Study of screening,transport pathway,and vasodilation mechanisms on angiotensin-Ⅰconverting enzyme inhibitory peptide from Ulva prolifera proteins

In this study,Ulva prolifera protein was used for preparing angiotensin-I converting enzyme(ACE)-inhibitory peptide via virtual gastrointestinal digestion and in silico screening.Some parameters of the obtained peptide,such as inhibition kinetics,docking mechanism,stability,transport pathway,were explored by Lineweaver-Burk plots,molecular docking,in vitro stimulate gastrointestinal(GI)digestion and Caco-2 cells monolayer model,respectively.Then,a novel anti-ACE peptide LDF(IC_(50),(1.66±0.34)μmol/L)was screened and synthesized by chemical synthesis.It was a no-competitive inhibitor and its anti-ACE inhibitory effect mainly attributable to four Conventional Hydrogen Bonds and Zn701 interactions.It could keep activity during simulated GI digestion in vitro and was transported by peptide transporter PepT1 and passive-mediated mode.Besides,it could activate Endothelial nitric oxide synthase(eNOS)activity to promote the production of NO and reduce Endothelin-1(ET-1)secretion induced by AngiotensinⅡ(AngⅡ)in Human Umbilical Vein Endothelial Cells(HUVECs).Meanwhile,it could promote mice splenocytes proliferation in a concentration-dependent manner.Our study indicated that this peptide was a potential ingredient functioning on vasodilation and enhancing immunity.

Antiplatelet Aggregation and Vasodilation Effects of RGDS

In an attempt to demonstrate the biological activities of a short peptide.Arg-Gly-Asp- Ser (RGDS) was synthesized and used for bioassay,The data obtained here proved that RGDS ob- viously inhibited PAF- and/or ADP-induced platelet aggregation.The present paper revealed that RG- DS had vasodilative action and the cGMP accumulation may be one of the mechanisms of RGDS exer- ting bioactivities.

Physiopathology of splanchnic vasodilation in portal hypertension

In liver cirrhosis, the circulatory hemodynamic alterations of portal hypertension signifi cantly contribute to many of the clinical manifestations of the disease. In the physiopathology of this vascular alteration, mesen- teric splanchnic vasodilation plays an essential role by initiating the hemodynamic process. Numerous studies performed in cirrhotic patients and animal models have shown that this splanchnic vasodilation is the result of an important increase in local and systemic vasodilators and the presence of a splanchnic vascular hyporesponsiveness to vasoconstrictors. Among the molecules and factors known to be potentially involved in this arterial vasodilation, nitric oxide seems to have a crucial role in the physiopathology of this vascular alteration. However, none of the wide variety of mediators can be described as solely responsible, since this phenomenon is multifactorial in origin. Moreover, angiogenesis and vascular remodeling processes alsoseem to play a role. Finally, the sympathetic nervous system is thought to be involved in the pathogenesis of the hyperdynamic circulation associated with portal hypertension, although the nature and extent of its role is not completely understood. In this review, we discuss the different mechanisms known to contribute to this complex phenomenon.

Role of HSP-90 for increased nNOS-mediated vasodilation in mesenteric arteries in portal hypertension

AIM:To explore the role of heat shock protein-90 (HSP-90) for nitrergic vasorelaxation in the splanchnic circulation in rats with and without portal hypertension. METHODS: Neuronal nitric oxide synthase (nNOS) and HSP-90 were analyzed by immunofluorescence, western blotting and co-immunoprecipitation in the mesenteric vasculature and isolated nerves of portal-vein-ligated (PVL) rats and sham operated rats. In vitro perfused de-endothelialized mesenteric arterial vasculature was preconstricted with norepinephrine (EC80) and tested for nNOS-mediated vasorelaxation by periarterial nerve stimulation (PNS, 2-12 Hz, 45V) before and after incubation with geldanamycin (specific inhibitor of HSP-90 signalling, 3 μg/mL) or L-NAME (non-specific NOSblocker, 10-4 mol/L). RESULTS: nNOS and HSP-90 expression was significantly increased in mesenteric nerves from PVL as compared to sham rats. Moreover, nNOS and HSP-90 were visualized in mesenteric nerves by immunofluorescence and immunoprecipitation of nNOS co-immunoprecitated HSP-90 in sham and PVL rats. PNS induced a frequencydependent vasorelaxation which was more pronounced in PVL as compared to sham rats. L-NAME and geldanamycin markedly reduced nNOS-mediated vasorelaxation abrogating differences between the study groups. The effect of L-NAME and geldanamycin on nNOS-mediated vasorelaxation was significantly greater in PVL than in sham animals. However, no difference in magnitude of effect between L-NAME and geldanamycin was noted. CONCLUSION: HSP-90 acts as a signalling mediator of nNOS-dependent nerve mediated vascular responses in mesenteric arteries, and the increased nitrergic vasorelaxation observed in portal hypertension is mediated largely by HSP-90.

