Zaprinast accelerates recovery from established acute renal failure in the rat

Abstract

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.

β2-Adrenoceptor Activation Attenuates Endotoxin-Induced Acute Renal Failure

“…The fall in renal cAMP level was correlated with the depression in GFR caused by the LPS challenge, suggesting the possibility that the protective effect of ␤ 2 -AR activation was exerted through the intracellular cAMP/cAMPdependent protein kinase (PKA) pathway. This would be compatible with previous reports that cAMP-PKA activation plays an important role in the protection against acute renal failure (39,40).…”

Guanine nucleotides and acute renal failure

“…Augmentation of blood flow after ischemia, either by hemodilution, treatment with atriopeptin, or removal of the contralateral nonischemic kidney, can ameliorate ischemic ARF (6). The effects of atriopeptin and nitric oxide on renal blood flow in these models are mediated by cyclic GMP, and it has been reported that inhibition of cyclic GMP phosphodiesterase with zaprinast increases renal blood flow and ameliorates ARF, even when given a full day after ischemic injury (19). It is conceivable, although not tested in the current report, that increasing intracellular guanine nucleotides affects generation of cyclic GMP, thus improving blood flow in the injured organ.…”

Pretreatment of sildenafil attenuates ischemia-reperfusion renal injury in rats

“…Guan et al (19) showed that treatment with zaprinast, a cGMP-specific phosphodiesterase inhibitor, 24 h after 60 min of bilateral renal artery clamping in the rat, accelerated renal recovery by improving regional renal blood flow. Early treatment with sildenafil ameliorated the progression of renal damage in a 5 ⁄6 nephrectomy model (32).…”