Influence of Thromboxane A2 Receptor Antagonism on Pulmonary Vasoconstrictor Responses

Abstract

ABSTRACT. Thromboxane A2 (TxA2) is an arachidonic PAP, pulmonary arterial pressure acid metabolite which causes severe pulmonary vasocon-LVEDP, left ventricular end diastolic pressure striction (PV) and may mediate the PV produced by platelet-activating factor (PAF-acether) and leukotriene D4 (LTD4). To determine the role of TxAz receptors on PAFacethe;, LTD4, and hypoxia-induced PV, we administered PAF-acether 0.1 nmollkg, the TxA2 analog U-46619 0.2 pg/kg/min, LTD4 3.0 pg/kg, or acute hypoxia (Fio2 = 0.12 for 3 min) before and during the infusion of the selective TxA2 receptor blocker SQ 29 548 50 pg/kg/min or vehicle into 27 open-chest, anesthetized newborn piglets, measuring pulmonary and systemic arterial pressures, cardiac index, and right and left ventricular pressures and dimensions. Mean pulmonary arterial pressure rose and cardiac index fell in response to PAF-acether (14 f 1 to 32 f 2 mm Hg and 91 f 5 to 15 f 5 mL/kg/min, both p < 0.01), U-46619 (11 f 1 to 28 f 2 mm Hg and 93 2 10 to 36 f 9 mL/kg/min, both p < 0.01), and LTD4 (13 f 3 to 22 f 2 mm Hg and 85 f 12 to 29 + 9 mL/kg/min, both p < 0.05). Acute hypoxia increased PAP (12 + 1 to 26 2 2 mm Hg, p < 0.01) but did not alter cardiac index. Infusion of S Q 29 548 prevented PAF-acether and U-46619-induced increases in pulmonary arterial pressure (13 f 1 to 14 f 1 mm Hg and 12 + 1 to 12 f 1 mm Hg) and decreases in cardiac index (70 f 4 to 70 f 3 mL/kg/min and 94 f 14 to 92 + 12 mL/kg/min) but failed to alter the response to LTD4 or hypoxia. Vehicle had no effect. We conclude that TxA2 receptors are not involved in LTD4 or hypoxiainduced PV but play an important role in the PV produced by PAF-acether and U-46619. (Pediatr Res 26:175-179, 1989) Abbreviations LT, cysteinyl leukotrienes PAF-acether, platelet activating factor (l-O-hexadecyl-2-acetyl-sn-glyceryl phosphocholine) PV, pulmonary vasoconstriction Tx, thromboxane 6-k-PGFI,, 6-keto-prostaglandin F1, SVRI, systematic vascular resistance index MAP, mean systemic arterial pressure RVEDP, right ventricular end-diastolic pressure PVRI, pulmonary vascular resistance index

Cyclooxygenase‐2 inhibition and thromboxane A2 receptor antagonism attenuate hypoxic pulmonary vasoconstriction in a porcine model

“…For instance, TXA 2 receptor antagonists have been shown not to have any effect on HPV in vivo in the piglet (Bradley et al . ) and isolated perfused rabbit lungs (Weissmann et al . ).…”

“…The role of TXA 2 in modulating HPV is however still debated, as it also has been suggested that TXA 2 inhibition exerts no effect on HPV (Bradley et al . , Weissmann et al . , Chlopicki et al .…”

“…Of further interest, hypoxia-induced TXA 2 release has been suggested to predispose for the development of high altitude pulmonary oedema (Schoene et al 1988). The role of TXA 2 in modulating HPV is however still debated, as it also has been suggested that TXA 2 inhibition exerts no effect on HPV (Bradley et al 1989, Weissmann et al 1998, Chlopicki et al 2002.…”

The principal pathways involved in the in vivo modulation of hypoxic pulmonary vasoconstriction, pulmonary arterial remodelling and pulmonary hypertension

“…) or on the acute phase of the HPV response in piglets (Bradley et al . ). Inhibition of TXA 2 synthase in humans did neither alter the acute phase of the HPV response (Naeije et al .…”

Sustained Effects of Platelet-Activating Factor Infusion in Piglets

“…aspiration) with accompanying leukocyte accumulation and tissue macrophage activation. Recent research has implicated inflammatory mediators (4)(5)(6)(7)(8)(9), particularly PAF (8,9) in the pathogenesis of pulmonary vasoconstriction in newborns of several species. Experimental findings in adult animals have confirmed the capacity of PAF to produce profound circulatory derangements, including severe increases in pulmonary vascular resistance with right ventricular failure and hypotension (10, 1 I), decreased coronary blood flow (12,13), myocardial dysfunction (14,15), and sudden death (16).…”