Effect of a thromboxane receptor antagonist on PGD2- and allergen-induced bronchoconstriction

Abstract

In this study we investigated the effect of the selective and potent thromboxane A2 (TxA2) receptor antagonist GR32191 on smooth muscle contraction induced by the TxA2 analogue U46619, prostaglandin (PG) D2, PGF2 alpha, and methacholine (MCh) in guinea pig airways in vitro and the airways response provoked by inhaled PGD2 and MCh in asthmatic subjects in vivo. GR32191 antagonized competitively the contractile responses of all three prostanoids to a similar degree but had no effect on MCh-induced contractions. In asthmatic subjects GR32191, in a single oral dose of 80 mg, did not affect base-line airway caliber or MCh-induced broncho-constriction but caused significant inhibition of PGD2-induced bronchoconstriction, displacing the concentration-response curves to the right by greater than 10-fold. The effect of the same oral dose of GR32191 on allergen-induced immediate bronchoconstriction was subsequently investigated in allergic asthmatic subjects. In individual subjects, GR32191 inhibited to varying degrees the overall bronchoconstrictor response, with the maximum effect occurring between 10 and 30 min after allergen challenge. These studies suggest that prostanoids contribute to the immediate bronchoconstriction induced by inhaled allergen in allergic asthmatics, and that this effect is mediated by stimulation of a thromboxane receptor.

Expression of functional prostaglandin D (DP) receptors in human corpus cavernosum smooth muscle

“…In contrast, Chinese hamster ovary cells transfected with the recombinant mouse DP receptor, PGD 2 and BW245C competitively inhibited binding of radiolabeled PGD 2 with K i values of 21 nM and 250 nM, respectively. 23 This data is consistent with the differences observed for DP receptor binding of BW245C in mice versus humans. 2 We have previously demonstrated that PGE 1 causes cAMP levels to increase to 750 -1000 pmol=mg protein in human cavernosal smooth muscle cells through either the EP2 and=or EP4 receptors.…”

“…A similar phenomenon has been reported in nonvascular smooth muscle in the lung, where PGD 2 plays a role in bronchoconstriction via TP receptors. 23 The pharmacological results are consistent with RT-PCR data demonstrating DP receptor mRNA in both corpus cavernosum smooth muscle biopsy specimens and cultured smooth muscle cells. The tissue distribution of the rat DP receptor has been characterized and found predominantly in the brain in the leptomeninges and peripherally in the eye and in the oviduct.…”

“…It is interesting to note that expression of the lipocalin PGD synthase has been shown in human prostate, epididymis, and testis and PGD synthase activity was detected in seminal plasma. 23 However, this is the first report of lipocalin PGD synthase in the human corpus cavernosum penis. In addition to the synthesis of PGD 2 , we demonstrated the presence of DP receptors by RT-PCR of DP mRNA in both human corpus cavernosum whole tissue and cultured smooth muscle cells.…”

Prostaglandin D2inhibits fibroblast migration

“…At least 10 receptors are involved in prostaglandin signalling, and many prostaglandins can interact with multiple receptors. In this regard, PGD 2 has been reported to interact with both the DP receptor and the TP receptor [26]. The DP receptor is believed to activate adenylyl cyclase and lead to an increase in cAMP [17].…”

“…Interestingly, the bronchoconstrictory effect exerted by PGD 2 is believed to be mediated through the TP receptor [26]. HIRAI et al [28], recently demonstrated that PGD 2 could induce chemotaxis of T-helper 2 cells, eosinophils and basophils by way of the seven-transmembrane receptor CRTH2.…”