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  • Title: Cyclosporine A attenuates the natriuretic action of loop diuretics by inhibition of renal COX-2 expression.
    Author: Höcherl K, Kees F, Krämer BK, Kurtz A.
    Journal: Kidney Int; 2004 Jun; 65(6):2071-80. PubMed ID: 15149320.
    Abstract:
    BACKGROUND: It is known that inhibition of cyclooxygenase (COX) impairs the renal actions of loop diuretics. Recently, we found that cyclosporine A (CsA) inhibits renal COX-2 expression. Therefore, we examined the interferences of CsA with the renal actions of loop diuretics. METHOD: We investigated the renal effects of furosemide administration (12 mg/day subcutaneously) in male Sprague-Dawley rats receiving in addition vehicle, CsA (15 mg/kg x day), rofecoxib (10 mg/kg x day), or a combination of both. RESULTS: CsA, rofecoxib, and their combination lowered the furosemide-induced increase of prostaglandin E(2) (PGE(2)) and of 6-keto prostaglandin F(1 alpha) (6-keto PGF(1 alpha)) excretion by 55% and by 70%. They also lowered furosemide stimulated renal excretion of sodium and water by about 65% and 60%. Basal as well as furosemide-induced stimulation of plasma renin activity (PRA) and of renal renin mRNA was further enhanced by CsA. In contrast, rofecoxib attenuated the furosemide-induced rise of PRA and of renin mRNA, both in the absence and in the presence of CsA. In addition, the increase in plasma 6-keto PGF(1 alpha) levels by furosemide was further enhanced by CsA and was attenuated by rofecoxib. CONCLUSION: Taken together, our data suggest that CsA acts as an antinatriuretic, likely by the inhibition of COX-2-mediated renal prostanoid formation. Since the furosemide-induced stimulation of the renin system is not attenuated by CsA but by COX-2 inhibition, we speculate that extrarenal COX-2-derived prostanoids may be involved in the stimulation of the renin system by CsA and by loop diuretics.
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