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: Competition studies using whole cryostat sections in the lungs from patients with PAH compared to normal control tissues did not detect a significant difference in binding affinities (KD) for ETA or ETB and no change in receptor densities (BMAX) or ratio of sub-types in human PAH lungs compared with control (Fig. 2B, Table 3). In agreement, there were no changes in these parameters in MCT lungs compared with control. However, following apposition of labelled sections to radiation sensitive film, image analysis permitted the measurement of densities in discrete cell types. In the medial layer of small pulmonary arteries identified by comparison with adjacent stained sections, there was a significant increase in vascular ETA receptors in PAH compared with control small vessels (Fig. 3A, Table 3). No equivalent changes were detected in the medial layer of MCT rat lungs compared with control (Fig. 3B, Table 3).
Affiliation: Clinical Pharmacology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.