Vasoconstrictor effects of iso-prostaglandin F2alpha type-III (8-iso-prostaglandin F2alpha) on human saphenous veins.
Free radical generation can initiate the peroxidation of arachidonic acid, resulting in a non-cyclooxygenase-dependent production of bioactive prostaglandin F2-like compounds. We have investigated the effects of iso-prostaglandin F2alpha type III, (iPF2alpha-III, formerly named 8-iso prostaglandin F2alpha) on human saphenous veins, and characterized the underlying mechanisms. In organ baths, the contractile effects of iPF2alpha-III were tested on saphenous vein rings coming from 22 patients. iPF2alpha-III induced concentration-dependent contractions of isolated human saphenous veins. The maximal contraction did not differ significantly from that of prostaglandin F2alpha (PGF2alpha). The pD2 values for iPF2alpha-III, PGF2alpha, endothelin-1 (ET-1), and U46619 (a stable thromboxane A2 mimetic) were 6.31+/-0.12, 5.66+/-0.13, 7.37+/-0.08, and 7.99+/-0.31, respectively (p < 0.001 for U46619 vs. iPF2alpha-III and PGF2alpha; and ET-1 vs. PGF2alpha). Emax values of iPF2alpha-III, PGF2alpha, ET-1, and U46619 were 137.7+/-24.3%, 145.9+/-7.5%, 92.9+/-16.8%, and 238.7+/-23.7%, respectively (p < 0.001 for U46619 vs. iPF2alpha-III, PGF2alpha and ET-1; and for PGF2alpha vs. ET-1). The responses to iPF2alpha-III were inhibited by GR 32191 10(-7) M, a TP-receptor antagonist, without affecting the maximal response (pD2 values were 5.98+/-0.06 in the absence, and 5.22+/-0.05 in the presence of GR32191; p < 0.001). Concentration-effect curves to iPF2alpha-III were not affected by phosphoramidon 10(-5) M (an endothelin converting enzyme inhibitor), BQ123 10(-6) M (a selective ET(A)-receptor antagonist), BQ788 10(-6) M (a selective ET(B)-receptor antagonist), and indomethacin 10(-5) M (a cyclooxygenase inhibitor). Finally, the contractile response of iPF2alpha-III did not involve the release of thromboxane B2 and ET-1, measured using enzyme immunoassays. This study demonstrates that iPF2alpha-III is a vasoconstrictor of human saphenous veins, with a potency fourfold greater than that of PGF2alpha, and 50 times less than that of the thromboxane A2 mimetic, U46619. These effects are mediated at least in part by TP-receptor stimulation, but do not involve thromboxane A2 or ET-1 release.
Gardan
B
B
Laboratory of Pharmacology, Faculté de Médecine de Grenoble, La Tronche, France.
Cracowski
J L
JL
Sessa
C
C
Hunt
M
M
Stanke-Labesque
F
F
Devillier
P
P
Bessard
G
G
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology; D004347:Drug Interactions; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology; D000072396:Endothelin-Converting Enzymes; D028441:F2-Isoprostanes; D006801:Humans; D066298:In Vitro Techniques; D008666:Metalloendopeptidases; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D012501:Saphenous Vein / Q000187:drug effects* / Q000502:physiology; D013928:Thromboxane A2 / Q000378:metabolism; D013929:Thromboxane B2 / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D028441:F2-Isoprostanes; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; C075750:8-epi-prostaglandin F2alpha; D013929:Thromboxane B2; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015237:Dinoprost; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes