Effects of Keishibukuryogan on Vascular Function in Adjuvant-Induced Arthritis Rats

Nozaki, Kazuya; Goto, Hirozo; Nakagawa, Takako; Hikiami, Hiroaki; Koizumi, Keiichi; Shibahara, Naotoshi; Shimada, Yutaka

doi:10.1248/bpb.30.1042

Cited by 23 publications

(18 citation statements)

References 41 publications

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“…To confirm that the abnormal response of vessels from AIA rats to ACh was not due to decreased response of vascular smooth muscle cells to NO, we demonstrated that the relaxing effect of the NO donor SNP was not impaired in the AIA rats. This result is in accordance with recent study findings in AIA rats (12,14,36) as well as in RA patients (37)(38)(39)(40). Likewise, we verified that the contractile response of vessels from AIA rats to NE was not different from that of control rats.…”

Section: Discussionsupporting

confidence: 93%

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Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Prati¹,

Berthelot²,

Wendling³

et al. 2011

Arthritis & Rheumatism

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Objective. To investigate whether arginase pathway abnormalities occur in vessels from rats with adjuvant-induced arthritis (AIA), and to determine whether the up-regulation of arginase, which reciprocally regulates nitric oxide synthase (NOS) by competing for the same substrate, L-arginine, contributes to endothelial dysfunction in AIA.Methods. We performed vascular reactivity experiments on thoracic aortic rings from AIA rats and control rats, and we investigated the response of rings to norepinephrine (NE), sodium nitroprusside (SNP), and acetylcholine (ACh). ACh-induced relaxation was evaluated in the presence (or not in the presence) of the NOS inhibitor N G -nitro-L-arginine methyl ester (L-NAME), the arginase inhibitor N -hydroxy-nor-Larginine (nor-NOHA), or both. Aortic arginase activity was measured using a spectrophotometric method, and the expression of arginase and endothelial NOS (eNOS) was evaluated by Western blotting.Results. ACh-induced vasodilation was significantly impaired in AIA rats, while the responses to NE and to SNP did not differ from those in control rats. L-NAME reduced ACh-induced vasodilation to a lesser extent in AIA rats than in control rats. Incubation of aortic rings with nor-NOHA enhanced the vascular response to ACh in AIA rats and reversed the effects of L-NAME. Compared with control rats, AIA rats exhibited increased vascular expression of arginase II (by 22%) (P < 0.05) as well as increased arginase activity (by 49%) (P < 0.05), whereas eNOS expression was unchanged. Finally, arginase activity and expression correlated positively with arthritis severity.Conclusion. Our results are consistent with the notion that arginase up-regulation plays a role in AIAassociated endothelial dysfunction. They suggest that arginase might be an attractive new target for treating endothelial dysfunction in arthritis.

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Section: Discussionsupporting

confidence: 93%

“…ment of reactive oxygen species and NO produced by inducible NOS (iNOS) in arginase up-regulation (22,(45)(46)(47). Since aortas from AIA rats were reported to overproduce O 2 Ϫ (12,13) and to exhibit increased iNOS expression (36), the contribution of these species cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Prati¹,

Berthelot²,

Wendling³

et al. 2011

Arthritis & Rheumatism

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“…An increase in NO production was observed mainly in the endothelium 30 min after Keishibukuryogan administration, suggesting that eNOS was the target enzyme of Keishibukuryogan. This finding is in agreement with a previous in vivo study showing effects of Keishibukuryogan on both eNOS and iNOS in the aorta of an adjuvant-induced arthritis model [21]. On the other hand, the vasodilation effect of Keishibukuryogan persisted for a total of 120 min after administration, whereas the increased blood flow was maintained for only up to 60 min, subsequently decreasing despite the increases in vessel diameter.…”

Section: Discussionsupporting

confidence: 93%

“…Moreover, regarding the components of Keishibukuryogan, cinnamic aldehyde contained in cinnamon, paeoniflorin contained in Paeonia lactiflora , and amygdalin contained in Semen Persicae are known to increase peripheral blood flow [14–16], and cinnamic aldehyde and paeoniflorin reportedly showed anti-inflammatory effects involving NO-related pathways [15, 17–20]. These results strongly suggest that the anti-Oketsu effect of Keishibukuryogan is closely related to NO and ROS; however, most of these reports involved in vitro studies, with few reports of in vivo effects [21]. …”

Section: Discussionmentioning

confidence: 99%

Effect of Keishibukuryogan, a Japanese Traditional Kampo Prescription, on Improvement of Microcirculation and Oketsu and Induction of Endothelial Nitric Oxide: A Live Imaging Study

Tomita

Hirayama

Matsui

et al. 2017

Evidence-Based Complementary and Alternative Medicine

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Oketsu is a characteristic condition that plays an important role in Kampo, Japanese traditional medicine, and includes multiple aspects of hemodynamic disorders. This study aims to clarify the microcirculation of Oketsu and the pharmacological effect of Keishibukuryogan, an anti-Oketsu Kampo prescription, using live imaging techniques. Oral administration of Keishibukuryogan induced significant vasodilation of murine subcutaneous arterioles compared to the preadministration level. This vasodilatation peaked 60 min after administration and persisted for 90 min. The blood velocity in the subcutaneous capillary was also increased by Keishibukuryogan in generally the same manner. In rat mesenteric arterioles, Keishibukuryogan administration improved microhemodynamic parameters, including the resolution of erythrocyte congestion and the cell-free layer, which are representative of Oketsu pathology. Live imaging revealed an increase of diaminofluorescein-2 diacetate fluorescence, a nitric oxide (NO) specific reagent, in the arterial endothelium following Keishibukuryogan administration. This fluorescence was most remarkable at vascular bifurcations but was present throughout the mesenteric arterioles. This study demonstrates the successful imaging of Oketsu pathology with respect to microcirculation and the anti-Oketsu effects of Keishibukuryogan, namely, vasodilation of arterioles, increased blood velocity, and resolution of erythrocyte congestion. The anti-Oketsu effect of Keishibukuryogan is related to endothelial NO production.

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“…Nozaki et al 15 reported that keishibukuryogan reduced the level of soluble vascular cell adhesion molecule-1, which is involved in the progression of atherosclerosis, in patients with rheumatoid arthritis and in rats with adjuvantinduced arthritis. 16 It has also been reported that keishibukuryogan inhibited the progression of atherosclerosis in cholesterol-fed rabbits 17 and improved endothelial function in cholesterol-fed rabbits and spontaneously hypertensive and diabetic rats 18<20 and that herbs such as Cinnamomi cortex and Paeoniae radix, which are included in keishibukuryogan, have a vascular endothelial relaxation effect through nitric oxide production. 21,22 MCP-1 is the primary chemokine responsible for the recruitment of monocytes to sites of active inflammation, including developing atheroma, and its expression is enhanced in endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Effects of Japanese traditional medicines on circulating cytokine levels in women with hot flashes

Matsui¹,

Yamamoto²,

Uemura

et al. 2011

Menopause

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Effects of Keishibukuryogan on Vascular Function in Adjuvant-Induced Arthritis Rats

Cited by 23 publications

References 41 publications

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Endothelial dysfunction in rat adjuvant‐induced arthritis: Up‐regulation of the vascular arginase pathway

Effect of Keishibukuryogan, a Japanese Traditional Kampo Prescription, on Improvement of Microcirculation and Oketsu and Induction of Endothelial Nitric Oxide: A Live Imaging Study

Effects of Japanese traditional medicines on circulating cytokine levels in women with hot flashes

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