title: The effects of blood pressure reduction on cyclosporine nephrotoxicity in the rat.
abstract: The effects of blood pressure reduction on cyclosporine nephrotoxicity were studied over 12 months in four groups of rats. Group 1 received no drugs and served as controls. Groups 2, 3, and 4 received cyclosporine (CyA), approximately 9 mg/kg.day, in their food. In addition, Group 3 received enalapril and Group 4 received minoxidil, hydrochlorothiazide, and reserpine. Time-averaged monthly systolic blood pressure was equal in Groups 1 and 2 (136 +/- 1 and 135 +/- 1 mm Hg, respectively). Antihypertensive agents reduced average systolic blood pressure in Groups 3 and 4 (116 +/- 1 and 117 +/- 1 mm Hg, respectively). Morphometric studies showed that 12 months of CyA treatment caused interstitial fibrosis with an increase in the fractional volume of cortical interstitium (VvInt: Group 2, 20 +/- 1%; Group 1, 11 +/- 1%) and a reduction in mean glomerular volume (VG. Group 2, (2.00 +/- 0.06) x 10(6) mu 3; Group 1, (2.48 +/- 0.06) x 10(6) mu 3). These structural changes were accompanied by a significant reduction in GFR (Group 2, 2.27 +/- 0.10 mL/min; Group 1, 2.76 +/- 0.10 mL/min). Cotreatment with enalapril reduced interstitial fibrosis (VvInt, 14 +/- 1%) and maintained VG (2.23 +/- 0.08 x 10(6) mu 3) and GFR (2.56 +/- 0.08 mL/min) at near-normal values in Group 3. In contrast, the combination antihypertensive regimen increased the extent of interstitial fibrosis (VvInt, 24 +/- 1%) and further lowered VG (1.72 +/- 0.05 x 10(6) mu 3) and GFR (1.72 +/- 0.05 mL/min) in Group 4. These results show that sustained treatment with a moderate dose of CyA causes interstitial fibrosis and impairs renal function in rats. The administration of enalapril, but not minoxidil, reserpine, and hydrochlorothiazide, limits renal injury in this model.
authors.affiliation: Department of Medicine, Palo Alto Veterans Administration Medical Center, CA.
authors.forename: R A
authors.initials: RA
authors.lastname: Lafayette
authors.forename: G
authors.initials: G
authors.lastname: Mayer
authors.forename: T W
authors.initials: TW
authors.lastname: Meyer
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure; D016572:Cyclosporine / Q000009:adverse effects* / Q000097:blood; D004656:Enalapril / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D011507:Proteinuria / Q000652:urine; D051381:Rats; D011919:Rats, Inbred Strains; D013599:Systole
chemical_list: D000959:Antihypertensive Agents; D004656:Enalapril; D016572:Cyclosporine