endothelin-1 and tetramethylpyrazine

To explore the mechanisms involved in the ligustrazine alleviation of the pulmonary artery hypertension (PAH) in patients of chronic obstructive pulmonary disease (COPD) associated with chronic cor pulmonale (CCP) during exacerbation.. Seventy patients of COPD and CCP with acute exacerbation were randomly and equally divided into control group and treatment group. The control group received standard treatment with antibiotics, antiasthmatic and expectorant medications, and oxygenation; and the ligustrazine treatment group received ligustrazine treatment (80 mg/d; i.v.; for 2 weeks) in addition to the standard treatment. Before and at the end of 2 week treatment, the clinic responses of the two regimens were evaluated, plasma levels of endothelin-1 (ET-1) and nitric oxide (NO) were determined; arterial oxygen partial pressure (PaO2, mean pulmonary arterial pressure (mPAP), outflow tract of right ventricle (RVOT), and internal diameter of right ventricle (RV) were measured.. Good clinic benefits were achieved in both the standard and ligustrazine regimens, plasma level of ET-1, values of mPAP, RV and RVOT decreased significantly, plasma level of NO and PaO2 values decreased (all P < 0.01 vs pre-treatment to all parameters). Compared with the control group, ligustrazine greatly enhanced the clinic efficacy from 77.1% to 97.1% (P < 0.05), and also resulted in more significant changes of all these parameters (P < 0.01 vs control group for all parameters). For both groups, the levels of plasma ET-1 were positively correlated with values of mPAP, RVOT, and RV (r = 0.710, 0.853, and 0.766, respectively, all P = 0.000), and negatively correlated with plasma NO and PaO2 (r = - 0.823, and - 0.752, respectively, all P = 0.000).. Ligustrazine is effective in treating pulmonary artery hypertension during acute exacerbation of COPD and CCP in patients from the plateau area. The observed changes in the plasma levels of NO and ET-1 in response to ligustrazine treatment suggest that ligustrazine may act through the selective effect on pulmonary blood vessels to enhance the synthesis and release of NO and suppress those of ET-1 from lung vascular endothelial cells, thus reducing pulmonary artery pressure and decreasing pulmonary arterial hypertension.

Topics: Altitude; Blood Gas Analysis; Chronic Disease; Endothelin-1; Humans; Hypertension, Pulmonary; Nitric Oxide; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pyrazines; Respiration

In the present study, we used a two-kidney-two-clip (2k2c) stroke-prone renovascular hypertension rat model (RHRSP) to investigate the protective effects of ligustrazine (TMP) on cerebral arteries and to examine PI3K/Akt pathway behavior under this protection.. The cerebral artery remodeling was induced by 2k2c-induced renovascular hypertension. Brain basilar artery tissues were isolated and their histological changes were detected through H&E and EVG staining, α-SMA IHC staining, and transmission electron microscopy at four, eight, and twelve weeks after 2k2c surgery, both with and without TMP treatment. Meanwhile, the ET-1, Ang II, and NO levels in basilar arteries and plasma were determined. Furthermore, the PTEN expression and the activation of PI3K/Akt in basilar artery tissues were detected through IHC and Western Blot. In addition, the primary basilar artery smooth muscle cells (BASMCs) were cultured and TMP protection of BASMCs stimulated with ET-1/Ang II in the presence or absence of insulin-like growth factor 1 (IGF-1) was determined.. TMP attenuated basilar artery remodeling, decreased ET-1 and Ang II levels and increased NO level in basilar arteries and plasma of RHRSP rats. Moreover, TMP reduced BASMCs proliferation upon ET-1/Ang II stimulation. We also found that TMP could effectively suppress the activation of PI3K/Akt in 2k2c-RHRSP rat basilar artery and ET-1/Ang II stimulated BASMCs. Most importantly, IGF-1, as an activator of PI3K/Akt, could damage the protective effect of TMP.. TMP exerts its protective effects and prevents basilar artery remodeling in RHRSP rats at least partly through the inhibition of PI3K/Akt pathway.

