PHARMACOLOGICAL CHARACTERIZATION OF THROMBOXANE AND PROSTANOID RECEPTORS IN HUMAN ISOLATED URINARY-BLADDER

1 Cumulative concentration-response curves (CRC) to prostaglandin E-1 (PGE(1)), PGE(2), PGD(2) and PGF(2 alpha) (0.01-30 mu M) and to the th romboxane A(2) (TXA(2)) receptor agonist U-46619 (0.01-30 mu M) were c onstructed in human isolated detrusor muscle strips both in basal cond itions and during electrical field stimulation. 2 All the agonists tes ted contracted the detrusor muscle. The rank order of agonist potency was: PGF(2 alpha) >U-46619 >PGE(2) whereas weak contractile responses were obtained with PGD(2) and PGE(1). Any of the agonists tested was a ble to induce a clear plateau of response even at 30 mu M. 3 The selec tive TXA(2) antagonist, GR 32191B (vapiprost), antagonized U-46619-ind uced contractions with an apparent pK(B) value of 8.27+/-0.12 (n=4 for each antagonist concentration). GR 32191B (0.3 mu M) did not antagoni ze the contractile responses to PGF(2 alpha) and it was a non-surmount able antagonist of PGE1 (apparent pKB of 7.09+/-0.04; n=5). The EP rec eptor antagonist AH 6809 at 10 mu M shifted to the right the CRC to U- 46619 (apparent pKB value of 5.88+/-0.04; n=4). 4 Electrical field sti mulation (20 Hz, 70 V, pulse width 0.1 ms, trains of 5 s every 60 s) e licited contractions fully sensitive to TTX (0.3 mu M) and atropine (1 mu M). U-46619 (0.01-3 mu M) potentiated the twitch contraction in a dose-dependent manner and this effect was competitively antagonized by GR 32191B with an estimated pKB of 8.54 +/- 0.14 (n = 4 for each anta gonist concentration). PGF(2 alpha) in the range 0.01-10 mu M (n=7), b ut not PGE2 and PGE(1) (n=3 for each), also potentiated the twitch con traction of detrusor muscle strips (23.5+/-0.3% of KCl 100 mM-induced contraction) but this potentiation was unaffected by 0.3 mu M GR 32191 B (n= 5). 5 Cumulative additions of U-46619 (0.01-30 mu M) were withou t effect on contractions induced by direct smooth muscle excitation (2 0 Hz, 40 V, 6 ms pulse width, trains of 2 s every 60 s, in the presenc e of TTX 1 mu M; n=3). Moreover, pretreatment of the tissue with 0.3 m u M U-46619 did not potentiate the smooth muscle response to 7 mu M be thanecol (n=2). 6 We concluded that TXA(2) can induce direct contracti on of human isolated urinary bladder through the classical TXA2 recept or. Prostanoid receptors, fully activated by PGE(2) and PGF(2 alpha) a re also present. All these receptors are probably located post-junctio nally. The rank order of agonist potency and the fact that GR32191B, b ut not AH6809, antagonized responses to PGE2 seem to indicate the pres ence of a new EP receptor subtype. Moreover, we suggest the presence o f prejuctional TXA2 and FP receptors, potentiating acetylcholine relea se from cholinergic nerve terminals.