Zaprinast accelerates recovery from established acute renal failure in the rat.
Atrial natriuretic factor (ANF) has been demonstrated to be effective in the treatment of acute renal failure (ARF) in both rat and humans. The biological effects of ANF are presumed to be mediated by the generation of intracellular 3',5'-cyclic guanosine monophosphate (cGMP). Therefore, the current investigation examined whether zaprinast (M&B 22948), a guanosine 3',5'-cyclic monophosphate (cGMP)-specific phosphodiesterase inhibitor, would be effective in the treatment of established acute renal failure in the rat. Acute renal failure was induced by 60 minutes of bilateral renal artery clamping. Twenty-four hours after the ischemic insult, rats received either vehicle (5% Dextrose), zaprinast (0.03 or 0.3 mg/kg/min) or ANF24 (0.2 micrograms/kg/min) intravenously for four hours. Renal function, as measured by daily serum creatinine (days 1 to 7) and day 2 inulin clearances, was dramatically improved by zaprinast but not ANF treatment. Forty-eight hours post-renal ischemia, glomerular filtration rate (GFR) was 0.14 +/- 0.04 (ml/min/100 g body wt) in the vehicle and 0.94 +/- 0.29 in the zaprinast treated animals. To evaluate the mechanism by which zaprinast accelerated renal recovery, we measured regional blood flow in the postischemic rat kidneys during drug treatment with a laser doppler flowmeter. Both high and low dose zaprinast significantly increased cortical (17%) and outer medullary blood flow (40% and 60%), an effect not seen with ANF. In summary, zaprinast is effective in the treatment of established ischemic ARF. The mechanism by which zaprinast accelerates renal recovery is due to its unique ability to stimulate regional renal blood flow and increase intracellular cGMP in the setting of tissue ischemia.
Guan
Z
Z
Department of Medicine, Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri, USA.
Miller
S B
SB
Greenwald
J E
JE
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D058186:Acute Kidney Injury / Q000503:physiopathology* / Q000628:therapy*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D003404:Creatinine / Q000097:blood; D000242:Cyclic AMP / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007444:Inulin / Q000097:blood; D007511:Ischemia / Q000503:physiopathology; D008297:Male; D011688:Purinones / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects
D011688:Purinones; D009320:Atrial Natriuretic Factor; D007444:Inulin; D003404:Creatinine; D000242:Cyclic AMP; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C011145:zaprinast