EETs or epoxyeicosanoids have been demonstrated to be endothelium-derived hyperpolarizing factors (EDHFs), protect from ischemic injury and possess anti-inflammatory actions in canine and rodent disease models.17-21 Conversion of EET epoxides to their corresponding diols (DHETs) by soluble epoxide hydrolase (sEH) enzyme are responsible for decreasing EET levels and thus diminishing their beneficial cardiovascular properties,20,21 and so inhibition of this enzyme would be a target for cardiovascular disease. enzymes, receptors and the eicosanoid metabolites of the arachidonate cascade are major therapeutic targets, particularly for inflammatory disease. The first pathway to be targeted was cyclooxygenase (COX), which leads to the generation of prostaglandins (PG). Indeed, aspirin and non-steriodal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors, are effective drugs that treat pain and inflammation.1,2 These drugs also may be useful for treating or preventing cardiovascular diseases inhibition of blood clotting by aspirin has been touted as a preventative for ischemic events such as heart attacks and stroke1 and prostacylin analogs are used for the treatment of pulmonary hypertension.3,4 On the other hand, enthusiasm for the COX pathway was greatly decreased because of the increased incidence of acute renal failure, myocardial infarction and thrombotic stroke in patients treated with COX-2 inhibitors.1,2,5,6 The second eicosanoid and inflammatory pathway targeted for therapeutics was the lipoxygenase (LOX) generation of leukotrienes (LT). 5-LOX and LT receptor antagonists have been developed for the treatment of asthma and seasonal allergies.7,8 These two eicosanoid pathways continue as important therapeutic targets as novel receptors and metabolites have been identified and their roles in a myriad of diseases are being better defined [figure 1]. Open in a separate window Figure 1 Therapeutic Targets of the Arachidonate CascadeThree major pathways the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways can metabolize arachidonic acid. Inhibitors of the COX-1 and COX-2 enzymes are used for the treatment of pain, inflammation and blood clotting and prostacyclin analogs are used to treat pulmonary hypertension. Leukotriene receptor antagonists that inhibit the cysteinyl leukotriene CysLT1 receptor are used to treat asthma and allergies. Soluble epoxide hydrolase inhibitors that increase epoxyeicosatrienoic acid levels are being developed for the treatment of cardiovascular diseases and inflammation. A third eicosanoid pathway, the cytochrome P450 (P450) was first described in 1980 and is comprised of two enzymatic pathways9,10,11 – the hydroxylases and the epoxygenases. The hydroxylase P450 enzymes convert arachidonic acid into hydroxyeicosatetraenoic acids (HETEs). 20-HETE is the major metabolite of this pathway and has been determined to be pro-inflammatory and important to vascular function.12,13 This pathway and metabolite are currently being targeted for the treatment of cardiovascular diseases such as hypertension and stroke.13-16. The second pathway is the generation of epoxyeicosatrienoic acids (EETs) by P450 enzymes, which catalyze the epoxidation of arachidonic acid olefin bonds resulting in the production of four regioisomeric EETs: 5,6-EET; 8,9-EET; 11,12-EET; 14,15-EET. EETs or epoxyeicosanoids have been demonstrated to be endothelium-derived hyperpolarizing factors (EDHFs), protect from ischemic injury and possess anti-inflammatory actions in canine and rodent disease models.17-21 Conversion of EET epoxides to their corresponding diols (DHETs) by soluble epoxide hydrolase (sEH) enzyme are responsible for decreasing EET levels and thus diminishing their beneficial cardiovascular properties,20,21 and so inhibition of this enzyme would be a target for cardiovascular disease. Recently, sEH inhibitors (sEHIs) have been developed to enhance the cardiovascular actions offered by EETs. This article will highlight the development of sEHIs as cardiovascular therapeutics and discuss the potential for this treatment and challenges that lie ahead. Biological Aspects of Epoxyeicosanoids Since the 1st descriptions of the biological actions of EETs, which included raises in epithelial transport in the kidney and dilation of small mesenteric resistance