The Effect of Herbal Medicine Toki-shakuyaku-san on Blood Pressure in an Nω-Nitro-L-Arginine Methyl Ester-Induced Pre-eclampsia Rat Model During Pregnancy and the Postpartum Period

Abstract

Abstract. The chronic inhibition of nitric oxide (NO) synthesis with N ω -nitro-L-arginine methyl ester (L-NAME) in pregnant rats induces a pre-eclampsia-like syndrome, including hypertension. We have previously reported the beneficial effects of Toki-shakuyaku-san (TS) in this model. In the present study we demonstrated the anti-hypertensive effect of TS in preeclampsia produced by prolonged L-NAME-infusion during the postpartum period. Analysis of blood sex steroids suggested that the level of progesterone differs between the TS-effective (gestational day 19 and postpartum day 7) and TS-ineffective (postpartum day 1) periods. Coadministration of TS and progesterone inhibited L-NAME-induced hypertension on postpartum day 1. Furthermore, the anti-hypertensive effect of TS on postpartum day 6 disappeared in the presence of a co-administered progesterone antagonist mifepristone. These data suggest that a certain level of progesterone may be an indispensable prerequisite for an anti-hypertensive effect of TS. Finally, the effects of TS are apparently unrelated to blood levels of NO, calcitonin generelated peptide, and endothelin-1, which have been reported to modulate systolic blood pressure in the L-NAME-induced pre-eclampsia model. Thus, the use of TS may provide a new therapeutic strategy for pre-eclampsia, although elucidation of the mechanism of action of TS would be necessary to optimize treatment protocols.

Potency of Tokishakuyakusan in treating preeclampsia: Drug repositioning method by in vitro screening of the Kampo library

“…This is because, apart from causing vasoconstriction, preeclampsia has a complex pathophysiology. Unlike many other antihypertensive drugs, TS does not lower blood pressure in normotensive pregnant rats [29]. This suggests that TS might be used more safely during pregnancy.…”

“…Some researchers have demonstrated the ameliorative effects of TS on preeclampsia, fetal growth restriction, and recurrent pregnancy loss [29,30]. It has been reported that TS regulates the immunity of invariant natural killer T cells during early pregnancy (in mice), and thus reduces the rate of pregnancy loss [31].…”

“…It has been reported that TS regulates the immunity of invariant natural killer T cells during early pregnancy (in mice), and thus reduces the rate of pregnancy loss [31]. The antihypertensive effects of TS have also been reported [29]. However, there are no previous reports examining TS-induced PlGF expression.…”

Effect of Toki‐shakuyaku‐san on acetylcholine level and blood flow in dorsal Hippocampus of intact and twice‐repeated ischemic rats

“…TSS could also affect the circulatory functions. It has been reported that TSS improves hypertension, in progesterone dependent preeclampsia rats (Takei et al, 2005). Moreover, TSS at a single dose improves blood flow in oketsu and normal mice (Ueda et al, 2004).…”