Topics: Angiotensin II; Animals; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Endothelin-1; Hypertension, Renovascular; Ligation; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nitric Oxide; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Pyrazines; Rats, Sprague-Dawley; Renal Artery; Signal Transduction; Temporal Arteries; Vascular Remodeling

Recent studies showed that pathology of alcoholic encephalopathy was associated with cerebral vascular damage. TMP (tetramethyl- pyrazine) is widely used in the treatment of cerebrovascular diseases, however, it has not been reported whether TMP can relieve alcohol-induced cerebral vascular damages. The study was performed to investigate the learning and memory, cerebrovascular pathological changes and the expressions of vascular endothelial growth factor (VEGF) and serum levelsofendothelin-1 (ET-1) in the rat model of chronic alcoholic encephalopathy, and explore the effects of TMP intervention on alcoholic encephalopathy. In the present study, the rat model of chronic alcoholic encephalopathy was established by the gavage administration of alcohol; the learning and memory ability was tested by Morris water maze; the expression of VEGF was measured by RT-PCR and Western blot; and the serum levels of ET-1 was measured by radioimmunoassay. We found that alcohol intoxication impaired learning and memory, induced VEGF overexpression and increased ET 1 concentrations. TMP intervention improved learning abilities, increased the VEGF expression and reduced ET-1 level. These results indicate that TMP exhibits therapeutic effects on chronic alcoholic encephalopathy.

Topics: Alcohol-Induced Disorders, Nervous System; Animals; Cerebrovascular Circulation; Disease Models, Animal; Endothelin-1; Learning; Male; Memory; Pyrazines; Random Allocation; Rats; Rats, Wistar; Vascular Endothelial Growth Factor A; Vasodilator Agents

The aim of the research was to investigate the antiendotoxin effects of Sinomenine, Fangchinoline, Stachydrine, Chuanxionggzine, Oxymartrine and Evodiamine. Endothelial cells were challenged with 1 μg/mL LPS for 3 h then treated respectively with six alkaloids at three concentrations (1, 5 and 10 μg/mL). The cells were incubated at 37°C in a cell incubator for 21 h. The supernatants were collected and analyzed the levels of interleukin-1α (IL-1α), thromboxane B(2) (TXB(2)), endothelin-1 (ET-1) and E-selectin by ELISA kits. The results revealed that Sinomenine, Oxymartrine and Evodiamine inhibited the production of IL-1α; Stachydrine, Chuanxionggzine and Evodiamine inhibited the secretion of TXB(2); Sinomenine and Oxymartrine down-regulated ET-1 expression; Fangchinoline and Evodiamine decreased the level of E-selectin. All these changes were significant. Taken together, the data suggested that six alkaloids may effectively reduce inflammatory response via these cytokines.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents; Benzylisoquinolines; Cells, Cultured; Down-Regulation; Drugs, Chinese Herbal; E-Selectin; Endothelin-1; Endothelium, Vascular; Evodia; Humans; Interleukin-1alpha; Lipopolysaccharides; Morphinans; Proline; Pyrazines; Quinazolines; Quinolizines; Swine; Thromboxane B2

To observe the relationship between protein sythesis and cardiomyocyte viability in neonatal rats.. The protein sythesis in neonatal rat cardiomyocytes was measured according to Brandford's method, the absorbance at 490 nm (A(490 nm)) of the cells was measured with MTT assay and the cell viability evaluated by the ratio of A(490 nm) to the total cell number.. ET-1 increased cardiomyocyte protein synthesis dose-dependently, and this effect was attenuated by the application of lacidipine and tetramethylpyrazines Higher doses of ET-1 resulted in lower A(490 nm)/total cell number ratio, which was further lowered by larcidipine and tetramethylpyrazine.. The status of protein synthesis is not associated with the viability of neonatal rat cardiomyocytes.

