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Intrinsic activity of the non‐prostanoid thromboxane A 2 receptor antagonist, daltroban (BM 13,505), in human platelets in vitro and in the rat vasculature in vivo
Author(s) -
Bertolino Frédéric,
Valentin JeanPierre,
Maffre Myriam,
Grelac Françoise,
Bessac AnneMarie,
Maclouf Jacques,
Delhon André,
LevyToledano Sylviane,
Patoiseau JeanFrançois,
Colpaert Francis C.,
John Gareth W.
Publication year - 1995
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.1476-5381.1995.tb16341.x
Subject(s) - prostanoid , thromboxane a2 , platelet , thromboxane , antagonist , agonist , in vivo , chemistry , thromboxane receptor , medicine , endocrinology , receptor antagonist , receptor , biology , microbiology and biotechnology
1 We evaluated the effects of daltroban on (i) human platelet shape change and aggregation in vitro , and (ii) mean systemic and pulmonary arterial pressures (MAP and MPAP, respectively) as well as haematocrit, in anaesthetized, open‐chest Sprague‐Dawley rats, compared with those of a chemically distinct prostanoid thromboxane A 2 (TxA 2 ) receptor antagonist, SQ 29,548, and agonist, U‐46619. 2 In human platelets in vitro , daltroban (10 nM‐100 μ M ; n = 6 per group) concentration‐dependently induced shape change, attaining at 50 μ M , a maximum amplitude of 0.83 ± 0.09 mV representing 46.4 ±4.8% of that evoked by U‐46619 (1.78 ± 0.20 mV at 0.2 μ M ; n = 9); and inhibited U‐46619‐induced platelet aggregation with an IC 50 of 77 (41–161)nM. SQ 29,548 (10 nM‐100 μ M ; n = 6 per group) failed to evoke any platelet shape change, but potently inhibited U‐46619‐induced platelet aggregation with an IC 50 < 10nM. 3 In anaesthetized rats in vivo , daltroban (10–2500 μg kg −1 , i.v. infused over 2 min; n = 4–8 per group) produced a bell‐shaped dose‐response curve for MPAP and haematocrit, and evoked maximal increases of 12.7 ± 2.1 mmHg and 5.8 ± 1.5% at 80 μg kg −1 (n = 6) and 630 μg kg −1 (n = 8), respectively (both P<0.05) with ED 50 S of 20 (16–29) and 217 (129–331) μg kg −1 , respectively. By comparison, U‐46619 (0.16–20 fig kg −1 , i.v.), induced dose‐dependent increases in MPAP and haematocrit (25.4 ± 1.0 mmHg and 16.1 ±2.9% at the highest dose; n = 12, both P<0.01), with ED 50 s of 1.8 (1.3‐2.5) and 3.9 (3.5‐5.4) fig kg −1 , respectively. Daltroban dose‐dependently increased MAP with a maximum amplitude of 42.2 ±4.4 mmHg at a dose of 80 μkg −1 [ED 50 = 94 (64–125) fig kg 1 ], similar to that induced by U‐46619 (41.3 ±9.6 mmHg) at a dose of 0.63 fig kg −1 [ED 50 = 0.22 (0.13‐0.24) fig kg −1 ]. SQ 29,548 (10–2500 μg kg −1 , i.v.; n = 4 per group) failed to modify significantly any of these parameters. 4 Our results clearly demonstrate that daltroban, in a similar manner to the TxA 2 analogue, U‐46619, but unlike the TxA 2 receptor antagonist, SQ 29,548, exhibits significant intrinsic activity in human platelets in vitro and in the rat vasculature in vivo , possibly through TxA 2 receptor activation.