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(Hypertension. 2005;46:1175.)
© 2005 American Heart Association, Inc.

Original Articles

Glomerular Cytochrome P-450 and Cyclooxygenase Metabolites Regulate Efferent Arteriole Resistance

Hong Wang; Jeffrey L. Garvin; John R. Falck; YiLin Ren; Steadman S. Sankey; Oscar A. Carretero

From the Hypertension and Vascular Research Division (H.W., J.L.G., Y.R., O.A.C.), Henry Ford Hospital, Detroit, Mich; Department of Biochemistry (J.R.F.), University of Texas, Southwestern Medical Center, Dallas, Tex; and the Department of Biostatistics and Research Epidemiology (S.S.S.), Henry Ford Hospital, Detroit, Mich.

Correspondence to Oscar A. Carretero, MD, Division of Hypertension and Vascular Research, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202. E-mail ocarret1{at}hfhs.org

Bradykinin dilates efferent arterioles via release of efferent arteriole epoxyeicosatrienoic acids when perfused retrograde (no glomerular autacoids). However, when efferent arterioles are perfused orthograde through the glomerulus, bradykinin-induced dilatation is caused by a balance between: (1) the glomerular vasoconstrictor 20-hydroxyeicosatetraenoic acid and vasodilator prostaglandins, and (2) epoxyeicosatrienoic acids from the efferent arteriole and possibly the glomerulus. However, the role of 20-hydroxyeicosatetraenoic acid has only been studied with a cyclooxygenase inhibitor, which may artificially enhance its production by shunting arachidonic acid into the cytochrome P450 pathway. We hypothesized that in the absence of cyclooxygenase inhibition, bradykinin induces release of 20-hydroxyeicosatetraenoic acid from the glomerulus, which blunts the vasodilator effect of bradykinin; and that prostaglandins released from glomeruli in response to bradykinin are generated by cyclooxygenase-1. Rabbit efferent arterioles preconstricted with norepinephrine were perfused orthograde from the end of the afferent arteriole. Bradykinin was added to the perfusate with or without a 20-hydroxyeicosatetraenoic acid antagonist (20-HEDE), epoxyeicosatrienoic acid synthesis inhibitor (MS-PPOH), and/or cyclooxygenase-1 (SC-58560) or cyclooxygenase-2 inhibitor (NS-398). Bradykinin-dependent dilatation was enhanced by 20-HEDE but blunted by MS-PPOH. When the inhibitors were present, bradykinin-induced dilatation was abolished by blockade of cyclooxygenase-1 but not cyclooxygenase-2. We concluded that: (1) in the absence of cyclooxygenase inhibitors, bradykinin causes the release of a glomerular vasoconstrictor (20-hydroxyeicosatetraenoic acid) that antagonizes the vasodilator effect of epoxyeicosatrienoic acids released from the efferent arteriole and perhaps from the glomerulus, and (2) bradykinin-induced vasodilatation is caused by the release of epoxyeicosatrienoic acids from the efferent arteriole and glomerular metabolites of cyclooxygenase-1.

Key Words: glomerulus • cyclooxygenase-1 • 20-hydroxyeicosatetraenoic acid • epoxyeicosatrienoic acid • renal vascular resistance

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