Attenuation of pulmonary vascular hypertension and cardiac hypertrophy with sitaxsentan sodium, an orally active ETAreceptor antagonist

Tilton, Ronald G.; Munsch, Christy L.; Sherwood, Sidney J.; Chen, Shi Juan; Chen, Yiu Fai; Wu, Chengda; Block, Natalie; Dixon, Richard A. F.; Brock, Tommy A.

doi:10.1006/pupt.2000.0237

Cited by 67 publications

(54 citation statements)

References 28 publications

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“…More importantly, this is the first demonstration that chronic blockade of ET A receptors with an orally active nonpeptidic ET A receptor antagonist can significantly reduce established hypoxia-induced neonatal pulmonary hypertension while hypoxic exposure remains. Our results in the neonate are similar to the ones reported in the adult rat, in which BQ-123 and the nonpeptidic ET antagonists, bosentan and TBC11251, were able to reverse hypoxia-induced pulmonary hypertensive changes (22,25,26). A previous demonstration in an ovine fetal preparation had also shown that preventive treatment with BQ-123 could attenuate chronic pulmonary hypertension (27).…”

Section: Discussionsupporting

confidence: 89%

TBC3711, an ETA Receptor Antagonist, Reduces Neonatal Hypoxia-Induced Pulmonary Hypertension in Piglets

et al. 2001

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The pulmonary vasculature of newborns with persistent pulmonary hypertension is characterized by active vasoconstriction and vascular remodeling. It has been suggested that endothelin-1 (ET-1), a potent vasoconstrictor and growth promoter, may be involved in the pathogenesis of persistent pulmonary hypertension of the newborn. To determine whether treatment with an ET A receptor antagonist can reverse pulmonary hypertension in the neonate, 1-d-old piglets were exposed to hypoxia for 3 d to induce pulmonary hypertension and then treated for the remainder of the 14 d with an orally active, nonpeptidic ET A antagonist (TBC3711, 22 mg·kg). At the end of the exposure, Hb, pulmonary artery pressure, right ventricle to left ventricle plus septum weight ratio, percentage wall thickness, ET-1 circulating levels, perfusion pressure, and dilator response to the nitric oxide (NO) donor, SIN-1 (3-morpholinosydnonimine-N-ethylcarbamide) in isolated perfused lungs were determined. Exhaled NO and hemodynamic variables were also examined in an intact anesthetized animal preparation that had undergone the same treatment. By 3 d of exposure to hypoxia, piglets had already developed significant pulmonary hypertension as estimated by their pulmonary artery pressure (24.0 Ϯ 1.3 mm Hg versus 14.2 Ϯ 3.4 mm Hg) and percentage wall thickness (26.6 Ϯ 5.9% versus 18.7 Ϯ 2.4% for vessels 0-30 m). Whereas further exposure to hypoxia for 14 d did not enhance the increase in pulmonary artery pressure and percentage wall thickness, it did augment the right ventricle to left ventricle plus septum weight ratio (0.71 Ϯ 0.09 versus 0.35 Ϯ 0.01). ET-1 circulating levels were increased only when exposure to hypoxia was prolonged to 14 d (5.1 Ϯ 2.4 pg/mL versus 1.0 Ϯ 0.4 pg/mL). Treatment with TBC3711 from d 3 to d 14, once pulmonary hypertensive changes were established and while hypoxic exposure persisted, caused significant reduction in the right ventricle to left ventricle plus septum weight ratio (0.60 Ϯ 0.06), pulmonary artery pressure (20.0 Ϯ 4.8 mm Hg), and percentage wall thickness (18.5 Ϯ 3.3%) and restored the dilator response to the NO donor SIN-1. Prolonged hypoxia markedly reduced exhaled NO concentrations (0.3 Ϯ 0.6 ppb), although treatment of hypoxic animals with TBC3711 restored the concentration of exhaled NO (4.4 Ϯ 2.8 ppb) to the level of normoxic controls (4.9 Ϯ 3.0 ppb). Lastly, treatment with TBC3711 increased ET-1 circulating levels in both the normoxic (5.4 Ϯ 2.8 pg/mL) and hypoxic (13.0 Ϯ 6.3 pg/mL) groups. In conclusion, the specific ET A receptor antagonist, TBC3711, can significantly ameliorate the morphologic changes encountered in hypoxia-induced pulmonary hypertension in the newborn piglet and may improve the dilator response to NO.

