Endothelium-derived Relaxing Factor Research Articles

Nitric Oxide Ameliorates the Effects of Hypoxia in Mice by Regulating Oxygen Transport by Hemoglobin.

Xiaoying Zhou, Wenting Su, Quanwei Bao, Yu Cui, Xiaoxu Li, Yidong Yang, Chengzhong Yang, Chengyuan Wang, Li Jiao, Dewei Chen, and Jian Huang. Nitric oxide ameliorates the effects of hypoxia in mice by regulating oxygen transport by hemoglobin. High Alt Med Biol. 00:00-00, 2024.-Hypoxia is a common pathological and physiological phenomenon in ischemia, cancer, and strenuous exercise. Nitric oxide (NO) acts as an endothelium-derived relaxing factor in hypoxic vasodilation and serves as an allosteric regulator of hemoglobin (Hb). However, the ultimate effects of NO on the hematological system invivo remain unknown, especially in extreme environmental hypoxia. Whether NO regulation of the structure of Hb improves oxygen transport remains unclear. Hence, we examined whether NO altered the oxygen affinity of Hb (Hb-O2 affinity) to protect extremely hypoxic mice. Mice were exposed to severe hypoxia with various concentrations of NO, and the survival time, exercise capacity, and other physical indexes were recorded. The survival time was prolonged in the 5 ppm NO (6.09 ± 1.29 minutes) and 10 ppm NO (6.39 ± 1.58 minutes) groups compared with the 0 ppm group (4.98 ± 1.23 minutes). Hypoxia of the brain was relieved, and the exercise exhaustion time was prolonged when mice inhaled 20 ppm NO (24.70 ± 6.87 minutes vs. 20.23 ± 6.51 minutes). In addition, the differences in arterial oxygen saturation (SO2%) (49.64 ± 7.29% vs. 42.90 ± 4.30%) and arteriovenous SO2% difference (25.14 ± 8.95% vs. 18.10 ± 6.90%) obviously increased. In ex vivo experiments, the oxygen equilibrium curve (OEC) left shifted as P50 decreased from 43.77 ± 2.49 mmHg (0 ppm NO) to 40.97 ± 1.40 mmHg (100 ppm NO) and 38.36 ± 2.78 mmHg (200 ppm NO). Furthermore, the Bohr effect of Hb was enhanced by the introduction of 200 ppm NO (-0.72 ± 0.062 vs.-0.65 ± 0.051), possibly allowing Hb to more easily offload oxygen in tissue at lower pH. The crystal structure reveals a greater distance between Asp94β-His146β in nitrosyl -Hb(NO-Hb), NO-HbβCSO93, and S-NitrosoHb(SNO-Hb) compared to tense Hb(T-Hb, 3.7 Å, 4.3 Å, and 5.8 Å respectively, versus 3.5 Å for T-Hb). Moreover, hydrogen bonds were less likely to form, representing a key limitation of relaxed Hb (R-Hb). Upon NO interaction with Hb, hydrogen bonds and salt bridges were less favored, facilitating relaxation. We speculated that NO ameliorated the effects of hypoxia in mice by promoting erythrocyte oxygen loading in the lung and offloading in tissues.

Innovative Treatments to Counteract Endothelial Dysfunction in Chronic Kidney Disease Patients.

In chronic kidney disease (CKD) patients, several risk factors contribute to the development of endothelial dysfunction (ED), which can be described as an alteration in the cell structure or in the function of the endothelium. Among the well-known CKD-related risk factors capable of altering the production of endothelium-derived relaxing factors, we include asymmetric dimethylarginine increase, reduced dimethylarginine dimethylamine hydrolase enzyme activity, low-grade chronic systemic inflammation, hyperhomocysteinemia, oxidative stress, insulin resistance, alteration of calcium phosphorus metabolism, and early aging. In this review, we also examined the most important techniques useful for studying ED in humans, which are divided into indirect and direct methods. The direct study of coronary endothelial function is considered the gold standard technique to evaluate if ED is present. In addition to the discussion of the main pharmacological treatments useful to counteract ED in CKD patients (namely sodium-glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonist), we elucidate innovative non-pharmacological treatments that are successful in accompanying the pharmacological ones. Among them, the most important are the consumption of extra virgin olive oil with high intake of minor polar compounds, adherence to a plant-dominant, low-protein diet (LPD), an adaptive physical activity program and, finally, ketoanalogue administration in combination with the LPD or the very low-protein diet.