Voluntary Thigh Muscle Strength with Resection Stump-Dependent Blood Flow and Vasodilation in an Amputated Lower Leg with Total Surface Bearing Prosthesis during Dynamic Knee Extensor: A Case Trial

Background: The magnitude of the hyperemic response due to repeated thigh stump exercise on incremental contraction intensity might be useful information in localized exercise tolerance for devising cardiovascular physical therapy for amputees. The effect of exercise on amputated leg blood flow (LBF) may potentially be altered due to voluntary muscle contractions after loss of the lower leg compared with the healthy leg. Case Presentation: A 57-year-old male patient with Burger disease attempted 3 min unilateral repeat/dynamic knee extensor exercise at a target muscle contraction frequency (1 s thigh muscle contraction and 1 s relaxation, 90 repetitions) with each leg <right transtibial amputated leg (AL) using a total surface-bearing prosthesis (TSB) and left non-AL> at six different contraction intensities (rubber resistance belt). Simultaneous measurement of blood velocity/flow (Doppler ultrasound) in the femoral artery, blood pressure, leg vascular conductance (LVC), and peak muscle strength (PMS) were performed during the 3 min exercise period. The maximum voluntary contraction by one-legged isometric knee muscle contraction was 14.7 kg in non-AL and 7.9 kg in the AL with prosthesis. The relative PMS was defined as “PMS/maximum voluntary contraction × 100 (%)”. Pre-exercise LBF was lower in the AL (200 ± 25 ml/min) than the non-AL (275 ± 74 ml/min). Both the non-AL and AL showed good positive linear relationships between absolute-/relative-PMS and LBF or LVC during 30 s at steady-state before the end of the exercise period. Furthermore, there was also similarity seen in the increase rate in LBF and/or LVC for the incremental relative PMS compared with the absolute PMS. Conclusion: In this case, the muscle strength depended on blood flow increase/vasodilation was seen in this “AL” using a TSB prosthesis for repeated dynamic knee extensor exercise. The present amputee’s limb muscle strengthening with the resection stump closely related to the degree of hyperemia in the amputated limb.

Vasodilation Effects of RGD Containing Peptides and De rivatives

The binding of Fgn to GPIIb / IIIa has confirmed that there are two distinct amino acid sequences within the Fgn molecule that are responsible for mediating its attachment to GP IIb / IIIa receptor. In addition to monoclonal antibodies, the binding function of GP IIb / IIIa can be blocked by synthetic small peptides containing the RGD and APLRV sequence. In our preliminary study it was found that besides inhibition of platelet aggregation and thrombus formation RGDS showed vasodilation effects as well. In an attempt to confirm the vasodilation effect of RGDS related peptides, RGDF, APLRV, APLRVRGDS and APLRVRGDF were investigated. The effects of these synthetic peptides on rat aortic strips pretreated with NE in vitro were observed. The relaxing extents of contracted strips for the peptides at three doses (10 5 mol / L, 10 6 mol / L and 10 7 mol / L) were recorded.

Resveratrol Reverses the Impaired Vasodilation Observed in 2K-1C Hypertension through Endothelial Function Improvement