arteries, there has been growing desire for these eicosanoid metabolites.22,23 Desire for EETs was greatly improved in 1996 with the recognition of EETs as an EDHF.17 Over the past decade it has become increasingly apparent that EETs have a myriad of cardiovascular actions, the overwhelming majority of which look like cardiovascular protective. The cellular signaling mechanisms responsible for the various EET biological actions have been and continue to be intensively investigated. There is sufficient evidence that helps the possibility that EETs bind to receptors that are coupled by a G-protein to intracellular signaling cascades;24,25 however, an EET receptor offers yet to be identified. EETs could also function inside the cell by coupling to and activating ion channels, signaling proteins or transcription factors. Experimental evidence helps an intracellular mechanism of action in that EETs are integrated into cell membrane phospholipids, bind to fatty acid binding proteins, and peroxisome proliferators-activated receptor (PPAR) .21,24,26,27 Please see the following evaluations for more comprehensive descriptions of EET biological activities and cellular signaling mechanisms.28,29 As with other eicosanoid pathways, there is heterogeneity with respect to cellular signaling mechanisms and biological activities.gene deficient mice have improved recovery of left ventricular developed pressure (LVDP) and reduced infarct size following ischemia and reperfusion and are also protected from developing pressure overload induced heart failure and cardiac arrhythmias.104 The ability of sEHIs to improve cardiac function has been established in various experimental models and varieties.19,104,108,121 AUDA reduces the cardiac infarct size in dogs and this safety is similar to that observed with 14,15-EET administration.19 Similar findings were observed in mice RPH-2823 that were administered AUDA-BE and subjected to left coronary artery occlusion followed by reperfusion.104 Furthermore, in dogs and mice the EET antagonist, 14,15-EEZE inhibits the safety to the heart provided by sEHIs.19,104 Acute myocardial infarction hypertension can result in cardiac hypertrophy due to ventricular remodeling.101,104,111,121 The 1st evidence that sEHIs could attenuate cardiovascular hypertrophy was the observation that heart weight and collagen were decreased in sEHI-treated deoxycorticosterone (DOCA) salt hypertensive rats.111 Likewise, cardiac hypertrophy in stroke-prone SHR and angiotensin infused rats was prevented by inhibition of sEH.101,122 The cardiac protective actions of sEHIs have also been found in mice with pressure overload induced myocardial hypertrophy, where sEHIs prevented the development or reversed remaining ventricular hypertrophy,104,121 which was linked to the ability of sEHIs to block NF-B activation.121 Although there is overwhelming evidence that deficiency and sEHIs provide cardiac safety, knockout mice had reduced survival from cardiac arrest and cardiopulmonary resuscitation.123 Long term experimental evidence is required to determine the potential for sEHIs as therapies for numerous heart ailments. Ischemic stroke protection & Vascular Disease Another potential therapeutic use for sEHIs is definitely safety from ischemic mind damage that accompanies stroke. the recent initiation of first in human being clinical trials offers highlighted the promise of sEHIs like a therapeutic target. Many of the enzymes, receptors and the eicosanoid metabolites of the arachidonate cascade are major therapeutic targets, particularly for inflammatory disease. The 1st pathway to be targeted was cyclooxygenase (COX), which leads to the generation of prostaglandins (PG). Indeed, aspirin and non-steriodal anti-inflammatory medicines (NSAIDs), including COX-2 inhibitors, are effective drugs that treat pain and swelling.1,2 These medicines also may be useful for treating or preventing cardiovascular diseases inhibition of blood clotting by aspirin has been touted like a preventative for ischemic events such as heart attacks and stroke1 and prostacylin analogs are used for the treatment of pulmonary hypertension.3,4 On the other hand, excitement for the COX pathway was greatly decreased because of the increased incidence of acute renal failure, myocardial infarction and thrombotic stroke in individuals treated with COX-2 inhibitors.1,2,5,6 The second eicosanoid and inflammatory pathway targeted for therapeutics was the lipoxygenase (LOX) generation of leukotrienes (LT). 