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.

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.

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.

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.

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.

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.

Effect of Xiongshao Capsule (芎芍胶囊) on the Function of Vascular Endothelium of Patients with Cervical Atherosclerosis

Objective: To study the effect of Xiongshao Capsule (芎芍胶囊, XSC), a TCM herb that can promote blood circulation to remove blood stasis, on the endothelial dependent relaxation function, serum nitric oxide (NO), and plasma endothelin-KET-1) of the patients with cervical atherosclerosis. Methods: Forty patients were randomly divided into two groups; XSC group and Probucol group (western medicine control). In addition, 20 healthy people were set as a normal control group. Plasma ET-1, serum NO, the internal diameter of basal brachial artery, endothelial dependent flow mediated dilation (FMD) and non-endothelial dependent nitroglycerin induced dilation (NID) to the trial group before and after therapy and to the healthy control group were determined respectively. Results; Compared to the healthy control group, FMD of patients with atherosclerosis was damaged obviously, the serum NO level decreased, plasma ET-1 increased (P< 0. 01), NID also decreased (P<0. 05), the internal diameter of basal brachial artery has no obvious difference (P>0. 05). After the patients with atherosclerosis were treated with Xiongshao Capsule for 12 weeks, FMD increased evidently, plasma ET-1 decreased, serum NO and the ratio of NO/ET-1 increased, compared with the level before therapy and Probucol group, the difference was significant (P<0.05, P<0.01), NID didn't change obviously (P>0.05). Conclusion: XSC could regulate vascular activity factor and improve the function of endothelial dependent vascular dilation of patients with atherosclerosis.

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.

Effects of Xin Mai Tong Capsule on Vasoregulatory Peptides in the Patients of Coronary Heart Disease

In order to inquire into the therapeutic effects of Xin Mai Tong Capsule (心脉通胶囊) on coronary heart disease with myocardial ischemia, 40 patients were randomly divided into two groups (Xin Mai Tong group and the control group). The plasma endothelin (ET) levels in the two groups of patients were markedly higher than that of the healthy people (P<0.001), and the calcitonin gene related peptide (CGRP) was similar to that of the healthy people (P>0.05). After treatment, ET and symptomatic scores in the two groups decreased markedly (P<0.01), and their S-T segments were elevated obviously (P<0.01). But the decrease of ET and symptomatic scores and elevation of S-T segment in Xin Mai Tong group were superior to those of the control group (P<0.05～0.01). The CGRP level in the control group did not vary obviously post-treatment, but it increased markedly (P<0.01) with the addition of Xin Mai Tong Capsule in Xin Mai Tong group.

How to select the appropriate candidate of pulmonary arterial hypertension： specific therapy in elderly patients with pulmonary hypertension

Recent reports from pulmonary arterial hypertension （PAH） registries suggest that the mean age at diagnosis is increasing in a growing proportion of elderly patients. The combination of several reasons such as aging popula- tion, increase in life expectancy, growing PAH awareness of physicians and patients, and availability of more treatment options could explain the changing picture of PAH. PAH should be considered as an emerging entity in the elderly.

Management of acute heart failure-Is there a paradigm shift around the corner?

It has become increasingly apparent that the looming epidemic of heart failure calls for systematic treatment approaches tailored to the needs of individual patient phenotypes. Although chronic heart failure (CHF) therapies are continuously evolving based on the increasing understanding of the involved etiology, acute heart failure (AHF) therapies are still based on hemodynamic improvements and symptom alleviation. Guidelines on AHF management have highlighted that the currently administered AHF therapies lack evidence and have raised concerns on the safety and efficacy of some of the hitherto accepted treatment modalities. Additionally, the high mortality and morbidity rates associated with the current AHF therapies also add to the imperative need to revisit AHF management. The last decade has witnessed a paradigm shift in the way we define and diagnose AHF. Apart from it being recognized as a distinct clinical entity, research has also led to new data on the pathophysiological changes associated with AHF. These developments along with the limited short- and long-term effects of currently used therapies may herald a paradigm shift in the way we plan and deliver management strategies to treat the pathological progression of heart failure.

