Inhibition of soluble epoxide hydrolase by t‐AUCB modulates coronary reactive hyperemia in isolated mouse hearts (1071.3)

Abstract

Coronary reactive hyperemia (RH) is impaired in hypertrophic hearts and in hearts with metabolic syndrome. Epoxyeicosatrienoic acids (EETs) exert cardioprotective effects against ischemia / reperfusion injury. Soluble epoxide hydrolase (sEH) is the main enzyme responsible for EETs breakdown. We hypothesized that the inhibition of sEH results in increased RH in C57BL/6J isolated mouse hearts through increased generation of EETs compared to non‐treated mouse hearts in response to no‐flow ischemia. Coronary flow (CF) in isolated C57BL/6J wild type mouse hearts was measured before and after sEH‐inhibition using a well characterized and selective sEH inhibitor, trans‐4‐[4‐(3‐adamantan‐1‐yl‐ureido)‐cyclohexyloxy]‐benzoic acid (t‐AUCB) in Langendorff system. In each experiment we used the same isolated heart as its own control. Perfused isolated hearts were exposed to 15‐second ischemia and RH parameters were assessed before and after 15‐minute infusion of t‐AUCB (10‐5 M). Following ischemia, flow repayment (calculated as the area under the curve and normalized to heart weight (ml/g)) was significantly increased in response to t‐AUCB (5.84 ± 0.80 in vehicle vs. 9.52 ± 1.68 in t‐AUCB, p<0.05). Moreover, t‐AUCB significantly increased baseline coronary flow (16.62 ± 0.85 in vehicle vs. 14.59 ± 0.63 in t‐AUCB, p<0.05). Also, we observed that t‐AUCB tends to increase repayment to debt ratio (1.53 ± 0.22 in vehicle vs. 2.32 ± 0.43 in t‐AUCB). No significant differences were observed in debt area, peak hyperemic flow and repayment duration between the two groups. Our results demonstrate that sEH inhibition by t‐AUCB significantly increases RH. These data suggest that sEH inhibition by t‐AUCB could have a beneficial effect on myocardial recovery from ischemic insult. Supported by HL‐114559 to MANGrant Funding Source: Supported by HL‐114559 to MAN