Pharmacological Interventions of the Epoxygenase Pathway in Hypertension and End-organ Damage.

摘要

End-organ damage is markedly accelerated by high-salt (HS) intake in stroke-prone spontaneously hypertensive rats (SHRSP). Since epoxyeicosatrienoic acids (EETs) possess vasodepressor, natriuretic and anti-inflammatory activities, we examined if either inhibition of soluble epoxide hydrolase (sEH) activity, an enzyme that converts EETs to less active dihydroxyeicosatrienoic acids (DHETs), or up-regulation of epoxygenases, would reduce blood pressure and protect against pathologic changes in SHRSP. AUDA, a sEH inhibitor, was administered orally (10 mg/Kg/day) to 7-week-old male SHRSP on HS intake (1% NaCl drinking solution) for 2 or 5 weeks. Systolic blood pressure (SBP) and urinary protein excretion (UPE) were significantly increased after 2 weeks of HS intake in vehicle-treated SHRSP and were significantly reduced in animals treated with AUDA. AUDA ameliorated early salt-dependent renal arteriolar fibrinoid degeneration and hypertrophy, and cardiac fibrosis and contraction band necrosis. Total plasma EET levels were significantly increased in SHRSP treated with AUDA compared with animals treated with HS alone. After 5 weeks of HS intake, vehicle-treated SHRSP developed heavy proteinuria and severe nephrosclerosis. In contrast, AUDA-treated SHRSP had lower UPE and reduced renal damage relative to vehicle-treated animals.;To investigate the effect of up-regulation of epoxygenase stimulation on salt-sensitive hypertension in SHRSP, clofibrate, a peroxisome proliferator activated receptor-alpha (PPARalpha) activator, was administered orally to induce epoxygenase protein and activity. SBP was significantly lower in SHRSP treated with clofibrate (200 mg/Kg/day, p.o.) compared with vehicle-treated animals. Kidneys of vehicle-treated SHRSP demonstrated mild to moderate glomerular swelling, mesangial expansion and fibrinoid degeneration whereas kidney from clofibrate-treated animals exhibited mild pathological lesions as well as significantly reduced UPE. Renal cortical protein expression of CYP2C23, the major epoxygenase in rat kidney, was significantly up-regulated with clofibrate treatment as were urinary excretion levels of EETs/DHETs. In contrast, two weeks treatment with an epoxygenase inhibitor, MS-PPOH (20 mg/day, i.v.), significantly increased UPE, in SHRSP on HS intake. Kidneys obtained from vehicle-treated SHRSP demonstrated only mild lesions whereas kidneys of MS-PPOH-treated SHRSP exhibited lesions of malignant nephrosclerosis characterized by fibrinoid necrosis of microvessels.;These results indicate that interventions to inhibit EET metabolism or increase EET synthesis can ameliorate salt-sensitive hypertension and/or end-organ damage, whereas inhibition of EET formation can exacerbate salt-sensitive end-organ damage in SHRSP.