| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
1 Department of Physiology, Medical College of Georgia, Augusta, GA, USA
2 Department of Pharmacology, New York Medical College, Valhalla, NY, USA
* To whom correspondence should be addressed. E-mail: mwang{at}mail.mcg.edu.
20-Hydroxyeicosatetraenoic acid (20-HETE), which promotes renal vasoconstriction, is formed in the rat kidney primarily by cytochrome P450 (CYP) 4A isoforms (4A1, 4A2, 4A3, 4A8). Nitric oxide (NO) has been shown to bind to the heme moiety of the CYP4A2 protein and to inhibit 20-HETE synthesis in renal arterioles of male rats. However, it is not known whether NO interacts with and affects the activity of CYP4A1 and CYP4A3, the major renal CYP4A isoforms in female rats. Incubation of recombinant CYP4A1 and 4A3 proteins with sodium nitroprusside (SNP) shifted the absorbance at 440 nm indicating the formation of ferric-nitrosyl-CYP4A complex. The absorbance for CYP4A3 was about two fold higher than that of CYP4A1. Incubation of SNP or PN (0.01-1 mM) with CYP4A recombinant membranes caused a concentration-dependent inhibition of 20-HETE synthesis, with both chemicals having a greater inhibitory effect on CYP4A3-catalyzed activity. Moreover, incubation of CYP4A1 and 4A3 proteins with PN (1 mM) resulted in nitration of tyrosine residues in both proteins. In addition, PN and SNP inhibited 20-HETE synthesis in renal microvessels from female rats by 65% and 59%, respectively. We have previously shown that microvessel CYP4A1/CYP4A3 expression and 20-HETE synthesis is decreased in late pregnancy. Therefore, we investigated whether such decrease is dependent on NO, the synthesis of which has been shown to increase in late pregnancy. Administration of N(G)-nitro-arginine methyl ester (L-NAME) to pregnant rats for 6 days (days 15-20 of pregnancy) caused a significant increase in systolic blood pressure, which was prevented by concurrent treatment with the CYP4A inhibitor 1-aminobenzotriazole (ABT). Urinary NO2 /NO3 excretion decreased by 40% and 52% in L-NAME and L-NAME + ABT treated group, respectively. Interestingly, renal microvessel 20-HETE synthesis showed a marked increase following L-NAME treatment, and this increase was diminished with co-administration of ABT. These results demonstrate that NO interacts with CYP4A proteins in a distinct manner and it interferes with renal microvessel 20-HETE synthesis, which may play an important role in the regulation of blood pressure and renal function during pregnancy.
This article has been cited by other articles:
|
|
 |
|
  Y.-J. Chen, J. Li, and J. Quilley Deficient renal 20-HETE release in the diabetic rat is not the result of oxidative stress Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2305 - H2312. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Nilakantan, C. Maenpaa, G. Jia, R. J. Roman, and F. Park 20-HETE-mediated cytotoxicity and apoptosis in ischemic kidney epithelial cells Am J Physiol Renal Physiol, March 1, 2008; 294(3): F562 - F570. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Cheng, J.-S. Ou, H. Singh, J. R. Falck, D. Narsimhaswamy, K. A. Pritchard Jr., and M. L. Schwartzman 20-Hydroxyeicosatetraenoic acid causes endothelial dysfunction via eNOS uncoupling Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H1018 - H1026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Guo, R. J. Roman, J. R. Falck, P. A. Edwards, and A. G. Scicli Human U251 Glioma Cell Proliferation Is Suppressed by HET0016 [N-Hydroxy-N'-(4-butyl-2-methylphenyl)formamidine], a Selective Inhibitor of CYP4A J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 526 - 533. [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. 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]
|
|
|
|
 |
|
 V. Randriamboavonjy, L. Kiss, J. R. Falck, R. Busse, and I. Fleming The synthesis of 20-HETE in small porcine coronary arteries antagonizes EDHF-mediated relaxation Cardiovasc Res, February 1, 2005; 65(2): 487 - 494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. T. Llinas, B. T. Alexander, M. F. Capparelli, M. A. Carroll, and J. P. Granger Cytochrome P-450 Inhibition Attenuates Hypertension Induced by Reductions in Uterine Perfusion Pressure in Pregnant Rats Hypertension, March 1, 2004; 43(3): 623 - 628. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
