The CYP450 hydroxylase pathway contributes to P2X receptor-mediated afferent arteriolar vasoconstriction

Xueying Zhao, Edward W. Inscho, Muralidhar Bondlela, John R. Falck, John D. Imig

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Abstract

This study was conducted to test the hypothesis that the cytochrome P-450 (CYP450) metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to the afferent arteriolar response to P2 receptor activation. Afferent arteriolar responses to ATP, the P2X agonist, α,β-methylene ATP and the P2Y agonist UTP were determined before and after treatment with the selective CYP450 hydroxylase inhibitor, N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS) or the 20-HETE antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE). Stimulation with 1.0 and 10 μM ATP elicited an initial preglomerular vasoconstriction of 12 ± 1% and 45 ± 4% and a sustained vasoconstriction of 11 ± 1% and 11 ± 2%, respectively. DDMS or 20-HEDE significantly attenuated the sustained afferent arteriolar constrictor response to ATP. α,β-Methylene ATP (1 μM) induced a rapid initial afferent vasoconstriction of 64 ± 3%, which partially recovered to a stable diameter 10 ± 1% smaller than control. Both DDMS and 20-HEDE significantly attenuated the initial vasoconstriction and abolished the sustained vasoconstrictor response to α,β-methylene ATP. UTP decreased afferent diameter by 50 ± 5% and 20-HEDE did not change this response. In addition, the ATP-induced increase in the intracellular Ca2+ concentration in preglomerular microvascular smooth muscle cells was significantly attenuated by 20-HEDE. Taken together, these results are consistent with the hypothesis that the CYP450 metabolite 20-HETE participates in the afferent arteriolar response to activation of P2X receptors.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume281
Issue number5 50-5
Publication statusPublished - 2001

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Keywords

  • α,β-methylene adenosine trisphosphate
  • 20-hydroxyeicosatetraenoic acid
  • Afferent arterioles
  • ATP
  • Renal microcirculation
  • UTP

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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