Background: The production of endothelial-derived factors induces either vasoconstriction or vasodilation;nitric oxide (NO) is the most distinguished relaxing factor. Endothelial dysfunction is associated with hypertension. The partial loss in the NO-promoted vasodilation is due to its decreased bioavailability and/or to an activity reduction of endothelium NO synthase (eNOS). Reactive oxygen species (ROS), present in oxidative stress, seize NO and diminish its bioavailability. Transresveratrol (RESV) has been proved to increase NO and eNOS levels. Thus, RESV could be capable of improving NO dependent vascular relaxation on aortic rings isolated from treated 2K-1C animals through ROS damage reduction. Aim: Evaluate the effects of RESV treatment on the relaxation of aortic rings isolated from treated 2K-1C rats while focusing on the effects of the treatment on systolic blood pressure. Methods: Male Wistar rats (180 g) were grouped: two 2K-1C and two Sham groups, one of each was treated with RESV (20 mg/kg, gavage) dissolved in Tween 80 and one of each was treated with water plus Tween 80 (control) for six weeks. The rats had their systolic blood pressure (SBP) measured before and after the treatments. Vascular reactivity studies were conducted in order to observe and compare acetylcholine (ACh)-induced relaxations in the presence and absence of the NOS inhibitor L-NAME (10-4 mol/L). Results: SBP for 2K-1C was significantly reduced in the treated group (179.13 ± 4.90 mmHg, n = 23) when compared to the untreated group (196.66 ± 6.06 mmHg, n = 15, p < 0.01). The maximum relaxation of aortic rings isolated from the 2K-1C treated group showed a higher efficacy (116.63% ± 1.72%, n = 12) than that from the untreated group (85.97% ± 0.69%, n = 6, p < 0.001);L-NAME exposure was responsible for a significant decrease in each group’s maximum relaxation efficacy. Conclusions: SBP reduction observed after RESV treatment in rat renal hypertension could be due to the reestablishment of vascular relaxation depend of NO.

Absorbed Bioactive Compounds Replicate GuanxinⅡ-Induced Endothelium-Associated in/ex vivo Vasodilation

Objective:To develop an interference-free and rapid method to elucidate GuanxinⅡ(GXⅡ)'s representative vasodilator absorbed bioactive compounds(ABCs)among enormous phytochemicals.Methods:The contents of ferulic acid,tanshinol,and hydroxysafflor yellow A(FTA)in GXⅡ/rat serum after the oral administration of GXⅡ(30 g/kg)were detected using ultra-performance liquid chromatography-mass spectrometry.Totally 18 rats were randomly assigned to the control group(0.9%normal saline),GXⅡ(30 g/kg)and FTA(5,28 and 77 mg/kg)by random number table method.Diastolic coronary flow velocity-time integral(VTI),i.e.,coronary flow or coronary flow-mediated dilation(CFMD),and endothelium-intact vascular tension of isolated aortic rings were measured.After 12 h of exposure to blank medium or 0.5 mmol/L H_(2)O_(2),endothelial cells(ECs)were treated with post-dose GXⅡof supernatant from deproteinized serum(PGSDS,300μL PGSDS per 1 m L of culture medium)or FTA(237,1539,and 1510 mg/m L)for 10 min as control,H_(2)O_(2),PGSDS and FTA groups.Nitric oxide(NO),vascular endothelial growth factor(VEGF),endothelin-1(ET-1),superoxide dismutase(SOD),malondialdehyde(MDA)and phosphorylated phosphoinositide 3 kinase(p-PI3K),phosphorylated protein kinase B(p-AKT),phosphorylated endothelial nitric oxide synthase(p-e NOS)were analyzed.PGSDS was developed as a GXⅡproxy of ex vivo herbal crude extracts.Results:PGSDS effectively eliminates false responses caused by crude GXⅡpreparations.When doses equaled the contents in GXⅡ/its post-dose serum,FTA accounted for 98.17%of GXⅡ-added CFMD and 92.99%of PGSDS-reduced vascular tension.In ECs,FTA/PGSDS was found to have significant antioxidant(lower MDA and higher SOD,P<0.01)and endothelial function-protective(lower VEGF,ET-1,P<0.01)effects.The increases in aortic relaxation,endothelial NO levels and phosphorylated PI3K/Akt/e NOS protein induced by FTA/PGSDS were markedly abolished by NG-nitro-L-arginine methyl ester(L-NA,e NOS inhibitor)and wortmannin(PI3K/AKT inhibitor),respectively,indicating an endothelium-dependent vasodilation via the PI3K/AKT-e NOS pathway(P<0.01).Conclusion:This study provides a strategy for rapidly and precisely elucidating GXⅡ's representative in/ex vivo cardioprotective absorbed bioactive compounds(ABCs)-FTA,suggesting its potential in advancing precision ethnomedicine.

