Endothelin_B receptor‐mediated contraction in human pulmonary resistance arteries

Abstract

Using wire myography, we have examined the endothelin (ET) receptor subtypes mediating vasoconstriction to ET peptides in human pulmonary resistance arteries (150–200 μm, i.d.). Cumulative concentration‐response curves to ET‐1, sarafotoxin 6c (SX6c) and ET‐3 were constructed in the presence and absence of the selective antagonists FR 139317 (ETA‐selective), BMS 182874 (ETA‐selective) and BQ‐788 (ETB‐selective). All agonists induced concentration‐dependent contractions. However, the response curves to ET‐1 were biphasic in nature. The first component demonstrated a shallow slope up to 1 nM ET‐1. Above 1 nM ET‐1 the response curve was markedly steeper. Maximum responses to ET‐3 and SX6c were the same as those to 1 nM ET‐1 and 30% of those to 0.1 μm ET‐1. The order of potency, taking 0.3 μm as a maximum concentration was SX6c > > ET‐3 > ET‐1 (pEC50 values of: 10.75 ± 0.27, 9.05 ± 0.19, 8.32 ± 0.08 respectively). Taking 1 nM ET‐1 as a maximum, the EC50 for ET‐1 was 10.08 ± 0.13 and therefore ET‐1 was equipotent to ET‐3 and SX6c over the first component of the response curve. Responses to ET‐1 up to 1 nM were resistant to the effects of the ETA receptor antagonists, FR 139317 and BMS 182874 but were inhibited by the ETB receptor antagonist, BQ‐788. Conversely, responses to ET‐1 over 1 nM were inhibited by the ETA receptor antagonists, FR 139317 and BMS 182874 but unaffected by the ETB receptor antagonist, BQ‐788. The results suggest that at concentrations up to 1 nM, responses to ET‐1 are mediated via the ETB receptor, whilst the responses to higher concentrations are mediated by ETA receptors.

Endothelin receptor expression in idiopathic pulmonary arterial hypertension: effect of bosentan and epoprostenol treatment

“…Other investigators, however, have reported a preferential increase in ETB receptors in pulmonary arteries of pulmonary hypertensive scleroderma patients [36]. Although both receptor subtypes mediate ET-1-induced contraction [37] and promote ETA and ETB expression was similar in normal and IPAH cell extracts.…”

Endothelin: setting the scene in PAH

“…One in vitro study in isolated human pulmonary arteries [12] has demonstrated that stimulation of pulmonary arteries with ETBselective agonists (sarafotoxin 6c) resulted in ,25% of the constriction caused by native ET-1. In agreement with this, animal studies using selected concentrations of antagonists to the two receptor subtypes in small pulmonary vessels were able to show that, while single receptor antagonists to each of the two receptors produced some inhibition of ET-1-induced contraction, use of their combination to achieve comprehensive dual ETA and ETB receptor antagonism significantly inhibits ET-1-induced constriction (52¡5.3%, p,0.001; fig.…”

Hemodynamic and Clinical Correlates of Endothelin-1 in Chronic Thromboembolic Pulmonary Hypertension

“…In addition, upregulation of the ET-B receptor gene in the hyperplastic media of pulmonary arterial biopsies of CTEPH patients has been demonstrated. 12 ET-B receptor activation on smooth muscle cells is considered to contribute to vasoconstriction 13 and vascular remodeling. 14 Taken together, these observations indicate that ET-1 may also play a role in CTEPH, but so far no correlation with pathophysiology has been shown.…”