings of the study groups exhibited similar contractile sensitivity (i.e., pD2 values) and maximal wall tensions to NE and KCl (Table 2). Therefore, no changes in vasoconstrictor responses were observed in the NTX-Calcium rats that could explain the enhanced vasorelaxation in the arterial rings of these animals.



View larger version (15K):
[in this window]
[in a new window]
  		Fig. 3. Relaxation responses to acetylcholine (A) and nitroprusside (B) after precontraction with 5 µM norepinephrine in endotheliumintact (A) and -denuded (B) mesenteric small arterial rings. Values represent means ± SE; n = 10–11 in each group; *P < 0.05, ANOVA for repeated measurements.

 

The present results showed that increased calcium intake, which reduced plasma phosphate and PTH and elevated plasma ionized calcium in NTX rats as expected, was also associated with favorable changes in the lipid profile and endothelium-dependent relaxation of resistance arteries. The scatterplots depicting the variables of plasma lipid profile and calcium-phosphorus metabolism in relation to the sensitivity of resistance arteries to endothelium-dependent vasorelaxation are illustrated in Fig. 4. These scatterplots showed clear clustering of data points in separate subgroups in the NTX and NTX-Calcium groups. Renal function was not different in the two NTX groups, and plasma creatinine and urea showed no correlation to the sensitivity to ACh in the NTX and NTX + Calcium groups (r = –0.255 and –0.186; P = 0.307 and P = 0.445, respectively).



View larger version (16K):
[in this window]
[in a new window]
  		Fig. 4. Scatterplots depicting the laboratory results in relation to the sensitivity of resistance arteries to endothelium-dependent vasorelaxation in NTX and NTX-Calcium groups. pD2, Negative logarithm. A: cholesterol; B: LDL; C: HDL-to-LDL ratio; D: ionized calcium; E: phosphate; F: PTH.

 


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
DISCLOSURES
 REFERENCES
 
In the present study, renal failure was induced in rats by 5/6 nephrectomy, and the subsequent 1.6- and 1.7-fold elevations in plasma creatinine and urea nitrogen, respectively, were comparable to those observed previously (13). The intake of drinking fluid and the output of urine were increased in the renal failure rats, suggesting a deteriorated urine concentration capacity in the remnant kidney.

Plasma total cholesterol and LDL levels were significantly increased in the NTX group, whereas a high-calcium diet normalized the total and LDL cholesterol levels. The HDL/LDL ratio was also reduced in experimental renal failure but was normalized by high-calcium intake. Plasma triglyceride levels were comparable between the groups. These results correspond to previous findings concerning calcium intake and plasma cholesterol levels in both humans and experimental animals (14, 34, 37). The lipid-lowering effect of dietary calcium probably results from the ability of Ca2+ to bind bile acids and saturated fatty acids in the intestine and form inabsorbable chelates thereby increasing the fecal excretion of these compounds (7, 34). The mechanisms of the detrimental effect of CRF on plasma cholesterol have also been elucidated previously. It is known that in the rat CRF is associated with down-regulation of hepatic lecithin:cholesterol acyltransferase (LCAT) gene expression and reduction of plasma LCAT activity, as well as upregulation of hepatic acyl-CoA:cholesterol acyltransferase-2 (ACAT-2) expression and total ACAT activity, both of which may contribute to the observed lipid disorders (15, 35).

Secondary hyperparathyroidism is a common complication of CRF. In this study, subtotal nephrectomy markedly raised plasma PTH and phosphate concentrations in the NTX group, whereas high-calcium intake effectively lowered plasma PTH and phosphate levels, as expected. Plasma levels of 1,25(OH)2D3 were slightly but significantly reduced by NTX but were not affected by increased calcium intake. The main regulators of 1,25(OH)2D3 synthesis by 1-{alpha}-hydroxylase in the kidney are phosphate, PTH, calcium, and 1,25(OH)2D3 itself (5). Modulation of phosphate concentration within the normal range can alter serum 1,25(OH)2D3: high level of phosphate inhibits and low level stimulates the synthesis. In addition, high PTH concentration increases, whereas hypercalcemia decreases active vitamin D production. 1,25(OH)2D3 also regulates its own synthesis by a negative feedback mechanism (5, 28). In this study, the long-term changes in plasma phosphate, PTH, and calcium provide an explanation why active vitamin D levels were not affected by increased calcium intake in NTX or Sham rats (5, 28).