Pharmacodynamic Mechanism of Kuanxiong Aerosol for Vasodilation and Improvement of Myocardial Ischemia

Objective: To explore the effect of Kuanxiong Aerosol(KXA)on isoproterenol(ISO)-induced myocardial injury in rat models.Methods: Totally 24 rats were radomly divided into control,ISO,KXA low-dose and high-dose groups according to the randomized block design method,and were administered by intragastric administration for 10 consecutive days,and on the 9th and 10th days,rats were injected with ISO for 2 consecutive days to construct an acute myocardial ischemia model to evaluate the improvement of myocardial ischemia by KXA.In addition,the diastolic effect of KXA on rat thoracic aorta and its regulation of ion channels were tested by in vitro vascular tension test.The influence of KXA on the expression of calcium-CaM-dependent protein kinase Ⅱ(CaMK Ⅱ)/extracellular regulated protein kinases(ERK)signaling pathway has also been tested.Results: KXA significantly reduced the ISO-induced increase in ST-segment,interventricular septal thickness,cardiac mass index and cardiac tissue pathological changes in rats.Moreover,the relaxation of isolated thoracic arterial rings that had been precontracted using norepinephrine(NE)or potassium chloride(KCl)was increased after KXA treatment in an endothelium-independent manner,and was attenuated by preincubation with verapamil,but not with tetraethylammonium chloride,4-aminopyridine,glibenclamide,or barium chloride.KXA pretreatment attenuated vasoconstriction induced by CaCl_(2)in Ca^(2+)-free solutions containing K^(+) or NE.In addition,KXA pretreatment inhibited accumulation of Ca^(2+)in A7r5 cells mediated by KCl and NE and significantly decreased p-CaMK Ⅱ and p-ERK levels.Conclusion: KXA may inhibit influx and release of calcium and activate the CaMK Ⅱ/ERK signaling pathway to produce vasodilatory effects,thereby improving myocardial injury.

Hypoadiponectinemia predicts impaired endothelium-independent vasodilation in newly diagnosed type 2 diabetic patients： an 8-year prospective study

Background Adiponectin is an adipokine with insulin-sensitising and anti-atherogenic properties. The aim of this study was to investigate whether low adiponectin levels predict the impairment of endothelial function in newly diagnosed type 2 diabetic patients in an 8-year prospective study. Methods In the prospective study, we enrolled 133 newly diagnosed type 2 diabetic patients without subclinical atherosclerosis and gave them intensive therapy; the mean treatment period was 8 years. Intensive treatment was a stepwise implementation of behavior modification and pharmacological therapy targeting hyperglycaemia, hypertension, dyslipidaemia and obesity. We measured baseline circulating adiponectin with an enzyme-linked immunosorbent assay, endothelium-dependent and -independent vasodilation by high-resolution vascular ultrasound. At year 8, 102 patients were reexamined for endothelium-dependent and -independent vasodilation. Results Sex-adjusted adiponectin level was positively correlated with endothelium-independent vasodilation both at baseline （r=0.150, P=0.043） and at year 8 （r=0.339, P=0.001）, whereas no association was found between adiponectin and endothelium-dependent vasodilation. In a stepwise multivariate linear regression model, adiponectin was an independent predictor for impaired endothelium-independent vasodilation at year 8 （P=0.001）. Conclusions Plasma adiponectin concentration was associated with endothelium-independent vasodilation and hypoadiponectinemia predicted the impairment of endothelium-independent vasodilation in newly diagnosed type 2 diabetic patients under multifactorial intervention. These data support the causative link of impairment of endothelium-independent vasodilation with hypoadiponectinemia.

Estrogen-Induced Uterine Vasodilation in Pregnancy and Preeclampsia

Normal pregnancy is associated with dramatically increased estrogen biosynthesis whose role is believed to raise uterine blood flow to facilitate the bi-directional maternal-fetal exchanges of gases(O_(2) and CO_(2)),to deliver nutrients,and exhaust wastes to support fetal development and survival.Constrained uterine blood flow in pregnancy is a leading cause of preeclampsia with fetal growth restriction,rendering investigations of uterine hemodynamics to hold a high promise to inform pathways as targets for therapeutic interventions for preeclampsia.The mechanisms of estrogen-induced uterine vasodilation in pregnancy have long been attributed to enhanced endothelium production of nitric oxide,but clinical trials targeting this pathway that dominates uterine hemodynamics have achieved no to little success.Emerging evidence has recently shown a novel proangiogenic vasodilatory role of hydrogen sulfide in regulating uterine hemodynamics in pregnancy and preeclampsia,provoking a new field of perinatal research in searching for alternative pathways for pregnancy disorders especially preeclampsia and intrauterine growth restriction.This minireview is intended to summarize the nitric oxide pathway and to discuss the emerging hydrogen sulfide pathway in modulating estrogen-induced uterine vasodilation in pregnancy and preeclampsia.

