(Hypertension. 1997;29:822-827.)
© 1997 American Heart Association, Inc.
Articles |
Effects of Dietary Sodium and Magnesium on Cyclosporin A–Induced Hypertension and Nephrotoxicity in Spontaneously Hypertensive Rats
the Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Helsinki (E.M.A.M., J.L., T.-L.T., K.K., H.V., H.K.); the Division of Transplantation Surgery, Fourth Department of Surgery, Helsinki University Central Hospital (A.-K.P., L.L., J.A.); Mila Ltd (J.L.); and the Department of Physiology, Faculty of Veterinary Medicine, University of Helsinki (T.-L.T.), Finland.
Correspondence to Eero Mervaala, MD, PhD, Institute of Biomedicine, Department of Pharmacology and Toxicology, PO Box 8, FIN-00014 University of Helsinki, Finland. E-mail eero.mervaala@helsinki.fi
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Abstract |
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Arterial hypertension, nephrotoxicity, and magnesium loss are common side effects of the immunosuppressive agent cyclosporin A (CsA). In the present study, the effects of dietary sodium and magnesium on CsA toxicity were examined in spontaneously hypertensive rats. A 6-week treatment with CsA during a moderately low-sodium diet (Na 0.3%, Mg 0.2% of the dry weight of the chow) raised blood pressure only slightly, without evidence of nephrotoxicity. By contrast, CsA during a high-sodium diet (Na 2.6%) produced a pronounced rise in blood pressure as well as marked nephrotoxicity, comprising decreased creatinine clearance, increased levels of serum creatinine and urea, and increased urinary protein excretion. During the high-sodium diet, CsA decreased myocardial and bone magnesium concentration and increased myocardial and renal calcium concentration. Magnesium supplementation (Mg 0.6%) protected against the CsA-induced hypertension and nephrotoxicity during the high-sodium diet. Magnesium supplementation also completely prevented the CsA-induced myocardial magnesium depletion and calcium accumulation in the heart and kidney during the high-sodium diet. Our findings indicate a detrimental interaction between increased sodium intake and CsA treatment and a marked protection by concomitant oral magnesium supplementation.
Key Words: cyclosporine • rats, spontaneously hypertensive • hypertrophy, left ventricular • proteinuria • sodium • magnesium • calcium
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Introduction |
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Cyclosporin A is a cyclic undecapeptidic immunosuppressive agent that has significantly improved long-term survival after organ transplantations.1 Hypertension and nephrotoxicity are common side effects during CsA treatment.2 Clinical and experimental studies have revealed that CsA-induced hypertension and nephrotoxicity may be mediated by several mechanisms, such as sodium retention, renal vasoconstriction, stimulation of the renin-angiotensin system, activation of the sympathetic nervous system, impaired synthesis of nitric oxide, increased synthesis of endothelins, and alterations in renal prostanoid and thromboxane production (for reviews, see References 2 and 3). Recent studies have demonstrated that CsA induces magnesium wasting both in experimental animals4 5 6 and in humans,7 8 9 10 suggesting that magnesium depletion may also be involved in the pathogenesis of CsA toxicity. Much evidence shows that a high sodium intake has a central role in the development of arterial hypertension.11 12 13 Therefore, in the present study, the influence of a high sodium intake and magnesium supplementation on CsA-induced hypertension and nephrotoxicity was examined in the SHR, the most widely used animal model for human essential hypertension. A part of the present study has been published previously as a preliminary report.14
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Methods |
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Experimental Animals, Diets, and CsA Treatment
Forty-six 8-week-old, male SHR (Harlan Sprague Dawley, Indianapolis, Ind) were used. The procedures and protocols of the study were in accord with our institutional guidelines and were approved by the Animal Experimentation Committee of the Institute of Biomedicine, University of Helsinki, Finland. In the beginning of the study, the blood pressure– and body weight–matched SHR were divided into six groups (n=7 or 8 in each group) to receive different diet and drug regimens for 6 weeks: (1) SHR control group receiving a moderately low-sodium diet (R36, Finnewos Aqua) (Na 0.3%, Mg 0.2%, K 0.8%, Ca 1.0%, P 0.75% of the dry weight of the chow); (2) SHR group on high-sodium diet (Na 2.6% of the dry weight of the chow produced by addition of sodium chloride [Merck] to the moderately low-sodium diet); (3) CsA group on moderately low-sodium diet; (4) CsA group on high-sodium diet; (5) CsA group on high-sodium plus high-magnesium diet (Mg 0.6% of the dry weight of the chow produced by addition of MgCl2 [Merck] to the chow); and (6) CsA group on a moderately low-sodium plus high-magnesium diet. The rats had free access to tap water and chow during the experiment. CsA (Sandimmun infusion concentrate 50 mg/mL, Sandoz Ltd) was diluted in a lipid solution (Intralipid, Kabi Pharmacia) to produce a 25-mg/mL solution that was administered once a day at a daily dose of 5 mg/kg SC for 6 weeks. The control rats received the same volume of the vehicle.