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Section: Discussionsupporting

confidence: 89%

TBC3711, an ETA Receptor Antagonist, Reduces Neonatal Hypoxia-Induced Pulmonary Hypertension in Piglets

et al. 2001

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“…Inter-species differences also probably exist in the role of ET-1 in hypoxic pulmonary hypertension. Wong et al (35) showed that the ET A receptor antagonist BQ 123 did not reduce acute hypoxic pulmonary vasoconstriction in intact newborn lambs, although this study and others have shown that ET A receptor antagonists are effective in similar rat (14,15) and porcine models (17,36). It is probable that ET-1 is also involved in human neonatal pulmonary hypertension, for it has been observed that circulating ET-1 levels are elevated in newborn infants with PPHN, are positively correlated with disease severity, and decline with resolution of disease in patients who do not require extracorporeal membrane oxygenation (only 2 of the 24 infants in this study had sepsis, the majority had aspiration syndromes) (7).…”

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confidence: 54%

“…Our previous studies have shown that selective ET A receptor antagonists attenuate acute hypoxic pulmonary hypertension (14,15) and reverse chronic hypoxic pulmonary hypertensive vascular and cardiac changes (15,16) in adult animals. However, the pulmonary circulation of the neonate and young infant is structurally and functionally different compared with the adult pulmonary circulation.…”

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confidence: 98%

Endothelin-A Receptor Blockade in Porcine Pulmonary Hypertension

et al. 2002

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Endothelin-1 can cause pulmonary vasoconstriction via endothelin-A (ET A ) receptor activation. We hypothesized that ET A blockers (EMD 122946 and BQ 610) would reduce hypoxiainduced (HYP) but not group B streptococcal infusion (GBS)-induced pulmonary hypertension in a juvenile whole animal model. Pulmonary hypertension was created by exposing chronically instrumented piglets to HYP (n ϭ 12) or heat-killed GBS (n ϭ 11). ET A blockade was produced by increasing bolus doses of EMD122946 or BQ 610. Pulmonary arterial pressure (PAP), systemic arterial pressure (SAP), left atrial pressure, central venous pressure, and cardiac output were continuously measured. Pulmonary and systemic vascular resistance indices (PVRI and SVRI) were calculated. HYP doubled PAP and PVRI. Both ET A blockers decreased PAP and PVRI in a dose-dependent manner in HYP, with high doses decreasing PVRI to baseline and reducing PAP by 50%. GBS also doubled both PAP and PVRI. EMD 122946 did not change PAP or PVRI in GBS, although BQ 610 markedly increased PVRI (Ͼ100% increase with 0.15 mg/kg) and showed a trend toward increasing PAP. Both models showed minimal (Ͻ25%) changes in SAP or SVRI.Neither ETA blocker changed baseline hemodynamics in the absence of HYP or GBS. PaO 2 did not change with GBS but decreased with BQ 610. ET A receptor blockade attenuated hypoxic, but not GBS induced pulmonary hypertension. BQ 610 worsened PVRI and oxygenation in the GBS model. Differences in response to ET A blockade in pulmonary hypertension may be seen depending on the etiology (hypoxia versus infectionassociated), and the specific ET A antagonist used. Persistent pulmonary hypertension of the newborn (PPHN) affects over 10,000 infants every year in the United States (1) and is associated with considerable morbidity and mortality. Prenatal hypoxia may predispose to PPHN (1). Disorders such as bronchopulmonary dysplasia are also associated with elevated pulmonary pressures and pulmonary vascular remodeling in infants (2). Endothelin-1 (ET-1) is a 21-amino acid polypeptide with strong vasoactive properties that vary depending on age (3), vascular bed, dosage (4), and species (5). ET-1 acts via two different receptors in the vascular bed, ET A and ET B . In the pulmonary artery, ET A receptors mediate vasoconstriction and are found on vascular smooth muscle cells, while ET B receptors that are mostly located on endothelial cells mediate vasodilation (6). There is substantial evidence that ET-1 is elevated in neonates, infants (7-9), and older children (10) with pulmonary hypertension, and is a marker of disease severity. Animal studies have also indicated that ET-1 may play a role in the pathogenesis of neonatal pulmonary hypertension due to hypoxia (11), meconium aspiration (12), and increased pulmonary blood flow (13). Therefore, there has been interest in endothelin receptor blockade as a possible therapy for pediatric pulmonary hypertension.Our previous studies have shown that selective ET A receptor antagonists attenuate acute hypoxic pulmonary hypertensio...

