Vasodilator Activity Research Articles

Nitrate Esters Alleviated Coronary Atherosclerosis Through Inhibition of NF-κB-Regulated Macrophage Polarization Shift in Epicardial Adipose Tissue.

Nitrate esters have been used in clinical practice for more than one century for the treatment of angina. Their clinical effectiveness is due to vasodilator activity in arteries through a method of delivering nitric oxide or a nitric oxide-like compound. Recently, an increasing numbers of functions of this molecule in biology and pathophysiology have been discovered. Macrophage polarization shift in epicardial adipose tissue (EAT) has been demonstrated to be correlated with the severity of coronary artery disease (CAD). In this study, we aimed to investigate whether nitrate esters could improve coronary atherosclerosis through inhibition of macrophage polarization shift in EAT. A case-control study enrolled 48 subjects in 2 groups: CAD patients with or without nitrate esters treatment. Infiltration of M1/M2 macrophages and the expressions of pro-inflammatory and anti-inflammatory cytokines in EAT and subcutaneous white adipose tissue were investigated by immunohistochemical stain among subjects undergoing coronary artery bypass graft surgery. The expression levels of metabolic genes were investigated by real-time reverse transcription-polymerase chain reaction (RT-PCR). We found that nitrate ester treatment significantly inhibited NF-кB activity and decreased macrophage infiltration and M1/M2 macrophage ratio in EAT in patients with CAD. The expressions of pro-inflammatory cytokines were significantly decreased, along with significantly elevated expressions of anti-inflammatory cytokines in CAD patients with nitrate ester treatment, corresponding EAT dysfunction was ameliorated and the severity of patients with CAD (Gensini score) was significantly decreased. The protective effects on macrophage polarization and EAT function through NF-кB activity inhibition suggested a potential mechanism of nitrate esters in alleviating the severity of CAD.

Hospital Burden of Migraine in United States Adults: A 15-year National Inpatient Sample Analysis.

Background:Migraine headache is associated with high costs, but changes over time of inpatient burden in the United States are unknown. Understanding longitudinal trends is necessary to determine the costs of evolving inpatient treatments that target biological factors in the generation of pain such as vasodilation and aberrant activity of trigeminal neurotransmitters. We report the migraine hospital burden trend in the United States over 15 years.Methods:Data from the Nationwide Inpatient Sample of the Hospitalization Cost and Utilization Project databases were analyzed from 1997 to 2012. Inpatient costs were reported in dollars for the cost to the institution, whereas charges reflect the amount billed. These parameters were trended and the average annual percent change was calculated to illustrate year-to-year changes.Results:Overall discharges for migraine headache reached a low of 30,761 discharges in 1999, and peaked in 2012 with 54,510 discharges. Average length of stay decreased from 3.5 days in 1997 to 2.8 days in 2012. Total inpatient charges increased from $176 million in 1999 to $1.2 billion in 2012. Inpatient costs totaled $322 million in 2012, with an average daily cost of $2,111.Conclusions:Inpatient burden rapidly increased over the analyzed period, with hospital charges increasing from $5,939 per admission and $176 million nationwide in 1997, to $21,576 per admission and $1.2 billion nationwide in 2012. This trend provides context for research examining cost-effectiveness and quality of life benefits for current treatments. The study of these parameters together with better prevention and improved outpatient treatment may help alleviate the inpatient burden of migraine.

Acute hypotensive effect of EET‐A, a stable analog of epoxyeicosatrienic acid (EET), in spontaneously hypertensive rats: dependence on endogenous EETs activity