Measurement of Systolic Blood Pressure
Systolic blood pressure and heart rate were measured weekly with a tail-cuff blood pressure analyzer (Apollo-2AB Blood Pressure Analyzer, model 179-2AB, IITC Life Science). The analog signals of systolic blood pressure and heart rate were automatically converted to digital values by an online microprocessor. Before the measurements, the rats were warmed for 10 to 15 minutes at 28°C to make the pulsations of the tail artery detectable. Values for systolic blood pressure and heart rate were obtained by averaging readings from three to five measurements. Body weight was measured daily during the experiment.
Metabolic Studies and Sample Preparation
At the age of 13 weeks, the rats were housed individually in metabolic cages for a 24-hour period; they had free access to tap water and chow. Twenty-four-hour food and water intakes as well as 24-hour urine volumes were measured. Urine samples were stored at -80°C until the biochemical determinations were performed. At the end of the experimental period, the animals were decapitated 20 hours after the last CsA administration. Blood samples for PRA and for whole-blood CsA determination were taken into chilled tubes on ice with EDTA (4.5 mmol/L) as anticoagulant. Blood samples for serum creatinine and serum aldosterone determinations were taken into glass tubes without an anticoagulant. The heart was excised; the great vessels, atria, and the free wall of the right ventricle were dissected; and the left ventricular mass was measured. The ratio of left ventricular wet weight to body weight was calculated as an index of LVH. The kidneys were washed with ice-cold saline and weighed. Tissue samples of heart, kidney, liver, and thigh muscle were taken for CsA determinations, and samples were taken from heart, kidney, and femur for electrolyte determinations.
Hormonal and Biochemical Determinations
PRA was determined by a radioimmunoassay of angiotensin I (Medix Angiotensin I test, Medix Biochemica). Serum aldosterone was determined by a solid-phase radioimmunoassay specific for aldosterone (Coat-A-Count Aldosterone, Diagnostic Products Corp). Total protein concentration of urine was determined by the method of Lowry et al15 after precipitation with 10% trichloroacetic acid. Urine and serum creatinine were analyzed with an enzymatic analyzer (Kone Specific, Kone Corp). The concentrations of the elements sodium, potassium, phosphorus, magnesium, and calcium in urine, heart, kidney, and bone were determined by use of a Baird PS-4 inductively coupled plasma emission spectrometer (Baird Co) as described in detail elsewhere.16
Whole-blood, renal, myocardial, hepatic, and striated muscle tissue CsA concentrations were determined by fluorescence polarization immunoassay (Abbott TDX cyclosporine monoclonal whole-blood method, Abbott Laboratories) using a monoclonal antibody specific for the parent molecule. Before CsA determinations, tissue samples (
100 mg) were weighed, minced, and homogenized in buffer (10 mmol/L PBS, 50 mmol/L Tris-HCl, 0.5% Triton). The volume of the homogenate was adjusted with buffer to give a final tissue amount of 100 g/L.
Statistical Analysis
Statistical analysis was carried out by one-way ANOVA followed by Tukey's test. Data for multiple observations over time were analyzed by two-way ANOVA with repeated measures for overall treatment effect, and Tukey's test was used for multiple pairwise comparisons of treatment groups at different times. Linear regression lines were calculated by the least-squares method. Differences between means of P<.05 were considered significant. The data were analyzed with SYSTAT statistical software (SYSTAT Inc). The results are expressed as mean±SEM.
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Results |
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Blood Pressure, LVH, and Body Weight Gain
Compared with the SHR group on the moderately low-sodium diet, a slight increase in blood pressure was produced by the high-sodium diet alone (Fig 1
). During the moderately low-sodium diet, CsA induced a slight rise in blood pressure both in the absence and in the presence of magnesium supplementation (Fig 1). A marked rise in blood pressure was produced by CsA during the high-sodium diet. In CsA-treated SHR, magnesium supplementation decreased blood pressure during the high-sodium diet (Fig 1). CsA did not affect the LVH index during the moderately low-sodium diet (Fig 2). The increase of LVH index produced by the high-sodium diet did not reach statistical significance. CsA markedly increased the LVH index during the high-sodium diet without magnesium supplementation but did not significantly increase it during magnesium supplementation (Fig 2).
