hypaconitine and Heart-Failure

The present study aimed to determine the protective effects of hypaconitine (HA) and glycyrrhetinic acid (GA) against chronic heart failure (CHF) in the rats and to explore the underlying molecular mechanisms.. The CHF rat model was established by transverse-aortic constriction (TAC) operation. Transthoracic echocardiography and hematoxylin eosin (HE) staining were used to evaluate the pathophysiological and histopathological changes of CHF model. The total cholesterol (TCHO) and triglyceride (TG) levels were determined by ELISA assay. The protein expression of fibroblast growth factor 2 (FGF2), vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS) in the rat ventricular tissues was determined by immunohistochemistry. The serum metabolites were determined by LC-MS/MS assay.. After applied the HA + GA, the cardiac tissue and structure were obviously improved, and the HA + GA treatment also significantly reduced the plasma levels of TCHO and TG in the CHF rats. The expression of FGF2 and VEGFA protein was up-regulated and the expression of eNOS protein was down-regulated in the ventricular tissues of CHF rats, which was significantly restored after HA + GA treatment. HA + GA treatment down-regulated serum isonicotinic acid, phosphatidylcholine, cardiolipin, estrogen glucuronide, and glycocholic acid, up-regulated serum sphingosine and deoxycholic acid in the CHF rats.. In conclusion, HA + GA showed protective effects on CHF in the rats, and the HA + GA may exert protective effects by reducing lipid levels, up-regulating the expression of FGF2 and VEGFA proteins, attenuating eNOS protein expression, and modulating metabolic pathways. However, the molecular mechanisms underlying HA + GA-mediated effects still require further examination.

Topics: Aconitine; Animals; Chromatography, Liquid; Fibroblast Growth Factor 2; Glycyrrhetinic Acid; Heart Failure; Rats; Tandem Mass Spectrometry; Vascular Endothelial Growth Factor A

Fuzi [the lateral root of Aconitum carmichaeli Debx (Ranunculaceae)] is a well-known traditional medicinal herb used to treat chronic heart failure (CHF). Aconitine-type alkaloids are major alkaloids that are responsible for the pharmacological activity and toxicity of this herb.To investigate therapeutic effects and pharmacokinetic profiles of aconitine-type alkaloids in CHF rats.. The plasma pharmacokinetic profiles of aconitine, mesaconitine, and hypaconitine were investigated after once treatment of Fuzi extract (containing aconitine 0.086 mg/g, mesaconitine 0.84 mg/g, and hypaconitine 1.97 mg/g) using a rapid and sensitive combinative method of ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and microdialysis (MD). The cardiac function and antioxidant enzyme activities were also evaluated.. Recoveries of MD sampling ranged from 35.06% to 45.74% with RSD below 6.05%. Fuzi extract improved the myocardial function and antioxidant enzymatic activities of rats with CHF. Aconitine, mesaconitine, and hypaconitine exhibited slower absorption into the bloodstream, and yielded 11-fold less values of area under concentration-time curve (AUC) in the CHF rats than those in normal rats. The plasma AUC showed that the maximum blood concentration (Cmax) was 5.561 ng/mL for aconitine, 17.30 ng/mL for mesaconitine, and 17.78 ng/mL for hypaconitine in normal rats, while these were 0.6059 ng/mL, 2.430, and 0.7461 ng/mL in CHF rats, respectively.. Aconitine-type alkaloids associated with Fuzi׳s efficacy have lower intake and slower elimination in the CHF rats, indicating a non-interdependent relationship between its efficacy and toxicity. It may contribute to the depth understanding of the toxicological and pharmacological profiles of Fuzi and further benefit the herbal drug development with safety and efficacy for CHF treatment.

Topics: Aconitine; Aconitum; Administration, Oral; Animals; Chromatography, High Pressure Liquid; Diterpenes; Drugs, Chinese Herbal; Heart Failure; Male; Microdialysis; Plant Extracts; Plant Roots; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry