Cyclosporine A attenuates the natriuretic action of loop diuretics by inhibition of renal COX-2 expression

Kidney Int. 2004 Jun;65(6):2071-80. doi: 10.1111/j.1523-1755.2004.00627.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 6-Ketoprostaglandin F1 alpha / blood
  • 6-Ketoprostaglandin F1 alpha / metabolism
  • Animals
  • Calcineurin Inhibitors
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / administration & dosage*
  • Cyclosporine / administration & dosage*
  • Dinoprostone / urine
  • Diuresis / drug effects
  • Diuretics / administration & dosage*
  • Drug Interactions
  • Furosemide / administration & dosage
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Kidney / drug effects
  • Kidney / enzymology
  • Lactones / administration & dosage
  • Loop of Henle / drug effects
  • Male
  • Membrane Proteins
  • Natriuresis / drug effects*
  • Potassium / urine
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Renin / blood
  • Renin / genetics
  • Sulfones

Substances

  • Calcineurin Inhibitors
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Diuretics
  • Isoenzymes
  • Lactones
  • Membrane Proteins
  • RNA, Messenger
  • Sulfones
  • rofecoxib
  • 6-Ketoprostaglandin F1 alpha
  • Furosemide
  • Cyclosporine
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Ptgs1 protein, rat
  • Renin
  • Dinoprostone
  • Potassium