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.

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.

Ragweed sensitization alters pulmonary vascular responses to bronchoprovocation in beagle dogs

1997 ◽  
Vol 83 (3) ◽  
pp. 912-917 ◽  
Author(s):  
Andreas Theodorou ◽  
Natalie Weger ◽  
Kathleen Kunke ◽  
Kyoo Rhee ◽  
David Bice ◽  
...  
Keyword(s):  
Vascular Resistance ◽  
Resistance Index ◽  
Lung Compliance ◽  
Pulmonary Vasculature ◽  
Beagle Dogs ◽  
Mechanically Ventilated ◽  
Vascular Responses ◽  
Before And After ◽  
Pulmonary Artery Catheters ◽  
Pulmonary Vascular Resistance Index

Theodorou, Andreas, Natalie Weger, Kathleen Kunke, Kyoo Rhee, David Bice, Bruce Muggenberg, and Richard Lemen. Ragweed sensitization alters pulmonary vascular responses to bronchoprovocation in beagle dogs. J. Appl. Physiol.83(3): 912–917, 1997.—In ragweed (RW)-sensitized beagle dogs, we tested the hypothesis that reactivity of the pulmonary vasculature was enhanced with aerosolized histamine (Hist) and RW. Seven dogs were neonatally sensitized with repeated intraperitoneal RW injections, and 12 dogs were controls (Con). The dogs were anesthetized with intravenous chloralose, mechanically ventilated, and instrumented with femoral arterial and pulmonary artery catheters. Specific lung compliance (Cl sp), specific lung conductance (Gsp), systemic vascular resistance index, and pulmonary vascular resistance index (PVRI) were measured before and after bronchoprovocation with Hist and RW. After Hist inhalation (5 breaths of 30 mg/ml), both Con and RW dogs had significant ( P < 0.05) decreases in Cl sp(−51 ± 4 and −53 ± 5%, respectively) and Gsp (−65 ± 5 and −69 ± 3%, respectively), but only RW-sensitized dogs had a significant increase in PVRI (38 ± 10%). After RW inhalation (60 breaths of 0.8 mg/ml), only RW-sensitized dogs had significant increases (62 ± 20%) in PVRI and decreases in Gsp (−77 ± 4%) and Cl sp(−65 ± 7%). We conclude that, compared with Con, RW-sensitized beagle dogs have increased pulmonary vasoconstrictive responses with Hist or RW inhalation.

Decline in arterial partial pressure of oxygen after exercise: a surrogate marker of pulmonary vascular obstructive disease in patients with atrial septal defect and severe pulmonary hypertension

2011 ◽  
Vol 21 (3) ◽  
pp. 292-298 ◽  
Author(s):  
Srinivas Laksmivenkateshiah ◽  
Anil K. Singhi ◽  
Balu Vaidyanathan ◽  
Edwin Francis ◽  
Sundaram R. Karimassery ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Partial Pressure ◽  
Atrial Septal Defect ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Septal Defect ◽  
Resistance Index ◽  
Partial Pressure Of Oxygen ◽  
Arterial Partial Pressure ◽  
Pulmonary Vascular Resistance Index

AbstractObjectivesTo examine the utility of decline in arterial partial pressure of oxygen after exercise as a marker of pulmonary vascular obstructive disease in patients with atrial septal defect and pulmonary hypertension.MethodsTreadmill exercise was performed in 18 patients with atrial septal defect and pulmonary hypertension. Arterial blood gas samples were obtained before and after peak exercise. A decline in the arterial pressure of oxygen of more than 10 millimetres of mercury after exercise was considered significant based on preliminary tests conducted on the controls. Cardiac catheterisation was performed in all patients and haemodynamic data sets were obtained on room air, oxygen, and a mixture of oxygen and nitric oxide (30–40 parts per million).ResultsThere were 10 patients who had more than a 10 millimetres of mercury drop in arterial partial pressure of oxygen after exercise and who had a basal pulmonary vascular resistance index of more than 7 Wood units per square metre. Out of eight patients who had less than a 10 millimetres of mercury drop in arterial partial pressure of oxygen after exercise, seven had a basal pulmonary vascular resistance index of less than 7 Wood units per square metre, p equals 0.0001. A decline in arterial partial pressure of oxygen of more than 10 millimetres of mercury predicted a basal pulmonary vascular resistance index of more than 7 Wood units per square metre with a specificity of 100% and a sensitivity of 90%.ConclusionsA decline in arterial partial pressure of oxygen following exercise appears to predict a high pulmonary vascular resistance index in patients with atrial septal defect and pulmonary hypertension. This test is a useful non-invasive marker of pulmonary vascular obstructive disease in this subset.

Endotracheal Administration of Tolazoline in Hypoxia-Induced Pulmonary Hypertension

PEDIATRICS ◽  
1993 ◽  
Vol 92 (3) ◽  
pp. 403-408
Author(s):  
Jerri Curtis ◽  
J. Timothy O'Neill ◽  
Gary Pettett
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Resistance ◽  
Resistance Index ◽  
Controlled Study ◽  
Control Group ◽  
Study Objective ◽  
Artery Pressure ◽  
Pulmonary Vascular Resistance Index ◽  
To Receive ◽  
Stabilization Period