Topics: Animals; Animals, Newborn; Calcium Channel Blockers; Cell Survival; Cells, Cultured; Dihydropyridines; Dose-Response Relationship, Drug; Endothelin-1; Myocytes, Cardiac; Protein Biosynthesis; Pyrazines; Rats; Rats, Sprague-Dawley

Tetramethylpyrazine (TMP) is the major component extracted from the Chinese herb, Chuanxiong, which is widely used in China for the treatment of cardiovascular problems. The aims of this study were to examine whether TMP may alter angiotenisn II (Ang II)-induced proliferation and to identify the putative underlying signaling pathways in rat aortic smooth muscle cells. Cultured rat aortic smooth muscle cells were preincubated with TMP and then stimulated with Ang II, [3H]-thymidine incorporation and the ET-1 expression was examined. Ang II increased DNA synthesis which was inhibited by TMP (1-100 microM). TMP inhibited the Ang II-induced ET-1 mRNA levels and ET-1 secretion. TMP also inhibited Ang II-increased NAD(P)H oxidase activity, intracellular reactive oxygen species (ROS) levels, and the ERK phosphorylation. Furthermore, TMP and antioxidants such as Trolox and diphenylene iodonium decreased Ang II-induced ERK phosphorylation, and activator protein-1 reporter activity. In summary, we demonstrate for the first time that TMP inhibits Ang II-induced proliferation and ET-1, partially by interfering with the ERK pathway via attenuation of Ang II-increased NAD(P)H oxidase and ROS generation. Thus, this study delivers important new insight in the molecular pathways that may contribute to the proposed beneficial effects of TMP in cardiovascular disease.

Topics: Angiotensin II; Animals; Aorta, Thoracic; Cell Proliferation; Cells, Cultured; DNA; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Male; Muscle, Smooth, Vascular; NADPH Oxidases; Pyrazines; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA, Messenger; Signal Transduction; Transcription Factor AP-1; Vasodilator Agents

1. Chuanxiong is a Chinese herb that has been used widely in China to treat vascular disorders. 2,3,5,6-Tetramethylpyrazine (TMP) is one of the major components purified from chuanxiong. Many studies have demonstrated that TMP is effective in the treatment of cardiovascular diseases. However, the mechanism of action by which TMP exerts relaxation in vascular vessels remains unclear. 2. Endothelin (ET)-1 is a potent vasopressor synthesised by endothelial cells both in culture and in vivo. The aims of the present study were to test the hypothesis that TMP may alter strain-induced ET-1 secretion and to identify the putative underlying signalling pathways in endothelial cells. 3. We showed that TMP inhibits strain-induced ET-1 secretion. 2,3,5,6-Tetramethylpyrazine also inhibits the strain-induced formation of reactive oxygen species (ROS) and phosphorylation of extracellular signal-regulated kinases (ERK) 1/2. Furthermore, pretreating cells with TMP or the anti-oxidant N-acetyl-cysteine decreased strain-induced increases in ET-1 secretion and ERK1/2 phosphorylation. Using a reporter gene assay, TMP and N-acetyl-cysteine were demonstrated to also attenuate the strain-induced activity of the activator protein-1 reporter. 4. In summary, we have demonstrated, for the first time, that TMP inhibits strain-induced ET-1 gene expression, in part by interfering with the ERK1/2 pathway via attenuation of ROS formation. Thus, the present study provides important new insights into the molecular pathways that may contribute to the proposed beneficial effects of TMP in the vascular system.

Topics: Cells, Cultured; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Endothelin-1; Endothelium, Vascular; Humans; Ligusticum; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Pyrazines; Reactive Oxygen Species; Transcription Factor AP-1

