Effects of thromboxane A2 receptor blockade on oliguric ischemic acute renal failure in conscious rats

Kramer, H.J.; Mohaupt, M.G.; Pinoli, F.; Bäcker, A.; Meyer-Lehnert, H.; Schlebusch, H.

Journal of the American Society of Nephrology Jasn 4(1): 50-57

1993


ISSN/ISBN: 1046-6673
PMID: 8400069
Accession: 008584608

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Abstract
To investigate the potential pathogenetic and therapeutic roles of thromboxane A-2 (TXA-2) and its receptor blockade, respectively, in the early phase of ischemic acute renal failure (ARF), renal function, TXB-2 excretion, and the effects of the specific TXA-2 receptor antagonist sulotroban (SU) in a model of unilateral renal artery occlusion in conscious female Sprague-Dawley rats were studied. Occlusion of the left renal artery for 1 h in untreated (i.e., vehicle-treated) rats (N = 8) resulted in oliguric ARF. In SU-treated rats (N = 8), the drug was given as an iv bolus of 5 mg/kg body wt, followed by a continuous infusion of 0.5 mg/min cntdot kg body wt from 1 h before and during ischemia and for 6 h after reflow. After 1 h of ischemia, urine volume of left ischemic kidneys from untreated rats had decreased from 13.2 +- 2.8 to 1.0 +- 0.3 and 0.5 +- 0.2 mu-L/min cntdot 100 g at 2 and 6 h of reflow, respectively, and GFR had decreased from 0.32 +- 0.04 mL/min cntdot 100 g body wt to undetectable values. At 6 h of reflow, medullary Na-K-ATPase was slightly (P lt 0.05) reduced in left ischemic kidneys, whereas medullary and papillary enzyme activities were compensatorily increased (P lt 0.01) in right intact kidneys. The ADP/O ratio of cortical mitochondria was 41% (P lt 0.05) and ATP synthesis was 77% (P lt 0.01) lower than in right intact kidneys. Within the first 3 h of reflow, TXB-2 excretion rose twofold to threefold in the urine from left ischemic and right intact kidneys (P lt 0.05). In left ischemic kidneys from SU-treated rats, urine volume of 17.0 +- 2.7 mu-L/min cntdot 100 g (P lt 0.01) at 2 h and GFR of 0.08 +- 0.04 (P lt 0.01) and 0.02 +- 0.01 mL/min cntdot 100 g (P lt 0.05) at 2 and 6 h of reflow were significantly higher than the corresponding values in untreated rats. Na-K-ATPase activities were similar to those of untreated rats, the cortical mitochondrial ADP/O-ratio was normal, and ATP synthesis, although still 35% lower than in intact right kidneys, was markedly protected by SU (P lt 0.01). At 6 h of reflow, the mitochondrial calcium concentrations of left ischemic and right intact kidneys (14.8 +- 1.3 and 8.5 +- 0.7 nmol/mg of protein) were lower (P lt 0.05) than in untreated rats (19.2 +- 1.5 and 10.2 +- 0.4 nmol/mg of protein). These results suggest that, in this model of experimental ischemic ARF, SU protects renal cortical energy metabolism but has no major effect on tubular dysfunction. It transiently converts oliguria into nonoliguria, probably via attenuation of TXA-2-mediated vascular constriction in the very early phase of reflow.