Comparative effects of lovastatin and L-arginine on endothelium-dependent vasodilation and atherosclerosis in hypercholesterolemic rabbit

Objectives To investigate whether lovastatin improves endothelium dependent relaxation and decreases atherosclerosis in hypercholesterolemic animals, as compared with L arginine. Methods Forty male rabbits, randomized into four groups with ten in each group, were fed with one of the following diets: ① normal rabbit chow; ② 1% cholesterol diet; ③ 1% cholesterol diet supplemented with 2.25 g/kg L arginine soluble in the physiological salt solution (PPS) by gavage; ④ 1% cholesterol diet supplemented with 10 mg/kg lovastatin soluble in the PSS by gavage. The rabbits were fed with these diets for 10 weeks, and blood samples were collected from animals for biochemical studies. Then aortic rings were obtained, and changes in isometric tension were recorded. Intimal atherosclerotic areas of the aortae were subsequently measured by planimetry. Results Serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL C) levels were lower￣ ed (30%±6%, 39%±4%, respectively) and high Department of Cardiovascular Internal Medicine, First Affiliated Hospital, Henan Medical University, Zhengzhou 450052, China (Zhang JY, Dong JZ, Li L, Zhao LS, Huang ZW, Wei JH and Liu RY) This work was supported by the Education Committee of Henan Province, China, and a grant from the Henan Science and Technology Committee. density lipoprotein cholesterol (HDL C) elevated (11%±3%) in the rabbits receiving 1% cholesterol diet supplemented with lovastatin, compared with those (including TC, LDL C, and HDL C) in the rabbits receiving 1% cholesterol diet and 1% cholesterol diet supplemented with L arginine, with alteration to the same degree. Endothelium dependent relaxations to acetylcholine were significantly impaired in aortae from the animals fed with a 1% cholesterol diet. By contrast, vessels from the hypercholesterolemic animals both receiving L arginine and lovastatin supplementation revealed significantly improved endothelium dependent relaxations. In addition, vessels from the hypercholesterolemic animals receiving L arginine were superior to those from those receiving lovastatin. Histomorphometric analysis showed a reduction in lesion surface area in aortae from the arginine and lovastatin supplemented animals compared to those from untreated hypercholesterolemic rabbits, moreover, lesion surface areas in aortae from both the arginine and lovastatin supplemented animals were similar (P>0.05). Conclusions This study demonstrates that lovastatin could improve endothelium dependent vasorelaxation. By contrast, L arginine is superior to lovastatin, but a reduced surface area in aortae is not different between the two drugs.

Magnesium:pathophysiological mechanisms and potential therapeutic roles in intracerebral hemorrhage

Intracerebral hemorrhage(ICH) remains the second-most common form of stroke with high morbidity and mortality.ICH can be divided into two pathophysiological stages:an acute primary phase,including hematoma volume expansion,and a subacute secondary phase consisting of blood-brain barrier disruption and perihematomal edema expansion.To date,all major trials for ICH have targeted the primary phase with therapies designed to reduce hematoma expansion through blood pressure control,surgical evacuation,and hemostasis.However,none of these trials has resulted in improved clinical outcomes.Magnesium is a ubiquitous element that also plays roles in vasodilation,hemostasis,and blood-brain barrier preservation.Animal models have highlighted potential therapeutic roles for magnesium in neurological diseases specifically targeting these pathophysiological mechanisms.Retrospective studies have also demonstrated inverse associations between admission magnesium levels and hematoma volume,hematoma expansion,and clinical outcome in patients with ICH.These associations,coupled with the multifactorial role of magnesium that targets both primary and secondary phases of ICH,suggest that magnesium may be a viable target of study in future ICH studies.

