Analysis of the pulmonary hypertensive effects of the isoprostane derivative, 8-iso-PGF(2 alpha), in the rat

1 We analysed the pulmonary hypertensive effects of the F-2-isoprostane derivative, 8-iso-prostaglandin F-2 alpha (8-iso-PGF(2 alpha)), 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). 2 8-iso-PGF(2 alpha) produced dose-dependent increases in mean pulmonary arterial pressure, with an ED50 of 39.0 (31.4-50.6) mu g kg(-1), i.v. (geometric mean with 95% confidence limits in parentheses) compared to 1.4 (1.1-2.3) mu g kg(-1) i.v., for U-46619. The maximum responses evoked by U-46619 and 8-iso-PGF(2 alpha), were not statistically significantly different (21.0 +/- 1.0 and 25.8 +/- 1.9 mmHg at 10 mu g kg(-1) of U-46619 and 630 mu g kg(-1) of 8-iso-PGF(2 alpha), respectively). 3 The TP receptor antagonist, SQ 29,548 (0.63 mg kg(-1), i.v. + 0.63 mg kg(-1) h(-1)) fully antagronised both U-46619 and 8-iso-PGF(2 alpha)-induced pulmonary hypertensive responses. 4 Further experiments were carried out to determine whether 8-iso-PGF(2 alpha) antagonized the pulmonary hypertensive responses evoked by U-46619, or those induced by itself as would be predicted for a partial agonist. However, ED10 or ED25 doses of 8-iso-PGF(2 alpha) (10 or 20 mu g kg(-1), i.v.) failed to reduce the pulmonary hypertensive responses induced either by U-46619 or by itself. 5 The data suggest that in the pulmonary vascular bed of the rat, 8-iso-PGF(2 alpha) acts as an agonist of high intrinsic activity at SQ 29,548-sensitive (probably TP) receptors.