The CYP450 hydroxylase pathway contributes to P2X receptor-mediated afferent arteriolar vasoconstriction.
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, alpha,beta-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 microM 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. alpha,beta-Methylene ATP (1 microM) 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 alpha,beta-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.
Zhao
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X
Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Inscho
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EW
Bondlela
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Falck
J R
JR
Imig
J D
JD
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000502:physiology; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058469:Receptors, Purinergic P2X; D058472:Receptors, Purinergic P2Y1; D012077:Renal Artery / Q000502:physiology; D013450:Sulfones / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
D000577:Amides; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D058472:Receptors, Purinergic P2Y1; D013450:Sulfones; D011189:Potassium Chloride; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D000255:Adenosine Triphosphate; C117975:DDMS; D001189:Aryl Hydrocarbon Hydroxylases; D014544:Uridine Triphosphate