5-LOX and LT receptor antagonists have been developed for the treatment of asthma and seasonal allergies.7,8 These two eicosanoid pathways continue as important therapeutic targets as novel receptors and metabolites have been identified and their roles in a myriad of diseases are becoming better defined [figure 1]. Open in a separate window Number 1 Therapeutic Focuses on of the Arachidonate CascadeThree major pathways the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways can metabolize arachidonic acid. Inhibitors of the COX-1 and COX-2 enzymes are used for the treating pain, irritation and bloodstream clotting and prostacyclin analogs are accustomed to deal with pulmonary hypertension. Leukotriene receptor antagonists that inhibit the cysteinyl leukotriene CysLT1 receptor are accustomed to deal with asthma and allergy symptoms. Soluble epoxide hydrolase inhibitors that boost epoxyeicosatrienoic acidity levels are getting developed for the treating cardiovascular illnesses and inflammation. Another eicosanoid pathway, the cytochrome P450 (P450) was initially defined in 1980 and it is made up of two enzymatic pathways9,10,11 – the hydroxylases as well as the epoxygenases. The hydroxylase P450 enzymes convert arachidonic acidity into hydroxyeicosatetraenoic acids (HETEs). 20-HETE may be the main metabolite of the pathway and continues to be determined to become pro-inflammatory and vital that you vascular function.12,13 This pathway and metabolite are getting targeted for the treating cardiovascular illnesses such as for example hypertension and stroke.13-16. The next pathway may be the era of epoxyeicosatrienoic acids (EETs) by P450 enzymes, which catalyze the epoxidation of arachidonic acidity olefin bonds leading to the creation of four regioisomeric EETs: 5,6-EET; 8,9-EET; 11,12-EET; 14,15-EET. EETs or epoxyeicosanoids have already been proven endothelium-derived hyperpolarizing elements (EDHFs), guard against ischemic injury and still have anti-inflammatory activities in canine and rodent disease versions.17-21 Transformation of EET epoxides with their matching diols (DHETs) by soluble epoxide hydrolase (sEH) enzyme are in charge of lowering EET levels and therefore diminishing their helpful cardiovascular properties,20,21 therefore inhibition of the enzyme will be a target for coronary disease. Lately, sEH inhibitors (sEHIs) have already been developed to improve the cardiovascular activities provided by EETs. This content will highlight the introduction of sEHIs as cardiovascular therapeutics and discuss the prospect of this treatment and issues that lie forward. Biological Areas of Epoxyeicosanoids Because the initial descriptions from the natural activities of EETs, including boosts in epithelial transportation in the kidney and dilation of little mesenteric level of resistance arteries, there’s been growing curiosity about these eicosanoid metabolites.22,23 Curiosity about EETs was greatly elevated in 1996 using the id of EETs as an EDHF.17 Within the last decade it is becoming increasingly apparent that EETs possess an array of cardiovascular activities, the overwhelming most which seem to be cardiovascular protective. The mobile signaling mechanisms in charge of the many EET natural activities have already been and continue being intensively investigated. There is certainly ample proof that supports the chance that EETs bind to receptors that are combined with a G-protein.Vasodilation in response to EETs continues to be observed in a genuine variety of organs like the center, brain, kidney, skeletal intestine and muscle.13,17,23,33,34 On the other hand, EETs trigger vasoconstriction in the lung – a discovering that was not unexpected since PGs also have opposite effects in this vasculature when compared to other organs.35,36 All regioisomeric EETs have been demonstrated to be vasodilators with 11,12-EET and 14,15-EET consistently exhibiting the most vasodilator activity.21,34 These two regioisomeric EETs generated by endothelial cells dilate blood vessels by activating large-conductance calcium-activated K+ (KCa) channels on vascular easy muscle