IntroductionArterial hypertension and related disorders are one of the main mortality causes world‐wide. Recent evidence points to epoxyeicosatrienoic acids (EETs) as significant factors in blood pressure regulation. These cytochrome P‐450 dependent metabolites of arachidonic acid, exhibit vasodilator and natriuretic activity. Therefore EETs might contribute to reduction of elevated blood pressure and have therapeutic potential. In our spontaneously hypertensive rats (SHR), potential hypotensive efficiency was examined of EET‐A (disodium (S)‐2‐(13‐(3‐entyl)ureido)‐tridec‐8(Z)‐enamido) succinate), a stable 14,15‐EET analog. EET‐A effects were studied in animals that were or were not pretreated with c‐AUCB (cis‐4‐[4‐(3‐adamantan‐1‐yl‐ureido)‐ cyclohexyloxy]‐benzoic acid), an inhibitor of soluble epoxide hydrolase (sEH) which prevents degradation of EETs. Inhibition of sEH increases endogenous EETs levels.MethodsAnesthetized SHR aged 16 weeks (established hypertension) received 1‐hour infusion of EET‐A (5 mg/kg BW iv) or its solvent. These acute experiments were performed in rats pretreated for 14 days with oral c‐AUCB (8.5 mg/kg/24 h, in drinking water) or in untreated rats receiving c‐AUCB solvent. Throughout experiments mean arterial blood pressure (MABP) and left kidney total blood flow (RBF, renal artery probe) and perfusion of the cortex, outer‐ and inner medulla (CBF, OMBF, IMBF; laser‐Doppler fluxes) were measured, along with renal excretion of water (V), total solute (UosmV), and sodium (UNaV).ResultsBasal MABP measured after chronic treatments tended to be lower after c‐AUCB compared to solvent‐treated group; otherwise no meaningful between‐group differences in renal hemodynamics and excretion parameters were seen. In control group pretreated with c‐AUCB‐solvent, EET‐A administration was followed by a delayed significant progressive decrease in MABP, down to a value 6% below control (p=0.01). In AUCB‐pretreated group no significant post‐EET‐A change in MABP was seen. During EET‐A infusion RBF and CBF significantly and fairly rapidly increased, to 130% and 124% of the control levels, respectively, comparably in untreated and c‐AUCB pretreated group and became almost always significant within the first 30 minutes of EET‐A infusion.SummaryIn acute experiments with anesthetized SHR, administration of EET analog (EET‐A) caused a significant delayed reduction of MABP. Not unexpectedly, previous enhancement of endogenous EETs activity after sEH blockade tended to reduce baseline MABP and virtually abolished the pressure reduction in response to exogenous EET analog. Irrespective of the baseline endogenous EET activity, EET‐A invariably induced renal vasodilation. The data indicate that in adult SHR a hypotensive effect can be obtained both by administration of EET analog and by enhancing endogenous EETs activity. On the other hand, only EET‐A treatment was found to improve renal hemodynamics.Support or Funding InformationNational Science Centre 2017/26/M/NZ5/00367

Effective Antihypertensive Treatment with Epoxyeicosatrienoic Acid Analog (EET‐A) and 20‐HETE Antagonist (AAA) of Spontaneously Hypertensive Rats (SHR)

IntroductionDespite decades of research the death toll of hypertension and associated disorders increases significantly each year. This impose the need to further determine the mechanisms underlying the development of hypertension and to implement more efficient therapeutic strategies. Growing number of research suggest the important role of cytochrome P‐450 dependent metabolites of arachidonic acid (AA) in blood pressure regulation. The epoxyeicosatrienoic acids (EETs) exhibit vasodilatory activity, they decrease sodium reabsorption and possess renoprotective and anti‐inflammatory properties. Considering the beneficial effects of EETs, we decided to test the efficiency of stable analog of 14,15‐EET [disodium (S)‐2‐(13‐(3‐entyl)ureido)‐tridec‐8(Z)‐enamido) succinate] called EET‐A, together with AAA [N‐disodium succinate‐20‐hydroxyeicosa‐6(Z),15(Z)‐diencarboxamide], a novel receptor antagonist of 20‐HETE which is another potent AA metabolite with both pro‐ and antihypertensive activity. To test the antihypertensive potential of both substances we employed spontaneously hypertensive rats (SHR), which are currently considered the best model to study human essential hypertension.MethodsMale SHR in the established stage of hypertension (16 week old) were treated for four weeks with EET‐A (n=8), AAA (n=6), as well as the combination of EET‐A and AAA (n=7) and compared to age‐matched untreated SHR (n=10) and WKY (n=5). Both tested substances were administered in drinking water in the dose of 10 mg/kg/day each. Systolic blood pressure (SBP) was measured by telemetry. Once a week observations in metabolic cages (food and water intake, feces, diuresis) were performed; urine, blood and tissue samples were collected for further analysis.ResultsEET‐A or AAA given alone had no significant effect on blood pressure of SHR. However, the combined treatment with AAA + EET‐A was significantly antihypertensive (161±5 vs 180±3 mmHg, p<0.05). Additionally, combined AAA and EET‐A attenuated cardiac hypertrophy expressed as left ventricle weight to tibia length (22.95±0.61 vs 24.75±0.35 mg/mm in untreated SHR, p<0.05), decreased kidney ANG II level, increased natriuresis and increased the excretion of nitric oxide metabolites (7.6±1.4 vs 4.8±0.7 μmol/24h in untreated SHR, p<0.05).SummaryTaking into account all the beneficial impact of the combined treatment with EET‐A and AAA on cardiovascular and renal function of adult SHR we suggest that it constitute a very promising novel antihypertensive strategy.Support or Funding InformationSupported by National Science Centre Poland (grant no 2017/26/M/NZ5/00367)and MH CZ ‐ DRO („Institute for Clinical and Experimental Medicine – IKEM, IN 00023001“)

Alteration of KCa Channel Function by Homocysteine in Human Internal Mammary Artery

