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Research ArticleCARDIOVASCULAR

Differential Effects of U46619 on Renal Regional Hemodynamics in the Rat: Involvement of Endothelin

Hercule Hantz, Ajayi Adesuyi and Oyekan Adebayo
Journal of Pharmacology and Experimental Therapeutics October 2001, 299 (1) 372-376;
Hercule Hantz
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Ajayi Adesuyi
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Oyekan Adebayo
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Abstract

Many vasoactive agents produce qualitatively similar effects on blood flow in the renal cortex and medulla, evoking reductions or increases in blood flow in both regions. We demonstrated previously that endothelin-1 (ET-1) is an exception because it evoked an increase in medullary perfusion despite a potent cortical vasoconstriction (Hercule and Oyekan, 2000). We report here that U46619 (11,9 epoxymethano-prostaglandin H2), a selective agonist of prostaglandin H2 (PGH2)/thromboxane A2 (TxA2) (TP) receptor, evokes similar effects as ET-1. In the pentobarbital-anesthetized (60 mg/kg) rat, 1, 3, and 5 μg/kg U46619 dose dependently reduced mean arterial blood pressure by −2 ± 4, −8 ± 10, and −31 ± 10 mm Hg, respectively; renal cortical blood flow (CBF) by −50 ± 11, −174 ± 45, and −349 ± 43 perfusion units (PU), respectively; but increased medullary blood flow (MBF) by 42 ± 16, 51 ± 18, and 61 ± 21 PU, respectively. Prostaglandin F2α, a TxA2 mimetic, produced similar effects as U46619. SQ29548 ([1S-[1α,2α(Z), 3α,4α]]-7-[3[[2-[(phenylamino)carbonyl[hydrazino] methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid) (0.1 mg/kg), an antagonist of PGH2/TxA2 (TP), blunted U46619-induced hemodynamic changes without affecting that produced by phenylephrine. BMS182874 [5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyd)-1-naphthalene sulfonamide] (40 mg/kg), an ETA-selective antagonist, blunted U46619-induced reduction in CBF by 54 ± 9% (p < 0.05) and the increase in MBF by 59 ± 18% (p < 0.05). Similarly, BQ788 (N-cis2,6-dimethylpiperidinocarbonyl-l-γ-methylleucyl-d-1-methoxycarbonyltryptophanyl-d-norleucine) (1 mg/kg), an ETB-selective antagonist, blunted the effects of U46619 on CBF and MBF by 19 ± 3% (p < 0.05) and 48 ± 19% (p < 0.05), respectively. Combined administration of BMS182874 and BQ788 further attenuated U46619-induced reduction in CBF by 67 ± 8% (p < 0.05) and that on MBF by 61 ± 18% (p < 0.05). Phosphoramidon (10 mg/kg), an endothelin converting enzyme inhibitor, markedly blunted U46619-induced changes on CBF and MBF (p < 0.05). These findings are the first to demonstrate that U46619, through activation of ETA and ETB receptors, elicits renal cortical vasoconstriction and medullary vasodilation in the rat.

Footnotes

  • This work was supported by National Institutes of Health Grants RO1 HL59884 and UH1 HL03674. Dr. Oyekan is an Established Investigator of the American Heart Association (Award 0040119N). The facilities of the Research Center in Minority Institutions' program at Texas Southern University were used for these studies.

  • Abbreviations:
    AII
    angiotensin II
    ET
    endothelin
    TxA2
    thromboxane A2
    PGH2
    prostaglandin H2
    TP
    PGH2/TxA2
    MABP
    mean arterial blood pressure
    CBF
    cortical blood flow
    PE
    phenylephrine
    PU
    profusion units
    MBF
    medullary blood flow
    CVR
    cortical vascular resistance
    MVR
    medullary vascular resistance
    U46619
    11,9 epoxymethano-prostaglandin H2
    SQ29548
    [1S-[1α,2α(Z), 3α,4α]]-7-[3[[2-[(phenylamino)carbonyl[hydrazino] methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
    BMS182874
    5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyd)-1-naphthalene sulfonamide
    BQ788
    N-cis 2,6 -dimethylpiperidinocarbonyl-l-γ-methylleucyl-d-1-methoxycarbonyltryptophanyl-d-norleucine
    • Received March 9, 2001.
    • Accepted July 6, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 1
1 Oct 2001
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Research ArticleCARDIOVASCULAR

Differential Effects of U46619 on Renal Regional Hemodynamics in the Rat: Involvement of Endothelin

Hercule Hantz, Ajayi Adesuyi and Oyekan Adebayo
Journal of Pharmacology and Experimental Therapeutics October 1, 2001, 299 (1) 372-376;

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Research ArticleCARDIOVASCULAR

Differential Effects of U46619 on Renal Regional Hemodynamics in the Rat: Involvement of Endothelin

Hercule Hantz, Ajayi Adesuyi and Oyekan Adebayo
Journal of Pharmacology and Experimental Therapeutics October 1, 2001, 299 (1) 372-376;
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