In previous studies, a high level of LDL cholesterol has been shown to inhibit endothelium-dependent vasodilatation in both humans (25) and rats (18). LDL can impair the vascular production of NO (25) or increase the generation of superoxide anion, which reacts with NO to form peroxynitrate, which in turn may play a significant role in oxidative tissue damage (20, 36). To examine endothelial function, we compared the ACh-induced relaxations between the study groups. The relaxations to ACh in the resistance arteries were clearly impaired in the NTX rats but were normalized by concomitant high-calcium diet. In subsequent analyses, we observed scattering of data points in separate subgroups when the plasma levels of total cholesterol, LDL-cholesterol, HDL/LDL cholesterol ratio, ionized calcium, phosphate, and PTH were depicted in relation to the sensitivity of resistance arteries to endothelium-mediated relaxation in the nephrectomized rats. Importantly, the variables reflecting renal function did not differ in the NTX and NTX-Calcium groups.

The detrimental effect of high plasma cholesterol (29), and also the beneficial effect of elevated HDL, on endothelium-dependent vasodilatation are well known from previous studies (20). In addition, HDL is an important antioxidant, which may improve the bioavailability of NO by decreasing the formation of superoxide anion and thus oppose the negative effect of LDL in the vasculature (20, 25). Moreover, oxidative stress is a known feature of CRF, which has been evidenced by the elevation of lipid peroxidation products, depression of antioxidant capacity and impairment of antioxidant enzyme activity in both human and experimental forms of CRF (36). In the present study, the plasma level of HDL cholesterol was increased in the NTX group but so were the levels of total and LDL cholesterol. In addition, a significant reduction in HDL/LDL ratio was observed, whereby this model of renal failure was associated with clear unfavorable changes in plasma lipid profile. All of these changes were reversed by increased calcium intake, which also induced a slight elevation in the HDL/total cholesterol ratio when compared with the Sham group. Therefore, improved plasma lipid profile may play an important role in the modulation of vascular function after increased calcium intake in CRF.

Because the high-calcium diet suppressed plasma phosphate and PTH in the NTX rats, these changes may also explain the observed improvement of endothelium-mediated vasodilator properties in the resistance artery. Previous studies (11, 26, 28) suggest that secondary hyperparathyroidism and hyperphosphatemia both contribute to vascular pathology in CRF. PTH excess increases cytoplasmic Ca2+ and alters the production of endothelium-derived vasoactive substances (26, 27). Elevated phosphate may directly influence the metabolism of vascular smooth muscle and induce phenotypic changes in smooth muscle cells that predispose the vessel wall to calcification (12). We found that increased calcium intake actually reduced signs of calcification in aortic cross sections of NTX rats. This underlying mechanism of the reduction of vascular calcification by increased calcium intake is a subject for future studies, but a very probable explanation is the effective suppression of plasma phosphate in the NTX rats by the high-calcium diet. Altogether, the present results suggest that alterations in the calcium-phosphate balance may significantly contribute to both morphological vascular changes and impairment of vasodilatation during reduced kidney function.

Earlier studies (22, 31) have demonstrated the detrimental effect of hypertension on the endothelium-dependent and -independent relaxations of the resistance arteries. The previous findings concerning the development of hypertension in rats with renal failure are inconsistent and depend on the rat strain and the renal ablation procedure (3, 8, 13, 32). Recently, reduction of functioning renal tissue by infarction, i.e., ligation of renal arteries, was shown to increase blood pressure (measured by a telemetric method) in rats, whereas surgical excision of an equal amount of renal parenchyma did not result in the development of hypertension during the 6-wk follow up (9). In the present investigation, renal failure was associated with a small (10 mmHg) increase in blood pressure during the 12-wk follow up. This modest elevation of blood pressure in the NTX rats suggests that the observed functional alterations of the resistance arteries potentially resulted from the metabolic alterations induced by CRF and not exclusively from increased blood pressure. Nevertheless, the beneficial effects of increased calcium intake on arterial tone could not be explained by reduction of blood pressure. It is of course possible that the tail plethysmography method employed in the present study failed to detect slight changes in blood pressure.

In conclusion, CRF in rats was associated with deteriorated plasma lipid profile, secondary hyperparathyroidism, and impaired endothelium-dependent vasorelaxation of the resistance arteries. Increased calcium intake improved the lipid profile, lowered plasma PTH and phosphate, and normalized the deficient resistance artery relaxation in experimental renal failure. The improved vasorelaxation after a high-calcium diet could thus be due to reduced plasma total cholesterol and ameliorated HDL/LDL ratio, but the decreased plasma phosphate and PTH levels may also play a significant role in the vascular effects of increased calcium intake.


