Abstract
Aconiti Lateralis Radix Praeparata (Fuzi) and Fritillariae Thunbergii bulbus (Beimu) have been widely used clinically to treat cardiopulmonary related diseases in China. However, according to the classic rules of traditional Chinese medicine, Fuzi and Beimu should be prohibited to use as a combination for their incompatibility. Therefore, it is critical to elucidate the paradox on the use of Fuzi and Beimu combination therapy. Monocrotaline-induced pulmonary hypertension rats were treated with either Fuzi, Beimu, or their combination at different stages of PH. We demonstrated that at the early stage of PH, Fuzi and Beimu combination significantly improved lung function and reduced pulmonary histopathology. However, as the disease progressed, when Fuzi and Beimu combination were used at the late stage of PH, right ventricular chamber dilation was histologically apparent and myocardial apoptosis was significantly increased compared with each drug alone. Western-blotting results indicated that the main chemical ingredient of Beimu could down-regulate the protein phosphorylation levels of Akt and PDE4D, whereas the combination of Fuzi and Beimu could up-regulate PKA and CaMKII signaling pathways. Therefore, we concluded that Fuzi and Beimu combination potentially aggravated the heart injury due to the inhibition of PDK1/Akt/PDE4D axis and subsequent synergistic activation of βAR-Gs-PKA/CaMKII signaling pathway.
Highlights
Pulmonary hypertension (PH) is a progressive and fatal hemodynamic problem, characterized by sustained raises in pulmonary arterial pressure and pulmonary vascular resistance, as well as thickening of small pulmonary arteries[1]
The levels of p-Akt Ser[473] and PDE4D were decreased after peimine, peiminine or peimisine treatment. These results indicated that PDK1/Akt/PDE4D axis is involved in the synergistic effect of Fuzi and Beimu combination treatment on activating cAMP signals
Our results showed that when administrated at the early stage of PH, the combination of Fuzi and Beimu showed a prominent therapeutic efficacy, characterized by decreasing lung weight, improving lung function, as well as abrogating the development of pulmonary arterial hypertension and pulmonary vascular remodeling, and the combination treatment had no serious effect on heart and liver (Supplementary Figs S1 and S2) in this stage
Summary
Pulmonary hypertension (PH) is a progressive and fatal hemodynamic problem, characterized by sustained raises in pulmonary arterial pressure and pulmonary vascular resistance, as well as thickening of small pulmonary arteries[1]. Previous studies have demonstrated that the activity and expression of PKA will be increased during heart failure. The previous studies suggested that long time overstimulation of βAR/cAMP-PKA-CaMKII signaling pathway could result in impairment of cardiac function. The present study is to explore whether and why Fuzi and Beimu combination caused any adverse effects, which would be an exemplification of the research on the safety of drugs compatibility. We hypothesized that Fuzi and Beimu combination is prone to develop severe heart adverse side-effects by synergic activating of cAMP-PKA-CaMKII signaling pathway. In the present study Monocrotaline (MCT) induced rats PH model which results in compensatory right ventricular hypertrophy and heart failure[18,19,20], were employed to evaluate the efficacy and safety of the combination treatment of Fuzi and Beimu
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