TxA2 receptor activation elicits organ-specific increases in microvascular permeability in the rat

Abstract

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)

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

“…Doses of the high efficacy agonist, U-46619 (1.25 µg/kg) and daltroban (80 µg/kg) which produced pulmonary hypertensive responses of similar amplitude were dose-dependently and fully antagonized by pretreatment with the silent TP receptor antagonist SQ 29,548. This observation indicates that the pulmonary hypertensive responses evoked by both U-46619 (Bertolino et al 1994(Bertolino et al , 1995aValentin et al 1996) and daltroban are mediated by TP receptors.…”

“…On the day of the experiment, rats were anaesthetized by i.p. injection of sodium pentobarbital (60 mg kg -1 ; 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(Bertolino et al , 1995aValentin et al 1996). Briefly, animals underwent tracheotomy and were mechanically ventilated (Harvard Apparatus, South Natick, Mass.).…”

“…TxA 2 and its prostanoid analogues induce platelet aggregation, smooth muscle contraction in vitro, pulmonary hypertension in vivo and haemoconcentration (reviewed by Hall 1991;Halushka and Mais 1989;Bertolino et al 1994Bertolino et al , 1995aValentin et al 1996). Evidence of efficacy of TP receptor antagonists in large clinical studies has not yet been established, particularly with respect to aspirin (Misra 1994), and it is conceivable that intrinsic activity could limit the therapeutic efficacy of certain of these agents.…”

Inhibitory Effect of a TP-Receptor Antagonist, S-1452, on Antigen-Induced Nasal Plasma Exudation in Guinea Pig Model for Allergic Rhinitis

“…Aerosolized histamine also caused nasal dye exudation, but S-1452 at a higher dose of 30 mg/kg did not affect histamine-induced nasal dye exudation. Previous reports have demonstrated that U-46619 could induce plasma exudation in upper (nasal) and lower airways of guinea pigs and rats, and it was significantly inhibited by TP-receptor antagonists [5,18,19]. In addition, plasma exudation in lower airways of guinea pigs and rats caused by leukotriene D 4 , PGF 2· , platelet-activating factor or endothelin-1 was inhibited by a TxA 2 synthase inhibitor or TP-receptor antagonists, but histamine-induced response was not affected by a TP-receptor antagonist [20][21][22].…”

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

“…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.…”