Effects of ACE inhibition on cyclosporine A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats on a high-sodium diet.
Cyclosporine A (CsA)-induced hypertension has been shown to be dependent on the level of dietary salt. The present study assessed the role of the renin-angiotensin system in the development of CsA-induced hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR) on a high-sodium diet. In addition, we examined whether ACE inhibition prevents the detrimental effects of CsA on blood pressure, kidney function and vascular morphology in SHR on high sodium intake. Eight-week-old SHR were divided into three different groups (n = 8 in each group): (i) SHR control group receiving a high-sodium diet (Na 2.6% of the dry weight of the chow), (ii) CsA group (5 mg/kg s.c.) on a high-sodium diet and (iii) CsA + enalapril group (30 mg/kg p.o.) on a high-sodium diet. At the end of the six-week experimental period, systolic blood pressure in the CsA group was significantly higher compared to the control group (245+/-6 vs 208+/-9 mmHg, respectively, p < 0.05). Plasma renin activity was increased 20-fold by CsA treatment (p < 0.05 compared to controls). CsA increased serum creatinine by 22%, the 24-h urinary protein excretion by 190% and the 24-h urinary excretions of calcium, phosphorus and magnesium by 150%, 25% and 140%, respectively (p < 0.05 compared to controls). Histologically, the kidneys of CsA-treated SHR showed severe thickening of the media of the afferent arteriole and fibrinoid necrosis of the arteriolar wall. Interestingly, CsA induced vascular injury also in the small myocardial arteries. Enalapril treatment prevented CsA-induced hypertension and deterioration of kidney function as well as CsA-induced vascular injuries in the kidneys and myocardium. Enalapril also decreased left ventricular weight-to body weight ratio and prevented CsA-induced increases in urinary calcium and phosphorus excretions. Our findings indicate that CsA has a detrimental effect on blood pressure, kidney function and vascular morphology in SHR on high sodium intake. ACE inhibition prevents the CsA-induced hypertension, nephrotoxicity and vascular injuries. Our findings thus suggest that increased activity of the renin-angiotensin system is involved in the pathogenesis of CsA-induced hypertension and nephrotoxicity in SHR on a high-sodium diet.
Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Helsinki, Finland. mervaala@madc-berlin.de
E
E
Mervaala
M
M
Lassila
T
T
Vaskonen
L
L
Krogerus
T
T
Lähteenmäki
H
H
Vapaatalo
H
H
Karppanen
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000378:metabolism; D016572:Cyclosporine / Q000009:adverse effects*; D004656:Enalapril / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000517:prevention & control*; D017379:Hypertrophy, Left Ventricular / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects*; D011188:Potassium / Q000097:blood; D051381:Rats; D011918:Rats, Inbred SHR; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012982:Sodium, Dietary / Q000009:adverse effects*
D000806:Angiotensin-Converting Enzyme Inhibitors; D012982:Sodium, Dietary; D004656:Enalapril; D016572:Cyclosporine; D003404:Creatinine; D011188:Potassium