Analysis of the pulmonary hypertensive effects of the isoprostane derivative, 8-iso-PGF2alpha, in the rat.
1. We analysed the pulmonary hypertensive effects of the F2-isoprostane derivative, 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), in comparison with those of the high efficacy thromboxane A2/prostanoid (TP) receptor agonist, U-46619, in pentobarbitone-anaesthetized, open-chest rats (n=4-15 per group). 2. 8-iso-PGF2alpha produced dose-dependent increases in mean pulmonary arterial pressure, with an ED50 of 39.0 (31.4-50.6) microg kg(-1), i.v. (geometric mean with 95% confidence limits in parentheses) compared to 1.4 (1.1-2.3) microg kg(-1), i.v., for U-46619. The maximum responses evoked by U-46619 and 8-iso-PGF2alpha were not statistically significantly different (21.0+/-1.0 and 25.8+/-1.9 mmHg at 10 microg kg(-1) of U-46619 and 630 microg kg(-1) of 8-iso-PGF2alpha, respectively). 3. 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-PGF2alpha-induced pulmonary hypertensive responses. 4. Further experiments were carried out to determine whether 8-iso-PGF2alpha 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-PGF2alpha (10 or 20 microg 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-PGF2alpha acts as an agonist of high intrinsic activity at SQ 29,548-sensitive (probably TP) receptors.
John
G W
GW
Centre de Recherche Pierre Fabre, Division of Cardiovascular Diseases, Castres, France.
Valentin
J P
JP
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic; D015237:Dinoprost / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D028441:F2-Isoprostanes; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines / Q000008:administration & dosage / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000503:physiopathology; D007262:Infusions, Intravenous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000008:administration & dosage / Q000633:toxicity
D019086:Bridged Bicyclo Compounds, Heterocyclic; D028441:F2-Isoprostanes; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; C075750:8-epi-prostaglandin F2alpha; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D015237:Dinoprost