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


METHODS
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.


CONCLUSIONS
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.
Höcherl
Klaus
K
Institut für Pharmakologie, Innere Medizin II and Physiologie, Universität Regensburg, Regensburg, Germany. klaus.hoecherl@chemie.uni-regensburg.de
Kees
Frieder
F
Krämer
Bernhard K
BK
Kurtz
Armin
A
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood / Q000378:metabolism; D000818:Animals; D065095:Calcineurin Inhibitors; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage*; D016572:Cyclosporine / Q000008:administration & dosage*; D015232:Dinoprostone / Q000652:urine; D004231:Diuresis / Q000187:drug effects; D004232:Diuretics / Q000008:administration & dosage*; D004347:Drug Interactions; D005665:Furosemide / Q000008:administration & dosage; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D007783:Lactones / Q000008:administration & dosage; D008138:Loop of Henle / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins; D009318:Natriuresis / Q000187:drug effects*; D011188:Potassium / Q000652:urine; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood / Q000235:genetics; D013450:Sulfones
D065095:Calcineurin Inhibitors; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004232:Diuretics; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D012333:RNA, Messenger; D013450:Sulfones; C116926:rofecoxib; D015121:6-Ketoprostaglandin F1 alpha; D005665:Furosemide; D016572:Cyclosporine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D012083:Renin; D015232:Dinoprostone; D011188:Potassium