PKA/β2-AR-Gs/Gi signaling pathway is associated with anti-inflammatory and pro-apoptotic effects of Fuzi and Banxia combination on rats subjected to pressure overload

Ethnopharmacological relevance: Either Aconite Lateralis Radix Praeparata (Fuzi) or Pinelliae Rhizoma (Banxia) exerts anti-inflammatory activity and their combination has long been used in China for treating cardiovascular diseases. However, combination of two drugs is controversially prohibited in clinical prescriptions because it serves a representative incompatible pairs in “eighteen antagonisms”. Up to date, whether the combination of Fuzi and Banxia could be used for treating heart failure with preserved ejection fraction (HFpEF) especially charactered by systemic inflammation and the potential mechanisms have not been elucidated. Aim of the study: The pros and cons of Fuzi in combination with Banxia were evaluated in pressure overload (PO) rat models of HF in vivo. Materials and methods: Male Sprague Dawley rats were subjected to abdominal aorta constriction or sham-op- erated procedure. From week 12, rats were administered with low dose Fuzi (5.4 g kg−1 d−1), Banxia (5.4 g kg−1 d−1), combination (5.4 g kg−1 d−1+5.4 g kg−1 d−1), high dose Fuzi (10.8 g kg−1 d−1) or with vehicle (n=15 per group) orally for additional 6 weeks. Results: Fuzi alone treatment led to exaggerated cardiac-renal response to PO, and occurred dramatically at high dose as manifested by markedly exacerbated cardiac-renal inflammation and myocardial fibrosis. Further studies revealed that cardiotoxicity of Fuzi may be associated with highly expression levels of β2-AR and PKA. In contrast, coadministration of Fuzi and Banxia restored cardiac function, as indicated by relieving inflammation and fibrosis as well as normalizing electrocardiogram parameters, which were accompanied by PKA down- regulation. More importantly, both high dose Fuzi and combination treatment enhanced induction of apoptosis, which could be partially associated with inhibition of β2-AR-Gi signaling. Conclusion: Thus, combination of Fuzi and Banxia elicited concurrent protective and toxic effects in PO induced HF. The protective effect appeared to predominate and was associated with suppression of PKA/β2-AR-Gs sig- naling pathway. Unlike the eighteen antagonisms theory where Fuzi and Banxia combination was considered incompatible, in the present study, this herb pairs appeared to be benefit, and probably had potential therapeutic prospect in treating HFpEF and diseases associated with inflammation.