Inhibition of mineralocorticoid receptors with eplerenone alleviates short-term cyclosporin A nephrotoxicity in conscious rats.
BACKGROUND
Recent data indicate that aldosterone aggravates cyclosporin A (CsA)-induced nephrotoxicity. We examined whether the mineralocorticoid receptor (MR) blocker eplerenone (EPL) antagonized early deterioration of renal function and blood pressure (BP) increase in CsA-treated rats.


METHODS
Male Sprague-Dawley rats received CsA (15 mg/kg/day i.p.) and/or EPL (100 mg/kg/day p.o.) for 21 days. After 2 weeks, arterial, venous and urinary bladder catheters were implanted and the rats were trained to accept a restraining device allowing arterial blood sampling and direct measurement of BP and renal function. BP was measured on-line in conscious rats.


RESULTS
CsA significantly increased systolic BP: 139 +/- 4 versus 134 +/- 2 mmHg, reduced body weight gain: -5 +/- 6 versus 36 +/- 7 g, glomerular filtration rate (GFR): 1.02 +/- 0.16 versus 2.64 +/- 0.27 ml/min, renal blood flow (RBF): 5.3 +/- 2.4 versus 13.5 +/- 2.1 ml/min and lithium clearance (C(Li+)): 0.16 +/- 0.04 versus 0.26 +/- 0.07 ml/min compared to controls. These changes were prevented by simultaneous EPL treatment: systolic BP, 130 +/- 4 mmHg; weight gain, 53 +/- 7 g; GFR, 1.67 +/- 0.26 ml/min; RBF, 12.3 +/- 2.1 ml/min and C(Li+), 0.27 +/- 0.03 ml/min. Analysis of kidney morphology after the CsA treatment showed hyaline vacuolization in tubules and vascular depositions in arterioles; these changes were less pronounced after combination therapy. No significant changes were seen regarding haemoglobin, haematocrit, plasma renin and vasopressin, plasma and urinary sodium, potassium, or osmolality.


CONCLUSIONS
MR blockade by EPL prevented short-term alterations in GFR, RBF and hypertension associated with CsA nephrotoxicity. We conclude that the aldosterone-MR pathway contributes markedly to the renal toxicity induced by this calcineurin inhibitor.
Nielsen
Finn Thomsen
FT
Institute of Physiology and Pharmacology, University of Southern Denmark, Winsløwparken 21, 3, DK-5000 Odense C, Denmark. ftn@dadlnet.dk
Jensen
Boye L
BL
Marcussen
Niels
N
Skøtt
Ole
O
Bie
Peter
P
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016572:Cyclosporine / Q000009:adverse effects* / Q000097:blood; D004195:Disease Models, Animal; D000077545:Eplerenone; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D007677:Kidney Function Tests; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000187:drug effects*; D012039:Regional Blood Flow; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology
D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000077545:Eplerenone; D016572:Cyclosporine