Comparison of enalapril and valsartan in cyclosporine A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats on high-sodium diet.
1. We compared the effects of the angiotensin converting enzyme (ACE) inhibitor enalapril and the angiotensin AT(1) receptor antagonist valsartan in cyclosporine A (CsA)-induced hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR). 2. SHR (8 - 9 weeks old) on high-sodium diet were given CsA (5 mg kg(-1)d (-1) s.c. ) for 6 weeks. The rats were treated concomitantly either with enalapril (30 mg kg(-1)d (-1) p.o.) or valsartan (3 or 30 mg kg(-1) d (-1) p.o.). To evaluate the role of bradykinin in the action of enalapril, some rats received a bradykinin B(2) receptor antagonist icatibant (HOE 140, 500 microg kg(-1) d (-1) s.c.) during the last 2 weeks of enalapril treatment. 3. Blood pressure was recorded every second week by tail cuff method. Renal function was measured by serum creatinine, creatinine clearance and urinary excretion of proteins at the end of the experiment. The activity of the renal kallikrein-kinin system was estimated by urinary kallikrein excretion. 4. CsA caused hypertension, impaired renal function and induced morphological nephrotoxicity with glomerular damage and interstitial fibrosis. Enalapril and the lower dose of valsartan attenuated the CsA-induced hypertension to the same extent, while the higher dose of valsartan totally abolished it. Icatibant did not reduce the antihypertensive effect of enalapril. Urinary kallikrein excretion was similar in all groups. 5. Enalapril and valsartan equally prevented the CsA-induced deterioration of kidney function and morphology. 6. The renin-angiotensin but not the kallikrein-kinin system plays a crucial role in CsA-toxicity during high intake of sodium in SHR.
Lassila
M
M
Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Helsinki, Finland. Research Laboratory, Fourth Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland. Department of Pathology, He.
Finckenberg
P
P
Pere
A K
AK
Krogerus
L
L
Ahonen
J
J
Vapaatalo
H
H
Nurminen
M L
ML
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D016572:Cyclosporine / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D004573:Electrolytes / Q000652:urine; D004656:Enalapril / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000517:prevention & control; D007610:Kallikreins / Q000187:drug effects / Q000652:urine; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D043782:Receptor, Bradykinin B2; D012083:Renin / Q000097:blood / Q000187:drug effects; D012982:Sodium, Dietary / Q000008:administration & dosage*; D013777:Tetrazoles / Q000494:pharmacology*; D014554:Urination / Q000187:drug effects; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D065168:Bradykinin Receptor Antagonists; D004573:Electrolytes; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D043782:Receptor, Bradykinin B2; D012982:Sodium, Dietary; D013777:Tetrazoles; D004656:Enalapril; C065679:icatibant; D000068756:Valsartan; D016572:Cyclosporine; D007610:Kallikreins; D012083:Renin; D014633:Valine; D001920:Bradykinin