L-arginine, inosine and meldonium effect on the vascular wall reactivity of adult rats

Changes in the structure, metabolism and cardiovascular system function that develop during ageing are the basis for the circulatory pathology occurrence in old age. Currently, cardiovascular system diseases are one of the main causes of mortality in almost all developed countries. Therefore, searching for new drugs to correct the metabolism and functions of organs and systems whose activity is disrupted during ageing is an urgent problem. The article presents the study influence results of the synthesis precursor of endothelial relaxing factor - NO (ERF-NO) L-arginine, the purine nucleoside inosine and the β-oxidation inhibitor of fatty acids meldonium on the vascular wall reactivity of adult rats. When used separately, these drugs have been shown to cause slight relaxation of the thoracic aorta isolated segments in adult animals. When L-arginine, inosine and meldonium are used together, there is no summation of their pharmacological effect on blood vessels, however, some vasodilator effect potentiation is observed. The acetylcholine (Ach) vasodilator effect was significantly more than the vasodilator effect of the studied composition (L-arginine + inosine + meldonium), conventionally called Melarginine. It should be noted that, although the vasodilator Ach effect was significant, it was short-term, and the vasodilator effect of the studied combination (Melarginine) was long-lasting. A pronounced vasodilator response to Ach indicates the preservation of the endothelium in adult rats. Therefore, with intact endothelium in adult animals, Melarginine does not cause significant vascular relaxation. In aged rats, which typically exhibit endothelial damage, the effect of Melarginine may be more significant compared to adults. This will be the subject of our further study. Still, Melarginine has a small but long-lasting vasodilatory effect in adult rats, which also helps regulate vascular tone. _________________________________________________________________________________________ Keywords: vessel reactivity; endothelial dysfunction; L-arginine; inosine; meldonium; Melarginine

Effects of Pamelo Orange Peel (Citrus maxima) Ethanol Extract on Macroscopic Kidney and Heart of Hypertensive Rats

Background: Hypertension, characterized by elevated blood pressure (≥140/90 mmHg), leads to kidney and heart damage. Hypertension causes increased heart rate, heart enlargement, risk of heart failure, and damage to kidney blood vessels. One way to treat hypertension is by administering drugs such as herbal medicines. Pamelo oranges (Citrus maxima) are starting to be developed in the treatment of diseases. The ethanol extract of pomelo orange peel (EEKJP) contains flavonoid compounds which have antihypertensive activity as a natural Angiotensin Converting Enzyme (ACE) inhibitor, diuretic, increases Nitric Oxide Synthase (NOS) activity and activates Endothelium Derived Relaxing Factor (EDRF). Objectives: This study aims to examine the effect of ethanol extract of pomelo orange peel on the macroscopic features of the heart and kidneys of hypertensive rats (Rattus norvegicus). Methods: This research uses The Posttest-Only Control Group Design. Thirty rats were divided into six groups, namely naive control, negative control (NaCMC 1%), positive control (Captopril 0,45 mg/200 gramBB), EEKJP 100 mg/KgBW group, EEKJP 150 mg/KgBW group, and EEKJP 200 mg/KgBW group. Hypertension condition through induction with prednisone 1.5 mg/KgBW and NaCl 2% for 21th days. The test preparation was administered orally for 14th days. Next, all rats were dissected to remove the heart and kidney organs for macroscopic observations. Results: The results of the study showed that ethanol extract of pomelo (Citrus maxima) orange peel had a varied effect on the macroscopic appearance of the heart and kidneys of rats with hypertension. The heart organ shows structural improvements, while the kidneys have not shown any improvement. Conclusions: Extract with a dose of 100 mg/KgBW has no changes in the macroscopic appearance of the heart so it is thought to be able to repair damage to the heart organ.

