Characterization of Signal Transduction Events Stimulated by 8-epi-Prostaglandin(PG)F2α in Rat Aortic Rings

Abstract

One of the most abundant F₂ isoprostanes formed under pathological conditions is 8-epi-prostaglandin F_2α (8-epi-PGF_2α), a potent vasoconstrictor. The purpose of this study was to determine the signal transduction events initiated by 8-epi-PGF_2α-induced vasoconstriction. Isolated arterial rings from male Sprague-Dawley rats were suspended in tissue baths containing Krebs-Henseleit salt solution, stretched to optimal resting tension and stimulated. 8-epi-PGF_2α induced concentration-dependent contractions in pulmonary arteries (EC₅₀: 7.7 ± 2.1 μM; n = 3) and aortas (EC₅₀: 0.9 ± 0.1μM; n = 4) which were blocked by the TXA₂ receptor antagonists SQ29548, L657925 and L657926. The contractile response to 8-epi-PGF_2α was significantly (★p < 0.05; n = 4) diminished by: 1) indomethacin and ibuprofen; 2) Ca⁺⁺ free media; 3) verapamil, a voltage gated Ca⁺⁺ channel blocker; 4) flunarizine, a T-type Ca⁺⁺ channel blocker; and 5) calphostin C, a protein kinase C inhibitor. These data suggest that the contractile response to 8-epi-PGF_2α is: 1) mediated via activation of TXA₂ receptors; 2) partially dependent on the synthesis and release of other cyclooxygenase derived products; 3) dependent on an influx of extracellular Ca⁺⁺ possibly via Ca⁺⁺ channels; and 4) may be PKC dependent.