   DISCLOSURES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
REFERENCES
 
This study was supported by the Finnish Kidney Foundation, the Medical Research Fund of Tampere University Hospital, the Paavo Nurmi Foundation, the Pirkanmaa Regional Fund of the Finnish Cultural Foundation, the Satakunta Regional Fund of the Finnish Cultural Foundation, the Finnish Medical Foundation, the Einar and Karin Stroem Foundation, the Aarne and Aili Turunen Foundation, the Sigrid Juselius Foundation, the Maud Kuistila Memorial Foundation, and the University of Tampere.


   FOOTNOTES
 

Address for reprint requests and other correspondence: I. Pörsti, Dept. of Pharmacological Sciences, Medical School, Univ. of Tampere, Tampere, FIN-33014, Finland (E-mail: ilkka.porsti{at}uta.fi).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 

  1. Amann K and Ritz E. Cardiac structure and function in renal disease. Curr Opin Nephrol Hypertens 5: 102–106, 1996.[Medline]
  2. Attman PO, Samuelsson O, and Alaupovic P. Lipoprotein metabolism and renal failure. Am J Kidney Dis 21: 573–592, 1993.[ISI][Medline]
  3. Bidani AK, Griffin KA, Plott W, and Schwartz MM. Genetic predisposition to hypertension and microvascular injury in the remnant kidney model. J Lab Clin Med 121: 284–291, 1993.
  4. Bohlen HG. Localization of vascular resistance changes during hypertension. Hypertension 8: 181–183, 1986.[Free Full Text]
  5. Brown AJ, Dusso A, and Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol 277: F157–F175, 1999.[Abstract/Free Full Text]
  6. Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, and Dzau VJ. Impaired vasodilatation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest 86: 228–234, 1990.[ISI][Medline]
  7. Denke MA, Fox MM, and Schulte MC. Short-term dietary calcium fortification increases fecal saturated fat content and reduces serum lipids in men. J Nutr 123: 1047–1053, 1993.[Abstract/Free Full Text]
  8. Griffin KA, Picken M, and Bidani AK. Method of renal mass reduction is a critical modulator of subsequent hypertension and glomerular injury. J Am Soc Nephrol 4: 2023–2031, 1994.[Abstract]
  9. Griffin KA, Picken MM, Churchill M, Churchill P, and Bidani AK. Functional and structural correlates of glomerulosclerosis after renal mass reduction in the rat. J Am Soc Nephrol 11: 497–506, 2000.[Abstract/Free Full Text]
  10. Hayakawa H and Raij L. Relationship between hypercholesterolaemia, endothelial dysfunction and hypertension. J Hypertens 17: 611–619, 1999.[ISI][Medline]
  11. Hsu CH. Are we mismanaging calcium and phosphate metabolism in renal failure? Am J Kidney Dis 29: 641–649, 1997.[ISI][Medline]
  12. Jono S, McKee MD, Murry CE, Shioi A, Nishizawa Y, Mori K, Morii H, and Giachelli CM. Phosphate regulation of vascular smooth muscle cell calcification. Circ Res 87: E10–E17, 2000.[ISI][Medline]
  13. Kalliovalkama J, Jolma P, Tolvanen JP, Kähönen M, Hutri-Kähönen N, Saha H, Tuorila S, Moilanen E, and Pörsti I. Potassium channel-mediated vasorelaxation is impaired in experimental renal failure. Am J Physiol Heart Circ Physiol 277: H1622–H1629, 1999.[Abstract/Free Full Text]
  14. Karanja N, Morris CD, Illingworth DR, and McCarron DA. Plasma lipids and hypertension: response to calcium supplementation. Am J Clin Nutr 45: 60–65, 1987.[Abstract/Free Full Text]
  15. Liang K and Vaziri ND. Upregulation of acyl-CoA: cholesterol acyltransferase in chronic renal failure. Am J Physiol Endocrinol Metab 283: E676–E681, 2002.[Abstract/Free Full Text]
  16. Luke RG. Chronic renal failure–a vasculopathic state. N Engl J Med 339: 841–843, 1998.[Free Full Text]
  17. Morris STW, McMurray JJV, Spiers A, and Jardine AG. Impaired endothelial function in isolated human uremic resistance arteries. Kidney Int 60: 1077–1082, 2001.[ISI][Medline]
  18. Mougenot N, Lesnik P, Ramirez-Gil JF, Nataf P, Diczfalusy U, Chapman MJ, and Lechat P. Effect of the oxidation state of LDL on the modulation of arterial vasomotor response in vitro. Atherosclerosis 133: 183–192, 1997.[ISI][Medline]
