Differential regulations of blood pressure and perturbed metabolism by total ginsenosides and conventional antihypertensive agents in spontaneously hypertensive rats

Abstract

Aim: To investigate the regulatory effects of total ginsenosides and the conventional antihypertensive agents (captopril, amlodipine, terazosin and hydrochlorothiazide) on the blood pressure and perturbed metabolism in spontaneously hypertensive rats (SHRs) and to analyze the cause-effect relationships between high blood pressure and the metabolic disorders of hypertension.

Methods: SHRs were administrated with total ginsenosides or the antihypertensive agents for eight weeks. Systolic blood pressure (SP) was measured every week and low-molecular-weight compounds in blood plasma were quantitatively analyzed using a nontargeted high-throughput metabolomic tool: gas chromatography/time of flight mass spectrometry (GC/TOFMS) . The metabolic patterns were evaluated using principal components analysis and potential markers of hypertension were identified.

Results: Total ginsenosides and the antihypertensive agents differentially regulated SP and the metabolic pattern in SHRs. Total ginsenosides caused a progressive and prolonged reduction of SP and markedly normalized the perturbed metabolism with 14 of 27 (51.8%) markers of hypertension which were regulated toward normal. Total ginsenosides also reduced free fatty acids' level toward normal levels. In contrast, captopril, amlodipine and terazosin efficiently depressed SP, but had little effect on metabolic perturbation with only 8 (29.6%), 4 (14.8%), and 4 (14.8%) markers, respectively, which were regulated.

Conclusion: The metabolic changes persisted when the blood pressure was lowered by the conventional antihypertensive agents, suggesting that hypertension may not be the cause of the metabolic perturbation in SHRs.

Figure 1

Systolic blood pressure (SP) measured from zero to eight weeks of treatment with total ginsenosides (TG), terazosin, captopril, amlodipine, or hydrochlorothiazide, and for two weeks after withdrawal of the drugs. Treatment with TG, amlodipine, captopril, terazosin, and hydrochlorothiazide led to a rapid reduction in SP. This effect was significant in the amlodipine-, captopril-, and terazosin-treated groups, whereas TG and hydrochlorothiazide exhibited a trend towards reduced SP. Two weeks after the withdrawal of the drugs, the SP of the animals in all groups increased rapidly, with the exception of those in the TG-treated groups. ^bP<0.05, ^cP<0.01 significantly different from SHR (one-way ANOVA).

Figure 2

A) The scores plot shows the metabolomic profiles of SHR, WKY, and SHR treated with total ginsenosides (TG) for two, four, six, and eight weeks. Treatment with TG led to a gradual repositioning of the plots from SHR and toward WKY, suggesting a clear rectification of the metabolome. B) The scores plot shows the metabolomic patterns for the total ginsenosides (TG)-, terazosin-, captopril-, amlodipine-, and hydrochlorothiazide-treated groups at week 8. Significantly different metabolic phenotypes were observed after eight weeks of treatment. The TG group clustered close to WKY, whereas the other groups overlapped with or were close to SHR, which suggests the rectification of endogenous metabolites after TG treatment and a lesser regulatory effect after treatment with the other drugs.