Role of arachidonic acid metabolites in oleic acid induced pulmonary injury in a canine model. Effect of ketoconazole (thromboxane synthetase inhibitor).

This study was designed to investigate the effects of ketoconazole, a thromboxane synthetase inhibitor, on pulmonary and systemic hemodynamics and pulmonary function in experimental respiratory distress syndrome. Pulmonary artery infusion of oleic acid (PAIOA), 0.1 ml/kg, was used to cause lung injury. Ten dogs were randomized into two groups (Gps): Gp I (n = 5) acted as control, whereas Gp II (n = 5) were treated with IV ketoconazole (2.5 mg/kg bolus then 10 mg/kg/hour for 2.5 hours). Hemodynamics, extravascular lung water (EVLW), serum levels of PGE2, and TxB2 were obtained at baseline (BL) and at 30-minute intervals for 2.5 hours (T30-T150). After 30 minutes of PAIOA the mean arterial pressure (MAP) decreased significantly in both Gps (131 +/- 17 vs. 88 +/- 9 mmHg Gp 1, 119 +/- 9 vs. 79 +/- 8 mmHg Gp II, P less than 0.05); however, while MAP returned to BL values in Gp II, it remained significantly lower throughout the experimental interval in Gp I. Mean pulmonary artery pressure (MAP) was not significantly affected by PAIOA in either Gp, while pulmonary vascular resistance increased significantly from BL at T120 in Gp II. Pulmonary function measured by partial pressure of arterial O2 (PaO2) and extravascular lung water (EVLW) were significantly affected by PAIOA. There was a significant decrease in PaO2 (66 +/- 6 vs. 96 +/- 8 mmHg, Gp I and 60 +/- 7 vs. 100 +/- 6 mmHg, Gp II) as well as an increase in EVLW (604 +/- 61 vs. 135 +/- 9 ml, Gp I and 641 +/- 110 vs. 117 +/- 18 ml, Gp II) in both Gps.(ABSTRACT TRUNCATED AT 250 WORDS)