Acanthopanax senticosus Root Extract Exerts Dual Action on Mouse Ileal Smooth Muscle Function, Leading to Modulation of Gastrointestinal Motility.

Diarrhea is often caused by changes in lifestyle, stress, or side effects of drugs. Acanthopanax senticosus root extract (ASRE) has long been used as a functional food remedy with anti-fatigue, neuroprotective, and immunomodulatory activities. However, it is unclear whether ASRE has beneficial effects on gastrointestinal (GI) motility. Therefore, we first investigated whether ASRE directly affects contractile functions of the isolated mouse ileum, and then assessed its effects on GI transit of a charcoal meal in normal mice and a carbachol (CCh)-induced diarrhea mouse model. ASRE caused contraction of the isolated mouse ileum and the maximum contraction was approximately half of that induced by acetylcholine (ACh) administration. In the presence of atropine, this ASRE-induced contraction disappeared, while relaxation responses were observed. However, ASRE reduced potassium chloride- and ACh-induced contractions, and the inhibitory effect was not counteracted by a ß-blocker. Administration of a nitric oxide synthase inhibitor or potassium channel blockers did not affect the ASRE-induced relaxation. Oral administration of ASRE for 1 and 4 d reduced the increased GI transit in CCh-treated but did not affect the GI transit of normal mice. These results indicate that ASRE exhibited dual effects of contraction via muscarinic receptors and direct relaxation on mouse ileal function, and its relaxant effect could be useful in treating diarrhea symptoms, resulting in an increase in the parasympathetic nerve activities.

Effects of Anticholinergic Drugs Used for the Therapy of Overactive Bladder on P-Glycoprotein Activity.

We evaluated the effects of anticholinergic drugs principally used for the therapy of overactive bladder (OAB) on the activity of P-glycoprotein, an efflux transport protein, in Caco-2 cells. The time-dependent changes in the fluorescence of residual rhodamine 123, a P-glycoprotein activity marker, in the apical region of Caco-2 cells were measured in the presence of anticholinergic drugs using time-lapse confocal laser scanning microscopy. The effect of anticholinergic drugs on human P-glycoprotein ATPase activity was also measured. The fluorescence of residual rhodamine 123 in untreated Caco-2 cells decreased over time. The gradual decrease in the fluorescence was significantly inhibited by treatment with cyclosporine A, darifenacin, and trospium. In contrast, oxybutynin, N-desethyl-oxybutynin (DEOB), propiverine, and its active metabolites (M-1, M-2), imidafenacin, solifenacin, or tolterodine had little effect on the efflux of rhodamine 123. P-Glycoprotein ATPase activity was increased by darifenacin. Darifenacin and trospium reduced the rhodamine 123 transfer across the apical cell membrane. These data suggest that darifenacin and trospium interact with P-glycoprotein. Additionally, darifenacin influenced P-glycoprotein ATPase activity. These results suggest that darifenacin may be a substrate of P-glycoprotein. This study is the first paper to test simultaneously the effects of 10 anticholinergic drugs used currently for the therapy of OAB, on the P-glycoprotein.

Acanthopanax senticosus Induces Vasorelaxation via Endothelial Nitric Oxide-Dependent and -Independent Pathways.

Although Acanthopanax senticosus root extract (ASRE), a functional food used in Japan, improves peripheral blood circulation and exerts vasorelaxant effects in rats under healthy conditions, the underlying mechanisms currently remain unclear. Therefore, we investigated the mechanisms responsible for ASRE-induced relaxation in isolated thoracic aortas using organ bath techniques and examined whether ASRE affects systemic and peripheral circulation using a photoplethysmographic tail-cuff system and noncontact laser tissue blood flow meter in Wistar rats. Similar to acetylcholine (ACh), ASRE induced dose-dependent relaxation in aortas pre-contracted with phenylephrine; however, in contrast to ACh, ASRE-induced relaxation was partially inhibited by treatments with antagonists of nitric oxide (NO) synthase and soluble guanylyl cyclase as well as by endothelium removal. Contractile responses to phenylephrine or potassium chloride were observed in the presence of ASRE. The oral administration of ASRE (900 mg/kg/d for 1 wk) decreased systolic blood pressure in rats 3 h after the treatment and did not affect heart rate, tail blood flow, mass, or velocity; this decreasing effect was not observed on day 2. A 1-wk treatment with ASRE did not affect vasorelaxation in response to ASRE. These results demonstrate that ASRE induces vasorelaxation via endothelial NO production and an NO-independent pathway in rats. Based on these findings, positive impacts of ASRE on blood pressure and peripheral blood circulation cannot be expected under healthy conditions as the systemic effects of ASRE are temporary. Instead, caution is needed to prevent the occurrence of side effects (i.e., orthostatic dizziness) at the beginning of ASRE dosing.