The Roles of Potassium Channels and Nitric oxide in the Modulation of Apelin induced-relaxation in Isolated Diabetic Rat Aorta

Diabetes is associated with endothelial dysfunction, which impairs blood vesselscapacity to maintain vascular tone. Apelin is an adipocyte-produced relaxing factor that has endothelium-dependent and nitric oxide (NO)-mediated vasorelaxant effects. The current study investigated how streptozotocin (STZ)-induced type one diabetes modulates the mechanisms involved in aortic vascular response to apelin, focusing on the role of potassium channels and endothelial derived relaxing factors (EDRF). In this study, precontracted rat thoracic aortic segments were pre-incubated with the NO inhibitor, cyclooxygenase (COX) inhibitor and potassium channels blockers including: non-selective calcium-activated potassium channel, big conductance calcium-activated potassium channels (BKca), intermediate conductance calcium activated potassium channels (IKca), delayed inward rectifier potassium channels (Kir), adenosine triphosphates-sensitive potassium channels (KATP) and voltage sensitive potassium channels (Kv) blockers, then cumulative concentrations of apelin were applied to each group in both non-diabetic and diabetic conditions. The statistical analysis between diabetic and non-diabetic groups revealed that endothelial impairment induced by diabetes in rat thoracic aorta remarkably attenuated the vascular responses to apelin. An important new finding in this study was that almost all potassium channels blockers noticeably P<0.001 increased apelin efficacy with relatively no changes in the peptide potency. However, in diabetic aortic segments, the non-selective Kca, BKca blockers, NO inhibitor and COX inhibitor reversed vascular responses to apelin, but Kir, KATP and Kv blockers significantly reduced vascular responses to apelin in comparison to control rats. It is worth noting that diabetes did not only alter the peptide potency in these experimental groups but also significantly increased the maximum responses when Kca and BKca blockers preincubated. In conclusion, our findings shed light on the mechanisms behind diabetes-induced aortic artery hypo-reactivity to apelin which involve the inhibition of endothelial NO synthase activities and decreased contribution of Kca, BKca, IKca, Kv, Kir and KATP channels.

The Role of Nitric Oxide in the Autoregulation of Cerebral Blood Flow and the Pathogenesis of Cerebral Vascular Spasm in Patients with Ruptured Cerebral Aneurysms

The presented literature review is devoted to the role of the endothelial relaxing factor – nitric oxide (NO) – in the regulation of cerebral blood flow in patients with ruptured intracranial aneurysms. Modern views on the physiology of NO, methods of regulation and autoregulation of its synthesis are described, experimental and clinical data on the disruption of the production of the endothelial relaxing factor in subarachnoid hemorrhage are presented.

Аrginine – biological role, biosynthesis and whey consumption

The article summarizes actual information about L-arginine (Arg), which is the semi-essential amino acid. L-arginine is classified as an essential amino acid for birds, carnivores and young mammals and a conditionally essential amino acid for adults. L-arginine plays very important role in the plant and animal body metabolism. It metabolically interconvertible with the amino acids proline and glutamate and also is the precursor of a large number of crucial metabolites. It is serves as a precursor for synthesis of molecules of great biological importance, including proteins, L-ornithine, polyamines, agmatine, creatine and urea, which is important in the urea cycle. The main importance of L-arginine is attributed to its role as a precursor for the synthesis of nitric oxide (NO), a free radical molecule that is synthesized in all mammalian cells from L-arginine by NO synthase. NO appears to be a major form of the endothelium-derived relaxing factor. So, L−arginine plays a special role in vascular system, where it is a source of endogenous nitric oxide, which is blood vessels dilator. The use of supplements with L-arginine is appropriate in the prevention and treatment of metabolic diseases. Thanks to relaxation of vascular smooth muscles, it takes part in regulation of blood vessels tone. Treatment by arginine as a medicine improves functions of cardiovascular system. L-Аrginine there is in plant and animal food and in seafood. L-arginine has a wide and varied application such as animal feeding, cosmetology, medical field. In recent years arginine production has been increasing. L−Arginine is obtained by hydrolysis of proteins, with the help of chemical and microbiological synthesis. Microbiological synthesis of L-arginine is the most promising and economically advantageous. Modern microbial technologies use monosubstrates and mixed substrates. Bacteria can synthesize all 20 proteinogenic amino acids, including the nine essential amino acids required for mammalian growth. In general, enzymes involved in the biosynthesis of amino acids are essential for the growth and survival of bacteria. Peat cause great scientific interest. Peat is a natural media for growing symbiotic microorganisms, and has advantages over other types of natural feedstocks. We obtained a peat-based bio-substrate using an inorganic sulfur-containing compound. As a result of bio-substrate composting the content arginine and some other amino asides increased. This bio-substrate was used in resіaches as a feed additive for broiler chickens. Under the action of the feed additive the metabolism in the body of chісkens, growth and live weight gain improved.

Endothelial Dysfunction in Superior Mesenteric Arteries Isolated from Adenine-Induced Renal Failure in Model Rats.

