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) 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 jLg kg-' (n = 6) and 630;Lg kg-' (n = 8), respectively (both 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.

Overview of the Pharmacological Properties of Daltroban, a Thromboxane A2/Prostanoid‐Receptor Partial Agonist

“…Like U-46619, but unlike SQ 29,548, daltroban induced platelet shape change in a concentration-dependent manner, with a maximal response representing about half of that evoked by the full agonist (10) (Fig. 2; Table 2) A transient alteration of platelet shape change has been reported for some (e.g., S-1452 and AH 23848; 49,57), but not all (e.g., vapiprost, ifetroban sodium, 16,3 1,50,84, loo), prostanoid TP-receptor antagonists.…”

“…The systemic cardiovascular effects of TP-receptor agonists have been conflicting: hyper-or hypotension or both, depending on the dose, have been reported (7)(8)(9)(10)135) (Table 3). In rats and rabbits, daltroban antagonized increases in arterial blood pressure induced by non-toxic doses of U-46619 in a dose-dependent manner (ED,, value of 0.23 mgkg i.v.…”

“…Originally presented as a silent TP-receptor antagonist (reviewed in ref. 67) recent reports have provided evidence for agonist-like properties of the drug (10,82,100). Evidence has also been made available which demonstrates that the intrinsic activity of daltroban is mediated by TP receptors, thus establishing that daltroban acts as a partial agonist at TP receptors (9).…”

Evidence for partial agonist properties of daltroban (BM 13,505) at TP receptors in the anæsthetized open-chest rat

“…Sulotroban (BM 13,177), and daltroban (BM 15,505), two well characterized non-prostanoid TP receptor antagonists (Smith and Lefer 1988;Lefer 1988), were shown to exert intrinsic activity in vascular smooth muscle cells in vitro (Miki et al 1992). We recently demonstrated that daltroban induced shape change responses in human platelets in vitro, and increased mean pulmonary (MP) and systemic arterial pressures (AP) in anaesthetized rats in vivo (Bertolino et al 1995b). However, it was not determined whether the intrinsic activity of daltroban was mediated through TP receptors (Bertolino et al 1995b), and consequently, it remains to be established whether the drug acts as a partial agonist at these receptors.…”

“…We recently demonstrated that daltroban induced shape change responses in human platelets in vitro, and increased mean pulmonary (MP) and systemic arterial pressures (AP) in anaesthetized rats in vivo (Bertolino et al 1995b). However, it was not determined whether the intrinsic activity of daltroban was mediated through TP receptors (Bertolino et al 1995b), and consequently, it remains to be established whether the drug acts as a partial agonist at these receptors.…”