cells,33,37,38,39 resulting in K+ efflux from the easy muscle cell and subsequent membrane hyperpolarization.17,38 There is evidence for cAMP activation of protein kinase A (PKA) and ADP ribosylation of Gs cell signaling mechanisms as being responsible for mediating EET activation of vascular easy muscle cell KCa channels.39-42 The ability of EETs to activate KCa channels and dilate blood vessels can be regulated by sEH-mediated conversion to DHETs that exhibit diminished or absent vasorelaxation.34,38,43 In this regard, sEH inhibition impedes the conversion of EETs to DHETs and improves dilator activity in human blood vessels.43 EETs or sEHIs have been demonstrated to oppose the vasoconstrictor activities of the pro-hypertensive hormones endothelin-1 and angiotensin II.20 Thus decreased endothelial EET conversion to DHETs could be one mechanism responsible for the anti-hypertensive actions observed with the administration of sEHIs as well as for other cardioprotective properties. Vascular homeostasis is usually controlled by endothelial cell and vascular easy muscle cell proliferation and migration, and EETs and sEH appear to be important regulators of these cellular processes.18,30,44-49 EETs promote endothelial cell proliferation and migration and are angiogenic, and it has been demonstrated RPH-2823 that this epoxides and not the corresponding diols resulted in proliferative effects.45 In murine and human cell lines, EETs or overexpression of CYP2C epoxygenases leads to proliferative responses,30,46 that have been attributed to activation of two cell-signaling pathways; the p38 mitogen-acitvated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase-Akt (PI3K/Akt) pathway.30 11,12-EET activates MAPK, which upregulates cyclin D, and Akt, which phosphorylates forkhead factors (FOXO) and decreases cyclin-dependent kinase inhibitor p27kip1 in endothelial cells.46,47 More recently, 11,12-EET-mediated proliferation, migration and tube formation in human umbilical vein cells (HUVECs) was demonstrated to be dependent on activation of sphingosine kinase 1 (SK1) that phosphorylates sphingosine to generate spingosine-1-phosphate (S1P).49 RPH-2823 On the other hand, EETs exhibit antimigratory actions in vascular easy muscle cells. initiation of first in human clinical trials has highlighted the promise of sEHIs as a therapeutic target. Many of the enzymes, receptors and the eicosanoid metabolites of the arachidonate cascade are major therapeutic targets, particularly for inflammatory disease. The first pathway to be targeted was cyclooxygenase (COX), which leads to the generation of prostaglandins (PG). Indeed, aspirin and non-steriodal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors, are effective drugs that treat pain and inflammation.1,2 These drugs also may be useful for treating or preventing cardiovascular diseases inhibition of blood clotting by aspirin has been touted as a preventative for ischemic events such as heart attacks and stroke1 and prostacylin analogs are used for the treatment of pulmonary hypertension.3,4 On the other hand, enthusiasm for the COX pathway was greatly decreased because of the increased incidence of acute renal failure, myocardial infarction and thrombotic stroke in patients treated with COX-2 inhibitors.1,2,5,6 The second eicosanoid and inflammatory pathway targeted for therapeutics was the lipoxygenase (LOX) generation of leukotrienes (LT). 5-LOX and LT receptor antagonists have been developed for the treatment of asthma and seasonal allergies.7,8 These two eicosanoid pathways continue as important therapeutic targets as novel receptors and metabolites have been identified and their roles in a myriad of diseases are being better defined [figure 1]. Open in a separate window Physique 1 Therapeutic Targets of the Arachidonate CascadeThree major pathways the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways can metabolize arachidonic acid. Inhibitors of the COX-1 and COX-2 enzymes are used for the treatment of pain, inflammation and blood clotting and prostacyclin analogs are used to treat pulmonary hypertension. Leukotriene receptor antagonists that inhibit the cysteinyl leukotriene CysLT1 receptor are used to treat asthma and allergies. Soluble epoxide hydrolase inhibitors that increase epoxyeicosatrienoic acid levels are being developed for the treatment of cardiovascular diseases and inflammation. A third eicosanoid pathway, the cytochrome P450 (P450) was first described in 1980 and is comprised of two enzymatic pathways9,10,11 – the hydroxylases and the epoxygenases. The hydroxylase P450 enzymes convert arachidonic acid into hydroxyeicosatetraenoic acids (HETEs). 