Study objective. To compare the pulmonary and systemic vascular responses to intravenously (IV) and endotracheally (ET) administered tolazoline (Tz) in newborn lambs with hypoxia-induced pulmonary hypertension. Design. Randomized, controlled study design. Methods. Twenty lambs, 2 to 7 days of age, were anesthetized, intubated, and surgically catheterized for continuous physiologic monitoring and cardiac output meassurements using radiolabeled microspheres. After a postoperative stabilization period, the lambs were ventilated with a hypoxic gas mixture which was titrated to increase mean pulmonary artery pressure (MPAP) 30% to 50% above baseline. Each animal was randomly assigned to receive either IV-Tz (2 mg/kg), ET-Tz (4 mg/kg), or ET-saline (Sal, control group). Results. ET-Tz significantly (P &lt; .05) reduced MPAP, PVRI (pulmonary vascular resistance index), MPAP/mean artery pressure (MAP) and PVRI/systemic vascular resistance index (SVRI), but not SVRI. IV-Tz lowered (P &lt; .05) MPAP, PVRI, and PVRI/SVRI but also produced significant reductions in MAP and SVRI while only transiently decreasing MPAP/MAP. MPAP/MAP and PVRI/SVRI ratios were consistently lower in the ET-Tz animals than either the IV-Tz or ET-Sal animals. Conclusions. Our results suggest that ET-Tz produced a more selective pulmonary vascular response than IV-Tz and may warrant further investigation for potential clinical applications.

Activation of the right ventricular endothelin (ET) system in the monocrotaline model of pulmonary hypertension: response to chronic ETA receptor blockade

2003 ◽  
Vol 105 (6) ◽  
pp. 647-653 ◽  
Author(s):  
Jean-François JASMIN ◽  
Peter CERNACEK ◽  
Jocelyn DUPUIS
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricle ◽  
Right Ventricular ◽  
Ventricular Hypertrophy ◽  
Right Ventricular Hypertrophy ◽  
Lower Percentage ◽  
Receptor Blockade ◽  
Eta Receptor ◽  
Eta Receptor Antagonist ◽  
The Right

Although activation of the endothelin (ET) system contributes to pulmonary hypertension, modifications of the cardiopulmonary ET system and its responses to chronic ET receptor blockade are not well known. To investigate this, rats were injected with monocrotaline (60 mg/kg intraperitoneal) or saline, followed with treatment with the selective ETA receptor antagonist LU135252 (LU; 50 mg·kg-1·day-1) or with saline. After 3 weeks, haemodynamics, cardiac hypertrophy, ET-1 levels and cardiopulmonary ET-receptor-binding profile were evaluated. Monocrotaline (n=7) elicited marked pulmonary hypertension and right ventricular hypertrophy compared with controls (n=8). Both variables were substantially attenuated by LU therapy (n=8; P<0.05 for both). After monocrotaline, right ventricular ET-1 levels were more significantly increased than in the left ventricle (+198% compared with +127%; P<0.05). ETB receptor density was augmented (3-fold) in the right ventricle, whereas that of ETA receptors was not affected. LU treatment also significantly attenuated these alterations (P<0.05). In the lungs, ET-1 levels were not increased after monocrotaline, whereas the balance of ETB to ETA receptors was altered, with a trend toward a lower percentage of ETB than in the control rats. LU treatment did not affect these variables in the lungs. Therefore monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy are associated with the up-regulation of ET-1 and ETB receptors in the right ventricle. These alterations are attenuated with the reduction of pulmonary hypertension and right ventricular hypertrophy after chronic blockade of the ETA receptors, supporting the role of the ET system in right ventricular hypertrophy.

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

scholarly journals Chronic Inhibition of Toll‐Like Receptor 9 Ameliorates Pulmonary Hypertension in Rats

2021 ◽  
Vol 10 (7) ◽  
Author(s):  
Tomohito Ishikawa ◽  
Kohtaro Abe ◽  
Mariko Takana‐Ishikawa ◽  
Keimei Yoshida ◽  
Takanori Watanabe ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Interleukin 6 ◽  
Vascular Remodeling ◽  
Mrna Level ◽  
Systolic Pressure ◽  
Resistance Index ◽  
Pulmonary Vascular Resistance Index ◽  
Macrophage Accumulation

Background Recent accumulating evidence suggests that toll‐like receptor 9 (TLR9) is involved in the pathogenesis of cardiovascular diseases. However, its role in pulmonary hypertension remains uncertain. We hypothesized that TLR9 is involved in the development of pulmonary hypertension. Methods and Results A rat model of monocrotaline‐induced pulmonary hypertension was used to investigate the effects of TLR9 on hemodynamic parameters, vascular remodeling, and survival. Monocrotaline‐exposed rats significantly showed increases in plasma levels of mitochondrial DNA markers, which are recognized by TLR9, TLR9 activation in the lung, and interleukin‐6 mRNA level in the lung on day 14 after monocrotaline injection. Meanwhile, monocrotaline‐exposed rats showed elevated right ventricular systolic pressure, total pulmonary vascular resistance index and vascular remodeling, together with macrophage accumulation on day 21. In the preventive protocol, administration (days −3 to 21 after monocrotaline injection) of selective (E6446) or nonselective TLR9 inhibitor (chloroquine) significantly ameliorated the elevations of right ventricular systolic pressure and total pulmonary vascular resistance index as well as vascular remodeling and macrophage accumulation on day 21. These inhibitors also significantly reduced NF‐κB activation and interleukin‐6 mRNA levels to a similar extent. In the short‐term reversal protocol, E646 treatment (days 14–17 after monocrotaline injection) almost normalized NF‐κB activation and interleukin‐6 mRNA level, and reduced macrophage accumulation. In the prolonged reversal protocol, E6446 treatment (days 14–24 after monocrotaline injection) reversed total pulmonary vascular resistance index and vascular remodeling, and improved survival in monocrotaline‐exposed rats. Conclusions TLR9 is involved in the development of pulmonary hypertension concomitant via activation of the NF‐κB‒IL‐6 pathway. Inhibition of TLR9 may be a novel therapeutic strategy for pulmonary hypertension.

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