Abstract
Soluble epoxide hydrolase inhibitors (sEHIs) are demonstrating promise as potential pharmaceutical agents for the treatment of cardiovascular disease, diabetes, inflammation, and kidney disease. The present study determined the ability of a first-in-class sEHI, AR9281, to decrease blood pressure, improve vascular function, and decrease renal inflammation and injury in angiotensin hypertension. Rats were infused with angiotensin and AR9281 was given orally during the 14-day infusion period. Systolic blood pressure averaged 180 ± 5 mmHg in vehicle treated and AR9281 treatment significantly lowered blood pressure to 142 ± 7 mmHg in angiotensin hypertension. Histological analysis demonstrated decreased injury to the juxtamedullary glomeruli. Renal expression of inflammatory genes was increased in angiotensin hypertension and two weeks of AR9281 treatment decreased this index of renal inflammation. Vascular function in angiotensin hypertension was also improved by AR9281 treatment. Decreased afferent arteriolar and mesenteric resistance endothelial dependent dilator responses were ameliorated by AR9281 treatment of angiotensin hypertensive rats. These data demonstrate that the first-in-class sEHI, AR9281, lowers blood pressure, improves vascular function and reduces renal damage in angiotensin hypertension.
Highlights
Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites generated by cytochrome P450 epoxygenase enzymes
The present study was conducted to test the ability of a firstin-class sEHI, AR9281 to decrease blood pressure and provide renal vascular protection in a rat model of angiotensin dependent hypertension
Sprague-Dawley rats were divided into three experimental groups; the first group was subjected to sham surgery, the second group received angiotensin and vehicle treatment (5% (2-hydroxypropyl)-βcyclodextrin), and the third group received angiotensin and AR9281
Summary
Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites generated by cytochrome P450 epoxygenase enzymes. Metabolism of EETs to DHETs is the primary mechanism whereby the biological actions of EETs are decreased or eliminated [1,2,3,4]. EETs are recognized as major regulators of cardiovascular and renal function and increasing EET levels protects the renal and cardiovascular systems [3,4]. SEHIs have been developed to enhance the renal and cardiovascular protective actions offered by EETs. Previous studies have demonstrated antihypertensive and renal protective properties for sEHIs [5,6,7,8,9]. Improvements in vascular function and anti-inflammatory actions for sEH inhibitors have been demonstrated in a number of cardiovascular disease states [7,10,11,12,13]. The present study was conducted to test the ability of a firstin-class sEHI, AR9281 to decrease blood pressure and provide renal vascular protection in a rat model of angiotensin dependent hypertension
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