20-HETE is the major metabolite of this pathway and has been determined to be pro-inflammatory and vital that you vascular function.12,13 This pathway and RPH-2823 metabolite are becoming targeted for the treating cardiovascular illnesses such as for example hypertension and stroke.13-16. The next pathway may be the era of epoxyeicosatrienoic acids (EETs) by P450 enzymes, which catalyze the epoxidation of arachidonic acidity olefin bonds leading to the creation of four regioisomeric EETs: 5,6-EET; 8,9-EET; 11,12-EET; 14,15-EET. EETs or epoxyeicosanoids have already been proven endothelium-derived hyperpolarizing elements (EDHFs), guard against ischemic injury and still have anti-inflammatory activities in canine and rodent disease versions.17-21 Transformation of EET epoxides with their related diols (DHETs) by soluble epoxide hydrolase (sEH) enzyme are in charge of lowering EET levels and therefore diminishing their helpful cardiovascular properties,20,21 therefore inhibition of the enzyme will be a target for coronary disease. Lately, sEH inhibitors (sEHIs) have already been developed to improve the cardiovascular activities provided by EETs. This content will highlight the introduction of sEHIs as cardiovascular therapeutics and discuss the prospect of this treatment and problems that lie forward. Biological Areas of Epoxyeicosanoids Because the 1st descriptions from the natural activities of EETs, including raises in epithelial transportation in the kidney and dilation of little mesenteric level of resistance arteries, there’s been growing fascination with these eicosanoid metabolites.22,23 Fascination with EETs was greatly improved in 1996 using the recognition of EETs as an EDHF.17 Within the last decade it is becoming increasingly apparent that EETs possess an array of cardiovascular activities, the overwhelming most which look like cardiovascular protective. The mobile signaling mechanisms in charge of the many EET natural activities have already been and continue being intensively investigated. There is certainly ample proof that supports the chance that EETs bind to receptors that are combined with a G-protein to intracellular signaling cascades;24,25 however, an EET receptor offers yet to become identified. EETs could function in the also.Since the discovering that certain sEHIs can vasodilate mesenteric level of resistance arteries there’s been improvement in attempts to create EET analogs that may also inhibit the sEH enzyme.148 You can envision the possible utility for EET analogs being used for acute myocardial infarction and medication eluting stents. and swelling.1,2 These medicines also may be useful for treating or preventing cardiovascular diseases inhibition of blood clotting by aspirin has been touted like RPH-2823 a preventative for ischemic events such as heart attacks and stroke1 and prostacylin analogs are used for the treatment of pulmonary hypertension.3,4 On the other hand, excitement for the COX pathway was greatly decreased because of the increased incidence of acute renal failure, myocardial infarction and thrombotic stroke in individuals treated with COX-2 inhibitors.1,2,5,6 The second eicosanoid and inflammatory pathway targeted for therapeutics was the lipoxygenase (LOX) generation of leukotrienes (LT). 5-LOX and LT receptor antagonists have been developed for the treatment of asthma and seasonal allergies.7,8 These two eicosanoid pathways continue as important therapeutic targets as novel receptors and metabolites have been identified and their roles in a myriad of diseases are becoming better defined [figure 1]. Open in a separate window Number 1 Therapeutic Focuses on of the Arachidonate CascadeThree major pathways the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways can metabolize arachidonic acid. Inhibitors of the COX-1 and COX-2 enzymes are used for the treatment of pain, swelling and blood clotting and prostacyclin analogs are used to treat pulmonary hypertension. Leukotriene receptor antagonists that inhibit the cysteinyl leukotriene CysLT1 receptor are used to treat asthma and allergies. Soluble epoxide hydrolase inhibitors that increase epoxyeicosatrienoic acid levels are becoming developed for the treatment of cardiovascular diseases and inflammation. A third eicosanoid pathway, the cytochrome P450 (P450) was first explained in 1980 and is comprised of two enzymatic pathways9,10,11 – the hydroxylases and the epoxygenases. The hydroxylase P450 enzymes convert arachidonic acid into hydroxyeicosatetraenoic acids (HETEs). 