[I-125] PD151242 - A SELECTIVE LIGAND FOR ENDOTHELIN ET(A) RECEPTORS IN HUMAN KIDNEY WHICH LOCALIZES TO RENAL VASCULATURE

被引:39
作者
DAVENPORT, AP [1 ]
KUC, RE [1 ]
HOSKINS, SL [1 ]
KARET, FE [1 ]
FITZGERALD, F [1 ]
机构
[1] AMERSHAM INT PLC,AMERSHAM,BUCKS,ENGLAND
基金
英国惠康基金;
关键词
ENDOTHELIN; PD151242; FR139317; BQ123; BQ3020; ET(A) RECEPTOR; ET(A) MESSENGER-RNA; ET(B) MESSENGER-RNA; KIDNEY; AUTORADIOGRAPHY; POLYMERASE CHAIN;
D O I
10.1111/j.1476-5381.1994.tb17140.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 The linear tetrapeptide radioligand, [I-125]-PD151242 was used to characterize ET(A) receptors in human kidney which is an ET(B)-rich tissue. Saturation binding assays with [I-125]-PD151242 revealed a single population of high affinity endothelin receptors: K-D = 0.75 +/- 0.07 nM and B-max = 48.4 +/- 1.6 fmol mg(-1) protein (n = 3 individuals +/- s.e.mean). Hill slopes were close to unity and a one site fit was preferred to a two site model. 2 ET(A)-receptor-selective ligands competed for [I-125]-PD151242 binding with sub-nanomolar affinity: BQ123 K-D = 0.43 +/- 0.10 nM, B-max = 46.6 +/- 7.9 fmol mg(-1) protein; FR139317, K-D = 0.37 +/- 0.06 nM, B-max = 39.5 +/- 6.5 fmol mg(-1) protein (n = 3 individuals +/- s.e. mean). In each case, monophasic inhibition curves were obtained and a one site fit was preferred to a two site model. The ET(B)-selective agonist, BQ3020 at the highest concentration tested (10 mu M) inhibited binding by only 50%. The non-selective R0462005 competed for the binding of [I-125]-PD15r242: K-D = 1.31 +/- 1.38 mu M, B-max = 33.0 +/- 9.7 fmol mg(-1) protein. Endothelin-2 and sarafotoxin S6B inhibited [I-125]-PD151242 binding to renal tissue whereas ET-3 and sarafotoxin S6C were less effective. Non-endothelin and non-sarafotoxin peptides did not compete. 3 No degradation of [I-125]-PD151242 was detected following incubation of the ligand with renal tissue under the conditions of the binding assay. 4 Polymerase chain reaction products corresponding to the expected size for mRNA encoding ET(A) and ET(B) receptor sub-types were detected in cortex and medulla in each of the five individuals examined. 5 Autoradiographical studies showed that ETA receptors visualised with [I-125]-PD151242 were mainly localized to blood vessels including interlobular and arcuate arteries, arterioles and adjacent arcuate veins. ET(B) receptors localized with [I-125]-BQ3020 were concentrated in the medulla and the density of binding to vessels was low. 6 These data suggest [I-125]-PD151242 is selective for ET(A) receptors in human kidney and this sub-type is mainly localized to the renal vasculature. The results provide further evidence that the human vasculature mainly expresses the ET(A) receptor.
引用
收藏
页码:1303 / 1310
页数:8
相关论文
共 56 条
  • [21] EFFECTS OF AN ET(1)-RECEPTOR ANTAGONIST, FR139317, ON REGIONAL HEMODYNAMIC-RESPONSES TO ENDOTHELIN-1 AND [ALA(11,15)]AC-ENDOTHELIN-1 (6-21) IN CONSCIOUS RATS
    GARDINER, SM
    KEMP, PA
    MARCH, JE
    BENNETT, T
    DAVENPORT, AP
    EDVINSSON, L
    [J]. BRITISH JOURNAL OF PHARMACOLOGY, 1994, 112 (02) : 477 - 486
  • [22] REGIONAL HEMODYNAMIC-EFFECTS OF ENDOTHELIN-1 IN CONSCIOUS, UNRESTRAINED, WISTAR RATS
    GARDINER, SM
    COMPTON, AM
    BENNETT, T
    [J]. JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1989, 13 : S202 - S204
  • [23] REGIONAL HEMODYNAMIC-EFFECTS AND CLEARANCE OF ENDOTHELIN-1 IN HUMANS - RENAL AND PERIPHERAL-TISSUES MAY CONTRIBUTE TO THE OVERALL DISPOSAL OF THE PEPTIDE
    GASIC, S
    WAGNER, OF
    VIERHAPPER, H
    NOWOTNY, P
    WALDHAUSL, W
    [J]. JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 1992, 19 (02) : 176 - 180
  • [24] LOCALIZATION AND QUANTIFICATION OF [I-125] ENDOTHELIN BINDING-SITES IN HUMAN FETAL AND ADULT KIDNEYS - RELEVANCE TO RENAL ONTOGENY AND PATHOPHYSIOLOGY
    GRONE, HJ
    LAUE, A
    FUCHS, E
    [J]. KLINISCHE WOCHENSCHRIFT, 1990, 68 (15): : 758 - 767
  • [25] BIOLOGICAL PROFILES OF HIGHLY POTENT NOVEL ENDOTHELIN ANTAGONISTS SELECTIVE FOR THE ETA RECEPTOR
    IHARA, M
    NOGUCHI, K
    SAEKI, T
    FUKURODA, T
    TSUCHIDA, S
    KIMURA, S
    FUKAMI, T
    ISHIKAWA, K
    NISHIKIBE, M
    YANO, M
    [J]. LIFE SCIENCES, 1992, 50 (04) : 247 - 255
  • [26] NOVEL LIGANDS BQ123 AND BQ3020 CHARACTERIZE ENDOTHELIN RECEPTOR SUBTYPES ET(A) AND ET(B) IN HUMAN KIDNEY
    KARET, FE
    KUC, RE
    DAVENPORT, AP
    [J]. KIDNEY INTERNATIONAL, 1993, 44 (01) : 36 - 42
  • [27] ENDOTHELIN AND THE HUMAN KIDNEY - A POTENTIAL TARGET FOR NEW DRUGS
    KARET, FE
    DAVENPORT, AP
    [J]. NEPHROLOGY DIALYSIS TRANSPLANTATION, 1994, 9 (05) : 465 - 468
  • [28] QUANTIFICATION OF MESSENGER-RNA IN HUMAN TISSUE USING FLUORESCENT NESTED REVERSE-TRANSCRIPTASE POLYMERASE CHAIN-REACTION
    KARET, FE
    CHARNOCKJONES, DS
    HARRISONWOOLRYCH, ML
    OREILLY, G
    DAVENPORT, AP
    SMITH, SK
    [J]. ANALYTICAL BIOCHEMISTRY, 1994, 220 (02) : 384 - 390
  • [29] KARET FE, 1993, J CARDIOVASC PHARM, V22, P29
  • [30] KOYAMA H, 1989, LANCET, V1, P991