Eicosanoid-induced Ca2+ release and sustained contraction in Ca(2+)-free media are mediated by different signal transduction pathways in rat aorta.
1. The effects of 12-O-tetradecanoyl 4 beta-phorbol 13-acetate (beta-TPA) on the inositol 1,4,5-trisphosphate (IP3) production, Ca2+ release from the intracellular Ca2+ stores and sensitization of contractile apparatus, induced by prostaglandin F2 alpha (PGF2 alpha) and U46619, a thromboxane A2-mimetic, were studied, using fura-2-loaded and -unloaded rat thoracic aortic strips. 2. Both eicosanoids had characteristic patterns of responses in Ca(2+)-free, 2 mM EGTA-containing solution (Ca(2+)-free solution). They induced transient increases in intracellular Ca2+ concentration ([Ca2+]i) without corresponding transient contraction, but produced delayed, sustained contraction, where [Ca2+]i was returned to the basal level. 3. Treatment with beta-TPA for 60 min reduced the eicosanoids-induced IP3 production, suggesting that the treatment inhibits PIP2 breakdown. 4. The treatment also attenuated [Ca2+]i transient induced by the eicosanoids, but not by caffeine (an IP3-independent releaser of stored Ca2+), in fura-2-loaded preparations incubated in Ca(2+)-free solution. 5. In contrast in the presence of beta-TPA, the sustained contractions evoked by the eicosanoids in Ca(2+)-free solution were potentiated, suggesting that the sites of actions of beta-TPA and the eicosanoids may differ from each other. 6. PGF2 alpha and U46619 utilize different and parallel signal transduction pathways to release Ca2+ by IP3 produced by PIP2 breakdown (beta-TPA-sensitive), and to increase the sensitivity of contractile apparatus, in which protein kinase C may not be involved (beta-TPA-insensitive).
Kurata
R
R
Department of Chemical Pharmacology, Toho University School of Pharmaceutical Sciences, Chiba, Japan.
Takayanagi
I
I
Hisayama
T
T
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D003470:Culture Media; D015237:Dinoprost / Q000494:pharmacology; D015777:Eicosanoids / Q000494:pharmacology*; D005480:Flurbiprofen / Q000494:pharmacology; D016257:Fura-2; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011493:Protein Kinase C / Q000494:pharmacology; D011796:Quinacrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D003470:Culture Media; D015777:Eicosanoids; D011450:Prostaglandin Endoperoxides, Synthetic; D014662:Vasoconstrictor Agents; D005480:Flurbiprofen; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015544:Inositol 1,4,5-Trisphosphate; D015237:Dinoprost; D011493:Protein Kinase C; D011796:Quinacrine; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D016257:Fura-2