Vasodilatory Effect of Guanxinning Tablet on Rabbit Thoracic Aorta is Modulated by Both Endothelium-Dependent and -Independent Mechanism

Abstract

Vasodilatory therapy plays an important role in the treatment of cardiovascular diseases, especially hypertension and coronary heart disease. Previous research found that Guanxinning tablet (GXNT), a traditional Chinese compound preparation composed of Salvia miltiorrhiza (Danshen) and Ligusticum chuanxiong (Chuanxiong), increase blood flow in the arteries, but whether vasodilation plays a role in this effect remains unclear. Here, we found that GXNT significantly alleviated the vasoconstriction of isolated rabbit thoracic aorta induced by phenylephrine (PE), norepinephrine (NE), and KCl in a dose-dependent manner with or without endothelial cells (ECs). Changes in calcium ion levels in vascular smooth muscle cells (VSMCs) showed that both intracellular calcium release and extracellular calcium influx through receptor-dependent calcium channel (ROC) declined with GXNT treatment. Experiments to examine potassium channels suggested that endothelium-denuded vessels were also regulated by calcium-activated potassium channels (Kca) and ATP-related potassium channels (KATP) but not voltage-gated potassium channels (kv) and inward rectifying potassium channels (KIR). For endothelium-intact vessels, the nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) contents in vascular tissue obviously increased after GXNT treatment, and pretreatment with the NO synthase inhibitor Nw-nitro-L-arginine methyl ester (L-NAME) or guanylyl cyclase inhibitor methylthionine chloride (MB) significantly inhibited vasodilation. An assessment of NO-related pathway protein expression revealed that GXNT enhanced the expression of phosphorylated endothelial NO synthase (eNOS) in a dose-dependent manner but had no effect on total eNOS, p-Akt, Akt, or PI3K levels in human umbilical vein ECs (HUVECs). In addition to PI3K/AKT signaling, Ca2+/calmodulin (CaM)-Ca2+/CaM-dependent protein kinase II (CaMKII) signaling is a major signal transduction pathway involved in eNOS activation in ECs. Further results showed that free calcium ion levels were decreased in HUVECs with GXNT treatment, accompanied by an increase in p-CaMKII expression, implying an increase in the Ca2+/CaM-Ca2+/CaMKII cascade. Taken together, these findings suggest that the GXNT may have exerted their vasodilative effect by activating the endothelial CaMKII/eNOS signaling pathway in endothelium-intact rings and calcium-related ion channels in endothelium-denuded vessels.

Guanxinning Tablet Attenuates Coronary Atherosclerosis via Regulating the Gut Microbiota and Their Metabolites in Tibetan Minipigs Induced by a High-Fat Diet

“…GXNT is clinically used for treating CHD and ischemic cardiomyopathy with significant curative effects [13]. Our previous pharmacological experiments confirmed that GXNT has the functions of reducing whole blood viscosity, improving blood rheology abnormalities, antimyocardial ischemia, antithrombosis, and vasodilation [14][15][16][17][18][19]. In this study, we established a CA model induced by a HF diet in Tibetan minipigs and simultaneously interfered with GXNT.…”

Molecular targets and mechanisms of Guanxinning tablet in treating atherosclerosis: Network pharmacology and molecular docking analysis

“…[ 10 ] Yun Ling et al found that opening of calcium and potassium channels in vascular smooth muscle cells (VSMCs) and activation of CaMKII/eNOS signaling pathway in vascular endothelial cells were significant mechanisms by which GXNT facilitated vasodilation. [ 11 ] The promotion of angiogenesis is a potential effect of GXNT observed in a study, which suggest that this may be due to the interaction between Salvianolic acid B and ferulic acid. [ 12 ] GXNT treatment can promote the restoration of various blood lipid indices as well as levels of VEGF, ET-1, and NO, thereby contributing to the protection of vascular endothelium.…”

Investigation Driven by Network Pharmacology on Potential Components and Mechanism of DGS, a Natural Vasoprotective Combination, for the Phytotherapy of Coronary Artery Disease

“…DGS was composed of three Chinese medicinal materials, namely, Salviae Miltiorrhizae Radix et Rhizoma (Danshen), Puerariae Lobatae Radix (Gegen), and Crataegi Folium (Shanzhaye). Modern pharmacological studies have shown that Danshen can increase blood flow [9], improve circulation [10], and preserve endothelial function [11]. Danshen is the most representative herbal medicine in the Chinese medicine formula repertoire for the treatment of ischemic diseases [12].…”