Vasoconstrictor endothelin receptors characterized in human renal artery and vein in vitro

1The aim of the present study was to characterize pharmacologically endothelin receptors that are present in human umbilical vessels. 2 Endothelin-1 (ET-1) and endothelin-2 (ET-2) are potent stimulants of both the human umbilical artery (pEC5o 7.9 and 7.5) and vein (pEC50 8.1 and 8.0). Endothelin-3 (ET-3) is inactive on the artery but contracts the vein (pEC50 7.6). IRL1620 is inactive in both vessels. The order of potency of agonists is suggestive of a typical ETA receptor in the artery (ET-1 = ET-2 > > ET-3) and a mixture of ETA and ETB receptors in the vein (ET-1 = ET-2> ET-3). 3 The selective ETA receptor antagonist, BQ123, competitively inhibits the effect of ET-1 in the human umbilical artery (pA2 6.9), while in the vein, only a mixture of BQ123 and BQ788 (a selective ETB antagonist) weakly displaces to the right the cumulative concentration-response curve to ET-1. Contractions induced by ET-3 in the vein are inhibited by BQ788 (pA2 7.6), but not by BQ123.4 Inhibition of Ca21 channels by nifedipine (0.1 ,uM) is accompanied by a significant decrease of the maximal response to ET-1 by 40% in the artery and by 30% in the vein. The response of the vein to ET-3 is almost abolished by nifedipine. 5 The results indicate that: (i) endothelins contract the human isolated umbilical artery via stimulation of an ETA receptor type; (ii) the contraction induced by ET-1 in the vein is mediated by both ETA and ETB receptors, while ET-3 stimulates the ETB receptor; (iii) the contribution of Ca21 channels to the contraction mediated by the ETB receptor appears to be more important than to that mediated by the ETA receptor.

Section: Resultssupporting

confidence: 57%

Characterization of endothelin receptors in the human umbilical artery and vein

Bogoni

Rizzi

Calò

et al. 1996

“…In support of this hypothesis, in isolated epicardial coronary arteries and renal vessels (Maguire et al, 1994b) ET-1-induced vasoconstriction appears to be mediated mainly by the ETA sub-type since is about two orders of magnitude less potent than ET-1. Secondly, the ETA-selective antagonists cause a rightward and parallel shift of the ET-1-induced constriction in these vessels.…”

Section: Introductionmentioning

confidence: 72%

Endothelin ET_A and ET_B mRNA and receptors expressed by smooth muscle in the human vasculature: majority of the ET_A sub‐type

Davenport

O’Reilly

Kuc

1995

Self Cite

149

1 We measured the ratio of ETA and ETB sub-types in the media (containing mainly smooth muscle) of human cardiac arteries (aorta, pulmonary and coronary), internal mammary 4 A single band corresponding to the expected position for mRNA encoding the ETA receptor (299 base pairs) was found in the media in each of the five vessels (n = 3 individuals) using reversetranscriptase polymerase chain reaction assays. A single band corresponding to the ETB sub-type (428 base pairs) was also always detected. 5 35S-labelled antisense probes to ETA and ETB hybridised to the media of epicardial coronary arteries as well as intramyocardial vessels, confirming the presence of mRNA encoding both sub-types in the vascular smooth muscle of the vessel wall. 6 Although mRNA for both receptors was detected, competition binding using BQ123 demonstrated that the majority (at least 85%) of ET receptors present in smooth muscle are the ETA sub-type. These results provide further support for the hypothesis that the ETA sub-type is the receptor that must be blocked in humans to produce a beneficial vasodilatation in pathophysiological conditions where there is an increase in peptide concentration or receptor density.

“…A similar discrepancy was observed in human aorta Gu et al, 1989;Bolger et al, 1990). Also, the dissocia- (Maguire et al, 1994 Molenaar et al, 1993) in human left ventricle. However, PD151242 competed only with 50% of the [125l]-ET-1 binding sites compared to 62% by FR139317.…”

Section: Calculation Of Binding Parametersmentioning

confidence: 99%

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

Peter

Davenport

1995

Self Cite

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.