EFFECTS OF THROMBOXANE-A2 RECEPTOR BLOCKADE ON OLIGURIC ISCHEMIC ACUTE-RENAL-FAILURE IN CONSCIOUS RATS

To investigate the potential pathogenetic and therapeutic roles of thr omboxane A2 (TXA2) and its receptor blockade, respectively, in the ear ly phase of ischemic acute renal failure (ARF), renal function, TXB2 e xcretion, and the effects of the specific TXA2 receptor antagonist sul otroban (SU) in a model of unilateral renal artery occlusion in consci ous female Sprague-Dawley rats were studied. Occlusion of the left ren al artery for 1 h in untreated (i.e., vehicle-treated) rats (N = 8) re sulted 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 . 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 ischemi c kidneys from untreated rots had decreased from 13.2 +/- 2.8 to 1.0 /-0.3 and 0.5 +/- 0.2 muL/min. 100 g at 2 and 6 h of reflow, respectiv ely, and GFR had decreased from 0.32 +/-0.04 mL/min . 100 g body wt to undetectable values. At 6 h of reflow, medullary Na-K-ATPase was slig htly (P < 0.05) reduced in left ischemic kidneys, whereas medullary an d papillary enzyme activities were compensatorily increased (P < 0.01) in right intact kidneys. The ADP/O ratio of cortical mitochondria was 41% (P < 0.05) and ATP synthesis was 77% (P < 0.01) lower than in rig ht intact kidneys. Within the first 3 h of reflow, TXB2 excretion rose twofold to threefold in the urine from left ischemic and right intact kidneys (P < 0.05). In left ischemic kidneys from SU-treated rats, ur ine volume of 17.0 +/- 2.7 muL/min. 100 g (P < 0.01) at 2 h and GFR of 0.08 +/- 0.04 (P < 0.01) and 0.02 +/- 0.01 mL/min . 100 g (P < 0.05) at 2 and 6 h of reflow were significantly higher than the correspondin g values in untreated rats. Na-K-ATPase activities were similar to tho se of untreated rats, the cortical mitochondrial ADP/O-ratio was norma l, and ATP synthesis, although still 35% lower than in intact right ki dneys, was markedly protected by SU (P < 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 < 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 ot experimen tal ischemic ARF, SU protects renal cortical energy metabolism but has no major effect on tubular dysfunction. It transiently converts oligu ria into nonoliguria, probably via attenuation of TXA2-mediated vascul ar constriction in the very early phase of reflow.