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Inhibition of soluble epoxide hydrolase by cis-4-[4-(3-adamantan-1-ylureido)cyclohexyl-oxy]benzoic acid exhibits antihypertensive and cardioprotective actions in transgenic rats with angiotensin II-dependent hypertension.

ABSTRACT: The present study was undertaken to evaluate the effects of chronic treatment with c-AUCB {cis-4-[4-(3-adamantan-1-ylureido)cyclohexyl-oxy]benzoic acid}, a novel inhibitor of sEH (soluble epoxide hydrolase), which is responsible for the conversion of biologically active EETs (epoxyeicosatrienoic acids) into biologically inactive DHETEs (dihydroxyeicosatrienoic acids), on BP (blood pressure) and myocardial infarct size in male heterozygous TGR (Ren-2 renin transgenic rats) with established hypertension. Normotensive HanSD (Hannover Sprague-Dawley) rats served as controls. Myocardial ischaemia was induced by coronary artery occlusion. Systolic BP was measured in conscious animals by tail plethysmography. c-AUCB was administrated in drinking water. Renal and myocardial concentrations of EETs and DHETEs served as markers of internal production of epoxygenase metabolites. Chronic treatment with c-AUCB, which resulted in significant increases in the availability of biologically active epoxygenase metabolites in TGR (assessed as the ratio of EETs to DHETEs), was accompanied by a significant reduction in BP and a significantly reduced infarct size in TGR as compared with untreated TGR. The cardioprotective action of c-AUCB treatment was completely prevented by acute administration of a selective EETs antagonist [14,15-epoxyeicosa-5(Z)-enoic acid], supporting the notion that the improved cardiac ischaemic tolerance conferred by sEH inhibition is mediated by EETs actions at the cellular level. These findings indicate that chronic inhibition of sEH exhibits antihypertensive and cardioprotective actions in this transgenic model of angiotensin II-dependent hypertension.

SUBMITTER: Neckar J

PROVIDER: S-EPMC3528350 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Despite their high risk of adverse cardiac outcomes, persons on long-term dialysis therapy have had lower use of antihypertensive medications with cardioprotective properties, such as angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs), ?-blockers, and calcium channel blockers, than might be expected. We constructed a novel database that permits detailed exploration into the demographic, clinical, and geographic factors associated with the use of these agents in hypertensive long-term dialysis patients.National cross-sectional retrospective analysis linking Medicaid prescription drug claims with US Renal Data System core data.48,882 hypertensive long-term dialysis patients who were dually eligible for Medicaid and Medicare services in 2005.Demographics, comorbid conditions, functional status, and state of residence.Prevalence of cardioprotective antihypertensive agents in Medicaid pharmacy claims and state-specific observed to expected ORs of medication exposure.Factors associated with medication use were modeled using multilevel logistic regression models.In multivariable analyses, cardioprotective antihypertensive medication exposure was associated significantly with younger age, female sex, nonwhite race, intact functional status, and use of in-center hemodialysis. Diabetes was associated with a statistically significant 28% higher odds of ACE-inhibitor/ARB use, but congestive heart failure was associated with only a 9% increase in the odds of ?-blocker use and no increase in ACE-inhibitor/ARB use. There was substantial state-by-state variation in the use of all classes of agents, with a greater than 2.9-fold difference in adjusted-rate ORs between the highest and lowest prescribing states for ACE inhibitors/ARBs and a 3.6-fold difference for ?-blockers.Limited generalizability beyond study population.In publicly insured long-term dialysis patients with hypertension, there were marked differences in use rates by state, potentially due in part to differences in Medicaid benefits. However, geographic characteristics also were associated with exposure, suggesting clinical uncertainty about the utility of these medications.

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Inhibition of soluble epoxide hydrolase by cis-4-[4-(3-adamantan-1-ylureido)cyclohexyl-oxy]benzoic acid exhibits antihypertensive and cardioprotective actions in transgenic rats with angiotensin II-dependent hypertension.

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