BQ123, an ETA-receptor antagonist, attenuates hypoxic pulmonary hypertension in rats

1994 ◽  
Vol 266 (4) ◽  
pp. H1327-H1331 ◽  
Author(s):  
S. T. Bonvallet ◽  
M. R. Zamora ◽  
K. Hasunuma ◽  
K. Sato ◽  
N. Hanasato ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Receptor Antagonist ◽  
Resistance Index ◽  
Sprague Dawley ◽  
Hypoxic Pulmonary Hypertension ◽  
Mean Pressure ◽  
Eta Receptor ◽  
Medial Wall Thickness ◽  
Eta Receptor Antagonist

To investigate the role of endothelin-1 (ET-1) in the pathogenesis of hypoxic pulmonary hypertension, we studied the effects of a recently described endothelin-receptor antagonist (ETA), BQ123, on the development of this process. Intraperitoneal osmotic pumps were placed into 8-wk-old Sprague-Dawley rats that received either saline or BQ123 (0.15 mg/h). The rats were maintained in room air normoxia or placed in a hypobaric chamber (380 Torr) for 2 wk to induce hypoxic pulmonary hypertension. There were no hemodynamic differences between normoxic rats treated with either saline or BQ123. However, treatment with BQ123 attenuated the hypoxia-induced increase in pulmonary arterial mean pressure and total pulmonary resistance index by 60 and 87% respectively. There was also a reduction in hypoxia-induced right ventricular hypertrophy in the BQ123 group. Histological studies performed using a barium-gelatin fixation technique in hypoxic BQ123-treated animals demonstrated a decrease in medial wall thickness in arteries corresponding to the respiratory and terminal bronchioles, respectively. Similarly, there was a significant reduction in the degree of muscularization of more distal vessels at the level of alveolar ducts in BQ123-treated hypoxic rats. We conclude that the ETA-receptor antagonist BQ123 attenuates the development of hypoxic pulmonary hypertension in rats in vivo, thereby suggesting a possible contributing role for ET-1 and the ETA receptor in the pathogenesis of this process.

Overexpression of endothelin-1 and enhanced growth of pulmonary artery smooth muscle cells from fawn-hooded rats

1996 ◽  
Vol 270 (1) ◽  
pp. L101-L109 ◽  
Author(s):  
M. R. Zamora ◽  
T. J. Stelzner ◽  
S. Webb ◽  
R. J. Panos ◽  
L. J. Ruff ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Sprague Dawley ◽  
Endothelin 1 ◽  
Serum Stimulation ◽  
Eta Receptor ◽  
Idiopathic Pulmonary Hypertension ◽  
Eta Receptor Antagonist

Increased production of endothelin-1 (ET-1) has been detected in lungs of fawn-hooded rats (FHR) with idiopathic pulmonary hypertension. Accelerated pulmonary artery (PA) smooth muscle cell (SMC) proliferation contributes to vascular remodeling in these rats. We hypothesized that PA SMC would be an important site of enhanced ET-1 expression in FHR lung, that these SMC would have increased growth compared with cells from a normotensive strain, and that this locally produced ET-1 would contribute to the increased growth of these cells. We found that isolated FHR PASMC overexpressed preproET-1 mRNA and produced more ET-1 peptide compared with cells from normotensive Sprague-Dawley control rats (SDR). PA SMC from FHR had increased growth compared with control cells under conditions of serum withdrawal (0.1%), submaximal serum stimulation (0.3%; a condition previously found to be required for detection of growth in response to the comitogen, ET-1), and maximal serum stimulation (10%). Enhanced growth of FHR PA SMC in the presence of 0.3% serum, but not under the other test conditions, was inhibited by the ETA receptor antagonist, BQ-123. In summary, PA SMC from rats with idiopathic pulmonary hypertension overproduce ET-1. This overproduction contributes to the enhanced growth of FHR PA SMC in the presence of 0.3% serum. These cells also possess other unique growth characteristics that are independent of ET-1. Together, these ET-1-dependent and -independent growth properties likely contribute to the hyperplasia of FHR PA SMC found in vivo.

Differential vasoactive response to endothelin receptor antagonists and prostacyclin in patients with severe pulmonary hypertension

2002 ◽  
Vol 103 (s2002) ◽  
pp. 298S-301S ◽  
Author(s):  
Sotiria C. APOSTOLOPOULOU ◽  
Georgios KOURGIANNIDIS ◽  
Athanassios MANGINAS ◽  
Zenon S. KYRIAKIDES ◽  
David WEBB ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Resistance Index ◽  
Pulmonary Vasculature ◽  
Endothelin Receptor ◽  
Vasoactive Substances ◽  
Endothelin A Receptor ◽  
Before And After ◽  
Eta Receptor ◽  
Pulmonary Vascular Resistance Index ◽  
Eta Receptor Antagonist

