title: Oxidant stress but not thromboxane decreases with epoprostenol therapy.
abstract: 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 A2 (TxA2) production. We hypothesized that oxidant stress is associated with increased TxA2 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-PGF2alpha (F2-IsoP-M), and of TxA2 (Tx-M) before and after treatment with epoprostenol in patients with PPH. Mean (+/-SE) levels of F2-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 F2-IsoP-M and follow-up pulmonary vascular resistance (R2 = 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 TxA2 production in patients with PPH.
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, 1161 21st Avenue S., T-1217 MCN, Nashville, TN 37232-2650, USA. Ivan.Robbins@mcmail.Vanderbilt.edu
authors.forename: Ivan M
authors.initials: IM
authors.lastname: Robbins
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
authors.forename: Brian W
authors.initials: BW
authors.lastname: Christman
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000652:urine; D011464:Epoprostenol / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D013928:Thromboxane A2 / Q000378:metabolism* / Q000652:urine; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; C075750:8-epi-prostaglandin F2alpha; D013928:Thromboxane A2; D015237:Dinoprost; D011464:Epoprostenol