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“…Increased expression of the peptide has been demonstrated in endothelial cells of pulmonary arteries from patients with idiopathic and secondary forms of pulmonary hypertension (15), and arterial-to-venous ratios of ET-1 protein were found to be elevated above the normal range in patients with pulmonary hypertension (40). Several studies have linked increased expression of ET-1 to the development of hypoxia-induced CPH in rats (5, 24), and use of ET-1 receptor antagonists has been shown both to inhibit progression of the disease and to promote recovery (4,10,43).Although these studies support a central role for ET-1 in the pathogenesis of CPH, the picture is likely more complicated than first suspected, in that prepro-ET-1 (ppET-1) mRNA is decreased in the monocrotaline model of CPH, and in addition, we recently reported regional variability in ppET-1 gene expression in the pulmonary artery of normal sheep. Furthermore, we found in a model of CPH, sheep receiving…”

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confidence: 99%

ET-1 receptor gene expression and distribution in L1 and L2 cells from hypertensive sheep pulmonary artery

Balyakina

Chen²,

Lawrence³

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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Exposure to exogenous ET-1 for 18 h revealed that only the L2 cells internalized ET-1, and internalization by hypertensive L2 cells was significantly reduced when compared with controls. Treatment with ET A (BQ-610) and ETB (BQ-788) receptor antagonists demonstrated that both receptors contributed to internalization of ET-1 in control L2 cells, whereas in hypertensive cells only when both receptor antagonists were used in combination was significant suppression of ET-1 internalization found. We conclude that in sheep receiving CAE, alterations in ET B receptors in cells of the L2 layer may contribute to the maintenance of CPH via alterations in their expression, distribution, and activity.ET A receptor; ETB receptor; smooth muscle cells; pulmonary hypertension; endothelin SINCE ITS DISCOVERY 12 YEARS AGO, endothelin (ET) has been shown to contribute to a wide variety of physiological and pathophysiological processes in various systems (22). The ET family of 21 amino acid peptides exists in three distinct isoforms: ET-1, ET-2, and ET-3. It is an extremely potent vasoconstrictor resulting in slowly developing and sustained contraction. Although the endothelial cell was originally described as the source of ET-1, it is now known that several other cell types, including pulmonary vascular smooth muscle cells, synthesize this peptide (33, 36).The biological effects of ET-1 are mediated by two distinct ET receptor subtypes, ET A and ET B (1, 35). The affinity of the ET A receptor for ET-1 has been shown to be ϳ100 times that for ET-3 (ET-1 Ͼ ET-2 Ͼ ET-3), whereas the affinity of the ET B receptor is equipotent for all three isoforms of ET (34). Early reports indicated that the ET A receptor on smooth muscle was responsible for the vasoconstrictor effect of ET-1, whereas the ET B receptor on endothelial cells modulated ET-1-induced vasodilation. However, recent pharmacological studies suggest that there are two classes of ET B with cell specific effects, ET B1 on endothelial cells mediating vasodilation and ET B2 on smooth muscle cells mediating vasoconstriction (9). The ET B receptor also functions as a "clearance receptor" and is particularly important in the lung, where 50% of ET-1 is retained (22,29).ET-1 has been linked to the development of chronic pulmonary hypertension (CPH). Increased expression of the peptide has been demonstrated in endothelial cells of pulmonary arteries from patients with idiopathic and secondary forms of pulmonary hypertension (15), and arterial-to-venous ratios of ET-1 protein were found to be elevated above the normal range in patients with pulmonary hypertension (40). Several studies have linked increased expression of ET-1 to the development of hypoxia-induced CPH in rats (5, 24), and use of ET-1 receptor antagonists has been shown both to inhibit progression of the disease and to promote recovery (4,10,43).Although these studies support a central role for ET-1 in the pathogenesis of CPH, the picture is likely more complicated than first suspected, in that prepro-ET-1 (ppET-1) mRNA is...

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Attenuation of pulmonary vascular hypertension and cardiac hypertrophy with sitaxsentan sodium, an orally active ETAreceptor antagonist

Cited by 67 publications

References 28 publications

TBC3711, an ETA Receptor Antagonist, Reduces Neonatal Hypoxia-Induced Pulmonary Hypertension in Piglets

TBC3711, an ETA Receptor Antagonist, Reduces Neonatal Hypoxia-Induced Pulmonary Hypertension in Piglets

Endothelin-A Receptor Blockade in Porcine Pulmonary Hypertension

ET-1 receptor gene expression and distribution in L1 and L2 cells from hypertensive sheep pulmonary artery

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