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indicates SHR group on moderately low-sodium diet (n=7) (C); 
, SHR group on high-sodium diet (n=7) (Na); 
, CsA group on moderately low-sodium diet (n=8) (CsA); 
, CsA group on high-sodium diet (n=8) (CsA+Na); 
, CsA group on high-sodium plus high-magnesium diet (n=8) (CsA+Na+Mg); and 
, CsA group on moderately low-sodium plus high-magnesium diet (n=8) (CsA+Mg). Repeated-measures ANOVA between-subjects effects, P<.0001; within-subject effect, P<.0001; time-group interaction, P<.0001. High-sodium diet alone produced a rise in blood pressure in SHR (P<.05 vs SHR group on moderately low-sodium diet). During moderately low-sodium diet, CsA treatment produced a slight rise in blood pressure in both absence and presence of magnesium supplementation (P<.05 vs SHR group on moderately low-sodium diet). CsA treatment during high-sodium diet produced a marked further rise in blood pressure (P<.05 vs all other groups). Values are mean±SEM.
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Body weight gain was decreased in the CsA-treated SHR on the high-sodium diet both in the absence and in the presence of magnesium supplementation (Table 1).
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Factors Associated With Renal Functions
There was not any significant difference in the total wet weight of the kidneys between the different experimental groups (ANOVA, P=.07). Serum creatinine, creatinine clearance, serum urea, PRA, serum aldosterone, and 24-hour urinary protein excretion were not significantly affected by high-sodium diet alone or by CsA treatment during the moderately low-sodium diet either in the absence or in the presence of magnesium supplementation (Table 1
). Creatinine clearance was decreased; serum creatinine and serum urea concentrations were increased; and PRA, serum aldosterone concentration, and 24-hour urinary protein excretion increased fivefold to sevenfold by CsA treatment during the high-sodium diet (Table 1). Magnesium supplementation prevented CsA-induced activation of the renin-angiotensin-aldosterone system and CsA-induced increases in serum urea concentration and 24-hour urinary protein excretion during the high-sodium diet.
Metabolic Variables
The 24-hour food intake did not differ significantly between the different experimental groups (Table 2). Water intake, urine volume, and sodium excretion rate were increased in all SHR receiving the high-sodium diet (Table 2). Urinary excretion of magnesium was markedly increased in the groups receiving magnesium supplementation. CsA increased the urinary excretion of phosphorus during both the moderately low-sodium and high-sodium diets. Magnesium supplementation prevented CsA-induced phosphaturia. The urinary excretion of calcium was markedly increased during the high-sodium diet irrespective of the dietary magnesium level (Table 2).
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Renal, Myocardial, and Bone Electrolyte Concentrations
Renal potassium concentration was slightly increased and calcium concentration was markedly increased by CsA during the high-sodium diet (Table 3). The CsA-induced rises in renal calcium and potassium contents during the high-sodium diet were blocked by magnesium supplementation. Renal magnesium concentration was slightly higher in the CsA group on the high-sodium diet compared with the CsA group on the moderately low-sodium diet. The renal calcium concentration correlated closely with the 24-hour urinary protein excretion (r=.72, P<.0001, n=46) (Fig 3).
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Myocardial magnesium depletion and calcium accumulation were produced by CsA during the high-sodium diet (Table 4). CsA-induced changes in myocardial magnesium and calcium concentrations during the high-sodium diet were completely blocked by magnesium supplementation. Myocardial sodium, potassium, and phosphorus concentrations did not differ significantly between different experimental groups (Table 4). CsA treatment caused magnesium wasting from the bone during the high-sodium diet, whereas during magnesium supplementation, the bone magnesium concentration of the CsA-treated SHR was significantly increased (Table 4).
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CsA Concentrations
There were no significant differences in the whole-blood, renal, myocardial, hepatic, or striated muscle CsA concentrations between the different CsA treatment groups (Table 5).
