Effect of the putative novel selective ETA-receptor antagonist HJP272, a 1,3,6-trisubstituted-2-carboxy-quinol-4-one, on infection-mediated premature delivery

Nicole Olgun, Hardik J. Patel, Ralph Stephani, Wei Wang, Haoting Yen, Sandra E. Reznik

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Preterm birth (PTB), defined as any birth occurring before 37 weeks of gestation, occurs in only 12% of all births, yet accounts for nearly half of long-term neurological morbidity, and 60%-80% of perinatal mortality. The single most common cause of PTB is intrauterine infection. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that is both upregulated by inflammatory cytokines and capable of increasing myometrial smooth muscle tone. We hypothesized, therefore, that ET-1 is a critical component of the parturition cascade in the setting of infection-associated PTB. In our previous work, we have shown that blockade of ET-1 synthesis through the use of the metalloproteinase inhibitor phosphoramidon results in control of preterm labor. In the current work, we showed that blockade of ET-1 action with 5-50 mg/kg i.p. 3-(3-carboxybenzyl)-1-((6-ethylbenzo[d][1,3]dioxol-5-yl)methyl)-6-hydroxy-4- oxo-1,4-dihydroquinoline-2-carboxylic acid (HJP272), a putative novel selective ETA-receptor antagonist (IC50, 70 nmol/L), prevents PTB induced with up to 50 mg/kg of i.p. lipopolysaccharide in a mouse model. This is the first report, to our knowledge, of control of infection-associated PTB with a specific ETA-receptor antagonist. The identification of a novel effective therapy for PTB could have important clinical implications.

Original languageEnglish (US)
Pages (from-to)571-575
Number of pages5
JournalCanadian Journal of Physiology and Pharmacology
Volume86
Issue number8
DOIs
StatePublished - Aug 1 2008
Externally publishedYes

Keywords

  • Endothelin A receptor antagonist
  • Endothelin-1
  • Inflammatory cytokines
  • Preterm delivery

ASJC Scopus subject areas

  • Physiology
  • Pharmacology
  • Physiology (medical)

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