Cardiovascular and heart diseases are leading causes of morbidity and mortality. Coronary artery endothelial and vascular dysfunction, inflammation, and mitochondrial dysfunction contribute to progression of heart diseases such as arrhythmias, congestive heart failure, and heart attacks. Classes of fatty acid epoxylipids and their enzymatic regulation by soluble epoxide hydrolase (sEH) have been implicated in coronary artery dysfunction, inflammation, and mitochondrial dysfunction in heart diseases. Likewise, genetic and pharmacological manipulations of epoxylipids have been demonstrated to have therapeutic benefits for heart diseases. Increasing epoxylipids reduce cardiac hypertrophy and fibrosis and improve cardiac function. Beneficial actions for epoxylipids have been demonstrated in cardiac ischemia reperfusion injury, electrical conductance abnormalities and arrhythmias, and ventricular tachycardia. This review discusses past and recent findings on the contribution of epoxylipids in heart diseases and the potential for their manipulation to treat heart attacks, arrhythmias, ventricular tachycardia, and heart failure.

• Klíčová slova
• Coronary artery, Cytochrome P450, Eicosanoids, Heart failure, Hypertension, Inflammation, Mitochondrial function, Myocardial infarction, Soluble epoxide hydrolase,
• MeSH
• epoxid hydrolasy antagonisté a inhibitory   metabolismus   MeSH
• epoxidové sloučeniny chemie   metabolismus   MeSH
• infarkt myokardu farmakoterapie   enzymologie   metabolismus   MeSH
• inhibitory enzymů terapeutické užití   MeSH
• komorová tachykardie farmakoterapie   enzymologie   metabolismus   MeSH
• lidé MeSH
• mastné kyseliny metabolismus   MeSH
• nemoci srdce farmakoterapie   enzymologie   metabolismus   MeSH
• rozpustnost MeSH
• srdeční arytmie farmakoterapie   enzymologie   metabolismus   MeSH
• srdeční selhání farmakoterapie   enzymologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• epoxid hydrolasy MeSH
• epoxidové sloučeniny MeSH
• inhibitory enzymů MeSH
• mastné kyseliny MeSH

Epoxyeicosatrienoic acids (EETs) are also known as epoxyeicosanoids that have renal and cardiovascular actions. These renal and cardiovascular actions can be regulated by soluble epoxide hydrolase (sEH) that degrades and inactivates EETs. Extensive animal hypertension studies have determined that vascular, epithelial transport, and anti-inflammatory actions of EETs lower blood pressure and decrease renal and cardiovascular disease progression. Human studies have also supported the notion that increasing EET levels in hypertension could be beneficial. Pharmacological and genetic approaches to increase epoxyeicosanoids in several animal models and humans have found improved endothelial vascular function, increased sodium excretion, and decreased inflammation to oppose hypertension and associated renal and cardiovascular complications. These compelling outcomes support the concept that increasing epoxyeicosanoids via sEH inhibitors or EET analogs could be a valuable hypertension treatment.

• MeSH
• antihypertenziva terapeutické užití   MeSH
• epoxid hydrolasy antagonisté a inhibitory   metabolismus   MeSH
• hypertenze farmakoterapie   metabolismus   patofyziologie   MeSH
• ikosanoidy metabolismus   terapeutické užití   MeSH
• inhibitory enzymů terapeutické užití   MeSH
• krevní tlak účinky léků   MeSH
• lidé MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antihypertenziva MeSH
• epoxid hydrolasy MeSH
• ikosanoidy MeSH
• inhibitory enzymů MeSH

Epoxyeicosatrienoic acids (EETs) and their synthetic analogs have cardiovascular protective effects. Here, we investigated the action of a novel EET analog EET-B on the progression of post-myocardial infarction (MI) heart failure in spontaneously hypertensive rats (SHR). Adult male SHR were divided into vehicle- and EET-B (10 mg/kg/day; p.o., 9 weeks)-treated groups. After 2 weeks of treatment, rats were subjected to 30-min left coronary artery occlusion or sham operation. Systolic blood pressure (SBP) and echocardiography (ECHO) measurements were performed at the beginning of study, 4 days before, and 7 weeks after MI. At the end of the study, tissue samples were collected for histological and biochemical analyses. We demonstrated that EET-B treatment did not affect blood pressure and cardiac parameters in SHR prior to MI. Fractional shortening (FS) was decreased to 18.4 ± 1.0% in vehicle-treated MI rats compared with corresponding sham (30.6 ± 1.0%) 7 weeks following MI induction. In infarcted SHR hearts, EET-B treatment improved FS (23.7 ± 0.7%), markedly increased heme oxygenase-1 (HO-1) immunopositivity in cardiomyocytes and reduced cardiac inflammation and fibrosis (by 13 and 19%, respectively). In conclusion, these findings suggest that EET analog EET-B has beneficial therapeutic actions to reduce cardiac remodeling in SHR subjected to MI.

