5 Losartan prevents thromboxane A2 receptor-mediated pulmonary hypertension

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

“…The TxA2 analogue, U-46619, dose-dependently induced pulmonary hypertension, as reported previously (Yoshimura et al, 1989;Nossaman et al, 1992;Bertolino et al, 1994;1995) via activation of TxA2/PGH2 receptors (Bertolino et al, 1994;1995). Similarly to U-46619, daltroban increased pulmonary arterial pressure, but with a maximum representing approximately half of that induced by the full agonist, and with an ED3o app that was about 10 fold higher than that of the full agonist, U-46619 (20 versus 1.8 pg kg-').…”

“…On the day of the experiment, rats were anaesthetized by i.p. injection of sodium pentobarbitone (60 mg kg-'; Sanofi Laboratories, France), placed on a heated table to maintain rectal temperature at 37 ± 0.5°C then prepared for acute experimentation as previously described (Bertolino et al, 1994;1995). Briefly, animals underwent tracheotomy and were mechanically ventilated (Harvard Apparatus, South Natick, MA, U.S.A.).…”

“…This class of agent was, in general, found to be safe, well tolerated, although clear evidence of efficacy in large studies remains to be established, particularly with respect to aspirin (Misra, 1994). Prostanoid analogues of TxA2 induce platelet aggregation, vascular smooth muscle cell contraction in vivo, pulmonary hypertension in vivo as well as haemoconcentration (reviewed by Hall, 1991;Halushka & Mais, 1989;Misra, 1994;Bertolino et al, 1994;1995). Intrinsic activity at TxA2/ PGH2 or other receptors could limit the therapeutic use of certain TxA2 receptor antagonists (Terres et al, 1987).…”

“…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. Keywords: Arterial pressure; daltroban; human platelet aggregation; shape change; pulmonary hypertension; thromboxane A2; TxA2/PGH2 receptors regation in vitro, and (ii) mean systemic and pulmonary arterial pressures and haematocrit, in anaesthetized, openchest Sprague-Dawley rats, a model we have previously shown to be particularly sensitive to TxA2/PGH2 receptor agonists (Bertolino et al, 1994;1995).…”