TY - JOUR
T1 - An epoxygenase metabolite of arachidonic acid 5,6 epoxy-eicosatrienoic acid mediates angiotensin-induced natriuresis in proximal tubular epithelium.
AU - Romero, M. F.
AU - Madhun, Z. T.
AU - Hopfer, U.
AU - Douglas, J. G.
PY - 1991
Y1 - 1991
N2 - Several laboratories have documented that angiotensin II (AII) induces natriuresis in proximal tubular epithelium by a mechanism that has as yet not been disclosed. The present studies were designed to test the hypothesis that cytochrome P450-dependent metabolites of arachidonic acid mediate this effect. In cultured rabbit proximal tubule a ketoconazole-sensitive product comigrating with 5,6-epoxy-eicosatrienoic acid (5,6-EET) on reverse phase and normal phase HPLC was stimulated two-fold by AII. We employed cultures of early S1 segments on a modified Ussing chamber as a bioassay to evaluate the effects of AII and 5,6-EET on unidirectional 22Na (apical to basolateral) flux (JNa). AII inhibited JNa, an effect that was abolished by ketoconazole. Furthermore, 5,6-EET decreased JNa in a manner analogous to AII, and the effect was potentiated by inhibition of endogenous 5,6-EET production. Employing the Ca2(+)-sensitive fluorescent probe, Fura 2, we observed a dose-dependent increase in [Ca2+]i with nM to microM 5,6-EET, effects that were abolished by depletion of extracellular Ca2+ and voltage-sensitive Ca-channel blockers. These observations support the hypothesis that 5,6-EET represents the second messenger that mediates AII-induced natriuresis via stimulation of Ca2+ influx through voltage-sensitive channels.
AB - Several laboratories have documented that angiotensin II (AII) induces natriuresis in proximal tubular epithelium by a mechanism that has as yet not been disclosed. The present studies were designed to test the hypothesis that cytochrome P450-dependent metabolites of arachidonic acid mediate this effect. In cultured rabbit proximal tubule a ketoconazole-sensitive product comigrating with 5,6-epoxy-eicosatrienoic acid (5,6-EET) on reverse phase and normal phase HPLC was stimulated two-fold by AII. We employed cultures of early S1 segments on a modified Ussing chamber as a bioassay to evaluate the effects of AII and 5,6-EET on unidirectional 22Na (apical to basolateral) flux (JNa). AII inhibited JNa, an effect that was abolished by ketoconazole. Furthermore, 5,6-EET decreased JNa in a manner analogous to AII, and the effect was potentiated by inhibition of endogenous 5,6-EET production. Employing the Ca2(+)-sensitive fluorescent probe, Fura 2, we observed a dose-dependent increase in [Ca2+]i with nM to microM 5,6-EET, effects that were abolished by depletion of extracellular Ca2+ and voltage-sensitive Ca-channel blockers. These observations support the hypothesis that 5,6-EET represents the second messenger that mediates AII-induced natriuresis via stimulation of Ca2+ influx through voltage-sensitive channels.
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M3 - Article
C2 - 1847766
AN - SCOPUS:0025928864
SN - 0732-8141
VL - 21 A
SP - 205
EP - 208
JO - Advances in prostaglandin, thromboxane, and leukotriene research
JF - Advances in prostaglandin, thromboxane, and leukotriene research
ER -