Soluble epoxide hydrolase inhibitor,<i>t</i>-TUCB, protects against myocardial ischaemic injury in rats

Shrestha, Ayush; Krishnamurthy, Praveen Thaggikuppe; Thomas, P C; Hammock, Bruce D.; Hwang, Sung Hee

doi:10.1111/jphp.12251

Cited by 16 publications

(17 citation statements)

References 31 publications

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“…Earlier, we reported the cardioprotective effect of t ‐TUCB at 3‐30 mg/kg against isoproterenol‐induced myocardial infarction in normal rats . In this study, we demonstrate that both t ‐TUCB and TPPU protect hearts at very low doses (ie, 0.1‐0.3 mg/kg).…”

Section: Discussionsupporting

confidence: 55%

Inhibitors of soluble epoxide hydrolase minimize ischemia‐reperfusion‐induced cardiac damage in normal, hypertensive, and diabetic rats

Islam

Patil

Goswami

et al. 2017

Cardiovascular Therapeutics

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Aim We designed a study to evaluate the cardioprotective effect of two soluble epoxide hydrolase (sEH) inhibitors, 1-(1-propanoylpiperidin-4-yl)-3-(4-trifluoromethoxy)phenyl)urea (TPPU) and trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid (t-TUCB), in ischemia-reperfusion (IR) model. Methods Cardioprotective effects of the sEH inhibitors were evaluated against IR-induced myocardial damage in hearts from normal, hypertensive and diabetic rats using Langendorff’s apparatus. In addition, the effect of sEH inhibitors on endothelial function was evaluated in vitro and ex vivo using isolated rat thoracic aorta. Results IR increased the myocardial damage in hearts from normal rats. IR-induced myocardial damage was augmented in hearts isolated from hypertensive and diabetic rats. Myocardial damage as evident from increase in the activities of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) in heart perfusate was associated with significant decrease in the heart rate and developed tension, and increase in the resting tension in isolated heart. Both sEH inhibitors protected the heart in normal, hypertensive and diabetic rats subjected to IR injury. The sEH inhibitor t-TUCB relaxed phenylephrine pre-contracted aorta from normal rats. Relaxant effect of acetylcholine (ACh) was reduced in aortas from diabetic and hypertensive rats compared to normal rats. Pre-treatment of sEH inhibitors to diabetic and hypertensive rats increased relaxant effect of ACh on aortas isolated from these rats. Conclusions Prophylactic treatment with sEH inhibitors decreased myocardial damage due to IR, hypertension and diabetes, and decreased endothelial dysfunction created by diabetes and hypertension. Therefore, inhibitors of sEH are useful probes to study cardiovascular pathology and inhibition of the sEH is a potential approach in the management of IR-induced cardiac damage and endothelial dysfunction related cardiovascular disorders.

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Section: Discussionsupporting

confidence: 55%

Inhibitors of soluble epoxide hydrolase minimize ischemia‐reperfusion‐induced cardiac damage in normal, hypertensive, and diabetic rats

Islam

Patil

Goswami

et al. 2017

Cardiovascular Therapeutics

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“…; Shrestha et al. ), in response to treatment with sEH inhibitors. To date, fewer studies have reported on the impact of sEH deficiency on physiological function aspects of the coronary circulation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of soluble epoxide hydrolase increases coronary perfusion in mice