• Klíčová slova
• blood pressure, epoxyeicosatrienoic acid, heart failure, myocardial infarction, spontaneously hypertensive rat,
• MeSH
• hemoxygenasa-1 genetika   metabolismus   MeSH
• infarkt myokardu farmakoterapie   genetika   metabolismus   patofyziologie   MeSH
• krevní tlak MeSH
• krysa rodu Rattus MeSH
• kyseliny arachidonové aplikace a dávkování   chemie   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• potkani inbrední SHR MeSH
• srdce patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• hemoxygenasa-1 MeSH
• kyseliny arachidonové MeSH

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.

• MeSH
• angiotensin II fyziologie   MeSH
• antihypertenziva farmakologie   MeSH
• benzoáty farmakologie   MeSH
• epoxid hydrolasy antagonisté a inhibitory   MeSH
• hypertenze farmakoterapie   genetika   metabolismus   MeSH
• ikosanoidy metabolismus   moč   MeSH
• infarkt myokardu farmakoterapie   patologie   MeSH
• kardiotonika farmakologie   MeSH
• krevní tlak MeSH
• krysa rodu Rattus MeSH
• močovina analogy a deriváty   farmakologie   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• srdeční arytmie farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• 4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid MeSH Prohlížeč
• angiotensin II MeSH
• antihypertenziva MeSH
• benzoáty MeSH
• epoxid hydrolasy MeSH
• ikosanoidy MeSH
• kardiotonika MeSH
• močovina MeSH

In the present study, we examined the effects of soluble epoxide hydrolase (sEH) inhibition on the development of angiotensin II-dependent hypertension and on renal function in transgenic rats with inducible expression of the mouse renin gene (strain name Cyp1a1-Ren-2). Hypertension was induced in these rats by indole-3-carbinol (I3C; 0.3% in the diet) for 12 days. The sEH inhibitor cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB) was given in two doses (13 or 26 mg l-1) in drinking water. Blood pressure (BP), body weight (BW) and renal excretory parameters were monitored in conscious animals during the experiment. Renal haemodynamics was assessed at the end of treatment in anaesthetized rats. I3C administration resulted in severe hypertension with a rise in systolic BP from 118 ± 2 to 202 ± 3 mmHg, a loss of BW from 266 ± 5 to 228 ± 4 g and a rise in proteinuria from 14 ± 2 to 34 ± 3 mg day-1. Both doses of c-AUCB significantly attenuated the development of hypertension (systolic BP of 181 ± 4 and 176 ± 4 mmHg, respectively), the loss in BW (256 ± 4 and 259 ± 3 g, respectively) and the degree of proteinuria (27 ± 2 and 25 ± 3 mg day-1, respectively) to a similar extent. Moreover, c-AUCB prevented the reduction in renal plasma flow (5.4 ± 0.4 vs. 4.6 ± 0.3 ml min-1 g-1) and significantly increased sodium excretion (0.84 ± 0.16 vs. 0.38 ± 0.08 μmol min-1 g-1) during I3C administration. These data suggest that the oral administration of c-AUCB displays antihypertensive effects in Ren-2 transgenic rats with inducible malignant hypertension via an improvement of renal function.