ObjectivesHyperhomocysteinemia is an independent risk factor for cardiovascular disease. We previously in porcine coronary arteries demonstrated that disruption of KCa channel activity is involved in homocysteine‐induced impairment of dilatory function. Whether homocysteine affects KCa channels in human arteries remains uninvestigated. In the present study, we aimed to investigate the effect of homocysteine on the expression and functionality of the members of KCa channel family, including large‐ (BKCa), intermediate‐ (IKCa) and small‐ (SKCa) conductance KCa channels in human internal mammary artery (IMA).MethodsResidual IMA segments collected from patients undergoing coronary artery bypass grafting (CABG) were used for myography study for KCa subtype‐mediated relaxation and contraction. Western blot and immunohistochemistry were employed to detect the expression and distribution of KCa subtypes in IMA.ResultsBKCa subtype in the KCa channel family significantly regulated the vasoreactivity of IMA. Blockade of BKCa channels inhibited acetylcholine‐induced relaxation and enhanced U46619‐induced contraction. In comparison, both IKCa and SKCa subtypes played a minor role in the control of relaxation and contraction of IMA. Exposure to homocysteine compromised the vasodilating activity of the BKCa subtype in IMA, evidenced by the suppressed relaxant response to the BKCa channel opener and the decreased impact of the BKCa channel blocker on acetylcholine‐induced relaxation and U46619‐evoked contraction. The functional loss of BKCa was associated with a downregulation of the protein expression of BKCa β1 subunits in the smooth muscle of IMA. Inhibition of endoplasmic reticulum (ER) stress showed protective effect against homocysteine on the function and expression of BKCa channels. In contrast, the role of IKCa and SKCa subtypes in mediating endothelium‐dependent relaxation was augmented by homocysteine though no alterations in the regulatory capacity on vasoconstriction were observed. Homocystine did not alter the protein expression level of IKCa and SKCa subtypes.ConclusionsHomocysteine compromises the vasodilating activity of BKCa channels in IMA, which may be attributed to the loss of BKCa β1 subunits mediated by ER stress. Unlike BKCa, IKCa and SKCa subtypes are unessential for vasoregulation in IMA, the loss of BKCa functionality in hyperhomocysteinemia enhances the role of IKCa and SKCa in mediating endothelial dilator function. Targeting BKCa may form a strategy to improve the postoperative graft performance in CABG patients with hyperhomocysteinemia who receives IMA grafting.Support or Funding InformationSupported by NSFC 81870227 & 81870288, Tianjin Science and Technology Commission (18PTZWHZ00060) & Binhai New Area Health Bureau (2018BWKZ005), and Non‐profit Central Research Institute Fund of Chinese Academy of Medical Sciences 2018TX31002 & 2019XK310001.

Hydrolase-treated royal jelly attenuates LPS-induced inflammation and IgE-antigen-mediated allergic reaction

Background: Royal jelly (RJ) is one of the most effectual and beneficial remedies for human beings and currently utilized in many sectors, ranging from the pharmaceutical and food industries to cosmetic and manufacturing sectors due to RJ possessing many bio-therapeutical activities including anti-tumor, antimicrobial and antioxidant activities, vasodilative and hypotensive activities, as well as growth-stimulating, infection-preventing, anti-hypercholesterolemic and anti-inflammatory activities. However, some reports showing direct consumption of RJ can lead to severe allergic reaction and has been linked with acute asthma, dermatitis, and life-threatening anaphylaxis. Thus, this research purposes to explore the potential anti-inflammatory and anti-allergic activities of hydrolyzed RJ as a function of enzyme and the extent of hydrolysis.Methods: RJ was enzymatically hydrolyzed with three commercial enzymes (AlcalaseÒ, FlavourzymeÒ and ProtamexÒ). Anti-inflammatory activity of the hydrolysates was measured by their inhibitory effect on nitric oxide (NO) production of lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Anti-allergy was determined from the ability of the hydrolysates to inhibit b-hexsosaminidase (b-HEX) release from RBL-2H3 mast cells. Cytotoxicity was also investigated in both RAW264.7 macrophage cells and RBL-2H3 mast cells.Results: The electrophoretic profiles indicated that AlcalaseÒ and FlavourzymeÒ hydrolysates did not show the presence of proteins causing allergic reaction after 60 mins of hydrolysis while these allergens disappeared from ProtamexÒ hydrolysate at the hydrolysis time of 240 min. It was observed that hydrolyzed RJ showed no toxicity on RAW264.7 and RBL-2H3 cells. With the progression of hydrolysis, IC50 values of NO production inhibition significantly decreased while degree of hydrolysis (DH) was increased in all hydrolyzed samples (p < 0.05). Results of b-HEX release inhibition were found in the same fashion. FlavourzymeÒ hydrolysate at the 240 min time point effectively mitigated the oxidative stress and protected DNA in a dose dependent manner.Conclusions: RJ hydrolysates from FlavourzymeÒ resulted in peptides with anti-inflammatory activity as determined by the inhibition of NO production in LPS-stimulated RAW264.7 macrophage cells and anti-allergic property as measured by the suppression of degranulation of sensitized RBL-2H3 cells. Anti-inflammatory effect may be due to their anti-oxidative capability. Inhibition of b-HEX release may be due to their membrane-stabilizing effects or/and blockade of IgE antibody binding to its receptors.Keywords: anti-inflammation, enzymatic hydrolysate, royal jelly, anti-allergy