Effect of Royal Jelly on Mouse Isolated Ileum and Gastrointestinal Motility.

Royal jelly (RJ) is widely used as a cosmetic or dietary supplement to relieve various health disorders, such as dry skin, fatigue, and menopause. RJ has been recommended to improve constipation on a commercial basis. However, the detailed mechanisms by which RJ influences intestinal motility and whether RJ improves constipation remain unclear. Therefore, we investigated the effects of RJ on the motility of mouse ileum both in vitro and in vivo. Using myograph methods, RJ dose-dependently induced contractions of isolated ileal segments, which were inhibited by treatment with atropine. Eserine sulfate, a cholinesterase inhibitor, enhanced the RJ-induced contractions, whereas RJ treated with acetylcholinesterase did not result in ileum contraction. RJ-induced contractions were not affected by NG-nitro-l-arginine methyl ester, a nitric oxide synthase inhibitor, although nicotine-induced contractions were significantly enhanced. In contrast, in a gastrointestinal (GI) transit model, single oral administration of 300 mg/kg RJ did not affect GI transit in both normal mice and the loperamide-induced constipation model mice. These results demonstrate that acetylcholine in RJ directly acted on the muscarinic receptors of the mouse intestinal smooth muscle, causing it to contract in vitro. In contrast, single oral administration of RJ did not improve constipation. This study is the first to evaluate the effects of RJ on the motility of mouse ileum in in vitro and in vivo experiments for the validation of application of RJ as a gentle laxative.

Royal jelly increases peripheral circulation by inducing vasorelaxation through nitric oxide production under healthy conditions.

AIMS: Royal jelly (RJ) has a variety of reported biological activities, including vasorelaxation and blood pressure-lowering effects. Although functional foods are positively used for health, the effects of RJ on the cardiovascular system in healthy individuals have not been well studied. Therefore, we investigated the mechanisms underlying the vasorelaxation effects of RJ in healthy control rats to evaluate whether the peripheral circulation was increased. MAIN METHODS: We used fresh RJ to examine the vasorelaxation effects and related mechanisms in Wistar rats using organ bath techniques. Furthermore, we measured changes in tail blood circulation, systolic blood pressure (sBP), and heart rate (HR) after the oral administration of RJ to control rats and nitro-l-arginine methyl ester (l-NAME)-treated rats (0.5 mg/ml dissolved in distilled drinking water for 1 week). Concentrations of acetylcholine (ACh) in the RJ were measured using a commercial kit. KEY FINDINGS: RJ caused vasorelaxation of isolated rat aortas and superior mesenteric arteries, and this effect was inhibited by atropine (10-5 M, 15 min) or L-NAME (10-4 M, 20 min) and endothelium-denuded arterial ring preparations. Oral RJ increased tail blood flow and mass in control rats 1 h after treatment without affecting velocity, sBP, or HR. These effects were not observed in L-NAME-treated rats. RJ contained approximately 1000 µg/g of ACh. SIGNIFICANCE: The present study demonstrated that RJ is composed of muscarinic receptor agonist(s), likely ACh, and induces vasorelaxation through nitric oxide (NO) production from the vascular endothelium of healthy rats, leading to increased tail blood circulation. Thus, fresh RJ may improve peripheral circulation in healthy individuals.