Effects of a selective endothelin A receptor antagonist, ABT-627, in healthy normotensive anaesthetized rats developing acute pulmonary air embolism

Ayach, Bilal; Tsang, John Y. C.; Jeng, Arco Y.; Blouin, A; Gosselin, Mélanie; Wang, Fu-Hou; Wu-Wong, Jinshyun R.; Wessale, Jerry L.; Opgenorth, Terry J.; Battistini, Bruno

doi:10.1042/cs103s371s

Cited by 6 publications

(7 citation statements)

References 21 publications

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“…12,20 In this regard, many studies have shown that nonselective ET-receptor antagonism or blockade of ET-1 type A (ETA) receptors attenuates the hemodynamic responses to APE. 4,5,23 Besides the fact that MMPs can modulate vascular tone, [10][11][12] our present observations that MMP-9 is activated after APE provides a potential mechanism involved in pulmonary vascular remodeling of chronic thromboembolic pul-monary hypertension. Similar to other forms of pulmonary hypertension, increased MMP activity may play a role in cell migration and in regulating the composition of extracellular matrix associated with the vascular remodeling processes.…”

Section: Discussionmentioning

confidence: 63%

Hemodynamic Benefits of Matrix Metalloproteinase-9 Inhibition by Doxycycline During Experimental Acute Pulmonary Embolism

et al. 2005

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The authors examined whether acute pulmonary embolism (APE) increases lung matrix metalloproteinase (MMP)-2 and MMP-9 activities and whether inhibition of MMPs with doxycycline attenuates the hemodynamic changes associated with APE. Anesthetized male Wistar rats were monitored for mean arterial blood pressure (MAP) and heart rate (HR). Rats in the control group (n = 5) received only saline IV; rats in the embolism (Emb) group (n = 8) received saline IV followed 10 minutes later by an injection of Sephadex microspheres (9 mg/kg) IV; rats in the doxycycline (Doxy) group (n = 4) received only doxycycline (30 mg/kg) IV, followed 10 minutes later by an injection of saline IV; rats in the Doxy + Emb group (n = 8) received the same dose of doxycycline followed 10 minutes later by the same amount of microspheres described above. Lung samples were homogenized and assayed by SDS-polyacrilamide gel electrophoresis gelatin zymography to evaluate lung MMP-2 and MMP-9 activities. Saline or doxycycline produced no significant changes in MAP, HR, and in MMP-2 and MMP-9 activities. Conversely, lung embolization significantly reduced MAP by > 32 mm Hg and HR by > 90 bpm for more than 60 minutes, and increased MMP-9 activity by 43% (all p < 0.05). No significant differences were observed in MMP-2 activity. However, lung embolization produced only transient hypotension in rats pretreated with doxycycline. In this group, MAP returned to baseline values 5 to 10 minutes after embolization. In addition, pretreatment with doxycycline blunted the increase in lung MMP-9 activity after lung embolization (p < 0.05). This study demonstrates for the first time that MMP-9 inhibition with doxycycline attenuates APE-induced hemodynamic changes in the animal model examined. These findings indicate that MMP-9 activation plays a role in the pathophysiology of APE and suggest that pharmacologic strategies targeting specific MMPs with selective inhibitors may prevent the detrimental acute hemodynamic consequences of APE.

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Section: Discussionmentioning

confidence: 63%

Hemodynamic Benefits of Matrix Metalloproteinase-9 Inhibition by Doxycycline During Experimental Acute Pulmonary Embolism

et al. 2005

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“…This hypothesis is supported by previous evidence demonstrating that neutrophil MMP-9 cleave big ET-1 producing further activation of neutrophils in a positive feedback loop that promotes leukocyte -endothelial cell adhesion and neutrophil migration into inflamed tissues [12,22]. Finally, many studies have shown that nonselective ET-receptor antagonism or blockade of ET-1 type A (ETA) receptors attenuates the hemodynamic responses to APE [4,5,27].…”

Section: Time (Min) After Apementioning

confidence: 74%

A role for matrix metalloproteinase-9 in the hemodynamic changes following acute pulmonary embolism

Fortuna

Figueiredo-Lopes

Dias‐Junior

et al. 2007

International Journal of Cardiology

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“…Furthermore, elevation of plasma ET-1 and effectiveness of selective ET-1 receptor antagonist have also been shown in the experimental pulmonary air embolism model (4,35,38). Collectively, it is suggested that ET-1 may contribute to development of several forms of PE.…”

Section: Discussionmentioning

confidence: 92%

Involvement of Rho kinase in the pathogenesis of acute pulmonary embolism-induced polystyrene microspheres in rats

Toba

Nagaoka

Morio

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Acute pulmonary embolism (PE) is a life-threatening disease, and several vasoconstrictors, including endothelin-1 (ET-1), play a key role in vasoconstriction and hypoxemia during the development of PE. Rho kinase is activated by various vasoconstrictors resulting in vascular contraction and remodeling. Recent evidence has revealed an important role of Rho kinase in the pathogenesis of systemic and pulmonary vascular diseases. However, contribution of Rho kinase in PE remains unclear. We thus investigated the role of Rho kinase in the PE rat model induced by intrajugular administration of polystyrene microspheres (mean diameter, 26 microm). At 6 h following the administration of microspheres (1.5 ml/kg), right ventricular systolic pressure (RVSP) was higher in the PE than in the control rats (15.8 +/- 1.6 vs. 32.9 +/- 7.5 mmHg). Arterial oxygen tension was lower (92.3 +/- 12.5 vs. 66.0 +/- 17.7 Torr), and alveolar-arterial difference in oxygen partial pressure was higher (3.9 +/- 3.8 vs. 36.5 +/- 26.9 Torr) in the PE rats. Western blotting analysis revealed upregulation and downregulation in expression of vascular cell adhesion molecule-1 and endothelial nitric oxide synthase in lungs from the PE rats, respectively, and radioimmunoassay demonstrated an increase in plasma ET-1 levels. Lung Rho kinase alpha expression was greater in the PE rats. At 5 h following administration of microspheres (0.75 ml/kg), intravenous Rho kinase inhibitors HA1077 and Y27632 (3 mg/kg each) attenuated elevation of RVSP (22.0 +/- 3.7, 17.1 +/- 3.2, 14.3 +/- 2.6 mmHg, PE, PE+HA1077, PE+Y27632) and the severity of hypoxemia (66.3 +/- 16.2, 94.9 +/- 23.0, 89.1 +/- 8.5 Torr, PE, PE+HA1077, PE+Y27632) in the PE rats. These results suggest that pulmonary endothelial dysfunction and activation of Rho kinase may contribute to the potentiation of vasoconstriction and hypoxemia in the PE rats.

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Effects of a selective endothelin A receptor antagonist, ABT-627, in healthy normotensive anaesthetized rats developing acute pulmonary air embolism

Cited by 6 publications

References 21 publications

Hemodynamic Benefits of Matrix Metalloproteinase-9 Inhibition by Doxycycline During Experimental Acute Pulmonary Embolism

Hemodynamic Benefits of Matrix Metalloproteinase-9 Inhibition by Doxycycline During Experimental Acute Pulmonary Embolism

A role for matrix metalloproteinase-9 in the hemodynamic changes following acute pulmonary embolism

Involvement of Rho kinase in the pathogenesis of acute pulmonary embolism-induced polystyrene microspheres in rats

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