Selectivity of [¹²⁵I]‐PD 151242 for human, rat and porcine endothelin ET_A receptors in the heart

Abstract

1 Endothelin-1 binds with high affinity to heart where it acts as a potent positive inotropic agent. Our aim was to characterize the labelled and unlabelled ETA-selective antagonist PD151242 in heart tissues derived from man, rat and pigs by use of radioligand binding techniques. 0.37 ± 0.10 nM), whereas the ETB-selective compound, BQ3020, competed with only micromolar affinity (KD = 1.5 ± 0.26 gM).6 The novel ETA-selective radioligand ['25I]-PD151242 binds with high affinity to human, rat and porcine heart. In human tissue, binding was shown to be reversible and highly selective for the ETA-subtype making ['251]-PD151242 a useful selective radioligand for further characterization of the ETA-receptor in human tissue.

Endothelin receptors in human coronary artery and aorta

“…Additionally, the ETA subtype has been demonstrated to mediate ET-1-induced constriction of small diameter, distal segments of human coronary artery (Godfraind, 1993) and human small omental vessels (Riezebos et al, 1994 (Tables 2 and 3). A similar difference has been observed previously in other studies with human tissue Peter & Davenport, 1995). A probable explanation is that a structural change accompanying radioiodination enhances the effectiveness of this ligand.…”

Endothelin ETA receptor expression in human cerebrovascular smooth muscle cells

“…Dissociation constants and receptor density were estimated using EBDA (McPherson, 1983) and an iterative non-linear curve-fitting programme LIGAND (Munson & Rodbard, 1980 . In competition binding studies, the affinity of PD151242 for the HBSMCs was in the nanomolar range, which parallels previous observations in other human tissue such as cardiac arteries, kidney and left ventricle of the heart Peter & Davenport, 1995 (Spatz et al, 1994). Endothelin production from bovine endothelial cells (Ohlstein & Storer, 1992;Kasuya et al, 1993), as well as from rat SMCs (Kasuya et al, 1993), has also been demonstrated to be upregulated by oxyhaemoglobin, which is likely to be one of the principal pathogenic agents responsible for cerebral vasospasm following subarachnoid haemorrhage (Macdonald & Weir, 1991).…”

“…[ was determined by the inclusion of 1 tIM unlabelled ET-i as previously described (Davenport et al, 1993;1994;Peter & Davenport, 1995). Dissociation constants and receptor density were estimated using EBDA (McPherson, 1983) and an iterative non-linear curve-fitting programme LIGAND (Munson & Rodbard, 1980 .…”

Characterization of the endothelin receptor selective agonist, BQ3020 and antagonists BQ123, FR139317, BQ788, 50235, Ro462005 and bosentan in the heart

“…The KD of the labelled ligand ['251]-ET-1 was 0.4 nM for human left ventricle , 2.4 nM for pig left ventricle (Peter & Davenport, 1995), and 0.4 nM for rat heart (Bolger et al, 1990).…”

“…The model adopted was that which provided the significantly best fit (P< 0.05). Molenaar et al (1993) and data marked (t) were taken from Peter & Davenport (1995) Figure 2b). However, the compound had a 100-200 fold lower affinity for ETA receptors than BQ123 and FR139317 (Tables 1,2 .…”