Pulmonary hypertension (PH) is a rare disease of the pulmonary vasculature with diverse pathogenetic mechanisms. Vasoactive substances such as endothelin A receptor (ETA) antagonists and prostanoids have been used to improve haemodynamics and clinical outcome. We compared the hemodynamic response to BQ-123 (an ETA receptor antagonist) and prostacyclin or its analogue iloprost in ten patients (four men) with a mean age of 35.9±15.6 years. Seven patients had primary PH and three had PH owing to connective tissue disease. Patients underwent haemodynamic evaluation before and after administration of intra-atrial BQ-123 (200mmol/min for 60min), intravenous prostacyclin (3ng·kg-1·min-1 for 4h) or iloprost as an aerosol (100µg over 24h). Response to vasodilator administration was defined as >15% decrease in pulmonary vascular resistance index (PVRI). Of the ten patients, five showed a response to BQ-123 and eight responded to prostanoids. Four patients were responders and one patient was a non-responder to both agents. PVRI decreased by 16.6±13.4% with BQ-123, and 24.4±15.7% with prostanoids (not statistically significant). The aetiology of PH did not affect the response to either drug. In conclusion, response to ETA antagonist or prostanoid administration can be achieved in a large group of patients with severe PH, however few patients respond identically to both agents. These findings are consistent with a multifactorial mechanism involved in this disease.

In vitro and in vivo effects of endothelin-1 and YM598, a selective endothelin ETA receptor antagonist, on the lower urinary tract

2008 ◽  
Vol 580 (3) ◽  
pp. 394-400 ◽  
Author(s):  
Masashi Ukai ◽  
Hironori Yuyama ◽  
Akira Fujimori ◽  
Akiko Koakutsu ◽  
Masanao Sanagi ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Receptor Antagonist ◽  
Lower Urinary Tract ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Eta Receptor Antagonist ◽  
In Vivo Effects ◽  
Lower Urinary

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

2001 ◽  
Vol 50 (3) ◽  
pp. 374-383 ◽  
Author(s):  
Thérèse Perreault ◽  
John W Berkenbosch ◽  
Keith J Barrington ◽  
E Radford Decker ◽  
Chengde Wu ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Receptor Antagonist ◽  
Neonatal Hypoxia ◽  
Eta Receptor ◽  
Eta Receptor Antagonist

ETA-receptor antagonist prevents and reverses chronic hypoxia-induced pulmonary hypertension in rat

1995 ◽  
Vol 269 (5) ◽  
pp. L690-L697 ◽  
Author(s):  
V. S. DiCarlo ◽  
S. J. Chen ◽  
Q. C. Meng ◽  
J. Durand ◽  
M. Yano ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Receptor Antagonist ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Right Ventricular Hypertrophy ◽  
Pulmonary Vascular Remodeling ◽  
Eta Receptor ◽  
Eta Receptor Antagonist

The selective endothelin-A (ETA)-receptor antagonist BQ-123 has been shown to prevent chronic hypoxia-induced pulmonary hypertension in the rat. Therefore in the current study we utilized BQ-123 to test the hypothesis that blockade of the ETA receptor can reverse as well as prevent the increase in mean pulmonary artery pressure, right ventricle-to-left ventricle plus septum ratio, and percent wall thickness in small (50-100 microns) pulmonary arteries observed in male Sprague-Dawley rats exposed to normobaric hypoxia (10% O2, 2 wk). Infusion of BQ-123 (0.4 mg.0.5 microliter-1.h-1 for 2 wk in 10% O2) begun after 2 wk of hypoxia significantly reversed the established pulmonary hypertension and prevented further progression of right ventricular hypertrophy during the third and fourth week of hypoxia. BQ-123 infusion instituted before exposure to hypoxia completely prevented the hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular remodeling. These findings suggest that, in the lung, hypoxia induced an increase synthesis of endothelin-1, which acts locally on ETA receptors to cause pulmonary hypertension, right heart hypertrophy, and pulmonary vascular remodeling, while ETA-receptor blockade can both prevent and reverse these processes.

Enhanced ETA-receptor-mediated inhibition of Kv channels in hypoxic hypertensive rat pulmonary artery myocytes

1999 ◽  
Vol 277 (1) ◽  
pp. H363-H370 ◽  
Author(s):  
Kai-Xun Li ◽  
Brian Fouty ◽  
Ivan F. McMurtry ◽  
David M. Rodman
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Hypoxic Pulmonary Hypertension ◽  
Voltage Gated ◽  
Receptor Coupling ◽  
Kv Channels ◽  
Whole Cell Patch Clamp ◽  
Intracellular Ca ◽  
Eta Receptor

Endothelin (ET)-1 has been implicated as a critical mediator in the pathogenesis of hypoxic pulmonary hypertension. We questioned whether, during exposure to chronic hypobaric hypoxia, rat pulmonary artery smooth muscle cells (PASMC) became sensitized to ET-1. Two effects of ET-1, inhibition of voltage-gated K+(Kv) channels and release of intracellular Ca2+, were studied using whole cell patch clamp and single cell indo 1 fluorescence, respectively. In both normotensive and chronically hypoxic-hypertensive PASMC, ET-1 caused concentration-dependent inhibition of voltage-gated K+ current [ I K(v)], with maximum inhibition of 12–18% seen at a concentration of 0.1–1 nM. Although the chronically hypoxic-hypertensive PASMC was no more susceptible to ET-1-mediated I K(v) inhibition, a switch in coupling between ET-1 and I K(v) from ETB to ETA receptors occurred. This switch in receptor coupling, combined with reduced I K(v) density and increased ET-1 production in the hypoxic rat lung, may help explain the ability of ETA-receptor blockers to attenuate the development of hypoxic pulmonary hypertension in vivo.

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