Naringinase-catalyzed hydrolysis of naringin adsorbed on macroporous resin

Naringenin, a natural plant flavonoid found in citrus fruits, has been reported to exhibit a wide range of pharmacological functions, including anticancer, antioxidant, antiatherogenic, antithrombotic, and vasodilator activities. Naringenin can be produced from the naringinase (NGase)-catalyzed enzymatic hydrolysis of naringin. However, the poor solubility of naringin in aqueous systems considerably limits the efficiency of naringenin biocatalysis. In this work, a novel substrate adsorption system was proposed for naringin adsorption to increase the efficiency of naringin hydrolysis and naringenin production. Three Amberlite macroporous resins, namely, XAD-4, XAD-7HP and XAD-16, were investigated for their naringin adsorption capacities and effects on NGase hydrolysis. Results indicated that the physical properties of the resins played a critical role in naringin adsorption and naringenin enzymatic synthesis. Naringin hydrolysis was carried out using free and adsorbed substrates. The substrate adsorption strategy could increase the catalytic efficiency at a high naringin concentration. In addition, the reaction conditions for enzymatic naringenin synthesis were optimized, and naringenin was prepared at a liter scale with a high substrate concentration. These results suggested that substrate adsorption is a promising strategy to increase the enzymatic hydrolysis efficiency of naringenin in aqueous systems.

Natriuretic peptide analogues with distinct vasodilatory or renal activity: integrated effects in health and experimental heart failure.

Management of acute decompensated heart failure (ADHF) requires disparate treatments depending on the state of systemic/peripheral perfusion and the presence/absence of expanded body-fluid volumes. There is an unmet need for therapeutics that differentially treat each aspect. Atrial natriuretic peptide (ANP) plays an important role in blood pressure and volume regulation. We investigate for the first time the integrated haemodynamic, endocrine and renal effects of human ANP analogues, modified for exclusive vasodilatory (ANP-DRD) or diuretic (ANP-DGD) activities, in normal health and experimental ADHF. We compared the effects of incremental infusions of ANP analogues ANP-DRD and ANP-DGD with native ANP, in normal (n = 8) and ADHF (n = 8) sheep. ANP-DRD administration increased plasma cyclic guanosine monophosphate (cGMP) in association with dose-dependent reductions in arterial pressure in normal and heart failure (HF) sheep similarly to ANP responses. In contrast to ANP, which in HF produced a diuresis/natriuresis, this analogue was without significant renal effect. Conversely, ANP-DGD induced marked stepwise increases in urinary cGMP, urine volume, and sodium excretion in HF comparable to ANP, but without accompanying vasodilatory effects. All peptides increased packed cell volume relative to control in both states, and in HF, decreased left atrial pressure. In response to ANP-DRD-induced blood pressure reductions, plasma renin activity rose compared to control only during the high dose in normals, and not at all in HF-suggesting relative renin inhibition, with no increase in aldosterone in either state, whereas renin and aldosterone were both significantly reduced by ANP-DGD in HF. These ANP analogues exhibit distinct vasodilatory (ANP-DRD) and diuretic/natriuretic (ANP-DGD) activities, and therefore have the potential to provide precision therapy for ADHF patients with differing pathophysiological derangement of pressure-volume homeostasis.

Vasodilatory Actions of Glucagon-Like Peptide 1 Are Preserved in Skeletal and Cardiac Muscle Microvasculature but Not in Conduit Artery in Obese Humans With Vascular Insulin Resistance.

