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Heterogeneity of thromboxane A 2 (TP‐) receptors: evidence from antagonist but not agonist potency measurements
Author(s) -
Tymkewycz Paulina M.,
Jones R.L.,
Wilson N.H.,
Marr C.G.
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb12220.x
Subject(s) - potency , agonist , chemistry , thromboxane a2 , antagonist , partial agonist , thromboxane , medicine , platelet , receptor , thromboxane receptor , endocrinology , guinea pig , pharmacology , biochemistry , biology , in vitro
1 Thromboxane A 2 (TP‐) receptors in human, rat and rabbit platelets and in smooth muscle of guinea‐pig trachea, rat aorta and rabbit aorta have been characterized by measurement of the potencies of agonists and antagonists having considerable variations in chemical structure. 2 On each washed platelet system, eight prostanoids induced maximal irreversible aggregation (full agonists) and the potency ranking was EP 171 > STA 2 > 9,11‐azo PGH 2 > 9,11‐endoxy‐10a‐homo PGH 2 > U‐46619 (standard) > PGH 2 = 16‐ p ‐fluorophenoxy‐ω‐tetranor PGF 2α > 16,16‐dimethyl PGF 2α . Correlations between the three platelet preparations for both absolute and relative potencies were good. On human platelets, STA 2 , at concentrations above that required for maximum aggregation, exerted an inhibitory effect which was independent of its interaction with the TP‐receptor. 3 Five prostanoids, EP 109, EP 167, EP 204, PTA 2 and 16,20‐methano PTA 2 , exhibited partial agonist activity on the platelet and smooth muscle preparations. There was good agreement between absolute potencies on the six preparations; on platelets potency was assessed from shape change measurements, since aggregation, when present, always showed a very shallow concentration‐response relationship. The magnitude of the maximum response induced by each compound decreased in the order listed above, to the extent that 16,20‐methano PTA 2 could be treated as a pure antagonist. 4 With U‐46619 as agonist, the pA 2 values of seven antagonists were found to be very similar on human and rat platelets. The potency ranking was EP 169 > AH 23848 > EP 092 > ONO 11120 > EP 115 = 16,20‐methano PTA 2 > BM 13177. There was a similar trend on rabbit platelets but pA 2 values were 1.0–1.5 log units smaller; the exception was BM 13177 which had similar affinities. The antagonism produced by EP 169 and AH 23848 was surmountable on rabbit platelets but not on human and rat platelets. 5 None of the antagonists was highly potent on the rabbit aorta (pA 2 values < 7.5 by Schild analysis). Affinities on the guinea‐pig trachea and the rat aorta were higher and in the same range as those obtained for human and rat platelets. However the correlations of pA 2 values between any pair of smooth muscle preparations and between any pair of platelet/smooth muscle preparations were either weak or not significant ( P > 0.05). 6 The excellent agreement for both full and partial agonist potencies between the six preparations provides no evidence for TP‐receptor subtypes and further suggests that the agonist recognition sites of the TP‐receptors could be very similar, if not identical, in nature. In contrast, the different antagonist affinities found in this and other published studies indicate heterogeneity of TP‐receptors. However, classification into TP 1 ‐, TP 2 ‐receptors, etc. on the basis of the limited antagonist data available does not appear appropriate at this time.