Modulation of endothelin receptors in the failing right ventricle of the heart and vasculature of the lung in human pulmonary arterial hypertension.
Bottom Line: In human PAH lungs, ETA receptors were significantly increased in the medial layer of small pulmonary arteries with no change detectable in MCT rat vessels.The increase in ETA receptors in arteries provides a mechanism for the beneficial vasodilator actions of ET antagonists.The increase in the ratio of ETA in RV also implicates changes to ET signalling although it is unclear if ET antagonism is beneficial but the results emphasise the unexploited potential for therapies that target the RV, to improve survival in patients with PAH.
Affiliation: Clinical Pharmacology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.Show MeSH
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Mentions: In human normal hearts, competition binding revealed the expected ratio of ETA to ETB receptors (Fig. 1A, Peter and Davenport, 1996a). FR139317 competed biphasically for the binding of [125I]-ET-1, with a two-site fit preferred over a one-site model with no significant difference in affinity constants (Table 1, KD) between patient groups (Fig. 1). Whilst there was no significant change in receptor sub-type ratio in LV, there is a significant increase in ETA with a concomitant decrease in ETB receptors in the failing RV (Fig. 1B, C).
Affiliation: Clinical Pharmacology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.