Renal 20-HETE inhibition attenuates changes in renal hemodynamics induced by L-NAME treatment in pregnant rats.
We previously reported that inhibition of nitric oxide (NO) synthesis by N-nitro-L-arginine methyl ester (L-NAME) during late pregnancy leads to increased production of renal vascular 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P-450 (CYP) 4A-derived vasoconstrictor, in pregnant rats. However, the effect of upregulation of vascular 20-HETE production on renal function after NO inhibition is not known. To test the hypothesis that increased gestational vascular 20-HETE synthesis after NO inhibition is involved in mediating blood pressure and renal functional changes, we first determined the IC(50) value of the effect of nitroprusside (SNP), a NO donor, on renal 20-HETE production in cortical microsomes. We then divided pregnant rats and age-matched virgin rats into a vehicle control group, an L-NAME treatment group (0.25 mg/ml in drinking water), and a group treated with L-NAME plus N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS; CYP4A-selective inhibitor, 10 mg.kg(-1).day(-1) iv). After 4 days of treatment, we measured blood pressure, renal blood flow (RBF), renal vascular resistance (RVR), and glomerular filtration rate (GFR) in each group. The addition of SNP (IC(50) = 22 microM) decreased renal cortical 20-HETE production. In pregnant rats, L-NAME treatment led to significantly higher mean arterial pressure (MAP) and RVR, and lower RBF and GFR. Combined treatment with DDMS and L-NAME significantly attenuated the increases in MAP and RVR and the decrease in GFR, but not the reduction in RBF induced by L-NAME treatment. L-NAME and L-NAME plus DDMS had no significant impact on renal hemodynamics in virgin rats. In addition, chronic treatment with DDMS selectively inhibited cortical 20-HETE production without a significant effect on CYP4A expression in L-NAME-treated pregnant rats. In conclusion, NO effectively inhibits renal cortical microsomal 20-HETE production in female rats. In pregnant rats, the augmentation of renal 20-HETE production after NO inhibition is associated with increased MAP and RVR, whereas decreased GFR is negated by treatment of a selective and competitive CYP4A inhibitor. These results demonstrate that the interaction between renal 20-HETE and NO is important in the regulation of renal function and blood pressure in pregnant rats.
Huang
Hui
H
Dept. of Physiology, Medical College of Georgia, Augusta, GA 30912, USA.
Zhou
Yiqiang
Y
Raju
Venugopal T
VT
Du
Juan
J
Chang
Hsin-Hsin
HH
Wang
Cong-Yi
CY
Brands
Michael W
MW
Falck
John R
JR
Wang
Mong-Heng
MH
D000367:Age Factors; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D005260:Female; D006439:Hemodynamics; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis*; D007672:Kidney Cortex / Q000098:blood supply* / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D051381:Rats; D012039:Regional Blood Flow; D013450:Sulfones / Q000494:pharmacology
D000577:Amides; D006893:Hydroxyeicosatetraenoic Acids; D013450:Sulfones; D009569:Nitric Oxide; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; C117975:DDMS; D019331:NG-Nitroarginine Methyl Ester