Potentiation of adrenaline vasoconstrictor response by sub-threshold concentrations of U-46619 in human umbilical vein: Involvement of smooth muscle prostanoid TP receptor isoform

ERRASTI ANDREA EMILSE, LUCIANI LAURA INÉS, CESIO CRISTIAN EMANUEL, TRAMONTANO JULIÁN, BOVERIS DANTE, DARAY FEDERICO MANUEL, NOWAK WANDA, PELOROSSO FACUNDO GERMÁN, ROTHLIN RODOLFO PEDRO

EUROPEAN JOURNAL OF PHARMACOLOGY

Elsevier Science

Lugar: Netherlands; Año: 2007 vol. 562 p. 227 - 235

0014-2999

Considering the potential physiological, pharmacological and therapeutic relevance of synergistic interaction of thromboxane A2 with adrenaline at postjunctional receptor sites, we examined whether sub-threshold concentrations of thromboxane A2 mimetic U-46619 (9,11-dideoxy-9, 11-methanoepoxy prostaglandin F2) 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(1,2(Z),3,4)]-5-Heptenoic acid), inhibited U-46619-induced contraction (pA2 = 8.22 ¡À 0.11). U-46619 sub-threshold concentrations (0.1¨C0.3 nM) potentiated adrenaline-vasoconstriction response in a concentration-dependent manner. SQ-29548 (0.1 ¦ÌM) abolished this potentiation. Using RT-PCR, we found that human umbilical vein rings with or without endothelium express the prostanoid TP, but not the prostanoid TP¦Â 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 receptor isoform. Collectively, present results demonstrate that prostanoid TP 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 A2 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. Considering the potential physiological, pharmacological and therapeutic relevance of synergistic interaction of thromboxane A2 with adrenaline at postjunctional receptor sites, we examined whether sub-threshold concentrations of thromboxane A2 mimetic U-46619 (9,11-dideoxy-9, 11-methanoepoxy prostaglandin F2) 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(1,2(Z),3,4)]-5-Heptenoic acid), inhibited U-46619-induced contraction (pA2 = 8.22 ¡À 0.11). U-46619 sub-threshold concentrations (0.1¨C0.3 nM) potentiated adrenaline-vasoconstriction response in a concentration-dependent manner. SQ-29548 (0.1 ¦ÌM) abolished this potentiation. Using RT-PCR, we found that human umbilical vein rings with or without endothelium express the prostanoid TP, but not the prostanoid TP¦Â 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 receptor isoform. Collectively, present results demonstrate that prostanoid TP 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 A2 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. Keywords: Human umbilical vein; Potentiation; Vasoconstriction; Adrenaline; Thromboxane A2 Analogue U-46619; SQ-29548; RT-PCR (Reverse transcription-polymerase chain reaction); Western blot; Prostanoid TP receptor isoform