1. Tetramethylpyrazine (TMP) is one of the active ingredients of the Chinese herb Ligusticum wallichii Franchat. It is well documented that TMP exerts a cardiovascular protective effect. The aims of the present study were to examine whether TMP alters angiotenisn (Ang) II-induced endothelin (ET)-1 gene expression and to identify the putative underlying signalling pathways in vascular endothelial cells. 2. Cultured vascular endothelial cells were pre-incubated with TMP, stimulated with AngII and ET-1 gene expression was then examined. The effects of TMP pretreatment on AngII-induced extracellular signal-regulated kinase (ERK) phosphorylation were investigated to elucidate the intracellular mechanism responsible for the effects of TMP on ET-1 gene expression. 3. Tetramethylpyrazine inhibited AngII-induced ET-1 gene expression, as revealed by nothern blotting and a promoter activity assay. Tetramethylpyrazine also inhibited the AngII-induced increase in intracellular reactive oxygen species (ROS), as measured by the redox sensitive fluorescent dye 2' 7'-dichlorofluorescin diacetate and ERK phosphorylation. 4. In summary, we have demonstrated, for the first time, that TMP inhibits AngII-induced ROS generation, ERK phosphorylation and ET-1 gene expression in vascular endothelial cells. Thus, the present study delivers important new insights into the molecular pathways that may contribute to the proposed beneficial effects of TMP in the cardiovascular system.

Topics: Angiotensin II; Antioxidants; Blotting, Northern; Blotting, Western; Cells, Cultured; Chloramphenicol O-Acetyltransferase; Down-Regulation; Endothelial Cells; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Gene Expression; Humans; Phosphorylation; Promoter Regions, Genetic; Pyrazines; Reactive Oxygen Species; Recombinant Fusion Proteins; RNA, Messenger; Superoxides; Transfection

To study the protective effect of Ligustrazine on IR after local cerebral ischemia of rat.. Models of rat IR after local cerebral ischemia were prepared by electrocagulation of the middle cerebral artery, and changes of serum insulin, tomer necrosis factor-alpha (TNF-alpha), plasma endothelin-1 (ET-1), nitric oxide (NO) and nitric oxide synthase (NOS) were observed 2 weeks after the ischemia.. Ligustrazine could significantly reduce serum insulin (P < 0.01), the content of plasma ET-1 (P < 0.01) and serum TNF-alpha (P < 0.01), the activity of brain tissue NO and NOS (P < 0.01). The drug also increased insulin sensitivity indexes (ISI).. The protective effects of Ligustrazion on IR cerebral ischemia may be related to decreasing ET-1 content in plasma, TNF-alpha content in serum, NO content and NOS activities in tissue.

Topics: Animals; Brain Ischemia; Endothelin-1; Female; Infarction, Middle Cerebral Artery; Insulin; Insulin Resistance; Male; Neuroprotective Agents; Pyrazines; Random Allocation; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Tumor Necrosis Factor-alpha

To investigate the protective effects of ligustrazine on renal ischemia-reperfusion injury, the influence of ligustrazine injection on plasma superoxide dismutase (SOD), malondialdehyde (MDA), and endothelin-1 (ET-1), as well as changes of morphology of renal tubules, were studied in rat kidney models with ischemia-reperfusion injury. The results showed that in the group treated with ligustrazine, the plasma SOD level was significantly higher than that of the control group (P < 0.05), but levels of plasma MDA and ET-1 and the pathological grading of injured renal tubules were significantly lower than those in the control group (P < 0.05). These findings suggest that ligustrazine has protective effects against ischemia-reperfusion injury in rat kidneys.

Topics: Animals; Disease Models, Animal; Endothelin-1; Free Radical Scavengers; Kidney; Kidney Diseases; Malondialdehyde; Pyrazines; Random Allocation; Rats; Rats, Wistar; Renal Artery; Reperfusion Injury; Superoxide Dismutase

To study the therapeutic mechanism of combination therapy of ligustrazine and nitrendipine in treating patients with chronic obstructive pulmonary disease (COPD).. Thirty COPD patients divided in to 3 groups (10 in each) were treated with ligustrazine, nitrendipine and ligustrazine plus nitrendipine respectively, and the changes of hemorrheologic parameters, plasma endothelin (ET-1), thromboxane A2(TXA2) and platelet-P-selectin (CD62P) before and after treatment were observed.. The combination therapy of ligustrazine and nitrendipine could lower the levels of plasma ET-1, TXA2, CD62P and the hemorrheologic parameters.. Combination of ligustrazine and nitrendipine showed a therapeutic effect better than that of the two drugs used separately. Its effect in lowering pulmonary circulation resistance is related with the lowering of plasma vaso-contrictive factor and the changing of hemorrheologic properties. The integrated traditional Chinese and western medical therapy is valuable in treating COPD.