Obesity is associated with microvascular insulin resistance, which is characterized by impaired insulin-mediated microvascular recruitment. Glucagon-like peptide 1 (GLP-1) recruits skeletal and cardiac muscle microvasculature, and this action is preserved in insulin-resistant rodents. We aimed to examine whether GLP-1 recruits microvasculature and improves the action of insulin in obese humans. Fifteen obese adults received intravenous infusion of either saline or GLP-1 (1.2 pmol/kg/min) for 150 min with or without a euglycemic insulin clamp (1 mU/kg/min) superimposed over the last 120 min. Skeletal and cardiac muscle microvascular blood volume (MBV), flow velocity and blood flow, brachial artery diameter and blood flow, and pulse wave velocity (PWV) were determined. Insulin failed to change MBV or flow in either skeletal or cardiac muscle, confirming the presence of microvascular insulin resistance. GLP-1 infusion alone increased MBV by ∼30% and ∼40% in skeletal and cardiac muscle, respectively, with no change in flow velocity, leading to a significant increase in microvascular blood flow in both skeletal and cardiac muscle. Superimposition of insulin to GLP-1 infusion did not further increase MBV or flow in either skeletal or cardiac muscle but raised the steady-state glucose infusion rate by ∼20%. Insulin, GLP-1, and GLP-1 + insulin infusion did not alter brachial artery diameter and blood flow or PWV. The vasodilatory actions of GLP-1 are preserved in both skeletal and cardiac muscle microvasculature, which may contribute to improving metabolic insulin responses and cardiovascular outcomes. In obese humans with microvascular insulin resistance, GLP-1's vasodilatory actions are preserved in both skeletal and cardiac muscle microvasculature, which may contribute to improving metabolic insulin responses and cardiovascular outcomes.

Improved neural control of body temperature following heat acclimation in humans.

With the advent of more frequent extreme heat events, adaptability to hot environments will be crucial for the survival of many species, including humans. However, the mechanisms that mediate human heat adaptation have remained elusive. We tested the hypothesis that heat acclimation improves the neural control of body temperature. Skin sympathetic nerve activity, comprising the efferent neural signal that activates heat loss thermoeffectors, was measured in healthy adults exposed to passive heat stress before and after a 7day heat acclimation protocol. Heat acclimation reduced the activation threshold for skin sympathetic nerve activity, leading to an earlier activation of cutaneous vasodilatation and sweat production. These findings demonstrate that heat acclimation improves the neural control of body temperature in humans. Heat acclimation improves autonomic temperature regulation in humans. However, the mechanisms that mediate human heat adaptation remain poorly understood. The present study tested the hypothesis that heat acclimation improves the neural control of body temperature. Body temperatures, skin sympathetic nerve activity, cutaneous vasodilatation, and sweat production were measured in 14healthy adults (nine men and five women, aged 27±5 years) during passive heat stress performed before and after a 7day heat acclimation protocol. Heat acclimation increased whole-body sweat rate [+0.54Lh-1 (0.32, 0.75), P<0.01] and reduced resting core temperature [-0.29°C (-0.40, -0.18), P<0.01]. During passive heat stress, the change in mean body temperature required to activate skin sympathetic nerve activity was reduced [-0.21°C (-0.34, -0.08), P<0.01] following heat acclimation. The earlier activation of skin sympathetic nerve activity resulted in lower activation thresholds for cutaneous vasodilatation [-0.18°C (-0.35, -0.01), P=0.04] and local sweat rate [-0.13°C (-0.24, -0.01), P=0.03]. These results demonstrate that heat acclimation leads to an earlier activation of the neural efferent outflow that activates the heat loss thermoeffectors of cutaneous vasodilatation and sweating.

Shenfu Injection Promotes Vasodilation by Enhancing eNOS Activity Through the PI3K/Akt Signaling Pathway In Vitro

Vasomotor dysfunction is one of the key pathological aspects of shock and heart failure (HF). Shenfu injection (SFI) has been widely used for the treatment of shock and HF in China. Pharmacological studies have suggested that SFI can reduce peripheral circulation resistance and improve microcirculation. However, whether it has a regulatory effect on macrovascular has not been elucidated. In this study, we used thoracic aorta rings isolated from Wistar rats and the human umbilical vein cell line (EA.hy926) to explore the vasodilative activity of SFI and its potential mechanisms. The relaxation due to SFI was measured after pre-treatment with selective soluble guanylate cyclase (sGC) inhibitor or cyclooxygenase (COX) inhibitor and compared with the vasodilation effect of SFI only treated with norepinephrine (NE). The contents of NO, endothelin-1 (ET-1), endothelial nitric oxide synthase (eNOS), COX-1, 6-K-PGF1α, and caveolin-1 were evaluated respectively. Additionally, the level of eNOS mRNA and total eNOS and its phosphorylation were studied to investigate the potential mechanisms involved. Experimental results showed that SFI markedly attenuated NE-induced vasoconstriction but that this effect was significantly eliminated after pre-incubation with the selective sGC inhibitor 1-H-[1, 2, 4] oxadiazolo [4, 3-α] quinoxaline-1-one (ODQ), instead of the COX inhibitor indomethacin (INDO). SFI significantly increased the eNOS content and up-regulated the eNOS mRNA expression, while it did not affect the content of COX-1 and 6-K-PGF1α. SFI also markedly increased NO content but significantly reduced the content of ET-1 and caveolin-1 in the cell supernatant. Furthermore, it promoted the expression of total eNOS and the phosphorylation of eNOS at serine (Ser) 1177 but inhibited the phosphorylation at threonine (Thr) 495, which was significantly reversed by PI3K-specific inhibitor LY294002. In conclusion, our study showed the vasodilation effect of SFI in thoracic aorta is mediated entirely by enhancing eNOS activity through the PI3K/Akt signaling pathway, providing novel knowledge on the effect of SFI on shock and HF for future clinical applications.

