Role of endothelin-1 clearance in the haemodynamic responses to endothelin-1 in the pulmonary and hindquarter vasculature of anaesthetised rats.

Affiliation

Cardiovascular Therapeutics Unit, Department of Pharmacology and Therapeutics, University of Melbourne, Victoria 3010, Australia. Electronic address: [Email]

Abstract

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.

Keywords

Ambrisentan,Ambrisentan (PubChem CID: 6918493),BQ788 (PubChem CID: 3081333),Bosentan,Bosentan sodium (PubChem CID: 44387533),ET(1)-Receptor antagonists,Endothelin clearance,Endothelin-1,Endothelin-1 (PubChem CID: 16132423),Hindquarter vascular constriction,Macitentan,Macitentan (PubChem CID: 16004692),Pulmonary vascular constriction,Sarafotoxin S6C,Sarafotoxin S6C (PubChem CID: 16132429),

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