Prevention and complete reversal of cyclosporine A-induced renal vasoconstriction and nephrotoxicity in the rat by fenoldopam.
The primary mechanism of cyclosporine A-induced nephrotoxicity involves renal vasoconstriction. In the present study, we have tested the effects of fenoldopam, a dopamine DA1, receptor agonist with renal vasodilator properties, on the changes in renal function induced by acute and subacute administration of cyclosporine A. In inactin-anesthetized rats, acute administration of cyclosporine A (100 mg/kg i.p.) significantly decreased paraaminohippuric acid (PAH) and inulin clearances. Fenoldopam, at a dose (10 micrograms/kg.min) which alone significantly increased PAH and inulin clearances, completely prevented the cyclosporine A-induced reductions in renal function. Similarly, subacute administration of cyclosporine A (20 mg/kg.day for 3 days) resulted in significant reductions in base-line PAH and inulin clearances which were normalized by administration of fenoldopam. These data indicate that administration of fenoldopam can both prevent and completely reverse cyclosporine A-induced renal vasoconstriction and nephrotoxicity.
Brooks
D P
DP
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
Drutz
D J
DJ
Ruffolo
R R
RR
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003524:Cyclosporins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D018818:Fenoldopam; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007444:Inulin / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000627:therapeutic use*; D010130:p-Aminohippuric Acid / Q000378:metabolism
D003524:Cyclosporins; D014665:Vasodilator Agents; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D007444:Inulin; D018818:Fenoldopam; D010130:p-Aminohippuric Acid