Topics: Aged; Drug Therapy, Combination; Endothelin-1; Female; Humans; Male; Middle Aged; Nitrendipine; P-Selectin; Pulmonary Disease, Chronic Obstructive; Pyrazines; Thromboxane B2; Vasodilator Agents

To investigate the effects of chronic hypoxic hypercapnia and ligustrazine on expression of endothelin-1 (ET-1) mRNA and the ultrastructure of pulmonary arterioles in rats.. Thirty rats were randomly divided into three groups: control group (A), hypoxic hypercapnic group (B), hypoxic hypercapnia + ligustrazine (lig.) group (C). ET-1 mRNA was observed in arterioles from rats by the technique of in situ hybridization. The average value of integral light density (LD) of ET-1 mRNA in pulmonary arterioles was detected by an image analysor and the relative content of ET-1 mRNA was calculated.. (1) mPAP was significantly higher in rats of B group than that of A group (P < 0.01) and it was much lower in rats of C group than that of B group (P < 0.01). Differences of mCAP were not significant in three groups (P > 0.05); plasma ET-1 concentration was significantly higher in rats of B group than that of A group (P < 0.01), plasma ET-1 concentration was significantly lower in rats of C group than that of B group (P < 0.01); (2) Light microscopy showed that WA/TA (vessel wall area/total area) and SMC (the density of medial smooth muscle cells) were significantly higher in rats of B group than those of A group (P < 0.01). WA/TA and SMC were significantly lower in rats of C group than those of B group (P < 0.01). Electron microscopy showed proliferation of medial smooth muscle cells and collageous fibers of pulmonary arterioles in rats of B group, and ligustrazine could reverse the changes mentioned above; (3) Hybridization in situ showed that LD of ET-1 mRNA in pulmonary arterioles was significantly higher in rats of B group than that of A group (P < 0.01); LD of ET-1 mRNA in pulmonary arterioles was significantly lower in rats of C group than that of B group (P < 0.01).. Increase of expression of ET-1 mRNA in pulmonary arterioles contributes to the development of pulmonary hypertension and structural remodeling of pulmonary arteries in chronic hypoxic hypercapnic rats. Ligustrazine can inhibit pulmonary hypertension by decreasing the expression of ET-1 mRNA in pulmonary arterioles.

Topics: Animals; Arterioles; Endothelin-1; Hypercapnia; Hypoxia; Male; Pulmonary Artery; Pyrazines; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger

The purpose of this study was to investigate effects of tetramethylpyrazine (TMP), a Chinese plant-derived medicine, on coronary vasoconstriction and related electrocardiographic and histologic changes caused by endothelin-1 (ET-1), and on plasma ET-1 levels. ET-1 (75 pmol) was administered into the left coronary artery (LCA) in anesthetized closed-chest dogs with and without prior infusion of TMP (80 mg/kg). Coronary arterial diameter (CAD) was determined by coronary arteriography (CAG). Blood pressure and electrocardiogram (ECG) were monitored continuously. Histologic damage in tissues was ascertained microscopically. Plasma ET-1 and 6-keto-PGF1 levels were determined by RIA 90 min after i.v. injection of TMP (25 mg/kg; n = 5) in rabbits. Intracoronary injection of ET-1 resulted in a significant vasoconstriction of the entire vascular bed of the LCA, with a decrease in CAD of 35.9 +/- 5.7% (n = 5; p < 0.01) and ischemic changes on ECG and in tissues of endocardium, myocardium, coronary endothelial cells, and capillary vessels. Pretreatment with TMP produced a significant increase in CAD by 38.5 +/- 7.8% (n = 5; p < 0.01) and greatly suppressed the vasoconstriction produced by ET-1. The myocardial tissue damage estimated from the ratio of ischemic area for the entire area after ET-1 injection (35.6%) was completely abolished by TMP (0.6%). In addition, TMP injection induced a significant decrease in plasma ET-1 levels and an increase in 6-keto-PGF1 levels in rabbits. The Chinese medicine TMP could be a useful therapeutic agent in ischemic heart disease by suppressing coronary vasoconstriction and ischemic changes in the tissues produced by ET-1.

