Blockage of the renin-angiotensin system attenuates mortality but not vascular calcification in uremic rats: sevelamer carbonate prevents vascular calcification.
OBJECTIVE
Hyperphosphatemia is associated with vascular calcification and increased cardiovascular morbidity and mortality. Angiotensin-converting enzyme inhibitors are beneficial in suppressing the progression of kidney and cardiovascular disease. The present studies explore the influence of enalapril and sevelamer carbonate on renal function, vascular calcification and mortality in long-term experimental uremia.


METHODS
Normal and 5/6 nephrectomized rats were fed a high-phosphorus diet for 4 months and treated with enalapril or the combination of both enalapril and sevelamer carbonate.


RESULTS
The rats treated with enalapril alone or both enalapril and sevelamer had less deterioration in renal function compared to uremic control as seen by lower serum creatinine (1.6, 1.6 vs. 2.1 mg/dl, respectively, p < 0.05) and higher creatinine clearance. They also exhibited attenuated mortality (23.5, 12.5 vs. 75%, respectively, p < 0.01) and inhibition of myocardial hypertrophy. Enalapril alone did not suppress secondary hyperparathyroidism or vascular calcification. Combination therapy with both enalapril and sevelamer carbonate ameliorated secondary hyperparathyroidism and vascular calcification (calcium content: 854 +/- 40 vs. 1,735 +/- 479 microg/g wet tissue) compared to uremic controls.


CONCLUSIONS
In these experiments, animal mortality and myocardial hypertrophy were significantly reduced by both enalapril alone and enalapril in combination with sevelamer. In addition, sevelamer carbonate induced beneficial effects on renal dysfunction, secondary hyperparathyroidism and vascular calcification.
Tokumoto
Masanori
M
Renal Division, Washington University School of Medicine, St. Louis, MO 63110, USA.
Mizobuchi
Masahide
M
Finch
Jane L
JL
Nakamura
Hironori
H
Martin
Daniel R
DR
Slatopolsky
Eduardo
E
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002114:Calcinosis / Q000188:drug therapy*; D006332:Cardiomegaly / Q000209:etiology / Q000517:prevention & control; D002614:Chelating Agents / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006962:Hyperparathyroidism, Secondary / Q000209:etiology / Q000517:prevention & control; D011073:Polyamines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects; D000069603:Sevelamer; D014511:Uremia / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000652:urine
D000806:Angiotensin-Converting Enzyme Inhibitors; D002614:Chelating Agents; D011073:Polyamines; D004656:Enalapril; D000069603:Sevelamer