salvianolic-acid-a and Myocardial-Ischemia

Salvia miltiorrhiza is used extensively to treat cardiovascular diseases. SAA is a major bioactive component in Salvia miltiorrhiza and mediates myocardial ischemia (MI). However, the industrial production of SAA is limited due to low yields. In addition, the direct targets of SAA are unknown. Here we explore cardioprotective mechanisms and targets of SAA in the cardiovascular system.. Transgelin and actin were identified as targets of SAA using a chemical biology method and were validated by Biacore analysis, microscale thermophoresis and single-molecule imaging. Studies of transgelin (-/-) knockout mice further verify the target. Cardioprotective mechanisms and targets of SAA were studied in cultured vascular smooth muscle cells and transgenic mice.. In WT mice, SAA targeted transgelin and had a protective effect on myocardium but did not have the same protective effect on transgelin (-/-) mice. SAA stabilizes the transgelin-actin complex, modulates the reorganization of the actin cytoskeleton, facilitates F-actin bundling, further enhances the contractility and blood flows of coronary arteries, and improves outcomes of myocardial ischemia. Based on the target, a more active SAA derivative offering myocardial protection, SAA-30, was obtained.. We report on the direct targets of SAA and mechanisms of myocardial ischemia treatment. We also find that transgelin may act as a novel therapeutic target of myocardial ischemia. Furthermore, a more effective derivative of SAA provides the basis for further clinical translational research.

Topics: Actins; Animals; Caffeic Acids; Cardiotonic Agents; Coronary Vessels; Lactates; Mice; Mice, Knockout; Microfilament Proteins; Multiprotein Complexes; Muscle Proteins; Muscle, Smooth, Vascular; Myocardial Ischemia; Myocytes, Smooth Muscle; Vasoconstriction

Salvianolic acid A (Sal A), an important constituent of Radix Salviae Miltiorrhizae (RSM), is effective for the treatment of myocardial infarction (MI) and coronary heart disease due to its potential in the improvement of acute myocardial ischemia. However, its content is very low in RSM. So it is obvious to find a rich source of Sal A or to improve its content by conversion of other related components into Sal A modifying reaction conditions. In this research we focused on the conversion of Sal B into Sal A in aqueous solutions of RSM by using different reaction conditions including pH, temperature, pressure and humidity. During the reactions, the contents of Sal A, Sal B and danshensu in the RSM were analyzed by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LCMS). The results indicated that the conversion of Sal B into Sal A in RSM tissues under the conditions of a high temperature, high pressure and high humidity was efficient and thereby, was readily utilized to prepare rich Sal A materials in practice.

Topics: Benzofurans; Caffeic Acids; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Hot Temperature; Humidity; Lactates; Mass Spectrometry; Myocardial Ischemia; Phytotherapy; Plant Roots; Pressure; Salvia miltiorrhiza

To study the effect of salvianolic acid A (SAA) on L-type calcium current (I-CaL) in isolated ventricular myocytes of Sprague-Dawley rats.. SAA powder was dissolved in normal Tyrode's solution to reach the concentrations of 1, 10, 100, and 1000 μmol/L. The traditional whole-cell patch-clamp recording technique was employed to evaluate the effects of SAA on I-CaL in single ventricular myocytes which were prepared by Langendorff perfusion apparatus from Sprague-Dawley rats.. SAA (1, 10, 100, and 1000 μmol/L) inhibited I-CaL peak value by 16.23%±1.3% (n=6, P<0.05), 22.9%±3.6% (n=6, P<0.05), 53.4%±3.0% (n=8, P<0.01), and 62.26%±2.9% (n=6, P<0.01), respectively. SAA reversibly inhibited I-CaL in a dose-dependent manner and with a half-blocking concentration (IC(50)) of 38.3 μmol/L. SAA at 100 μmol/L elevated the I-V curve obviously, and shifted the half-active voltage (V(0.5)) from (-15.78±0.86) mV to (-11.24 ±0.77) mV (n=6, P<0.05) and the slope (K) from 5.33±0.74 to 4.35±0.74 (n=6, P>0.05). However, it did not alter the shapes of I-V curve, steady-state inactivation curve, or recovery from inactivation curve.. SAA inhibited I-CaL in a dose-dependent manner. It shifted the steady-state activation curve to a more positive voltage, which indicated that the drug affected the activated state of calcium channels, and suggested that the Ca(2+) antagonistic effect of SAA be beneficial in the treatment of myocardial ischemia reperfusion injury.

Topics: Animals; Caffeic Acids; Calcium Channel Blockers; Calcium Channels, L-Type; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Lactates; Myocardial Ischemia; Myocytes, Cardiac; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Reperfusion Injury

The purpose of this study was to determine the therapeutic effect of salvianolic acid b and paeonol on coronary disease. The ischemia myocardial animal model is induced by administering pituitrin (20 μg·kg(-1)) intravenously via the abdominal vein. A combination of salvianolic acid b and paeonol (CSAP) (5, 10 and 15 mg/kg BW) was administrated to experimental rabbits. Biochemical indices were evaluated during six weeks of intervention. We found that the compound of salvianolic acid b and paeonol (5, 10 and 15 mg/kg BW) can markedly and dose-dependently reduce fibrinogen and malonaldehyde levels, increase the HDL level, improve blood viscosity and plasma viscosity in rabbits. In addition, the medicine can still reduce the ratio of NO/ET and the contents of lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) in a dose-dependent manner. This study demonstrates that compound of salvianolic acid b and paeonol (5, 10 and 15 mg/kg BW) can improve the blood hemorrheology, decrease oxidative injury and repair the function of blood vessel endothelium, and subsequently prevent the development of Coronary disease.

Topics: Acetophenones; Alkenes; Animals; Creatine Kinase; Drug Therapy, Combination; Fibrinogen; Hemorheology; L-Lactate Dehydrogenase; Lipid Metabolism; Lipoproteins, HDL; Malondialdehyde; Myocardial Ischemia; Nitric Oxide; Pituitary Hormones, Posterior; Polyphenols; Rabbits