HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 551/3/971    most recent jphysiol.2003.049981v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hercule, H. C. Articles by Oyekan, A. O. Search for Related Content PubMed PubMed Citation Articles by Hercule, H. C. Articles by Oyekan, A. O.

Contribution of cytochrome P450 4A isoforms to renal functional response to inhibition of nitric oxide production in the rat

Hantz C. Hercule, Mong-Heng Wang* and Adebayo O. Oyekan

20-Hydroxyeicosatetraenoic acid (20-HETE), a major renal eicosanoid, regulates renal function and contributes to renal responses following withdrawal of nitric oxide (NO). However, the role of 20-HETE-synthesizing isoforms in renal function resulting from NO inhibition is unknown. The present study evaluated the role of cytochrome (CYP)4A1, -4A2 and -4A3 isoforms on renal function in the presence and absence of NO. Antisense oligonucleotides (ASODN) to CYP4A1, -4A2 and -4A3 reduced 20-HETE synthesis and downregulated the expression of CYP4A isoforms in renal microsomes. N-L-nitromethyl arginine ester (L-NAME, 25 mg kg^-1), an inhibitor of NO production, increased mean arterial blood pressure (MABP, = +18 to 26 mmHg), reduced renal blood flow (RBF, = -1.8 to 2.9 ml min^-1), increased renal vascular resistance (RVR, = +47 to 54 mmHg ml^-1 min^-1), reduced glomerular filtration rate (GFR), but increased sodium excretion (U_NaV). ASODN to CYP4A1 and -4A2 but not -4A3 reduced basal MABP and RVR and increased basal GFR, while ASODN to CYP4A2 significantly reduced basal U_NaV suggesting a differential role for CYP4A isoforms in the regulation of renal function. ASODN to CYP4A2 but not -4A1 or -4A3 blunted the increase in MABP by L-NAME (38 ± 9 %, P < 0.05). ASODN to CYP4A1, -4A2 and -4A3 attenuated the reduction in RBF and the consequent increase in RVR by L-NAME with a potency order of CYP4A2 = CYP4A1 > CYP4A3. ASODN to CYP4A1 and -4A2 but not -4A3 attenuated L-NAME-induced reduction in GFR, but ASODN to all three CYP4A isoforms blunted the L-NAME-induced increase in U_NaV (CYP4A3 > CYP4A1 >> CYP4A2). We conclude from these data that CYP4A isoforms contribute to different extents to basal renal function. Moreover, CYP4A2 contributes greatest to haemodynamic responses while CYP4A3 contributes greatest to tubular responses following NO inhibition. We therefore propose that NO differentially regulates the function of CYP4A1, -4A2, and -4A3 isoforms in the renal vasculature and the nephron.

This article has been cited by other articles:

				K. Takeuchi, N. Miyata, M. Renic, D. R. Harder, and R. J. Roman Hemoglobin, NO, and 20-HETE interactions in mediating cerebral vasoconstriction following SAH Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R84 - R89. [Abstract] [Full Text] [PDF]

				H. Huang, Y. Zhou, V. T. Raju, J. Du, H.-H. Chang, C.-Y. Wang, M. W. Brands, J. R. Falck, and M.-H. Wang Renal 20-HETE inhibition attenuates changes in renal hemodynamics induced by L-NAME treatment in pregnant rats Am J Physiol Renal Physiol, November 1, 2005; 289(5): F1116 - F1122. [Abstract] [Full Text] [PDF]

				A. Huang, D. Sun, C. Yan, J. R. Falck, and G. Kaley Contribution of 20-HETE to Augmented Myogenic Constriction in Coronary Arteries of Endothelial NO Synthase Knockout Mice Hypertension, September 1, 2005; 46(3): 607 - 613. [Abstract] [Full Text] [PDF]

				A. D. Baines and P. Ho 20-HETE-mediated vasoconstriction by hemoglobin-O2 carrier in Sprague-Dawley but not Wistar rats J Appl Physiol, March 1, 2005; 98(3): 772 - 779. [Abstract] [Full Text] [PDF]