Abstract
Epoxyeicosatrienoic acids (EETs) contribute to blood pressure regulation leading to the concept that EETs can be therapeutically targeted for hypertension and the associated end organ damage. In the present study, we investigated anti-hypertensive and kidney protective actions of an EET analog, EET-B in angiotensin II (ANG II)-induced hypertension. EET-B was administered in drinking water for 14 days (10 mg/kg/d) and resulted in a decreased blood pressure elevation in ANG II hypertension. At the end of the two-week period, blood pressure was 30 mmHg lower in EET analog-treated ANG II hypertensive rats. The vasodilation of mesenteric resistance arteries to acetylcholine was impaired in ANG II hypertension; however, it was improved with EET-B treatment. Further, EET-B protected the kidney in ANG II hypertension as evidenced by a marked 90% decrease in albuminuria and 54% decrease in nephrinuria. Kidney histology demonstrated a decrease in renal tubular cast formation in EET analog-treated hypertensive rats. In ANG II hypertension, EET-B treatment markedly lowered renal inflammation. Urinary monocyte chemoattractant protein-1 excretion was decreased by 55% and kidney macrophage infiltration was reduced by 52% with EET-B treatment. Overall, our results demonstrate that EET-B has anti-hypertensive properties, improves vascular function, and decreases renal inflammation and injury in ANG II hypertension.
Highlights
Cytochrome P450 epoxygenase metabolites of arachidonic acid, epoxyeicosatrienoic acids (EETs), have numerous cardiovascular and renal actions that make them therapeutically promising in cardiovascular and renal diseases (Imig, 2008, 2010, 2012; Imig and Hammock, 2009; Sudhahar et al, 2010)
EET-B REDUCES BLOOD PRESSURE IN angiotensin II (ANG II) HYPERTENSIVE RATS As demonstrated in Figure 2, oral administration of EET-B markedly blunted the development of ANG II hypertension without affecting heart rate
Urinary sodium excretion on day 14 was similar between EET-B (2.2 ± 0.3 mmol/d) and vehicle (2.7 ± 0.4 mmol/d) treated ANG II hypertensive rats
Summary
Cytochrome P450 epoxygenase metabolites of arachidonic acid, epoxyeicosatrienoic acids (EETs), have numerous cardiovascular and renal actions that make them therapeutically promising in cardiovascular and renal diseases (Imig, 2008, 2010, 2012; Imig and Hammock, 2009; Sudhahar et al, 2010). Inhibition of soluble epoxide hydrolase (sEH), which hydrolyzes EETs to their less biologically active dihydroxyeicosatrienoic acid metabolites, increases EETs bioavailability and exhibited therapeutically important cardiovascular effects (Imig et al, 2002, 2005; Imig and Hammock, 2009; Imig, 2010, 2012). An EET analog, NUDSA, dilated renal afferent arterioles, reduced blood pressure in hypertensive rats and mice, improved insulin sensitivity in metabolic syndrome mice, and decreased experimental cardiac reperfusion injury (Seubert et al, 2007; Sodhi et al, 2009; Imig et al, 2010)
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