The Novel Small-molecule Annexin-A1 Mimetic, Compound 17b, Elicits Vasoprotective Actions in Streptozotocin-induced Diabetic Mice.

The formyl peptide receptor (FPR) family are a group of G-protein coupled receptors that play an important role in the regulation of inflammatory processes. It is well-established that activation of FPRs can have cardioprotective properties. Recently, more stable small-molecule FPR1/2 agonists have been described, including both Compound 17b (Cmpd17b) and Compound 43 (Cmpd43). Both agonists activate a range of signals downstream of FPR1/2 activation in human-engineered FPR-expressing cells, including ERK1/2 and Akt. Importantly, Cmpd17b (but not Cmpd43) favours bias away from intracellular Ca2+ mobilisation in this context, which has been associated with greater cardioprotection in response to Cmpd17b over Cmpd43. However, it is unknown whether these FPR agonists impact vascular physiology and/or elicit vasoprotective effects in the context of diabetes. First, we localized FPR1 and FPR2 receptors predominantly in vascular smooth muscle cells in the aortae of male C57BL/6 mice. We then analysed the vascular effects of Cmpd17b and Cmpd43 on the aorta using wire-myography. Cmpd17b but not Cmpd43 evoked a concentration-dependent relaxation of the mouse aorta. Removal of the endothelium or blockade of endothelium-derived relaxing factors using pharmacological inhibitors had no effect on Cmpd17b-evoked relaxation, demonstrating that its direct vasodilator actions were endothelium-independent. In aortae primed with elevated K+ concentration, increasing concentrations of CaCl2 evoked concentration-dependent contraction that is abolished by Cmpd17b, suggesting the involvement of the inhibition of Ca2+ mobilisation via voltage-gated calcium channels. Treatment with Cmpd17b for eight weeks reversed endothelial dysfunction in STZ-induced diabetic aorta through the upregulation of vasodilator prostanoids. Our data indicate that Cmpd17b is a direct endothelium-independent vasodilator, and a vasoprotective molecule in the context of diabetes.

EFFECT OF ACUPUNCTURE IN HEART AURICULAR POINT IN TWO INDEXES OF DIGITAL VOLUME PULSE IN HEALTHY SUBJECTS

Objective: The aim of the study was to determine the changes in two indices derived from the digital volume pulse (DVP) elicited by acupuncture in auricular heart acupoint in healthy subjects.&#x0D; Methods: Eighteen healthy subjects aged 26.22±2.98 years (mean±standard deviation) were assigned to receive auricular acupuncture in auricular heart acupoint in the right ear. The DVP was recorded by photoplethysmography. RIDVP was determined by the relative amplitudes of systolic and diastolic components of the DVP and SIDVP, by the relative timing of these components. Auricular acupoint heart was stimulated by manual acupuncture. The RIDVP and SIDVP indices were calculated for basal and post-acupuncture conditions.&#x0D; Results: Both RIDVP (p=0.0375) and SIDVP (p=0.0063) were significantly decreased by acupuncture of the right auricular acupoint heart when comparing the pre- and post-acupuncture values.&#x0D; Conclusions: These results indicate that manual acupuncture of auricular acupoint heart produces acute effects on vascular physiology. RIDVP and SIDVP indices can be used to assess and demonstrate a vasodilatory activity of auricular acupoint heart.

Phytochemical evaluation and vasodilatory activity of O. elongatum, C. salviifolius and C. laurifolius

The high blood pressure is one of the main causes of death and cardiovascular diseases. Vasodilator medications are frequently used to treat arterial hypertension. The aim of this study was to evaluate vasodilator properties of three plants from North of Morocco then to quantify phenolic compounds and flavonoids in each plant extracts. The leaves of Origanum elongatum, Cistus salviifolius and Cistus laurifolius were extracted with hexane, methanol and ethyl acetate by ultrasonic apparatus. The total phenolic content, analyzed using Folin–Ciocalteu’s reagent, of the samples varied from 46.6 µg/100 mg to 153 µg/100 mg dry weight, expressed as gallic acid equivalents (GAE). The total flavonoid concentrations, detected using 2% aluminum chloride, varied from 3.63 to 5.54 µg equivalents (RE)/mg dry weight. Under different plant growth regulators induce a vasodilator effect on Wistar rat mesenteric vascular bed pre-contracted with norepinephrine. for O.elongatum, the methanolic extracts at (PP = 50 mmHg) were found to be more active than the acetylcholine with a concentration of 10 -4 M taken as a reference (PP = 40 mmHg) and The vasodilator activity of methanolic extract of Cistus laurifolius at 100 μg/ml is the same as the reference (PP=40 mmHg). the vasodilator activity found in the three plants studied is due to their antioxidant power.

