Elevated systemic levels of endothelin-1 and blood pressure correlate with blunted constrictor responses and downregulation of endothelinA, but not endothelinB, receptors in an animal model of hypertension

Sabine Télémaque-Potts, Rhoda E. Kuc, Janet J. Maguire, Eliot Ohlstein, Masashi Yanagisawa, Anthony P. Davenport

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Hypertension is a major risk factor in the development of cardiovascular disease. Adenovirus gene transfer of endothelin-1 (Ad.CMV.ET-1) in rats produced significant (5-fold) increases in plasma ET-1 and systemic blood pressure (46%) 4 days after viral administration, compared with β-galactosidase (Ad.CMV.β-gal) injected as control. The density (Bmax) of the ET receptor ETA measured in aortas was reduced significantly by more than 50% to 17±2 fmol·mg-1 of protein for the Ad.CMV.ET-1 group compared with 39±6 fmol·mg-1 of protein for the control. There was no change in the density of the smaller population of the ETB sub-type. In agreement, the ratio of ETA mRNA to cyclophilin mRNA (a housekeeping gene) measured by Northern analysis was reduced in Ad.CMV.ET-1 rats compared with controls. The ratio of m RNA encoding the ETB subtype did not change. ET-1 vasoconstriction was significantly reduced (P < 0.05) in aortas from Ad.CMV.ET-1-treated rats [pD2 = 8.67±0.14 (where pD2 is -log10EC50); n = 11] versus the control (pD2 = 9.11±0.06; n = 14) but there was no significant difference in the potency of two other vasoconstrictors tested (noradrenaline and Arg-vasopressin), indicating this was a specific effect on ET receptors. There was no change in the affinity of ET-1 binding to either receptor subtype in the experimental group compared with the control, demonstrating that the attenuation in the constrictor response is the result of the reduced density of receptors rather than a change in affinity. The results show that ETA (but not ETB) receptors are modulated in this experimental model of hypertension and provide further evidence for selective blockade of the ETA receptor as a therapeutic strategy.

Original languageEnglish (US)
JournalClinical Science
Volume103
Issue numberSUPPL. 48
StatePublished - Aug 2002

Fingerprint

Endothelin-1
Down-Regulation
Animal Models
Blood Pressure
Hypertension
Aorta
Galactosidases
Cyclophilins
Messenger RNA
Arginine Vasopressin
Essential Genes
Vasoconstrictor Agents
Population Density
Vasoconstriction
Adenoviridae
Norepinephrine
Proteins
Theoretical Models
Cardiovascular Diseases
RNA

Keywords

  • Adenovirus
  • Aorta
  • Heart
  • Lung
  • mRNA
  • PD156707

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Elevated systemic levels of endothelin-1 and blood pressure correlate with blunted constrictor responses and downregulation of endothelinA, but not endothelinB, receptors in an animal model of hypertension. / Télémaque-Potts, Sabine; Kuc, Rhoda E.; Maguire, Janet J.; Ohlstein, Eliot; Yanagisawa, Masashi; Davenport, Anthony P.

In: Clinical Science, Vol. 103, No. SUPPL. 48, 08.2002.

Research output: Contribution to journalArticle

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abstract = "Hypertension is a major risk factor in the development of cardiovascular disease. Adenovirus gene transfer of endothelin-1 (Ad.CMV.ET-1) in rats produced significant (5-fold) increases in plasma ET-1 and systemic blood pressure (46{\%}) 4 days after viral administration, compared with β-galactosidase (Ad.CMV.β-gal) injected as control. The density (Bmax) of the ET receptor ETA measured in aortas was reduced significantly by more than 50{\%} to 17±2 fmol·mg-1 of protein for the Ad.CMV.ET-1 group compared with 39±6 fmol·mg-1 of protein for the control. There was no change in the density of the smaller population of the ETB sub-type. In agreement, the ratio of ETA mRNA to cyclophilin mRNA (a housekeeping gene) measured by Northern analysis was reduced in Ad.CMV.ET-1 rats compared with controls. The ratio of m RNA encoding the ETB subtype did not change. ET-1 vasoconstriction was significantly reduced (P < 0.05) in aortas from Ad.CMV.ET-1-treated rats [pD2 = 8.67±0.14 (where pD2 is -log10EC50); n = 11] versus the control (pD2 = 9.11±0.06; n = 14) but there was no significant difference in the potency of two other vasoconstrictors tested (noradrenaline and Arg-vasopressin), indicating this was a specific effect on ET receptors. There was no change in the affinity of ET-1 binding to either receptor subtype in the experimental group compared with the control, demonstrating that the attenuation in the constrictor response is the result of the reduced density of receptors rather than a change in affinity. The results show that ETA (but not ETB) receptors are modulated in this experimental model of hypertension and provide further evidence for selective blockade of the ETA receptor as a therapeutic strategy.",
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