Inhibitory effect of vapiprost on contractile responses of isolated dog renal arteries to thromboxane A2 analogue, U46619

Sakanashi, Matao; Matsuzaki, Toshihiro; Noguchi, Katsuhiko; Nakasone, Junko; Itomine, Tatsushi; Uza, Miyoko; Toyama, Fujiko; Higuchi, Makie

doi:10.1016/0306-3623(94)90236-4

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“…Interestingly, we found that human isolated detrusor contracted in the presence of PGF 2α and PGE 2 . Since there is evidence that both PGF 2α and PGE 2 can activate TP receptors (Dorn et al , 1992; Sakanashi et al , 1994; He & Yang, 1995) we decided to test the effect of GR 32191B on the contractile response mediated by these two agonists. Surprisingly, we found that, although GR 32191B was without effect versus PGF 2α , it antagonized quite well the response mediated by PGE 2 with a pK B value (7.09) approximately 10–30 times lower than values originally obtained for TP receptors in various tissues (8.2–8.8; Lumley et al , 1989).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological characterization of thromboxane and prostanoid receptors in human isolated urinary bladder

Palea

Toson

Pietra

et al. 1998

British J Pharmacology

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1 Cumulative concentration-response curves (CRC) to prostaglandin E 1 (PGE 1 ), PGE 2 , PGD 2 and PGF 2a (0.01 ± 30 mM) and to the thromboxane A 2 (TXA 2 ) receptor agonist U-46619 (0.01 ± 30 mM) were constructed in human isolated detrusor muscle strips both in basal conditions and during electrical ®eld stimulation. 2 All the agonists tested contracted the detrusor muscle. The rank order of agonist potency was: PGF 2a 4U-466194PGE 2 whereas weak contractile responses were obtained with PGD 2 and PGE 1 . Any of the agonists tested was able to induce a clear plateau of response even at 30 mM. 3 The selective TXA 2 antagonist, GR 32191B (vapiprost), antagonized U-46619-induced contractions with an apparent pK B value of 8.27+0.12 (n=4 for each antagonist concentration). GR 32191B (0.3 mM) did not antagonize the contractile responses to PGF 2a and it was a non-surmountable antagonist of PGE 2 (apparent pK B of 7.09+0.04; n=5). The EP receptor antagonist AH 6809 at 10 mM shifted to the right the CRC to U-46619 (apparent pK B value of 5.88+0.04; n=4). 4 Electrical ®eld stimulation (20 Hz, 70 V, pulse width 0.1 ms, trains of 5 s every 60 s) elicited contractions fully sensitive to TTX (0.3 mM) and atropine (1 mM). U-46619 (0.01 ± 3 mM) potentiated the twitch contraction in a dose-dependent manner and this e ect was competitively antagonized by GR 32191B with an estimated pK B of 8.54+0.14 (n=4 for each antagonist concentration). PGF 2a in the range 0.01 ± 10 mM (n=7), but not PGE 2 and PGE 1 (n=3 for each), also potentiated the twitch contraction of detrusor muscle strips (23.5+0.3% of KCl 100 mM-induced contraction) but this potentiation was una ected by 0.3 mM GR 32191B (n=5). 5 Cumulative additions of U-46619 (0.01 ± 30 mM) were without e ect on contractions induced by direct smooth muscle excitation (20 Hz, 40 V, 6 ms pulse width, trains of 2 s every 60 s, in the presence of TTX 1 mM; n=3). Moreover, pretreatment of the tissue with 0.3 mM U-46619 did not potentiate the smooth muscle response to 7 mM bethanecol (n=2). 6 We concluded that TXA 2 can induce direct contraction of human isolated urinary bladder through the classical TXA 2 receptor. Prostanoid receptors, fully activated by PGE 2 and PGF 2a are also present. All these receptors are probably located post-junctionally. The rank order of agonist potency and the fact that GR32191B, but not AH6809, antagonized responses to PGE 2 seem to indicate the presence of a new EP receptor subtype. Moreover, we suggest the presence of prejuctional TXA 2 and FP receptors, potentiating acetylcholine release from cholinergic nerve terminals.

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Section: Discussionmentioning

confidence: 99%