Role of the potassium channels in vasorelaxant effect of asafoetida essential oil.

In a previous work, we showed that asafoetida essential oil (AEO), from oleo-gum resin of Ferula asafoetida L. from the Apiaceae family, has a vasodilatory effect. This effect was both endothelium-dependent and endothelium-independent. The present study was designed to determine whether potassium channels and intracellular calcium release contribute to AEO-induced vasodilation. Rats' thoracic aorta were isolated and denuded. Following induction of contraction by potassium chloride (60 mM), concentration-response curve was plotted by the cumulative addition of AEO (0.625-80 µl/l to the medium of rings. The vasodilatory effect of AEO was assessed before and after addition of phenylephrine and potassium channel blockers (including barium chloride (BC), 4-aminopyridine (4A) and glibenclamide (Gl)). AEO relaxed the precontracted rings in a concentration-dependent manner (IC50=23 µl/l). All potassium channel blockers significantly attenuated the vasodilatory activity of AEO when they were added to rings medium before addition of KCl (p<0.01, 4A and Gl groups and p< 0.001, BC group vs. control group) but not after that. In contrast to K channel blockers, adding AEO before or after phenylephrine, the tension was reduced significantly (p<0.05 vs. the control group). The findings of this study indicated that the vasodilatory effect of AEO on denuded-endothelium aortic ring was mediated through activation of potassium channels and reduced intracellular calcium release.

Phylogenic Determinants of Cardiovascular Frailty, Focus on Hemodynamics and Arterial Smooth Muscle Cells.

The evolution of the circulatory system from invertebrates to mammals has involved the passage from an open system to a closed in-parallel system via a closed in-series system, accompanying the increasing complexity and efficiency of life's biological functions. The archaic heart enables pulsatile motion waves of hemolymph in invertebrates, and the in-series circulation in fish occurs with only an endothelium, whereas mural smooth muscle cells appear later. The present review focuses on evolution of the circulatory system. In particular, we address how and why this evolution took place from a closed, flowing, longitudinal conductance at low pressure to a flowing, highly pressurized and bifurcating arterial compartment. However, although arterial pressure was the latest acquired hemodynamic variable, the general teleonomy of the evolution of species is the differentiation of individual organ function, supported by specific fueling allowing and favoring partial metabolic autonomy. This was achieved via the establishment of an active contractile tone in resistance arteries, which permitted the regulation of blood supply to specific organ activities via its localized function-dependent inhibition (active vasodilation). The global resistance to viscous blood flow is the peripheral increase in frictional forces caused by the tonic change in arterial and arteriolar radius, which backscatter as systemic arterial blood pressure. Consequently, the arterial pressure gradient from circulating blood to the adventitial interstitium generates the unidirectional outward radial advective conductance of plasma solutes across the wall of conductance arteries. This hemodynamic evolution was accompanied by important changes in arterial wall structure, supported by smooth muscle cell functional plasticity, including contractility, matrix synthesis and proliferation, endocytosis and phagocytosis, etc. These adaptive phenotypic shifts are due to epigenetic regulation, mainly related to mechanotransduction. These paradigms actively participate in cardio-arterial pathologies such as atheroma, valve disease, heart failure, aneurysms, hypertension, and physiological aging.

Effect of Simvastatin Use in Free Tissue Transfer: An Experimental Study in a Rat Epigastric Free Flap Model.

Statins are traditionally used in lowering cholesterol and low-density lipoprotein biosynthesis, but recent reports show their beneficial effect on microcirculation. The aim of this study was to investigate the effect of simvastatin on the microcirculation and in conjunction with aspirin in a rat free epigastric flap model. Thirty-six Sprague-Dawley rats were divided into group A (control, n = 12), group B (simvastatin treated, n = 12), and group C (simvastatin and aspirin, n = 12). Bilateral free epigastric skin flap was used to evaluate the effect. At 48 hours, flaps biopsies were evaluated for inflammatory activity, nitric oxide content, and thrombomodulin regulation in the endothelial lining of microvessels. Flap survival was evaluated on day 7. The diameter of microvessels and nitric oxide activity in groups B and C were significantly higher than in group A (p < 0.005 and 0.015, respectively). The perivascular inflammatory cell infiltrates and intravascular adhesions were predominant in group A compared with groups B and C (p < 0.005). Groups B and C demonstrated significant higher degree of thrombomodulin expression. The flap survival rate on day 7 was 70.8% for group A, and 87.5% and 91.7%, respectively, for groups B and C without significance between the two (p = 0.675). Simvastatin significantly improves the free flap survival by effective anti-inflammatory, vasodilator, and anticoagulant activities. Combined therapy did not have an antagonistic effect and further study is needed to see synergistic action through different mechanisms.

