Ogungbade G O, Akinsanmi L A, Jiang H, Oyekan A O
Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX 77004, USA.
Am J Physiol Renal Physiol. 2003 Nov;285(5):F955-64. doi: 10.1152/ajprenal.00092.2003. Epub 2003 Jul 15.
Nitric oxide (NO) inhibits hemoproteins, including cytochrome (CYP) 2C, the gene responsible for the production of epoxyeicosatrienoic acids (EETs). EETs and NO are produced in the kidney, and both regulate renal vascular tone and Na+ transport. However, the role of EETs in NO-mediated renal function is not known. This study tested the hypothesis that NO tonically regulates the renal production of EETs, thereby impacting renal vasomotor tone and electrolyte balance. LPS (10 mg/kg i.v.) inhibited microsomal conversion of 14C-labeled arachidonic acid to EETs and reduced mean arterial blood pressure (MABP; Delta = 63 +/- 5 mmHg). Nitro-l-arginine methyl ester (l-NAME, 10 mg/kg), an inhibitor of NO synthase, increased MABP (Delta = 26 +/- 6 mmHg), reduced cortical (CBF) and medullary (MBF) blood flow (Delta = -0.86 +/- 0.15 and -0.34 +/- 0.09 V, respectively) and glomerular filtration rate (GFR; from 0.82 +/- 0.16 to 0.32 +/- 0.10 ml x g kidney-1 x min-1), and increased Na+ excretion (UNaV, from 0.16 +/- 0.04 to 0.30 +/- 0.06 micromol x g kidney-1 x min-1). 2-(2-Propynyloxy)-benzenehexanoic acid (PPOH), a suicide substrate inhibitor of EET production, did not affect the l-NAME-induced increase in MABP but attenuated the effects of l-NAME on CBF (31 +/- 7%, P < 0.05%), GFR (44 +/- 6%, P < 0.05), and UNaV (78 +/- 7%, P < 0.05). Miconazole (1.3 mg x kg-1 x h-1), a heme inhibitor of epoxygenase enzymes, produced effects similar to those of PPOH. Renal intraarterial infusion of 5,6-, 8,9-, 11,12-, and 14,15-EET (1-10 ng/min) elicited dose-dependent reductions in CBF and GFR accompanied by regioisomeric changes in MBF, UNaV, and urine flow rate. In addition, 11,12-EET dose dependently restored the PPOH blunting the effects of l-NAME on CBF, MBF, and GFR. We conclude that NO tonically regulates epoxygenase activity and that EETs are renal vaosoconstrictors in vivo and contribute, at least in part, to the renal functional responses following inhibition of NO production.
一氧化氮（NO）可抑制包括细胞色素（CYP）2C在内的血红素蛋白，CYP2C是负责产生环氧二十碳三烯酸（EETs）的基因。EETs和NO在肾脏中产生，二者均可调节肾血管张力和钠转运。然而，EETs在NO介导的肾功能中的作用尚不清楚。本研究检验了以下假设：NO持续性调节EETs的肾脏生成，从而影响肾血管舒缩张力和电解质平衡。脂多糖（10 mg/kg静脉注射）抑制了14C标记的花生四烯酸向EETs的微粒体转化，并降低了平均动脉血压（MABP；变化量=63±5 mmHg）。一氧化氮合酶抑制剂N-硝基-L-精氨酸甲酯（L-NAME，10 mg/kg）使MABP升高（变化量=26±6 mmHg），降低了皮质（CBF）和髓质（MBF）血流量（分别为-0.86±0.15和-0.34±0.09 V）以及肾小球滤过率（GFR；从0.82±0.16降至0.32±0.10 ml·g肾-1·min-1），并增加了钠排泄（UNaV，从0.16±0.04增至0.30±0.06 μmol·g肾-1·min-1）。EET生成的自杀底物抑制剂2-（2-丙炔氧基）-苯己酸（PPOH）不影响L-NAME诱导的MABP升高，但减弱了L-NAME对CBF（31±7%，P<0.05%）、GFR（44±6%，P<0.05）和UNaV（78±7%，P<0.05）的影响。环氧酶的血红素抑制剂咪康唑（1.3 mg·kg-1·h-1）产生了与PPOH类似的作用。经肾动脉输注5,6-、8,9-、11,12-和14,15-EET（1 - 10 ng/min）可引起CBF和GFR剂量依赖性降低，同时伴有MBF、UNaV和尿流率的区域异构体变化。此外，1,12-EET剂量依赖性地恢复了PPOH对L-NAME所致CBF、MBF和GFR影响的减弱作用。我们得出结论，NO持续性调节环氧酶活性，EETs在体内是肾血管收缩剂，并且至少部分地参与了抑制NO生成后的肾功能反应。