Topics: 6-Ketoprostaglandin F1 alpha; Angiography; Animals; Coronary Vessels; Dogs; Drugs, Chinese Herbal; Electrocardiography; Endothelin-1; Male; Pyrazines; Rabbits; Vasoconstriction; Vasodilator Agents

Our study was designed to elucidate the effects of tetramethylpyrazine (TMP), a Chinese medicine, on plasma endothelin-1 (ET-1) levels in dogs with acute pulmonary alveolar hypoxia. Anesthetized dogs were used under artificial ventilation with room air or a hypoxic gas mixture (10% O2 and 90% N2) (n = 10) for 60 min. Effects of TMP (80 mg/kg) were studied by i.v. injection of TMP before exposure to hypoxia (n = 8). Mean pulmonary arterial pressure (PAPm), systemic arterial pressure (SAPm), right atrial pressure (RAP), pulmonary capillary wedge pressure (PCWP), cardiac output (CO), and heart rate (HR) were measured. The pulmonary vascular resistance (PVR) was calculated by the equation of (PAPm-PCWP) x 8/CO. Plasma ET-1 levels were determined in the abdominal aorta and pulmonary artery by RIA. The effects of TMP on PAP and plasma ET-1 level were evaluated by using percent increase in PAPm and the change of Da-pET (delta ET) before and after hypoxia. Both PAPm and PVR were significantly elevated 5 min after acute hypoxia over a period of 60 min, whereas CO and PCWP did not change. Plasma ET-1 levels in the abdominal aorta and Da-pET showed a significant increase. Administration of TMP significantly decreased the hypoxia-induced increase in the PAPm, PVR, and delta ET. These results suggest that TMP could be a useful therapeutic agent in the treatment of pulmonary hypertension induced by acute hypoxia through decrease of plasma ET-1 levels.

Topics: Anesthesia, General; Animals; Blood Pressure; Dogs; Drugs, Chinese Herbal; Endothelin-1; Hemodynamics; Hypoxia; Lung Diseases; Pulmonary Alveoli; Pulmonary Circulation; Pyrazines; Vascular Resistance; Vasodilator Agents

The purpose of this study was to determine the antagonistic effect of tetramethyl pyrazine (TMP), a sort of chinese herbal medicine, on coronary vasoconstriction induced by endothelin-1 (ET-1) in closed chest dogs. ET-1 at doses of 50, 75 and 100 pmol was selectively administered into left main coronary artery and coronary angiogram was performed in 1, 3 and 10 minutes after intracoronary administration of ET-1. After a 60 minute interval ET-1 administration and coronary angiogram were repeated in two groups in group A with 5 dogs intravenous infusion of saline solution was administered while in group B with 4 dogs TMP was infused at a dose of 80 mg/kg. Blood pressure of intra-femoral artery, heart rate and ECG were monitored during the experiment. The study demonstrated that coronary vessel diameter significantly decreased by 17% (P < 0.02) in group A and 20% (P < 0.02) in group B, associated with ischemia in ECG (4/5 in group A and 3/4 in group B) after intracoronary administration of ET-1. Endothelin-1 induced coronary vasoconstriction and ischemic changes in ECG were significantly inhibited by intravenous TMP. The coronary diameter increased by 20% (P < 0.03) after administration of TMP, comparing with the control group. Heart rate had an increased response to TMP. In conclusion this study demonstrated that intracoronary administration of ET-1 caused significant myocardial ischemia through coronary vasoconstriction, which was inhibited by TMP. TMP significantly dilated coronary artery.

Topics: Animals; Coronary Angiography; Coronary Vessels; Dogs; Endothelin-1; Heart Rate; Male; Myocardial Ischemia; Pyrazines; Vasoconstriction; Vasodilator Agents