Nobiletin Relaxes Isolated Mesenteric Arteries by Activating the Endothelial Ca2+-eNOS Pathway in Rats

Abstract

Aims: Nobiletin, a natural polymethoxylated flavonoid compound, has various beneficial properties, such as anticancer, anti-inflammatory, and antioxidant effects, and it also improves memory. Therefore, we investigated the effects and mechanisms of nobiletin on rat isolated mesenteric arteries (MAs). Methods: We examined vasodilation induced by nobiletin on rat isolated MA rings with a tension study, the expression and activity of endothelial nitric oxide synthase (eNOS) with Western blotting, NO production with DAF- FMDA fluorescence, and intracellular Ca²⁺ concentration ([Ca²⁺]i) with Fluo-3AM. Results and Conclusion: Our study showed that nobiletin elicited a dose-dependent vasodilation in phenylephrine precontracted MA rings, but it did not elicit the same response in pulmonary artery rings. Vasodilation was related to endothelium and activated partly by eNOS. Vasodilation was inhibited by denudation of the endothelium or inhibition of eNOS activity. Nobiletin increased NO production by promoting the phosphorylation of eNOS at Ser-1177 without changing the level of eNOS expression in rat mesenteric artery endothelial cells (RMAECs). Nobiletin increased the concentration of endothelial [Ca²⁺]i, which enhances eNOS activity in RMAECs. In summary, vasodilation induced by nobiletin was dependent on the endothelium and partly on eNOS activation, which is mediated by high endothelial [Ca²⁺]i. Results suggest nobiletin may offer a therapeutic benefit and could potentially be used as a vasodilator for the treatment of hypertension.