Adrenomedullin in cirrhotic and non-cirrhotic portal hypertension

AIM:Adrenomedullin (ADM) is a potent vasodilator peptide. ADM and nitric oxide (NO) are produced in vascular endothelial cells.Increased ADM level has been linked to hyperdynamic circulation and arterial vasodilatation in cirrhotic portal hypertension (CPH).The role of ADM in non-cirrhotic portal hypertension (NCPH) is unknown,plasma ADM levels were studied in patients with NCPH,compensated and decompensated cirrhosis in order to determine its contribution to portal hypertension (PH) in these groups. METHODS:There were 4 groups of subjects.Group 1 consisted of 27 patients (F/M:12/15) with NCPH due to portal and/or splenic vein thrombosis (mean age:41±12 years),group 2 consisted of 14 patients (F/M:6/8) with compensated (Child-Pugh A) cirrhosis (mean age:46±4), group 3 consisted of 16 patients (F/M:6/10) with decompensated (Child-Pugh C) cirrhosis (mean age:47±12). Fourteen healthy subjects (F/M:6/8) (mean age:44±8) were used as controls in Group 4.ADM level was measured by ELISA.NO was determined as nitrite/nitrate level by chemoluminescence. RESULTS:ADM level in Group 1 (236±61.4 pg/mL) was significantly higher than that in group 2 (108.4±28.3 pg/mL) and group 4 (84.1±31.5 pg/mL) (both P<0.0001) but was lower than that in Group3 (324±93.7 pg/mL) (P=0.002).NO level in group 1 (27±1.4 μmol/L) was significantly higher than that in group 2 (19.8±2.8 μmol/L) and group 4 (16.9±1.6 μmol/L) but was lower than that in Group 3 (39±3.6 μmol/L) (for all three P<0.0001).A strong correlation was observed between ADM and NO levels (r=0.827,P<0.0001). CONCLUSION:Adrenomedullin and NO levels were high in both non-cirrhotic and cirrhotic portal hypertension and were closely correlated,Adrenomedullin and NO levels increased proportionally with the severity of cirrhosis,and were significantly higher than those in patients with NCPH. Portal hypertension plays an important role in the increase of ADM and NO.Parenchymal damage in cirrhosis may contribute to the increase in these parameters.

Radial artery access site complications during cardiac procedures,clinical implications and potential solutions: The role of nitric oxide

Percutaneous coronary intervention for the treatment of coronary artery disease is most commonly performed in the UK through the radial artery,as this is considered to be safer than the femoral approach.However,despite improvements in technology and techniques,complications can occur.The most common complication,arterial spasm,can cause intense pain and,in some cases,procedural failure.The incidence of spasm is dependent on several variables,including operator experience,artery size,and equipment used.An antispasmolytic cocktail can be applied to reduce spasm,which usually includes an exogenous nitric oxide(NO)donor(glyceryl trinitrate).NO is an endogenous local vasodilator and therefore is a potential target for anti-spasm intervention.However,systemic administration can result in unwanted side-effects,such as hypotension.A method that adopts local delivery of NO might be advantageous.This review article describes the mechanisms involved in radial artery spasm,discusses the advantages and disadvantages of current strategies to reduce spasm,and highlight the potential of NO-loaded nanoporous materials for use in this setting.

Gut-liver axis in cirrhosis:Are hemodynamic changes a missing link?

Recent evidence suggests that the condition of the gut and its microbiota greatly influence the course of liver disease,especially cirrhosis.This introduces the concept of the gut-liver axis,which can be imagined as a chain connected by several links.Gut dysbiosis,small intestinal bacterial overgrowth,and intestinal barrier alteration lead to bacterial translocation,resulting in systemic inflammation.Systemic inflammation further causes vasodilation,arterial hypotension,and hyperdynamic circulation,leading to the aggravation of portal hypertension,which contributes to the development of complications of cirrhosis,resulting in a poorer prognosis.The majority of the data underlying this model were obtained initially from animal experiments,and most of these correlations were further reproduced in studies including patients with cirrhosis.However,despite the published data on the relationship of the disorders of the gut microbiota with the complications of cirrhosis and the proposed pathogenetic role of hemodynamic disorders in their development,the direct relations between gut dysbiosis and hemodynamic changes in this disease are poorly studied.They remain a missing link in the gut-liver axis and a challenge for future research.