Interference with AGEs formation and AGEs-induced vascular injury mediates curcumin vascular protection in metabolic syndrome

Vascular dysfunction predisposes to cardiovascular complications of metabolic syndrome (MetS). The current study investigated the mechanism(s) of curcumin’s (CUR) protective effect against vascular reactivity irregularities in MetS. MetS was induced by feeding rats on high fructose high salt diet. Tension studies were undertaken in aortic rings to assess the influence of CUR on vasoconstrictor or vasorelaxant responses. The effect on advanced glycation endproducts (AGEs) was studied by incubating aortic tissues with methylglyoxal, the AGEs precursor, in the absence and presence of CUR. In addition, CUR effects on in-vitro generation of AGEs and diphenyl-2-picrylhydrazyl (DPPH) free radicals were studied. The incubation with CUR for 1 hr produced significant and concentration-dependent alleviation of the exaggerated vasoconstriction observed in aortas isolated from MetS, however failed to improve the concomitant attenuation of vasodilatory responses to ACh in PE-precontracted aortas. By contrast, CUR caused direct concentration-dependent vasodilations of precontracted aortas, effects that were blunted after nitric oxide synthase inhibition by L-NAME. Similar to its effects in MetS aortas, CUR alleviated exaggerated PE vasoconstriction but did not affect impaired ACh vasodilations in AGEs-exposed aortas. In addition, CUR showed significant dose-dependent DPPH free radicals scavenging activity and inhibited both MG and fructose induced AGEs formation at the level of protein oxidation step as evident from the effect on dityrosine and N-formylkyramine. CUR alleviates exaggerated vasoconstriction in MetS through interfering with AGEs formation and AGEs-induced vascular injury. Free radical scavenging and direct vasodilatory activities could also participate in the advantageous vascular actions of CUR.

Major flavonoids from Psiadia punctulata produce vasodilation via activation of endothelial dependent NO signaling

Vasodilators are important pharmacologic agents for managing and/or treating hypertension. Medicinal plants are considered as valuable source of bioactive compounds. We used a bioguided approach to isolate, identify, and investigate the possible vasodilation activities and mechanism(s) of the prepared methanol extract from aerial parts of Psiadia punctulata (MAPP), its bioactive fraction and active compounds. Vascular effects of MAPP were studied using isolated artery technique in the presence or absence of specific candidate pathways inhibitors, and found to produce a significant vasodilation of phenylephrine preconstricted rat aortae. The bioactive chloroform fraction yielded five methoxylated flavonoids: umuhengerin (1), gardenin A (2), gardenin B (3), luteolin-3′,4′ -dimethyl ether (4), and 5,3′-dihydroxy-6,7,4′,5′-tetramethoxyflavone (5). Metabolites 1, 4, and 5 produced a significant vasodilation. Removal of the endothelium significantly inhibited MAPP vasodilation. Nitric oxide synthase inhibition and not prostacycline inhibition or K+ channel blocking, was found to cause the observed vasodilation inhibition. Both guanylate cyclase and adenylate cyclase inhibitions markedly inhibited MAPP vasodilation. In conclusion MAPP possesses vasodilation activities that is mediated through endothelial nitric oxide pathway, calcium dependent endothelial nitric oxide synthase activation, and interference with the depolarization process through calcium channel blocking activity.

A comparative study between nitroglycerine spray and lignocaine spray to attenuate hemodynamic changes during laryngoscopy and intubation

Endotracheal intubation which is a frequent maneuver in general anaesthesia is accompanied by adverse hemodynamic changes like hypertension, tachycardia and cardiac dysrhythmias. This study aims at comparing the efficacy of nitroglycerine spray and lignocaine spray to attenuate the hemodynamic changes during direct larngoscopy and intubation. This prospective study included 60 patients of age group 20 to 45 years of either sex belonging to American Society of Anaesthesiologist (ASA) grade 1 & 2 posted for elective surgery under general anaesthesia. These patients were randomly allocated in 3 groups of 20 each. Prior to induction, patients in Group N received one puff of nitroglycerine (0.4 mg) spray sublingually, Group L received five puffs of lignocaine spray (10 mg each) in oropharynx and group C received none of the two drugs serving as control group. Hemodynamic parameters including heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure and oxygen saturation were recorded at fixed time intervals. Both nitroglycerine spray and lignocaine spray attenuate the hemodynamic changes during laryngoscopy and intubation. Nitroglycerine spray is more effective in attenuating the blood pressure changes accompanied by a significant rise in heart rate due to its vasodilatory action whereas lignocaine spray is more effective in attenuating the changes in heart rate. No complications or side effects were observed in any of the group.