Endothelial dysfunction-a hallmark of chronic kidney disease (CKD)-is one of the major risk factors for cardiovascular diseases (CVD). Imbalances in endothelium-derived relaxing factors (EDRFs) and contracting factors (EDCFs) specific to endothelial dysfunction in CKD are yet to be studied. Therefore, using adenine-treated rats-a CKD rat model-we investigated the responsiveness of superior mesenteric artery (SMA) endothelium to acetylcholine (ACh) stimulation under different experimental conditions. Nine-week-old male Wistar rats were treated daily with adenine (200 and 600 mg/kg body weight) by oral gavage, for 10 d; the two groups were named adenine-200 (200 mg/kg body weight) and adenine-600 (600 mg/kg body weight). The systolic blood pressure (measured 1-, 8-, and 15 d post-treatment) was significantly increased in the adenine-600 group compared with that in the control group; whereas that in the adenine-200 group showed only a slight increase. Moreover, in the adenine-600 group the serum creatinine and blood urea nitrogen (BUN) levels (measured at 18 d post-treatment) were significantly elevated when compared with those in control or adenine-200 groups. The ACh-mediated relaxation was slightly reduced in the adenine-200 group. The ACh- and sodium nitroprusside (SNP)-mediated relaxations were impaired in the adenine-600 group. Although no ACh-mediated contraction was observed in the presence of a nitric oxide (NO) synthase inhibitor, ACh-induced endothelium-derived hyperpolarizing factor-mediated relaxation was largely impaired in the adenine-600 mg/kg group. This study revealed that in the SMA of adenine-induced CKD model rats, EDCF signaling remained unaltered while the NO and EDHF signaling were impaired.

Moderate-Intensity Exercise Improves Mesenteric Arterial Function in Male UC Davis Type-2 Diabetes Mellitus (UCD-T2DM) Rats: A Shift in the Relative Importance of Endothelium-Derived Relaxing Factors (EDRF)

The beneficial cardiovascular effects of exercise are well documented, however the mechanisms by which exercise improves vascular function in diabetes are not fully understood. This study investigates whether there are (1) improvements in blood pressure and endothelium-dependent vasorelaxation (EDV) and (2) alterations in the relative contribution of endothelium-derived relaxing factors (EDRF) in modulating mesenteric arterial reactivity in male UC Davis type-2 diabetes mellitus (UCD-T2DM) rats, following an 8-week moderate-intensity exercise (MIE) intervention. EDV to acetylcholine (ACh) was measured before and after exposure to pharmacological inhibitors. Contractile responses to phenylephrine and myogenic tone were determined. The arterial expressions of endothelial nitric oxide (NO) synthase (eNOS), cyclooxygenase (COX), and calcium-activated potassium channel (KCa) channels were also measured. T2DM significantly impaired EDV, increased contractile responses and myogenic tone. The impairment of EDV was accompanied by elevated NO and COX importance, whereas the contribution of prostanoid- and NO-independent (endothelium-derived hyperpolarization, EDH) relaxation was not apparent compared to controls. MIE 1) enhanced EDV, while it reduced contractile responses, myogenic tone and systolic blood pressure (SBP), and 2) caused a shift away from a reliance on COX toward a greater reliance on EDH in diabetic arteries. We provide the first evidence of the beneficial effects of MIE via the altered importance of EDRF in mesenteric arterial relaxation in male UCD-T2DM rats.

