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.

We investigated whether the stable thromboxane A2 (TxA2) analogue U-46619 had any direct effect on extracellular fluid partition. In anesthetized open-chest rats, U-46619 (1.25 and 20 micrograms/kg iv) dose dependently increased mean pulmonary arterial pressure and hematocrit, whereas mean systemic arterial pressure was raised only at the low dose of agonist. The increase in hematocrit (13.2 +/- 2.9% at 20 micrograms/kg; P < 0.05) still occurred in bilaterally nephrectomized rats and in binephrectomized plus splenectomized rats (11.6 +/- 2.7 and 12.2 +/- 4.6%, respectively; both P = NS vs. U-46619 in control rats), corresponding to a calculated decrease in plasma volume of 22.1 +/- 4.5, 19.6 +/- 4.0, and 19.2 +/- 5.8%, respectively. Plasma protein concentration increased less than hematocrit, and the coefficient of reflection was significantly lower in these groups, suggesting protein extravasation. Additional experiments showed that U-46619 (1.25 and 10 micrograms/kg iv) dose dependently increased the vascular leak of albumin mainly in lung, kidneys, and spleen but not in brain, liver, mesentery, and cardiac and skeletal muscles. Pretreatment with the TxA2 receptor antagonist SQ-29,548 (2.5 mg/kg iv bolus plus 2.5 mg.kg-1.h-1 as maintenance) abolished all effects of U-46619, including the increase in mean pulmonary arterial pressure, hematocrit, plasma protein concentration, and albumin extravasation and the decrease in mean systemic arterial pressure, plasma volume, and coefficient of reflection.(ABSTRACT TRUNCATED AT 250 WORDS)

We explored the putative inhibitory effects of losartan, a potent nonpeptide, AT1 receptor antagonist, against thromboxane A2 (TxA2)/prostanoid (TP) receptor-mediated transcapillary shift of plasma fluid and proteins. The effects of the TP receptor agonist U-46619 (1.25 or 10 microg/kg intravenously) on hematocrit (Hct), albumin extravasation (AE), and mean arterial pressure (MAP) were evaluated in anesthetized Sprague-Dawley rats. U-46619 dose-dependently increased Hct (by 4.5% +/- 0.7% and 7.5% +/- 1.0% at the low and high dose, respectively; both P < .05 v vehicle-infused group) and decreased MAP (by 7.9% +/- 4.1% and 16.8% +/- 5.7% at the low and high dose, respectively; P = NS and P < .05 v vehicle-infused group, respectively). In these experiments, using a quantitative Evans blue technique, we showed that U-46619 dose-dependently increased AE in kidney, lung, spleen, and testis (by approximately 31%, 172%, 52%, and 57% at the highest dose) but not in adipose tissue, brain, liver, mesentery, and skeletal muscle. In the heart, AE was maximally increased by the low dose of U-46619. The U-46619 (10 microg/kg)-induced increases in Hct and AE and decreases in MAP were blocked by pretreatment with the TP receptor antagonist SQ 29,548 (2.5 mg/kg intravenously + 2.5 mg/kg/h) and the high dose of losartan (40 mg/kg intravenously). The low dose of losartan (10 mg/kg intravenously) did not significantly alter the responses to U-46619 except for the AE, which was reduced in some but not all tissues. Furthermore, the U-46619-induced changes in Hct (+6.3% +/- 1.7%), MAP (-13.9% +/- 8.4%) and AE were not affected in rats pretreated with the converting-enzyme inhibitor enalapril. Thus, selective activation of TP receptors by U-46619 induced plasma fluid and protein exudation; these responses were specifically attenuated by the relatively high dose of losartan, suggesting that this compound acts as a TP receptor antagonist in this experimental model.

We sought to determine whether the intrinsic pulmonary hypertensive activity of the purported thromboxane A2/prostanoid (TP) receptor antagonist, daltroban, was mediated by TP receptors, using the high efficacy TP receptor agonist, U-46619, and the silent TP receptor antagonist, SQ 29,548. In pentobarbitone-anesthetized, open-chest rats (n = 4-10 per group), non-cumulative injections of U-46619, dose-dependently increased mean pulmonary arterial pressure (MPAP) with an ED50 (geometric mean with 95% confidence limits in parentheses) of 1.4 (1.1-2.3) microg/kg i.v.. Daltroban increased MPAP in a bell-shaped manner, with an apparent ED50 [29 (21-35) microg/kg i.v.] being 21 fold less potent than that of U-46619. The maximal pulmonary hypertensive responses evoked by daltroban represented about half those induced by U-46619 (25.4+/-1.0 vs. 12.7+/-2 mmHg; P < 0.05 between groups). The TP receptor antagonist SQ 29,548 fully antagonized increases in MPAP evoked by equihypertensive doses of U-46619 (1.25 microg/kg) or daltroban (80 microg/kg). Further experiments were carried out to determine whether daltroban antagonized the pulmonary hypertensive responses evoked by the high efficacy agonist, U-46619, or by itself as receptor theory would predict for a partial agonist. Daltroban (10-2500 microg/kg) antagonized, although not fully, U-46619 (20 microg/kg)-evoked pulmonary hypertensive responses, since prominent intrinsic pulmonary hypertensive effects of daltroban were observed in the same range of doses. Furthermore, in contrast to U-46619 (1.25 microg/kg), daltroban (80 microg/kg) failed to evoke a second pulmonary hypertensive response following a previous injection, as would be expected for a partial agonist. Collectively, the results strongly suggest that daltroban behaves as a partial agonist at TP receptors in the pulmonary vascular bed of the rat in vivo.

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