Oxidant stress but not thromboxane decreases with epoprostenol therapy

Epoprostenol has improved the outcome of patients with primary pulmonary hypertension (PPH); however, its mechanism of action remains poorly understood. Isoprostanes are easily measured markers of oxidant stress and can activate platelets leading to increased thromboxane A(2) (TxA(2)) production. We hypothesized that oxidant stress is associated with increased TxA(2) synthesis and that epoprostenol decreases oxidant stress and TxA2 production in patients with PPH. Morning urine samples were obtained from 19 patients with PPH. We measured urinary metabolites of the isoprostane, 8-iso-PGF(2alpha) (F-2-IsoP-M), and of TxA(2) (Tx-M) before and after treatment with epoprostenol in patients with PPH. Mean (+/-SE) levels of F-2-IsoP-M were elevated at baseline in our patients, 863 +/- 97 pg/mg creatinine. During treatment with epoprostenol, values decreased to 636 +/- 77 pg/mg creatinine (P = 0.011), and there was a strong correlation between the change in F-2-IsoP-M and follow-up pulmonary vascular resistance (R-2 = 0.69, P < 0.001). Tx-M levels were markedly elevated at baseline and were unchanged with therapy. These results indicate that oxidant stress decreases with epoprostenol therapy and is associated with hemodynamic and clinical improvement. The failure of Tx-M to decrease with therapy suggests that epoprostenol does not exert a beneficial effect through inhibition of TxA(2) production in patients with PPH. (C) 2004 Elsevier Inc. All rights reserved.