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Discussion |
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In the present study, the influence of a high intake of sodium and magnesium supplementation on CsA-induced hypertension and nephrotoxicity was examined in SHR during the development phase of hypertension. In agreement with previous findings,17 18 19 20 a high sodium intake alone increased blood pressure in SHR. In the presence of a high intake of sodium, CsA produced a marked further rise in blood pressure, induced LVH, and caused nephrotoxicity in SHR. These adverse effects of CsA greatly exceeded those produced by CsA during the moderately low intake of sodium. Our finding of the aggravation of CsA-induced hypertension in SHR by a high intake of sodium is in good accordance with the previous short-term clinical study of Curtis and coworkers21 demonstrating that sodium restriction has a pronounced antihypertensive effect in CsA-treated transplant recipients. Our study was also able to confirm the previous finding that the relatively low-dose CsA treatment (5 mg·kg-1·d-1) used in the present study increases blood pressure in SHR receiving a moderately low-sodium diet without any significant changes in creatinine clearance.22 It has been shown previously that chronic administration of CsA is able to impair endothelium-dependent vascular relaxation in response to acetylcholine both in normotensive23 and in hypertensive rats (K.K., unpublished data, 1996). Hence, the slight increase in blood pressure in CsA-treated SHR receiving the moderately low-sodium diet, both in the presence and in the absence of concomitant magnesium supplementation, could have been mediated, at least in part, by CsA-induced endothelial dysfunction.
Our findings clearly contradict the conclusion by Elzinga et al24 and Gerkens et al25 that sodium restriction may potentiate CsA-induced nephrotoxicity, whereas a high intake of sodium may even protect against renal damage induced by CsA treatment. It should be noted that both studies examined the effect of sodium deficiency rather than the effect of a moderately low sodium intake on CsA toxicity. A severe sodium depletion was produced by a salt-free diet, and in the study by Elzinga et al,24 the sodium depletion was further potentiated by furosemide given to the animals. Therefore, it appears that both a high-sodium diet and severe sodium deficiency exaggerate CsA toxicity. Elzinga et al24 implicated activation of the renin-angiotensin system in the pathogenesis of CsA nephrotoxicity during sodium-depleted diets. Interestingly, remarkable rises in both PRA and serum aldosterone were found in the present study in CsA-treated SHR during the high-sodium diet. This was unexpected, because physiologically, an increased intake of sodium results in lowered renin and aldosterone levels.26 An increased PRA level has also been demonstrated during a high-sodium diet in stroke-prone SHR with histologically verified renal damage.27 Much evidence suggests that long-term treatment with CsA may reduce renal blood flow and induce local ischemia in kidney tissue.28 Previous studies have also revealed that renin secretion is tonically elevated from ischemic nephrons.29 Interestingly, most salt-sensitive hypertensive patients seem to respond to increased sodium intake by decreasing renal blood flow and increasing renal vascular resistance.30 Therefore, the rise of PRA found in CsA-treated SHR receiving the high-sodium diet may be a consequence rather than the cause of renal damage. Nevertheless, once activated, the renin-angiotensin-aldosterone system may further contribute to the renal damage and be part of a vicious circle in the worsening of renal injury.26 31
It has been shown previously32 that high blood pressure is one of the most powerful determinants of the development of LVH. Therefore, severe arterial hypertension leading to increased pressure load on the myocardium is likely to explain to a great extent the development of LVH in CsA-treated SHR on a high-sodium diet. However, the pressure-independent effect of sodium may also have been involved.33 34 35
Even though CsA also tended to induce magnesium depletion in SHR receiving the moderately low-sodium diet, CsA decreased magnesium levels in the heart and bone significantly only during the high-sodium diet. An important role of the magnesium depletion in CsA-induced toxicity is suggested by our findings that an increased dietary magnesium intake was able to prevent both the decrease in myocardial and bone magnesium levels and the detrimental effects of CsA on blood pressure, LVH, and renal functions during the high intake of sodium. The protective effect of magnesium supplementation during the high-sodium diet could not be explained by disparate sodium intake or CsA concentrations, because we did not find any differences between the high-sodium diet groups either in food intake, 24-hour urinary sodium excretion, or CsA concentrations determined from several tissues. The action of magnesium as a natural calcium channel blocking agent36 37 38 may largely explain our findings. This assumption is supported by the rise of calcium levels in both kidneys and myocardium in the CsA-treated SHR on the high-sodium diet. An increased entry of calcium into the cells is known to be able to produce damage and even death of the cells.39 40
In conclusion, our findings indicate that a high sodium intake exacerbates CsA-induced hypertension and nephrotoxicity in SHR. The detrimental interaction between increased sodium intake and CsA treatment can be markedly antagonized by oral magnesium supplementation. Therefore, clinical studies on CsA toxicity in transplant patients to assess the possible protective effects of moderate sodium restriction with concurrent magnesium supplementation would appear to be worthwhile.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grants from the Academy of Finland and the Sigrid Juselius Foundation. We thank Remi Hakama, Kaija Inkinen, Marja-Liisa Rasanen, and Toini Siiskonen for providing excellent technical assistance.
Received June 4, 1996;
first decision June 19, 1996;
first decision October 10, 1996;
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