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.

Worsening of coronary spasm during the perioperative period:A case report

We present the case of a 65-year-old male with vasospastic angina(VSA)whose condition worsened during the perioperative period.He had been diagnosed with VSA 10 years prior.He was treated with two types of vasodilators and had not experienced any chest symptoms for 5 years.At this juncture,he underwent surgery for relapsed maxillary sublingual carcinoma.He had taken two vasodilators one day prior to surgery.Intravenous infusion of nitroglycerin(NTG)was initiated immediately before the surgery and continued the following day.Instead of stopping NTG,a dermal isosorbide dinitrate tape was applied on post-operative day 1.Two days later,a complete atrioventricular block with pulseless electrical activity appeared.After cardiopulmonary resuscitation,emergent coronary angiography showed severe coronary spasm in both the left and right coronary arteries.Intracoronary infusion of nitroglycerin and epinephrine with percutaneous cardiopulmonary support relieved the coronary spasm.During the perioperative period,several factors can trigger coronary vasospasm,including the discontinuation of vasodilators.Thus,surgeons,anesthetists,and cardiologists should watch for coronary vasospasm during this period and for worsening coronary spasm when discontinuing vasodilators in patients at risk for VSA.

Pharmacological basis for the medicinal use of Michelia champaca in gut, airways and cardiovascular disorders

Objective: To discover the mechanism behind ameliorative effects of Michelia champaca(M. champaca) in gastrointestinal, respiratory and cardiovascular disorders. Methods: Antispasmodic potential was evaluated by trying the M. champaca extract(aqueous:ethanolic) on rabbit aorta, trachea and jejunum in vitro. Isotonic and isometric transducers coupled with Power Lab data acquisition system was used to record the responses of isolated tissues. Results: M. champaca extract relaxed the spontaneous and high K^+(80 mmol/L)-induced contractions of isolated jejunum preparation of rabbit showing a Ca^(2+) channel blocking mechanism. Moreover, extract shifted calcium concentration response curves towards right like standard calcium channel blocker verapamil. In rabbit tracheal preparation, M. champaca relaxed both carbachol(1 μmol/L) and high K^+-induced contractions, likewise verapamil. In rabbit aorta preparation, M. champaca relaxed phenylephrine(1 μmol/L) and high K^+-induced contractions similar to verapamil. Conclusion: M. champaca possesses spasmolytic, airways relaxant and vasodilator actions mediated perhaps due to blocking of Ca^(2+) channels, hence validating its therapeutic usage in diarrhea, asthma and hypertension.

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.

Nitric Oxide Formation Contributes toβ-adrenergic Dilation of Epicardial Coronary Arteries in Response to Intravenous Administration of Dobutamine in Dogs

To examine the role of nitric oxide in the β-adrenergic vasodilation of epicardial coronary arteries in dogs, 12 dogs were instrumented for measurement of left anterior descending coronary artery diameter by transthoracic echocardiography before and after dobutamine (5 μg/kg/min IV) with and without intracoronary infusion of N G-monomethyl-L-arginine (L-NMMA) (1 mg/kg). In all 12 dogs, the diameter of left anterior descending coronary artery increased significantly from 2.35±0.25 mm to 2.59±0.24 mm (P<0.001) after dobutamine administration. In 6 of the 12 dogs, the percent change in left anterior descending coronary artery diameter induced by dobutamine decreased significantly from 12.5%±8.6% to -1.5%±5.4% (P<0.05) after the administration of intracoronary L-NMMA (1 mg/kg for 5 min) to block nitric oxide synthesis from L-arginine. The study demonstrated that nitric oxide formation contributes to the β-adrenergic dilatory response of epicardial coronary arteries to dobutamine in dogs.