Inhibition of Thromboxane (Tx) Synthesis by Free Radical Scavengers

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Abstract
Treatment with thromboxane (Tx) synthase inhibitors or free radical scavangers has been shown to afford protection from renal ischemia. Since free radicals are closely associated with thromboxane (Tx) synthesis, this study examines the thesis that free radical scavengers inhibit formation of Tx. Anesthetized rats (n = 42) underwent right nephrectomy. By random choice, before 45 min of left renal pedicle clamping, rats received: 0.5 ml dextrose placebo IV (n = 6); the hydroxyl radical scavenger dimethyl-thiourea (DMTU), 500 mg/kg IV (n = 10); or the superoxide scavenger superoxide dismutase (SOD), 24,000 Sigma Units (SU)/kg IV (n = 12). This dose of SOD was repeated before release of the clamp. Treatment with DMTU and SOD decreased plasma TxB2 levels following 5 min of reperfusion from 2,480 pg/ml in dextrose treated controls to 1,155 pg/ml (p < 0.01) and 1,419 pg/ml (p < 0.03), respectively. At 24 hr, DMTU and SOD therapy decreased creatinine from 3.0 mg/dl in controls to 1.6 mg/dl (P < 0.01) and 2.1 mg/dl (p < 0.05), respectively. AT 24 hr, DMTU but not SOD decreased left renal weight from 113 to 94% (p < 0.0003) of the weight of the previously removed right kidney, and histologically prevented acute tubular necrosis (p < 0.05). In nephrectomized but nonischemic sham control rats (n = 7) plasma TxB2 and 6-keto-PGF1.alpha. concentrations were 757 pg/ml and 82 pg/ml, creatinine level 0.9 mg/dl and kidney weight 94% of the previously removed right kidney. Sham rats treated with DMTU (n = 4) or SOD (n = 3) had similar values of creatinine but TxB2 levels were decreased to 225 pg/ml (p < 0.05) and 262 pg/ml (p < 0.05), respectively. In a second study, platelet-rich plasma (PRP) was incubated with DMTU 10-6 to 10-4 M (n = 7) or SOD 10.8 to 1,080 SU (n = 7). Treated PRP was activated with ADP for 1 min, centrifuged, and the supernatant assayed for TxB2. At the highest dose DMTU and SOD decreased supernatant TxB2 from 12.0 to 2.5 ng TxB2/106 plts (p < 0.004) and 19.9 to 7.3 ng TxB2/106 plts (p < 0.05), respectively. Inhibition of TxB2 by DMTU and SOD was dose dependent. These data indicate that the salutary effects of DMTU and SOD in minimizing renal ischemic injury may be the direct antagonism of free radicals as well as by an indirect effect on Tx synthesis.