• MeSH
• angiotensin II MeSH
• antihypertenziva aplikace a dávkování   farmakologie   MeSH
• aplikace orální MeSH
• benzoáty aplikace a dávkování   farmakologie   MeSH
• časové faktory MeSH
• cytochrom P-450 CYP1A1 genetika   MeSH
• epoxid hydrolasy antagonisté a inhibitory   metabolismus   MeSH
• hodnoty glomerulární filtrace účinky léků   MeSH
• hypertenze chemicky indukované   enzymologie   genetika   patofyziologie   prevence a kontrola   MeSH
• inhibitory enzymů aplikace a dávkování   farmakologie   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu Rattus MeSH
• kyseliny arachidonové metabolismus   MeSH
• kyseliny hydroxyeikosatetraenové metabolismus   MeSH
• ledviny krevní zásobení   účinky léků   enzymologie   patofyziologie   MeSH
• močovina aplikace a dávkování   analogy a deriváty   farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• promotorové oblasti (genetika) MeSH
• proteinurie metabolismus   patofyziologie   prevence a kontrola   MeSH
• renální průtok plazmy účinky léků   MeSH
• renin genetika   metabolismus   MeSH
• sodík moč   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• 4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid MeSH Prohlížeč
• angiotensin II MeSH
• antihypertenziva MeSH
• benzoáty MeSH
• cytochrom P-450 CYP1A1 MeSH
• EPHX2 protein, rat MeSH Prohlížeč
• epoxid hydrolasy MeSH
• inhibitory enzymů MeSH
• kyseliny arachidonové MeSH
• kyseliny hydroxyeikosatetraenové MeSH
• močovina MeSH
• Ren2 protein, mouse MeSH Prohlížeč
• renin MeSH
• sodík MeSH

Recent studies have shown that the renal CYP450 (cytochrome P450) metabolites of AA (arachidonic acid), the vasoconstrictor 20-HETE (20-hydroxyeicosatetraenoic acid) and the vasodilator EETs (epoxyeicosatrienoic acids), play an important role in the pathophysiology of AngII (angiotensin II)-dependent forms of hypertension and the associated target organ damage. The present studies were performed in Ren-2 renin transgenic rats (TGR) to evaluate the effects of chronic selective inhibition of 20-HETE formation or elevation of the level of EETs, alone or in combination, on the course of hypertension and hypertension-associated end-organ damage. Both young (30 days of age) prehypertensive TGR and adult (190 days of age) TGR with established hypertension were examined. Normotensive HanSD (Hannover Sprague-Dawley) rats served as controls. The rats were treated with N-methylsulfonyl-12,12-dibromododec-11-enamide to inhibit 20-HETE formation and/or with N-cyclohexyl-N-dodecyl urea to inhibit soluble epoxide hydrolase and prevent degradation of EETs. Inhibition in TGR of 20-HETE formation combined with enhanced bioavailability of EETs attenuated the development of hypertension, cardiac hypertrophy, proteinuria, glomerular hypertrophy and sclerosis as well as renal tubulointerstitial injury. This was also associated with attenuation of the responsiveness of the systemic and renal vascular beds to AngII without modifying their responses to noradrenaline (norepinephrine). Our findings suggest that altered production and/or action of 20-HETE and EETs plays a permissive role in the development of hypertension and hypertension-associated end-organ damage in this model of AngII-dependent hypertension. This information provides a basis for a search for new therapeutic approaches for the treatment of hypertension.

• MeSH
• amidy farmakologie   terapeutické užití   MeSH
• angiotensin II farmakologie   MeSH
• antihypertenziva farmakologie   terapeutické užití   MeSH
• hypertenze komplikace   farmakoterapie   patofyziologie   MeSH
• krevní tlak účinky léků   MeSH
• krysa rodu Rattus MeSH
• kyselina 8,11,14-eikosatrienová analogy a deriváty   metabolismus   MeSH
• kyseliny hydroxyeikosatetraenové biosyntéza   MeSH
• multiorgánové selhání etiologie   prevence a kontrola   MeSH
• noradrenalin farmakologie   MeSH
• potkani Sprague-Dawley MeSH
• potkani transgenní MeSH
• preklinické hodnocení léčiv metody   MeSH
• renální oběh účinky léků   MeSH
• sulfony farmakologie   terapeutické užití   MeSH
• vazokonstriktory farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• 11,12-epoxy-5,8,14-eicosatrienoic acid MeSH Prohlížeč
• 20-hydroxy-5,8,11,14-eicosatetraenoic acid MeSH Prohlížeč
• amidy MeSH
• angiotensin II MeSH
• antihypertenziva MeSH
• DDMS MeSH Prohlížeč
• kyselina 8,11,14-eikosatrienová MeSH
• kyseliny hydroxyeikosatetraenové MeSH
• noradrenalin MeSH
• sulfony MeSH
• vazokonstriktory MeSH