salvianolic-acid-a and Hypertension

Danhong injection (DHI), which is a Chinese clinical prescription consists of Radix et Rhizoma Salviae Miltiorrhizae (Salvia miltiorrhiza Bge., Labiatae, Danshen in Chinese) and Flos Carthami (Carthamus tinctorius L., Compositae, Honghua in Chinese)(Plant names have been checked with http://www.theplantlist.org on March 1st, 2022), has been mainly used in the clinical therapy of cardiovascular diseases, including hypertension in China for many years.. Cardiovascular diseases (CVDs) are the major causes of death all around the world. Due to the various stimulation, a series of vasoconstrictor substances are secreted to regulate the vasoconstriction function and then change blood pressure. The representative substances leading to abnormal vasoconstriction include renin-angiotensin system, endothelin, vasopressin and adrenaline, which act on the corresponding receptors on vascular smooth muscle to constrict blood vessels. Finally, blood pressure increases, followed by a series of cardiovascular diseases, including hypertension. However, little is known about Danhong injection's specific vasodilating mechanisms and active substances. The aims of the study were to determine the vasodilating substances of Danhong injection and explain its molecular mechanism of vasodilation.. The effects of DHI and its active components on vascular tension were measured by myograph system in the aortic or mesenteric rings of mice. Based on this, the pharmacodynamic substances were analyzed and effective molecules were found. Combined with multiple types of vascular myograph experiments and network pharmacological analysis, the molecular pathway was preliminarily determined. With molecular biology experiments, it was verified that the relevant mechanisms were closely related to calcium-mediated vasoconstriction in smooth muscle cells.. DHI could relax endothelium-removed aortic rings pre-constricted with PE and 3 possible active vasodilator substances, including salvianolic acid A, salvianolic acid B and danshensu, were screened out by network pharmacology and vascular myograph experiments, among which the effects of salvianolic acid A were dominant. Meanwhile, salvianolic acid A could dilate mesenteric artery in a pressure-dependent manner. Interestingly, salvianolic acid A could still relax the vascular rings under the stimulation of KCl and Bayk8644, two agonists of L-type calcium channel. By contrast, inhibitors of Kir, Kv, Katp and BKCa channels did not block the effect of salvianolic acid A on vasodilation. Salvianolic acid A alleviated Ca. Our results indicate that salvianolic acid A is the major vasodilator substance in DHI and the vasorelaxation pharmacology mechanism involved in inhibiting the L-type calcium channel signaling in smooth muscle cell. Hence, there are potential therapeutic effects of taking salvianolic acid A preparation which may be beneficial to protect cardiovascular system and reduce blood pressure.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Arteries; Caffeic Acids; Calcium; Calcium Channels, L-Type; Cardiovascular Diseases; Drugs, Chinese Herbal; Hypertension; Lactates; Mice; Salvia miltiorrhiza; Vasodilation; Vasodilator Agents

Cardiac fibrosis is a deleterious consequence of hypertension which may further advance to heart failure and increased matrix metalloproteinase-9 (MMP-9) contributes to the underlying mechanism. Therefore, new therapeutic strategies to attenuate the effects of MMP-9 are urgently needed. In the present study, we characterize salvianolic acid A (SalA) as a novel MMP-9 inhibitor at molecular, cellular and animal level. We expressed a truncated form of MMP-9 which contains only the catalytic domain (MMP-9 CD), and used this active protein for enzymatic kinetic analysis and Biacore detection. Data generated from these assays indicated that SalA functioned as the strongest competitive inhibitor of MMP-9 among 7 phenolic acids from Salvia miltiorrhiza. In neonatal cardiac fibroblast, SalA inhibited fibroblast migration, blocked myofibroblast transformation, inhibited secretion of intercellular adhesion molecule (ICAM), interleukin-6 (IL-6) and soluble vascular cell adhesion molecule-1 (sVCAM-1) as well as collagen induced by MMP-9 CD. Functional effects of SalA inhibition on MMP-9 was further confirmed in cultured cardiac H9c2 cell overexpressing MMP-9 in vitro and in heart of spontaneously hypertensive rats (SHR) in vivo. Moreover, SalA treatment in SHR resulted in decreased heart fibrosis and attenuated heart hypertrophy. These results indicated that SalA is a novel inhibitor of MMP-9, thus playing an inhibitory role in hypertensive fibrosis. Further studies to develop SalA and its analogues for their potential clinical application of cardioprotection are warranted.

Topics: Animals; Animals, Newborn; Caffeic Acids; Cell Line; Cell Movement; Cell Proliferation; Cells, Cultured; Hypertension; Lactates; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Rats; Rats, Inbred SHR