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Research ArticleCARDIOVASCULAR

The Endothelin A Receptor Antagonists PD 156707 (CI-1020) and PD 180988 (CI-1034) Reverse the Hypoxic Pulmonary Vasoconstriction in the Perinatal Lamb

Yashu Coe, Stephen J. Haleen, Kathleen M. Welch, You-An Liu and Flavio Coceani
Journal of Pharmacology and Experimental Therapeutics August 2002, 302 (2) 672-680; DOI: https://doi.org/10.1124/jpet.302.2.672
Yashu Coe
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Stephen J. Haleen
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Kathleen M. Welch
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You-An Liu
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Flavio Coceani
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Abstract

Endothelin-1 (ET-1) is considered an intermediary in the constrictor response of the pulmonary vasculature to hypoxia and, by extension, is assigned a prime role in the pathogenesis of pulmonary hypertension. We report here the antihypertensive action in the conscious newborn lamb of two novel endothelin A receptor antagonists, sodium 2-benzo-[1,3]dioxol-5-yl-4- (4-methoxy-phenyl)-4-oxo-3-(3,4,5-trimethoxy-benzyl)-but-2- enoate (PD 156707) and 4-(7-ethyl-benzo[1,3]dioxol-5-yl)-1, 1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1l6-benzo-[e][1,2]thiazine-3-carboxylic acid potassium (PD 180988), differing in chemical properties and half-life within the body. PD 156707 and PD 180988, given in the right atrium as a bolus followed by infusion, had little or no effect on pulmonary and systemic hemodynamics under normoxia. Conversely, they both reversed the pulmonary hypertension due to alveolar hypoxia while producing minor changes, or no change at all, in systemic vascular resistance. Furthermore, their pulmonary vascular effect outlasted administration. Pulmonary hypertension being elicited by infusion of the thromboxane A2 analog, 9,11-epithio-11,12-methano-thromboxane A2 (ONO-11113) was instead not amenable to ETAR inhibition. Blood levels of ET-1, which rose with hypoxia but not ONO-11113 treatment, were not changed by either antagonist. Consistent with findings in vivo, when using isolated pulmonary resistance arteries from term fetal lamb, PD 156707 curtailed the hypoxia- but not the ONO-11113-induced constriction. We conclude that PD 156707 and PD 180988 are selective inhibitors of pulmonary vasoconstriction resulting from hypoxia. Our findings support the use of these or allied compounds in the management of pulmonary hypertension in the neonate.

Footnotes

  • This work was supported by the Heart and Stroke Foundation of Ontario (Grant T-3329 to F.C.) and by Pfizer (formerly Parke-Davis).

  • Abbreviations:
    ET-1
    endothelin-1
    ETAR
    endothelin A receptor
    ETBR
    endothelin B receptor
    Ao
    aorta
    BSA
    bovine serum albumin
    P
    pressure
    PA
    pulmonary artery
    PV
    pulmonary vein
    R
    resistance, RA, right atrium
    NO
    nitric oxide
    ONO-11113
    9,11-epithio-11,12-methano-thromboxane A2
    PD 156707
    (sodium 2-benzo-[1,3]dioxol-5-yl-4-(4-methoxy-phenyl)-4-oxo-3-(3,4,5-trimethoxy-benzyl)-but-2-enoate)
    PD 158312
    2-benzo[1,3]dioxol-5-yl-4-(4-methoxy-3-methylphenyl)-4-oxo-3-(3,4,5-trimethoxybenzyl)-but-2-enoic acid
    PD 166793
    (S)-2-(4′-bromo-byphenyl-4-sulfonylamino)-3-methyl-butyric acid
    PD 180988
    4-(7-ethyl-benzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1l6-benzo[e][1,2] thiazine-3-carboxylic acid potassium salt
    pO2
    partial pressure of O2
    pCO2
    partial pressure of CO2
    • Received December 14, 2001.
    • Accepted April 19, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 302 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 302, Issue 2
1 Aug 2002
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Research ArticleCARDIOVASCULAR

The Endothelin A Receptor Antagonists PD 156707 (CI-1020) and PD 180988 (CI-1034) Reverse the Hypoxic Pulmonary Vasoconstriction in the Perinatal Lamb

Yashu Coe, Stephen J. Haleen, Kathleen M. Welch, You-An Liu and Flavio Coceani
Journal of Pharmacology and Experimental Therapeutics August 1, 2002, 302 (2) 672-680; DOI: https://doi.org/10.1124/jpet.302.2.672

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Research ArticleCARDIOVASCULAR

The Endothelin A Receptor Antagonists PD 156707 (CI-1020) and PD 180988 (CI-1034) Reverse the Hypoxic Pulmonary Vasoconstriction in the Perinatal Lamb

Yashu Coe, Stephen J. Haleen, Kathleen M. Welch, You-An Liu and Flavio Coceani
Journal of Pharmacology and Experimental Therapeutics August 1, 2002, 302 (2) 672-680; DOI: https://doi.org/10.1124/jpet.302.2.672
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