20-HETE is the major metabolite of this pathway and has been determined to be pro-inflammatory and important to vascular function.12,13 This pathway and metabolite are currently becoming targeted for the treatment of cardiovascular diseases such as hypertension and stroke.13-16. The second pathway is the generation of epoxyeicosatrienoic acids (EETs) by P450 enzymes, which catalyze the epoxidation of arachidonic acid olefin bonds resulting in the production of four regioisomeric EETs: 5,6-EET; 8,9-EET; 11,12-EET; 14,15-EET. EETs or epoxyeicosanoids have been demonstrated to be endothelium-derived hyperpolarizing factors (EDHFs), protect from ischemic injury and possess anti-inflammatory actions in canine and rodent disease models.17-21 Conversion of EET epoxides to their related diols (DHETs) by soluble epoxide hydrolase (sEH) enzyme are responsible for decreasing EET levels and thus diminishing their beneficial cardiovascular properties,20,21 and so inhibition of this enzyme would be a target for cardiovascular disease. Recently, sEH inhibitors (sEHIs) have been developed to enhance the cardiovascular actions offered by EETs. This article will highlight the development of sEHIs as cardiovascular therapeutics and discuss the potential for this treatment and difficulties that lie ahead. Biological Aspects of Epoxyeicosanoids Since the 1st descriptions of the biological actions of EETs, which included raises in epithelial transport in the kidney and dilation of small mesenteric resistance arteries, there has been growing desire for these eicosanoid metabolites.22,23 Desire for EETs was greatly improved in 1996 with the recognition of EETs as an EDHF.17 Over the past decade it has become increasingly apparent that EETs have a myriad of cardiovascular actions, the overwhelming majority of which look like cardiovascular protective. The cellular signaling mechanisms responsible for the various EET biological actions have been and continue to be intensively investigated. There is ample evidence that supports the possibility that EETs bind to receptors that are combined with a G-protein to intracellular signaling cascades;24,25 however, an EET receptor provides yet to become identified. EETs may possibly also function in the cell by coupling to and activating ion stations, signaling protein or transcription elements. Experimental evidence works with an intracellular system of action for the reason that EETs are included into cell membrane phospholipids, bind to fatty acidity binding protein, and peroxisome proliferators-activated receptor (PPAR) .21,24,26,27 Make sure you start to see the following testimonials for more in depth explanations of EET biological actions and cellular signaling systems.28,29 Much like other eicosanoid pathways, there is certainly heterogeneity regarding cellular signaling mechanisms and biological activities in a variety of cell tissues and types. Other experimental problems have made analysis of EETs as well as the P450 enzymatic.EETs may possibly also function in the cell by coupling to and activating ion stations, signaling protein or transcription elements. and finding improved ways to focus on sEHIs to particular tissues the latest initiation of initial in human scientific trials provides highlighted the guarantee of sEHIs being a healing focus on. Lots of the enzymes, receptors as well as the eicosanoid metabolites from the arachidonate cascade are main healing targets, especially for inflammatory disease. The initial pathway to become targeted was cyclooxygenase (COX), that leads to the era of prostaglandins (PG). Certainly, aspirin and non-steriodal anti-inflammatory medications (NSAIDs), including COX-2 inhibitors, work drugs that deal with pain and