Thromboxane inhibition reduces an early stage of chronic hypoxia-induced pulmonary hypertension in piglets

Abstract

-The pulmonary vasoconstrictor, thromboxane, may contribute to the development of pulmonary hypertension. Our objective was to determine whether a combined thromboxane synthase inhibitor-receptor antagonist, terbogrel, prevents pulmonary hypertension and the development of aberrant pulmonary arterial responses in newborn piglets exposed to 3 days of hypoxia. Piglets were maintained in room air (control) or 11% O2 (hypoxic) for 3 days. Some hypoxic piglets received terbogrel (10 mg/kg po bid). Pulmonary arterial pressure, pulmonary wedge pressure, and cardiac output were measured in anesthetized animals. A cannulated artery technique was used to measure responses to acetylcholine. Pulmonary vascular resistance for terbogrel-treated hypoxic piglets was almost one-half the value of untreated hypoxic piglets but remained greater than values for control piglets. Dilation to acetylcholine in preconstricted pulmonary arteries was greater for terbogrel-treated hypoxic than for untreated hypoxic piglets, but it was less for pulmonary arteries from both groups of hypoxic piglets than for control piglets. Terbogrel may ameliorate pulmonary artery dysfunction and attenuate the development of chronic hypoxia-induced pulmonary hypertension in newborns.terbogrel; neonatal pulmonary hypertension; acetylcholine; prostacyclin NEWBORNS WITH SERIOUS, UNRESOLVED lung and heart disorders sometimes develop pulmonary hypertension. Unfortunately, treatment of infants suffering from chronic types of pulmonary hypertension has advanced minimally and is largely limited to attempts to maintain good oxygenation and reverse the underlying pathology (1, 4). Moreover, most research has been aimed at devising therapies to acutely decrease pulmonary arterial pressure once pulmonary hypertension is well established. Therapies to prevent the development and progression of pulmonary hypertension in infants with chronic cardiorespiratory disorders have received little attention.Chronic hypoxia has long been implicated in the pathogenesis of pulmonary hypertension in infants with chronic cardiorespiratory conditions (4, 38, 39). For example, it is has been shown by many investigators, including us, that pulmonary hypertension develops when newborn animals are exposed to chronic hypoxia (6,8,13,18,28). Identification of the changes in the pulmonary circulation that occur at early stages of chronic hypoxia-induced pulmonary hypertension is key to understanding the pathogenesis and to developing therapies to intervene with its progression. Our laboratory has previously found that newborn piglets exposed to 3 days of chronic hypoxia develop pulmonary hypertension and exhibit diminished pulmonary arterial dilation to acetylcholine (ACh) (17,20). Our laboratory has also provided evidence that production of the potent pulmonary vasoconstrictor, thromboxane (Tx) A 2 , is elevated and partially mediates the diminished pulmonary arterial dilation in the hypertensive piglets (19,20). The purpose of this study was to test the hypothesis that treatment with a comb...

Characteristics of myogenic tone in the rat ophthalmic artery

“…Similar observations were reported earlier that provided evidence for a differential role of endothelium-derived factors on arterial tone in different pathophysiological conditions. Endothelial COX-mediated constrictor, likely to be thromboxane, was shown to be involved in hypoxic pulmonary constriction in newborn pigs (13). An elegant study by Ungvari and Koller (57) showed that endothelin and prostaglandin H 2 /thromboxane A 2 mediate increased myogenic tone by potentiating Ca 2ϩ sensitivity of smooth muscle in skeletal muscle arterioles of spontaneously hypertensive rats.…”

Heat shock protein 90-eNOS interactions mature with postnatal age in the pulmonary circulation of the piglet

“…Piglet PRA (80-to 250-m diameter) were isolated, cannulated, and pressurized for continuous measurement of diameter according to our previously published methods (4,5,13,15,16,20). Briefly, PRA measuring Ͻ250-m diameter were dissected in oxygenated KrebsHenseleit buffer with the following millimolar composition: 118 NaCl, 25 NaHCO 3, 4.5 KCl, 1.2 MgCl2 ⅐ 6H2O, 1.2 KH2PO4, 11 dextrose, 2.5 CaCl 2 ⅐ 2H2O, and 0.026 EDTA equilibrated with 21% O 2, 5% CO2, and balance N2 to maintain pH 7.4.…”

Mediators and modulators of pulmonary arterial hypertension

“…2, 19, 31, 73). In a related study, terbogrel, a combined thromboxane synthase inhibitor-receptor antagonist, attenuated pulmonary vasoconstriction in hypoxic piglets and increased the pulmonary vasodilator response to acetylcholine (31). Similarly, ozagrel, another thromboxane synthesis inhibitor, reduced PH and improved symptoms in a patient with portopulmonary hypertension (73).…”