Гомоцистеїн як біомаркер судинної патології

The purpose of the study was to analyze professional literature sources devoted to the influence of homocysteine on the development of vascular disorders. The role of homocysteine as a biomarker of vascular pathology is considered. Materials and methods. Bibliosemantic and analytical methods were used in the study. The analysis of the specialized literature (47 sources) was carried out using information in the scientific-metric databases MEDLINE/PubMed, Scopus and Google Scholar. Results and discussion. Homocysteinemia is a pathological condition associated with quite serious consequences for the body; the endothelium of vessels suffers mostly: systemic endothelial dysfunction develops (including disruption of the synthesis and exchange of the endothelium-relaxing factor – nitric oxide), oxidative stress, activation of platelet aggregation, hypercoagulation occurs (due to a decrease in the activity of heparin, thrombomodulin and an increase in the activity of thromboxane A2). The prevalence of hyperhomocysteinemia in Ukraine is quite high and reaches 10% among healthy adults, 2% among young people and adolescents, from 13% to 43% in patients with cardiovascular pathology. The C677T polymorphism of the methylenetetrahydrofolate reductase gene is widespread among the population of Ukraine (40.7%). Researchers believe that hyperhomocysteinemia is an independent and modifiable risk factor for vascular pathology. Conclusion. Homocysteine is recognized as one of the markers of vascular pathology. Scientists consider the activation of oxidative stress, damage to the endothelium, stimulation of the proliferation of smooth muscle cells, and pro-inflammatory effects to be the main mechanisms of vascular damage in hyperhomocysteinemia. The described pathological changes are accompanied by a violation of the regulation of vascular tone, mostly due to a decrease in the synthesis of nitric oxide. Unbalanced synthesis of nitric oxide causes and potentiates oxidative stress, the processes of atherothrombogenesis. The professional literature presents enough scientific data that convincingly prove the role of homocysteine in the development of cardiovascular and neurological pathology. However, there is a small number of studies devoted to the relationship between hyperhomocysteinemia and periodontal diseases, and the pathogenetic mechanisms of the influence of hyperhomocysteinemia on the development of vascular disorders in coronavirus disease are not fully disclosed

Pathogenic Mechanisms of Pulmonary Arterial Hypertension: Homeostasis Imbalance of Endothelium-Derived Relaxing and Contracting Factors.

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Sustained pulmonary vasoconstriction and concentric pulmonary vascular remodeling contribute to the elevated pulmonary vascular resistance and pulmonary artery pressure in PAH. Endothelial cells regulate vascular tension by producing endothelium-derived relaxing factors (EDRFs) and endothelium-derived contracting factors (EDCFs). Homeostasis of EDRF and EDCF production has been identified as a marker of the endothelium integrity. Impaired synthesis or release of EDRFs induces persistent vascular contraction and pulmonary artery remodeling, which subsequently leads to the development and progression of PAH. In this review, the authors summarize how EDRFs and EDCFs affect pulmonary vascular homeostasis, with special attention to the recently published novel mechanisms related to endothelial dysfunction in PAH and drugs associated with EDRFs and EDCFs.

Endothelium-Derived Relaxing Factors and Endothelial Function: A Systematic Review.

The endothelium plays a pivotal role in homeostatic mechanisms. It specifically modulates vascular tone by releasing vasodilatory mediators, which act on the vascular smooth muscle. Large amounts of work have been dedicated towards identifying mediators of vasodilation and vasoconstriction alongside the deleterious effects of reactive oxygen species on the endothelium. We conducted a systematic review to study the role of the factors released by the endothelium and the effects on the vessels alongside its role in atherosclerosis. A search was conducted with appropriate search terms. Specific attention was offered to the effects of emerging modulators of endothelial functions focusing the analysis on studies that investigated the role of reactive oxygen species (ROS), perivascular adipose tissue, shear stress, AMP-activated protein kinase, potassium channels, bone morphogenic protein 4, and P2Y2 receptor. 530 citations were reviewed, with 35 studies included in the final systematic review. The endpoints were evaluated in these studies which offered an extensive discussion on emerging modulators of endothelial functions. Specific factors such as reactive oxygen species had deleterious effects, especially in the obese and elderly. Another important finding included the shear stress-induced endothelial nitric oxide (NO), which may delay development of atherosclerosis. Perivascular Adipose Tissue (PVAT) also contributes to reparative measures against atherosclerosis, although this may turn pathological in obese subjects. Some of these factors may be targets for pharmaceutical agents in the near future. The complex role and function of the endothelium is vital for regular homeostasis. Dysregulation may drive atherogenesis; thus, efforts should be placed at considering therapeutic options by targeting some of the factors noted.

