Combination therapy with paricalcitol and enalapril ameliorates cardiac oxidative injury in uremic rats.
OBJECTIVE
This study investigated the protective effect of the angiotensin-converting enzyme inhibitor, enalapril, and the vitamin D analog, paricalcitol, alone or in combination, on cardiac oxidative stress in uremic rats.


METHODS
Rats were made uremic by 5/6 nephrectomy and treated for 4 months as follows: (1) uremic + vehicle (n = 11); (2) uremic + enalapril (30 mg/l in drinking water, n = 13); (3) uremic + paricalcitol (200 ng 3x week, n = 6); (4) uremic + enalapril + paricalcitol (n = 14), and (5) controls (n = 6).


RESULTS
Cardiac NADPH oxidase activity increased by 300% in uremic rats compared to normal controls. Treatment with enalapril, paricalcitol or the combination of the two protected uremic rats from cardiac oxidative stress by inhibiting enzyme activity. Cardiac malondialdehyde (MDA) levels were significantly increased in uremic rats compared to normal controls. Only the combination therapy inhibited the increase in MDA levels in uremic rats. Cardiac glutathione was significantly reduced in uremic rats compared to normal controls. Enalapril, paricalcitol or the two in combination all protected against this reduction in glutathione. Cardiac copper/zinc superoxide dismutase (CuZn-SOD) activity decreased whereas manganese (Mn-SOD) activity increased in uremic rats compared to controls. Both mono and combination therapies ameliorated the alterations in cardiac SOD activity seen in uremic rats.


CONCLUSIONS
Enalapril, paricalcitol and their combined therapy afford protection against cardiac oxidative stress in uremia.
Husain
Kazim
K
Department of Physiology, Pharmacology and Toxicology, Ponce School of Medicine, Ponce, PR 00732, USA. kazimhusain@hotmail.com
Ferder
Leon
L
Mizobuchi
Masahide
M
Finch
Jane
J
Slatopolsky
Eduardo
E
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000494:pharmacology / Q000627:therapeutic use*; D004872:Ergocalciferols / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006331:Heart Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008315:Malondialdehyde / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D014511:Uremia / Q000150:complications*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000975:Antioxidants; D004872:Ergocalciferols; D008315:Malondialdehyde; C084656:paricalcitol; D004656:Enalapril; D013482:Superoxide Dismutase; D019255:NADPH Oxidases