An ethanolic extract of Lindera obtusiloba stems causes NO-mediated endothelium-dependent relaxations in rat aortic rings and prevents angiotensin II-induced hypertension and endothelial dysfunction in rats

Abstract

Lindera obtusiloba is a medical herb traditionally used in Asia for the improvement of blood circulation, treatment of inflammation, and prevention of liver damage. The possibility that L. obtusiloba affects vascular reactivity remains to be examined. Therefore, the aim of the present study was to evaluate both the in vitro and in vivo vascular effects of an ethanolic extract of L. obtusiloba stems (LOE). Vascular reactivity was assessed in organ chambers using rat aortic rings and the activation of endothelial NO synthase (eNOS) in cultured bovine aortic endothelial cells. LOE induced endothelium-dependent relaxations, which were abolished by inhibitors of nitric oxide synthase (N (ω)-nitro-L: -arginine) and guanylyl cyclase (1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-L-one), significantly reduced by inhibitors of PI3 kinase (wortmannin and LY294002), and not affected by inhibitors of cyclooxygenase (indomethacin) and endothelium-derived hyperpolarizing factor-mediated responses (charybdotoxin plus apamin). LOE prevented contractile responses to phenylephrine and angiotensin II in rings with endothelium, but not in those without endothelium. LOE caused a concentration-dependent phosphorylation of Akt at Serine473 and eNOS at Serine1177 in endothelial cells. Thereafter, the vasoprotective effect of LOE was investigated in an experimental model of hypertension in rats. Intake of LOE prevented the angiotensin II-induced increase in systolic blood pressure, and endothelial dysfunction to acetylcholine and oxidative stress as assessed using dihydroethidine in aortic rings. The present findings indicate that LOE has vasoprotective and antihypertensive properties most likely by stimulating the endothelial formation of NO and inhibiting oxidative stress.

An Ethanolic Extract of Lindera obtusiloba Stems, YJP-14, Improves Endothelial Dysfunction, Metabolic Parameters and Physical Performance in Diabetic db/db Mice

“…Previous studies have indicated that several polyphenol-rich natural products are able to induce endothelium-dependent relaxations by increasing the endothelial formation of major vasoprotective factors such as NO and EDH, and also to prevent and/or improve an established endothelial dysfunction in several types of cardiovascular diseases such as hypertension [32], [33], [34], [35], [36]. In addition, our previous investigations have indicated that LOE is a potent inducer of NO-mediated relaxations in aortic rings and stimulator of the PI3-kinase/Akt-dependent phosphorylation of eNOS at the activator site Ser 1177 and, also, that LOE prevented the angiotensin II-induced hypertension and endothelial dysfunction in rats [27]. The present findings indicate that chronic administration of LOE to db/db mice, an experimental model of T2DM, fully restored the severely blunted endothelium-dependent relaxations to Ach in aortic rings as well as improved partially hyperglycemia.…”

“…Since previous studies have shown that LOE prevented Ang II-induced hypertension and endothelial dysfunction in rats [27], and that increased levels of Ang II and its major receptor, Ang II type 1 receptor (AT1R), are observed in aortic sections of db/db mice [28], the possibility that LOE affects the local angiotensin system was assessed. The expression level of Ang II and AT1R in aortic sections was significantly increased to about 305.0±83.2% and 245.7±57.2%, respectively, in the db/db group compared to the db/+ group (Fig.…”

“…In several previous studies, polyphenols have been shown to improve in part vascular oxidative stress due to their direct antioxidant properties, their ability to inhibit NADPH oxidase activity [45], and possibly also to the induction of changes in the expression pattern of endogenous pro-oxidant and anti-oxidant enzymes in the arterial wall [46], [47], [48]. An improved vascular oxidative stress and endothelium-dependent NO-mediated relaxation in response to polyphenol-rich products has also been observed in several experimental models of diabetes mellitus and vascular diseases including hypertension and ageing [27], [32], [49], [50]. Such a combination of effects most likely accounts for the effectiveness of the LOE treatment to restore a normal endothelial function and vascular oxidative stress level despite the persistent hyperglycemia in db/db mice.…”

“…The preparation of the extract of L. obtusiloba was prepared and standardized as described previously [27]. The dried stems of L. obtusiloba were collected in the vicinity of Hongcheon and were bought from Yakcho119 (Hongcheon, Republic of Korea).…”

“…Moreover, our previous study has indicated that an ethanolic extract of Lindera obtusiloba stems (LOE) at a dose of 100 mg/kg/day prevented endothelial dysfunction and hypertension induced by the chronic infusion of Ang II to rats, in part, by normalizing the NADPH oxidase-dependent vascular oxidative stress [27]. Therefore, the aim of the present study was to determine whether LOE prevents endothelial dysfunction in an experimental model of T2DM, the db/db mice, through inhibition of oxidative stress and the angiotensin system.…”