Local regulator adrenomedullin contributes to the circulatory disturbance in cirrhotic rats

AIM： To investigate whether adrenomedullin, a potent vasodilator peptide, plays a role in the circulatory disturbance in cirrhosis. METHODS： Cirrhosis was induced in rats by weekly gavage of carbon tetrachloride. Hemodynamic studies were performed in vivo using radioactive microspheres and in vitro using isolated aortic rings. The adrenomedullin concentrations were measured by radioimmunoassay. RESULTS： Acute administration of adrenomedullin to the control rats reduced the systemic arterial pressure along with an increase of serum levels of the stable metabolite of nitric oxide （NOx）, in a dose-dependent manner. Chronic infusion of adrenomedullin reduced the vascular resistance and increased the blood flow in the systemic and splanchnic circulation. Intravenous administration of anti-adrenomedullin antibody did not affect any hemodynamic parameters in the cirrhotic rats, whereas this antibody ameliorated the blunted contractile response to phenylephrine, o-adrenergic receptor agonist, in the aortic rings of the cirrhotic rats. The adrenomedullin concentrations in the aorta were higher in the cirrhotic rats than in the controls, and correlated with the mean arterial pressure in the cirrhotic rats. Moreover, adrenomedullin blunted the contractile response to phenylephrine in both of the control aorta and cirrhotic aorta, but not in the presence of NG-nitro L-arginine methyl ester, an NO synthase inhibitor. CONCLUSION： Adrenomedullin overproduced in the vascular wall may contribute to the circulatory disturbance in cirrhosis as a local regulator of the vascular tonus rather than a circulating hormone.

Central and peripheral testosterone effects in men with heart failure:An approach for cardiovascular research

Heart failure(HF) is a syndrome recognized as a health problem worldwide. Despite advances in treatment, patients with HF still have increased morbidity and mortality. Testosterone is one of the most researched hormones in the course of HF. Growing interest regarding the effect of testosterone, on a variety of body systems, has increased the knowledge about its mechanisms of action. The terms central and peripheral effects are used to distinguish the effects of testosterone on cardiac and extracardiac structures. Central effects include influences on cardiomyocytes and electrophysiology. Peripheral effects include influences on blood vessels, baroreceptor reactivity, skeletal muscles and erythropoesis. Current knowledge about peripheral effects of testosterone may explain much about beneficiary effects in the pathophysiology of HF syndrome. However, central, i.e., cardiac effects of testosterone are to be further explored.

Cerebral vasorelaxant material basis of Xiaoxuming decoction study with rat basilar artery

OBJECTIVE To investigate the cerebralvasorelaxant material basis of Xiaoxuming decoction.METHODS According to the Xiaoxuming decoction herb sources,we retrieved the chemical structure from the literatures and the Chinese Natural Product Database(http://pharmdata.ncmi.cn).By using microvessel tension system,we checked the vasorelaxanteffects of Xiaoxuming decoction anti-cerebral ischemia effective components group(XXMDECG)and the available composition compounds on pre-contracted basilar artery ring.RESULTS963 compoundsin the decoction,including 81Fangfeng,77 Mahuang,130 Shengjiang,31 Guizhi,91 Huangqin,127 Renshen,73 Chuanxiong,44 Shaoyao,39 Xingren,42 Fangji,62 Fuzi and 166 Gancao were collected.The five largest number classes of compounds in the decoction are volatile oil(32%),flavone(32%),alkaloid(13%),saponin(7%),polyphenol and organic acid(5%).XXMDECG at concentration from 1 to 400μg·mL-1can dilate the KCl(60 mmol·L-1)and ET-1(0.01μmol·L-1)pre-contracted rat basilar artery rings in a dose-dependent manner.There are 6 compounds with vasorelaxant ratio more than 50%at the concentration of 10μmol·L-1.CONCLUSION Xiaoxuming decoction contains abundant chemical structure.It has the material basis of multiple ingredients and multiple targets.The XXMDECG are able to dilate the rat basilar artery rings in a dose-dependent manner.The network interactions between varies of chemical compounds in Xiaoxuming decoction and the vasoconstriction associated targets result in the comprehensive regulation mechanisms of vascular function.

Synthesis of 2 (Alkylthio) 1,2,4 triazolopyrimidines and 3 (Alkythio) 1,2,4 triazolopyrimidines and Their Vasodilator Activity *

A series of new 2 (alkylthio) 5,7 dimethyl 1,2,4 triazolopyrimidines and 3 (alkylthio) 5,7 dimethyl 1,2,4 triazolopyrimidines have been synthesized. These derivatives were evaluated for inhibitory effects on 85 7 mmol·L 1 K + and 10 4 mmol·L -1 NE (nor epinephrine) induced contraction of rat aorta strips.