irritation.1,2 These medications also could be helpful for treating or preventing cardiovascular illnesses inhibition of bloodstream clotting by aspirin continues to be touted being a preventative for ischemic occasions such as center episodes and stroke1 and prostacylin analogs are used for the treating pulmonary hypertension.3,4 Alternatively, passion for the COX pathway was greatly decreased due to the increased occurrence of acute renal failing, myocardial infarction and thrombotic heart stroke in sufferers treated with COX-2 inhibitors.1,2,5,6 The next eicosanoid and inflammatory pathway targeted for therapeutics was the lipoxygenase (LOX) era of leukotrienes (LT). 5-LOX and LT receptor antagonists have already been developed for the treating asthma and seasonal allergy symptoms.7,8 Both of these eicosanoid pathways continue as important therapeutic focuses on as book receptors and metabolites have already been identified and their roles in an array of illnesses Rabbit Polyclonal to USP43 are getting better defined [figure 1]. Open up in another window Figure 1 Therapeutic Targets of the Arachidonate CascadeThree major pathways the cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) pathways can metabolize arachidonic acid. Inhibitors of the COX-1 and COX-2 enzymes are used for the treatment of pain, inflammation and blood clotting and prostacyclin analogs are used to treat pulmonary hypertension. Leukotriene receptor antagonists that inhibit the cysteinyl leukotriene CysLT1 receptor are used to treat asthma and allergies. Soluble epoxide hydrolase inhibitors that increase epoxyeicosatrienoic acid levels are being developed for the treatment of cardiovascular diseases and inflammation. A third eicosanoid pathway, the cytochrome P450 (P450) was first described in 1980 and is comprised of two enzymatic pathways9,10,11 – the hydroxylases and the epoxygenases. The hydroxylase P450 enzymes convert arachidonic acid into hydroxyeicosatetraenoic acids (HETEs). 20-HETE is the major metabolite of this pathway and has been determined to be pro-inflammatory and important to vascular function.12,13 This pathway and metabolite are currently being targeted for the treatment of cardiovascular diseases such as hypertension and stroke.13-16. The second pathway is the generation of epoxyeicosatrienoic acids (EETs) by P450 enzymes, which catalyze the epoxidation of arachidonic acid olefin bonds resulting in the production of four regioisomeric EETs: 5,6-EET; 8,9-EET; 11,12-EET; 14,15-EET. EETs or epoxyeicosanoids have been demonstrated to be endothelium-derived hyperpolarizing factors (EDHFs), protect from ischemic injury and possess anti-inflammatory actions in canine and rodent disease models.17-21 Conversion of EET epoxides to their corresponding diols (DHETs) by soluble epoxide hydrolase (sEH) enzyme are responsible for decreasing EET levels and thus diminishing their beneficial cardiovascular properties,20,21 and so inhibition of this enzyme would be a target for cardiovascular disease. Recently, sEH inhibitors (sEHIs) have been developed to enhance the cardiovascular actions offered by EETs. This article will highlight the development of sEHIs as cardiovascular therapeutics and discuss the potential for this treatment and challenges that lie ahead. Biological Aspects of Epoxyeicosanoids Since the first descriptions of the biological actions of EETs, which included increases in epithelial transport in the kidney and dilation of small mesenteric resistance arteries, there has been growing interest in these eicosanoid metabolites.22,23 Interest in EETs was greatly increased in 1996 with the identification of EETs as an EDHF.17 Over the past decade it has become increasingly apparent that EETs have a myriad of cardiovascular actions, the overwhelming majority of which appear to be cardiovascular protective. The cellular signaling mechanisms responsible for the various EET biological actions have been and continue to be intensively investigated. There is ample evidence that supports the possibility that EETs bind to receptors that are coupled by a G-protein to intracellular signaling cascades;24,25 however, an EET receptor has yet to be identified. EETs could also function inside the cell by coupling to and activating ion channels, signaling proteins or transcription.