et al. 2015

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Roles of soluble epoxide hydrolase (sEH), the enzyme responsible for hydrolysis of epoxyeicosatrienoic acids (EETs) to their diols (DHETs), in the coronary circulation and cardiac function remain unknown. We tested the hypothesis that compromising EET hydrolysis/degradation, via sEH deficiency, lowers the coronary resistance to promote cardiac perfusion and function. Hearts were isolated from wild type (WT), sEH knockout (KO) mice and WT mice chronically treated with t-TUCB (sEH inhibitor), and perfused with constant flow at different pre-loads. Compared to WT controls, sEH-deficient hearts required significantly greater basal coronary flow to maintain the perfusion pressure at 100 mmHg and exhibited a greater reduction in vascular resistance during tension-induced heart work, implying a better coronary perfusion during cardiac performance. Cardiac contractility, characterized by developed tension in response to changes in preload, was potentially increased in sEH-KO hearts, manifested by an enlarged magnitude at each step-wise increase in end-diastolic to peak-systolic tension. 14,15-EEZE (EET antagonist) prevented the adaptation of coronary circulation in sEH null hearts whereas responses in WT hearts were sensitive to the inhibition of NO. Cardiac expression of EET synthases (CYP2J2/2C29) was comparable in both genotypic mice whereas, levels of 14,15-, 11,12- and 8,9-EETs were significantly higher in sEH-KO hearts, accompanied with lower levels of DHETs. In conclusion, the elevation of cardiac EETs, as a function of sEH deficiency, plays key roles in the adaptation of coronary flow and cardiac function.

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“…The cytoprotective effect of EETs, however, is limited by their metabolism via soluble epoxide hydrolase [23,25,33–38]. Therefore, we hypothesize that increasing the half life of endogenous EET’s through inhibition of its major metabolizing enzyme, soluble epoxide hydrolase [39], is, therefore a novel approach to prevent/treat the PD [21,40–44].…”

Section: The Hypothesis Proposedmentioning

confidence: 99%

“…EETs have been reported to inhibit cardiac L-type calcium channels which play an important role in regulating cardiac contractility, heart rate etc [62]. Similar mechanisms, may sequester the excessive Ca 2+ overload and Ca 2+ mediated glutamate excitotoxicity in PD [25,37]. Isradipine a L-type calcium channel inhibitor is in the Phase III clinical trial, which has therapeutic potential in slowing the progression of the PD in pre-clinical studies [63].…”

Section: Justification Of Proposed Hypothesismentioning

confidence: 99%

“…Some of the sEH inhibitors have been extensively studied for their cytoprotective benefits in hypertension, ischemic heart disease, heart failure, renocardiac failure, diabetic neuropathy, cancer and obesity [23–31]. Although EETs are widely distributed in the brain, little research has been carried out to exploit their cytoprotective benefits in the treatment/prevention of PD [25,32]. …”

Section: Introductionmentioning

confidence: 99%

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Possible role of Epoxyeicosatrienoic acid in prevention of oxidative stress mediated neuroinflammation in Parkinson disorders

et al. 2016

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Parkinson’s disease (PD) is a multifactorial neurodegenerative disease involving oxidative stress, neuroinflammation and apoptosis. Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites and they play a role in cytoprotection by modulating various cell signaling pathways. This cytoprotective role of EETs are well established in cerebral stroke, cardiac failure, and hypertension, and it is due to their ability to attenuate oxidative stress, endoplasmic reticulum stress, inflammation, caspase activation and apoptosis. The actions of EETs in brain closely parallel the effects which is observed in the peripheral tissues. Since many of these effects could potentially contribute to neuroprotection, EETs are, therefore, one of the potential therapeutic candidates in PD. Therefore, by increasing the half life of endogenous EETs in vivo via inhibition of sEH, its metabolizing enzyme can, therefore, constitutes an important therapeutic strategy in PD.

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Soluble epoxide hydrolase inhibitor,t-TUCB, protects against myocardial ischaemic injury in rats

Cited by 16 publications

References 31 publications

Inhibitors of soluble epoxide hydrolase minimize ischemia‐reperfusion‐induced cardiac damage in normal, hypertensive, and diabetic rats

Inhibitors of soluble epoxide hydrolase minimize ischemia‐reperfusion‐induced cardiac damage in normal, hypertensive, and diabetic rats

Inhibition of soluble epoxide hydrolase increases coronary perfusion in mice

Possible role of Epoxyeicosatrienoic acid in prevention of oxidative stress mediated neuroinflammation in Parkinson disorders

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