Analysis of the pulmonary hypertensive effects of the isoprostane derivative, 8‐iso‐PGF 2 α , in the rat

We analysed the pulmonary hypertensive effects of the F 2 ‐isoprostane derivative, 8‐iso‐prostaglandin F 2α (8‐iso‐PGF 2α ), in comparison with those of the high efficacy thromboxane A 2 /prostanoid (TP) receptor agonist, U‐46619, in pentobarbitone‐anaesthetized, open‐chest rats ( n =4–15 per group). 8‐iso‐PGF 2α produced dose‐dependent increases in mean pulmonary arterial pressure, with an ED 50 of 39.0 (31.4–50.6) μg kg −1 , i.v. (geometric mean with 95% confidence limits in parentheses) compared to 1.4 (1.1–2.3) μg kg −1 , i.v., for U‐46619. The maximum responses evoked by U‐46619 and 8‐iso‐PGF 2α were not statistically significantly different (21.0±1.0 and 25.8±1.9 mmHg at 10 μg kg −1 of U‐46619 and 630 μg kg −1 of 8‐iso‐PGF 2α , respectively). The TP receptor antagonist, SQ 29,548 (0.63 mg kg −1 , i.v. + 0.63 mg kg −1 h −1 ) fully antagonised both U‐46619 and 8‐iso‐PGF 2α ‐induced pulmonary hypertensive responses. Further experiments were carried out to determine whether 8‐iso‐PGF 2α antagonized the pulmonary hypertensive responses evoked by U‐46619, or those induced by itself, as would be predicted for a partial agonist. However, ED 10 or ED 25 doses of 8‐iso‐PGF 2α (10 or 20 μg kg −1 , i.v.) failed to reduce the pulmonary hypertensive responses induced either by U‐46619 or by itself. The data suggest that in the pulmonary vascular bed of the rat, 8‐iso‐PGF 2α acts as an agonist of high intrinsic activity at SQ 29,548‐sensitive (probably TP) receptors. British Journal of Pharmacology (1997) 122 , 899–905; doi: 10.1038/sj.bjp.0701441