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

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. In human platelets in vitro, daltroban (10 nM‐100 μM; n = 6 per group) concentration‐dependently induced shape change, attaining at 50 μM, 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 μM; n = 9); and inhibited U‐46619‐induced platelet aggregation with an IC₅₀ of 77 (41–161)nM. SQ 29,548 (10 nM‐100 μM; n = 6 per group) failed to evoke any platelet shape change, but potently inhibited U‐46619‐induced platelet aggregation with an IC₅₀< 10nM. 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 ED₅₀S 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 ED₅₀s 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 [ED₅₀ = 94 (64–125) fig kg¹], similar to that induced by U‐46619 (41.3 ±9.6 mmHg) at a dose of 0.63 fig kg⁻¹ [ED₅₀ = 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. 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. 1995 British Pharmacological Society