Limits...
Modulation of endothelin receptors in the failing right ventricle of the heart and vasculature of the lung in human pulmonary arterial hypertension.

Kuc RE, Carlebur M, Maguire JJ, Yang P, Long L, Toshner M, Morrell NW, Davenport AP - Life Sci. (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Clinical Pharmacology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

Show MeSH

Related in: MedlinePlus

A–C Competition of FR139317 for [125I]-ET-1 binding in human left (LV) and right (RV) ventricles from (A) normal controls and (B) patients transplanted for PAH. A biphasic curve was obtained as expected in each case corresponding to a high affinity ETA and low affinity ETB site, allowing the affinities (KD), densities (BMAX) and ratio of the two sub-types to be measured. (C) Comparison of ET sub-type ratio in LV and RV in hearts from normal controls and patients with PAH showing a significant increase in ETA but decrease in ETB in the right ventricle (n = 12 PAH and 9 control individuals, mean ± s.e.mean; Student's t-test, *p < 0.05 t-test).D–F. Competition of FR139317 for [125I]-ET-1 binding in rat left and right ventricles from (D) normal controls and (E) MCT rats. A biphasic curve was also obtained as expected in each case corresponding to a high affinity ETA and low affinity ETB site. (F) Comparison of ET sub-type ratio in LV and RV in hearts from controls and MCT rats showing a significant decrease in ETA but increase in ETB, in the right ventricle (n = 6 MCT and 6 control rats ± s.e.mean, *p < 0.05 Student's t-test).
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4288792&req=5

f0015: A–C Competition of FR139317 for [125I]-ET-1 binding in human left (LV) and right (RV) ventricles from (A) normal controls and (B) patients transplanted for PAH. A biphasic curve was obtained as expected in each case corresponding to a high affinity ETA and low affinity ETB site, allowing the affinities (KD), densities (BMAX) and ratio of the two sub-types to be measured. (C) Comparison of ET sub-type ratio in LV and RV in hearts from normal controls and patients with PAH showing a significant increase in ETA but decrease in ETB in the right ventricle (n = 12 PAH and 9 control individuals, mean ± s.e.mean; Student's t-test, *p < 0.05 t-test).D–F. Competition of FR139317 for [125I]-ET-1 binding in rat left and right ventricles from (D) normal controls and (E) MCT rats. A biphasic curve was also obtained as expected in each case corresponding to a high affinity ETA and low affinity ETB site. (F) Comparison of ET sub-type ratio in LV and RV in hearts from controls and MCT rats showing a significant decrease in ETA but increase in ETB, in the right ventricle (n = 6 MCT and 6 control rats ± s.e.mean, *p < 0.05 Student's t-test).

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).


Modulation of endothelin receptors in the failing right ventricle of the heart and vasculature of the lung in human pulmonary arterial hypertension.

Kuc RE, Carlebur M, Maguire JJ, Yang P, Long L, Toshner M, Morrell NW, Davenport AP - Life Sci. (2014)

A–C Competition of FR139317 for [125I]-ET-1 binding in human left (LV) and right (RV) ventricles from (A) normal controls and (B) patients transplanted for PAH. A biphasic curve was obtained as expected in each case corresponding to a high affinity ETA and low affinity ETB site, allowing the affinities (KD), densities (BMAX) and ratio of the two sub-types to be measured. (C) Comparison of ET sub-type ratio in LV and RV in hearts from normal controls and patients with PAH showing a significant increase in ETA but decrease in ETB in the right ventricle (n = 12 PAH and 9 control individuals, mean ± s.e.mean; Student's t-test, *p < 0.05 t-test).D–F. Competition of FR139317 for [125I]-ET-1 binding in rat left and right ventricles from (D) normal controls and (E) MCT rats. A biphasic curve was also obtained as expected in each case corresponding to a high affinity ETA and low affinity ETB site. (F) Comparison of ET sub-type ratio in LV and RV in hearts from controls and MCT rats showing a significant decrease in ETA but increase in ETB, in the right ventricle (n = 6 MCT and 6 control rats ± s.e.mean, *p < 0.05 Student's t-test).
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4288792&req=5

f0015: A–C Competition of FR139317 for [125I]-ET-1 binding in human left (LV) and right (RV) ventricles from (A) normal controls and (B) patients transplanted for PAH. A biphasic curve was obtained as expected in each case corresponding to a high affinity ETA and low affinity ETB site, allowing the affinities (KD), densities (BMAX) and ratio of the two sub-types to be measured. (C) Comparison of ET sub-type ratio in LV and RV in hearts from normal controls and patients with PAH showing a significant increase in ETA but decrease in ETB in the right ventricle (n = 12 PAH and 9 control individuals, mean ± s.e.mean; Student's t-test, *p < 0.05 t-test).D–F. Competition of FR139317 for [125I]-ET-1 binding in rat left and right ventricles from (D) normal controls and (E) MCT rats. A biphasic curve was also obtained as expected in each case corresponding to a high affinity ETA and low affinity ETB site. (F) Comparison of ET sub-type ratio in LV and RV in hearts from controls and MCT rats showing a significant decrease in ETA but increase in ETB, in the right ventricle (n = 6 MCT and 6 control rats ± s.e.mean, *p < 0.05 Student's t-test).
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Clinical Pharmacology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

Show MeSH
Related in: MedlinePlus