Role of endothelin-1 clearance in the haemodynamic responses to endothelin-1 in the pulmonary and hindquarter vasculature of anaesthetised rats
Autor: | James A. Angus, Christine E. Wright |
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Rok vydání: | 2019 |
Předmět: |
Male
0301 basic medicine medicine.medical_specialty Ambrisentan medicine.drug_class Neovascularization Physiologic Viper Venoms Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Hypoxic pulmonary vasoconstriction medicine.artery Internal medicine medicine Animals Anesthesia Drug Interactions Lung Macitentan Pharmacology Sulfonamides Endothelin-1 business.industry Hemodynamics Bosentan Receptor antagonist Endothelin 1 Rats NG-Nitroarginine Methyl Ester Pyrimidines 030104 developmental biology chemistry Pulmonary artery cardiovascular system Cardiology Female business Endothelin receptor 030217 neurology & neurosurgery medicine.drug |
Zdroj: | European Journal of Pharmacology. 855:124-136 |
ISSN: | 0014-2999 |
Popis: | In the pulmonary vasculature there is clearance of endothelin-1 from the circulation mediated by endothelin ETB receptors. This study explored the haemodynamic effects of endothelin-1 and its clearance in the pulmonary and hindquarter vasculature in anaesthetised rats. Carotid and pulmonary artery pressures and pulmonary and hindquarter blood flows were measured. In each rat, a single endothelin-1 or sarafotoxin S6C cumulative dose-response curve was generated with or without antagonist pretreatment (i.v.). Endothelin-1 caused an acute fall in MAP and rise in hindquarter vascular conductance (HVC) followed by a marked increase in MAP at 5 min with falls in HVC and pulmonary vascular conductance (PVC). Bosentan (10, 20 & 30 mg/kg) pretreatment caused dose-dependent inhibition of the MAP increase as well as PVC and HVC decreases to endothelin-1. Similarly, macitentan (30 mg/kg) or ambrisentan (10 mg/kg) caused significant block of responses to endothelin-1. Sarafotoxin S6C caused acute falls in MAP and increases in HVC and then small falls in PVC and HVC, all prevented by pretreatment with ETB antagonist BQ788 (1 mg/kg). Pretreatment with BQ788 enhanced endothelin-1 potency by 2.5-fold in PVC and 2.4-fold in HVC. With BQ788 and bosentan, the fall in HVC response was completely blocked, but there were residual MAP rises and PVC falls at the highest endothelin-1 dose. Our work confirms the role of ETB receptors in the pulmonary vasculature that decrease the circulating levels of endothelin-1. This has important consequences in selecting an appropriate ETA and ETB dual receptor antagonist to effectively block endothelin-1-mediated pulmonary vasoconstriction. |
Databáze: | OpenAIRE |
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