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ObjectiveTo explore the effect and toxicity change rule of Aconiti Lateralis Radix Praeparata（ALRP） and Zingiberis Rhizoma（ZR） before and after compatibility， and to reveal the compatibility connotation of them. MethodSixty SD rats were randomly divided into blank group， blank-ALRP group， blank-ALRP-ZR group， model group， model-ALRP group and model-ALRP-ZR group， the latter three groups were injected with adriamycin via tail vein to establish the model of heart failure， and the former three groups were injected with the same amount of physiological saline via tail vein. The effects of ALRP single decoction and ALRP-ZR mixed decoction on biochemical indexes and myocardial histopathological morphology of normal rats and model rats were compared. Metabolomics analysis was performed on rat serum samples， principal component analysis（PCA） and orthogonal partial least squares-discriminant analysis（OPLS-DA） were used to screen the differential metabolites between groups， and the differential metabolic pathways were analyzed. Combined with network pharmacology technology， the metabolites and their associated targets and pathways related to enhancing anti-heart failure efficacy and reducing cardiotoxicity were screened before and after the compatibility of ALRP and ZR， the screened representative pathways were verified by Western blot. ResultCompared with the blank group， the model group showed significant increases in the contents of brain natriuretic peptide（BNP）， creatine kinase（CK）， lactate dehydrogenase（LDH） and cardiac troponin（cTn）-T（P<0.01）， the blank-ALRP group showed obvious increases in CK， LDH， and cTn-T contents（P<0.05， P<0.01）， while the normal-ALRP-ZR group showed a significant increase in CK content（P<0.01）. Compared with the blank-ALRP group， the blank-ALRP-ZR group showed a obvious decrease in LDH content（P<0.05）， and pathological sections showed that both decoctions could lead to myocardial histopathological damage in normal rats. Compared with the model group， the model-ALRP-ZR group showed obvious decreases in BNP， CK， LDH and cTn-T contents（P<0.05， P<0.01）， and the model-ALRP group showed obvious decreases in BNP， LDH and cTn-T contents（P<0.05， P<0.01）. Compared with the model-ALRP group， the model-ALRP-ZR group showed a significant decrease in CK content（P<0.01）， and both decoctions could improve the pathological morphology of myocardial tissue in the model rats. Metabolomics results showed that ALRP single decoction and ALRP-ZR mixed decoction could recover 422 and 459 metabolites in model rats， respectively. And the metabolic disruption of ALRP-ZR mixed decoction on normal rats was weaker than that of ALRP single decoction. The results of network pharmacological association analysis showed that in the aspect of ZR enhancing the anti-heart failure efficacy of ALRP， 3 metabolites such as deoxyuridylic acid were correlated to 56 metabolites， 82 targets and 13 pathways， including calcium signaling pathway， renin secretion， renin-angiotensin system， etc. In the aspect of ZR reducing the cardiotoxicity of ALRP， 3 metabolites such as tyrosol were associated with 24 metabolites， 55 targets and 14 pathways， including adrenergic signaling in cardiomyocytes and carbon metabolism and so on. Western blot results showed that the expression of angiotensin-converting enzyme（ACE）， angiotensin-converting enzyme 2（ACE2） and angiotensin Ⅱ（Ang Ⅱ） in myocardial tissues of rats from the model group was significantly elevated by comparing with the blank group（P<0.01）. Compared with the model group， the model-ALRP group and the model-ALRP-ZR group showed significantly decreased expression of ACE， ACE2 and Ang Ⅱ（P<0.01）. Compared with the model-ALRP group， the expression of ACE2 and AngⅡ was significantly decreased in the model-ALRP-ZR group. Compared with the blank group， the expression of extracellular signal regulated kinase（ERK）， protein kinase B（Akt） and cTn-I3 was significantly elevated in the blank-ALRP group and blank-ALRP-ZR group（P<0.01）. Compared with the blank-ALRP group， the blank-ALRP-ZR group showed decreased expression of ERK， Akt and cTn-I3， but there was no statistical significance. ConclusionTo a certain extent， the combination of ALRP and ZR shows synergistic relationship under pathological state， and attenuated effect of compatibility under normal physiological state， and the pharmacodynamic characteristics and compatibility relationship of ALRP and ZR are closely related to the physiological state.
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OBJECTIVE:To investigate the protective effect of the compatibilities of ginsenosides Rg1 and aconitine on myocar-dial cell of in vitro cultured heart failure model. METHODS:The myocardial cells of neonate rat were grouped into normal control group,model group,positive control group(Deslanoside injection,1×10-7 mol/L),ginsenosides Rg1 group(1×10-8 mol/L),acon-itine group (1 × 10-9 mol/L) or their compatibilities groups (1∶1,2∶1,1∶2,V/V). Except for normal control group,other groups were given 0.8%pentobarbital sodium to induce heart failure model of myocardial cells. After modeling,each group was given rele-vant medicine for 1 h,and then the activities of T-ATPase,Ca2+-Mg2+-ATPase,Na+-K+-ATPase in cells were all detected. The activi-ties of acyl carrier protein(ACP)and lactate dehydrogenase(LDH),and the contents of brain natriuretic party(BNP),TNF-α and total glycogen were measured in cell culture fluid. RESULTS:Compared with normal control group, T-ATPase and Ca2+-Mg2+-ATPase activities were decreased significantly in model group;meanwhile,Na+-K+-ATPase activity was increased signifi-cantly,and ACP,LDH activities and BNP content in cell culture fluid were increased significantly(P0.05). CONCLUSIONS:Compatibility of ginsenosides Rg1 and aconitine can improve ATPase activities and membranous permeability,regulate BNP secretion and protect myocardial cell of heart failure model,especially the compatibility of ginsenosides Rg1 to aconitine of 2∶1 ratio.
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AIM To study the effects of strophanthidin (Str) on cardiac function and Na +,K +-ATPase activity in isolated guinea pig heart failure model. METHODS Langendorff isolated heart failure models made by perfusing heart with K-H solution containing sodium pentobarbital. Eight-channel physiological recording instrument was used to determine cardiac function. Colorimetry method was used to determine cardiac sarcolemmal Na +,K +-ATPase activity. RESULTS Str increased the heart rate, left ventricular systolic pressure and the maximum rise or decline rate of left ventricular pressure in a concentration-dependent manner at 1?10 -9～1?10 -7 mol?L -1. But Str caused first a rise, then a reduction of contractility and arrhythmia accompanied by inhibition of Na +,K +-ATPase when the concentration of Str was higher than 1?10 -6 mol?L -1. Str had no obvious effect on Na +,K +-ATPase activity at 1?10 -7 mol?L -1, but increased cardiac activity at 1?10 -10～1?10 -8 mol?L -1. CONCLUSION The inotropic effect and heart toxicity of Str at higher concentration is due to inhibition of Na +,K +-ATPase, but the inotropic effect of Str at lower concentration is not the result of inhibition of Na +,K +-ATPase activity.