title: Potentiation of adrenaline vasoconstrictor response by sub-threshold concentrations of U-46619 in human umbilical vein: involvement of smooth muscle prostanoid TP(alpha) receptor isoform.
abstract: Considering the potential physiological, pharmacological and therapeutic relevance of synergistic interaction of thromboxane A(2) with adrenaline at postjunctional receptor sites, we examined whether sub-threshold concentrations of thromboxane A(2) mimetic U-46619 (9,11-dideoxy-9alpha, 11alpha-methanoepoxy prostaglandin F(2alpha)) could amplify adrenaline-induced contraction in human umbilical vein. The receptor involved in U-46619-induced potentiation of adrenaline contractility was also investigated. Umbilical cords (n=125) from healthy patients after full-term vaginal or caesarean deliveries were employed. The vein was dissected out of cords and rings used for isolated organ bath experiments or reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Presence of endothelium did not modify U-46619-induced contraction in human umbilical vein. Prostanoid TP-selective receptor antagonist, SQ-29548 (7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-[1S(1alpha,2alpha(Z),3alpha,4alpha)]-5-Heptenoic acid), inhibited U-46619-induced contraction (pA(2)=8.22+/-0.11). U-46619 sub-threshold concentrations (0.1-0.3 nM) potentiated adrenaline-vasoconstriction response in a concentration-dependent manner. SQ-29548 (0.1 microM) abolished this potentiation. Using RT-PCR, we found that human umbilical vein rings with or without endothelium express the prostanoid TP(alpha), but not the prostanoid TP(beta) receptor isoform. Western blot allowed the identification of proteins with an electrophoretic mobility (47- and 55-kDa) indistinguishable from human platelet prostanoid TP receptor, a rich source of prostanoid TP(alpha) receptor isoform. Collectively, present results demonstrate that prostanoid TP(alpha) is the major receptor isoform localized on smooth muscle cells which participate in both direct vasoconstriction and potentiating effects of U-46619 on adrenaline contractions in human umbilical vein. These results suggest that thromboxane A(2) may interact synergistically with adrenaline in pathophysiological situations that lead to an increase of its umbilical venous levels (e.g. preeclampsia associated with fetal distress) raising the possibility of vasoconstriction affecting fetal blood flow.
authors.affiliation: Departamento de Farmacología, Universidad de Buenos Aires, Paraguay 2155, Piso 9, 1121, Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: Andrea Emilse
authors.initials: AE
authors.lastname: Errasti
authors.forename: Laura Inés
authors.initials: LI
authors.lastname: Luciani
authors.forename: Cristián Emanuel
authors.initials: CE
authors.lastname: Cesio
authors.forename: Julián
authors.initials: J
authors.lastname: Tramontano
authors.forename: Dante
authors.initials: D
authors.lastname: Boveris
authors.forename: Federico Manuel
authors.initials: FM
authors.lastname: Daray
authors.forename: Wanda
authors.initials: W
authors.lastname: Nowak
authors.forename: Facundo Germán
authors.initials: FG
authors.lastname: Pelorosso
authors.forename: Rodolfo Pedro
authors.initials: RP
authors.lastname: Rothlin
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology*; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated; D005260:Female; D006801:Humans; D006834:Hydrazines; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D017482:Receptors, Thromboxane / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014471:Umbilical Veins / Q000187:drug effects* / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D020033:Protein Isoforms; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D004837:Epinephrine