  19. Mulvany MJ and Halpern W. Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res 41: 19–26, 1977.[Free Full Text]
  20. O'Connel BJ and Genest J. High-density lipoproteins and endothelial function. Circulation 104: 1978–1983, 2001.[Abstract/Free Full Text]
  21. O'Rourke M and Docherty JR. Effects of a high-cholesterol diet on vascular and endothelial function in rat aorta. Pharmacology 56: 1–6, 1998.[ISI][Medline]
  22. Panza JA, Quyyumi AA, Brush JE Jr, and Epstein SE. Abrnomal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 323: 22–27, 1990.[Abstract]
  23. Rabelink TJ and Koomans HA. Endothelial function and the kidney. Drugs 53: 11–19, 1997.[Medline]
  24. Reinharth TA, Horst RL, Orf JW, and Hollis BW. A microassay for 1,25-dihydroxyvitamin D not requiring high performance liquid chromatography: application to clinical studies. J Clin Endocrinol Metab 58: 91–98, 1984.[Abstract]
  25. Rosendorff C. Effects of LDL cholesterol on vascular function. J Hum Hypertens 16, Suppl 1: S26–S28, 2002.
  26. Rostand SG and Drüeke TB. Parathyroid hormone, vitamin D, and cardiovascular disease in chronic renal failure. Kidney Int 56: 383–392, 1999.[ISI][Medline]
  27. Schleiffer R, Pernot F, and Jones R. Endothelium is a target organ of parathyroid secretions in genetic hypertensive rats. Horm Metab Res 27: 16–18, 1995.[ISI][Medline]
  28. Slatopolsky E, Brown A, and Dusso A. Role of phosphorus in the pathogenesis of secondary hyperparathyroidism. Am J Kidney Dis 37, Suppl 2: S54–S57, 2001.[ISI][Medline]
  29. Steinberg HO, Bayazeed B, Hook G, Johnson A, Cronin J, and Baron AD. Endothelial dysfunction is associated with cholesterol levels in the high normal range in humans. Circulation 96: 3287–3293, 1997.[Abstract/Free Full Text]
  30. Suo M, Kalliovalkama J, Pörsti I, Jolma P, Tolvanen JP, Vuolteenaho O, and Ruskoaho H. N(G)-nitro-L-arginine methyl ester-induced hypertension and natriuretic peptide gene expression: inhibition by angiotensin II type 1 receptor antagonism. J Cardiovasc Pharmacol 40: 478–486, 2002.[ISI][Medline]
  31. Tesfamariam B and Halpern W. Endothelium-dependent and endothelium-independent vasodilatation in resistance arteries from hypertensive rats. Hypertension 11: 440–444, 1988.[Abstract/Free Full Text]
  32. Terzi F, Beaufils H, Laouari D, Burtin M, and Kleinknecht C. Renal effects of anti-hypertensive drugs depends on sodium diet in the excision remnant kidney model. Kidney Int 42: 354–363, 1992.[ISI][Medline]
  33. Van Guldener C, Lambert J, Janssen MJFM, Donker AJM, and Stehouwer CDA. Endothelium-dependent vasodilatation and distensibility of large arteries in chronic hemodialysis patients. Nephrol Dial Transplant 12, Suppl 2: 14–18, 1997.[ISI][Medline]
  34. Vaskonen T, Mervaala E, Sumuvuori V, Seppänen-Laakso T, and Karppanen H. Effects of calcium and plant sterols on serum lipids in obese Zucker rats on a low fat diet. Br J Nutr 87: 239–245, 2002.[ISI][Medline]
  35. Vaziri ND, Liang K, and Parks JS. Down-regulation of hepatic lecithin:cholesterol acyltransferase gene expression in chronic renal failure. Kidney Int 59: 2192–2196, 2001.[ISI][Medline]
  36. Vaziri ND, Ni Z, Oveisi F, Liang K, and Pandian R. Enhanced nitric oxide inactivation and protein nitration by reactive oxygen species in renal insufficiency. Hypertension 39: 135–141, 2002.[Abstract/Free Full Text]
  37. Yacowitz H, Fleischman AI, and Bierenbaum ML. Effects of oral calcium upon serum lipids in man. Br Med J 1: 1352–1354, 1965.[Medline]
  38. Ylitalo P, Hepp R, Oster P, Möhring J, and Gross F. Effects of varying sodium intake on blood pressure and renin-angiotensin system in subtotally nephrectomized rats. J Lab Clin Med 88: 807–816, 1976.[ISI][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via ISI Web of Science (4)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jolma, P.
Right arrow Articles by Pörsti, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jolma, P.
Right arrow Articles by Pörsti, I.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2003 by the American Physiological Society.