title: Intrinsic activity of the non-prostanoid thromboxane A2 receptor antagonist, daltroban (BM 13,505), in human platelets in vitro and in the rat vasculature in vivo.
abstract: 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 A2 (TxA2) receptor antagonist, SQ 29,548, and agonist, U-46619. 2. In human platelets in vitro, daltroban (10 nM-100 microM; n = 6 per group) concentration-dependently induced shape change, attaining at 50 microM, 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 microM; n = 9); and inhibited U-46619-induced platelet aggregation with an IC50 of 77 (41-161)nM. SQ 29,548 (10 nM-100 microM; n = 6 per group) failed to evoke any platelet shape change, but potently inhibited U-46619-induced platelet aggregation with an IC50 < 10 nM. 3. In anaesthetized rats in vivo, daltroban (10-2500 micrograms 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 micrograms kg-1 (n = 6) and 630 micrograms kg-1 (n = 8), respectively (both P < 0.05) with ED50s of 20 (16-29) and 217 (129-331) micrograms kg-1, respectively. By comparison, U-46619(0.16-20 microg 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 ED50s of 1.8 (1.3-2.5) and 3.9(3.5- 5.4) microg kg- 1, respectively. Daltroban dose-dependently increased MAP with a maximum amplitude of 42.2 +/- 4.4 mmHg at a dose of 80 microg kg-1 [ED50 = 94 (64-125) microg kg-1], similar to that induced by U-46619 (41.3 +/- 9.6 mmHg) at a dose of 0.63 microg kg-1 [ED50= 0.22 (0.13-0.24) microg kg-1]. SQ 29,548(10-2500 microg 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 TxA2 analogue, U-46619,but unlike the TxA2 receptor antagonist, SQ 29,548, exhibits significant intrinsic activity in human platelets in vitro and in the rat vasculature in vivo, possibly through TxA2 receptor activation.
authors.affiliation: Centre de Recherche Pierre Fabre, Castres, France.
authors.forename: F
authors.initials: F
authors.lastname: Bertolino
authors.forename: J P
authors.initials: JP
authors.lastname: Valentin
authors.forename: M
authors.initials: M
authors.lastname: Maffre
authors.forename: F
authors.initials: F
authors.lastname: Grelac
authors.forename: A M
authors.initials: AM
authors.lastname: Bessac
authors.forename: J
authors.initials: J
authors.lastname: Maclouf
authors.forename: A
authors.initials: A
authors.lastname: Delhon
authors.forename: S
authors.initials: S
authors.lastname: Lévy-Toledano
authors.forename: J F
authors.initials: JF
authors.lastname: Patoiseau
authors.forename: F C
authors.initials: FC
authors.lastname: Colpaert
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated; D006400:Hematocrit; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D010648:Phenylacetates / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D013931:Thromboxanes / Q000037:antagonists & inhibitors*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D010648:Phenylacetates; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D013449:Sulfonamides; D013931:Thromboxanes; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; C051762:daltroban