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

Abstract

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.

Phloroglucinol, a nutraceutical for IR‐induced cardiac damage in diabetic rats

“…Resting tension and developed tension also decreased in the diabetic rat hearts in our study, in line with the findings of Oliul Islam . The decrease in tension may be due to stimulation of β 2 receptors in the heart, resulting in the formation of cAMP through G s ‐protein.…”

An inhibitor of soluble epoxide hydrolase ameliorates diabetes-induced learning and memory impairment in rats

“…In our experiment, we observed marginal decrease in hyperglycemia, therefore, the amelioration of memory dysfunction could be due to effect of TPPU on hyperglycemia in addition to its direct effect of on CNS. Microvascular disease [31], and altered cerebral hemodynamic are few of the potential mechanisms [6] responsible for low cerebral blood perfusion and subsequent memory dysfunction in diabetes [13, 32]. Pre-treatment of TPPU to diabetic rat is known to increase the relaxant response of ACh on aorta ex vivo [13] and 5, 6-EET is known to dilate cerebral arterioles [33].…”

“…Microvascular disease [31], and altered cerebral hemodynamic are few of the potential mechanisms [6] responsible for low cerebral blood perfusion and subsequent memory dysfunction in diabetes [13, 32]. Pre-treatment of TPPU to diabetic rat is known to increase the relaxant response of ACh on aorta ex vivo [13] and 5, 6-EET is known to dilate cerebral arterioles [33]. Therefore, TPPU also might have ameliorated memory dysfunction by dilating arterioles and increasing blood perfusion in the brain via stabilization of EETs.…”

Regulation of CYP2J2 and EET Levels in Cardiac Disease and Diabetes

“…These observations imply that cardiomyocyte CYP2J2, and not endothelial CYP2J2, protects the hearts from ischemic-reperfusion injury. In an ex vivo study of rat hearts, treatment with an sEH inhibitor in normal, hypertensive, and diabetic hearts minimized cardiac damage associated with ischemic-reperfusion injury presumably by increasing or maintaining EET levels [ 70 ]. Interestingly, a study by Chaudhary and colleagues [ 84 ] showed that this protection is age-dependent.…”