1,25(OH)2D3 alleviates LPS-induced preeclampsia-like rats impairment in the protective effect by TLR4/NF-kB pathway

IntroductionAccumulating epidemiological studies support that Vitamin D deficiency is associated with the pathogenesis of preeclampsia. However, it is unknown whether vitamin D can be used as a treatment for preeclampsia. This study aimed to explore whether vitamin D supplementation could improve the rat model of preeclampsia. MethodsLPS was used to establish a rat model of preeclampsia. Inflammatory cytokines were examined by QRT-PCR and ELISA assays, and the concentration of sfit-1 and NO was assessed by ELISA. Analyzing the pathological features of the placenta with hematoxylin-eosin. The spatial learning and memory abilities of offspring were evaluated by the Morris water maze. Immune histology and western blot were performed to evaluate the expression levels of inflammatory pathway-associated Factor and vascular endothelium-associated Factor in the placenta. ResultsVitamin D treatment reduced the blood pressure and urine protein of PE model rats, alleviated pathological damage to the placenta and pregnancy outcomes, and protected PE offspring from impaired memory and learning abilities. Moreover, TLR4 signaling pathway in the placenta was inhibited. Furthermore, vitamin D supplementation increased the expression of endothelial growth factor and vascular relaxing factor, and there was no significant difference compared with the control group. DiscussionWe generated the result that Vitamin D supplementation significantly improved the phenotype of preeclampsia and adverse pregnancy outcome caused by an abnormal inflammatory reaction and endothelial dysfunction in the placenta, and improved the learning and cognitive ability of offspring.

Acute Effects Of The Passive Static Stretching On Central And Peripheral Hemodynamics

Acute one-legged intermittent static stretching reduces arterial stiffness only in the stretched leg. Continuous high shear stress (e.g., shear rate) on endothelial cells induces vasodilation with increased endothelial-derived relaxation factor. Our recent study showed that shear rate and blood flow in the posterior tibial artery of the stretched leg was increased after acute passive one-legged calf intermittent stretching. Thus, the static stretching increases shear rate after stretching and may consequently decreases arterial stiffness. However, it remains unclear whether changes in central and peripheral circulation are related to a mechanism of static stretching-induced decrease in arterial stiffness. PURPOSE: This study aimed to clarify the time-course of changes in central and peripheral circulation on the acute static stretching-induced increase in shear rate. METHODS: The changes in cardiac output as central hemodynamics and blood flow and shear rate in the posterior tibial artery as peripheral hemodynamics by using echocardiography and doppler ultrasound, and blood volume in the calf muscle as peripheral hemodynamics by using near-infrared spectrophotometer were measured during recovery (0-60s) from a single bout of one-legged passive calf stretching (0-30s) in 12 healthy young men (22.8 ± 1.1 years). Blood pressure was measured before and after stretching session. RESULTS: The stretched leg’s blood flow and shear rate in posterior tibial artery significantly increased from 0 to 10th s after stretching (each P < 0.05). The muscle blood volume in the stretched leg significantly reduced during stretching, and then significantly increased during the recovery period after stretching (each P < 0.05); however, blood pressure and cardiac output remained unchanged during stretching and recovery. CONCLUSION: These findings indicate that mild ischemia-reperfusion was caused mechanically by the stretching calf muscles rather than by central hemodynamics, and consequently, it may have induced the increases in blood flow and shear rate in the posterior tibial artery of the stretched leg.

17β-Estradiol Treatment Improves Acetylcholine-Induced Relaxation of Mesenteric Arteries in Ovariectomized UC Davis Type 2 Diabetes Mellitus Rats in Prediabetic State.

We recently reported sex differences in mesenteric arterial function of the UC Davis type-2 diabetes mellitus (UCD-T2DM) rats as early as the prediabetic state. We reported that mesenteric arteries (MA) from prediabetic male rats exhibited a greater impairment compared to that in prediabetic females. However, when females became diabetic, they exhibited a greater vascular dysfunction than males. Thus, the aim of this study was to investigate whether the female sex hormone, estrogen preserves mesenteric arterial vasorelaxation in UCD-T2DM female rats at an early prediabetic state. Age-matched female Sprague Dawley and prediabetic (PD) UCD-T2DM rats were ovariectomized (OVX) and subcutaneously implanted with either placebo or 17β-estradiol (E2, 1.5 mg) pellets for 45 days. We assessed the contribution of endothelium-derived relaxing factors (EDRF) to acetylcholine (ACh)-induced vasorelaxation, using pharmacological inhibitors. Responses to sodium nitroprusside (SNP) and phenylephrine (PE) were also measured. Additionally, metabolic parameters and expression of some targets associated with vascular and insulin signaling were determined. We demonstrated that the responses to ACh and SNP were severely impaired in the prediabetic state (PD OVX) rats, while E2 treatment restored vasorelaxation in the PD OVX + E2. Moreover, the responses to PE was significantly enhanced in MA of PD OVX groups, regardless of placebo or E2 treatment. Overall, our data suggest that 1) the impairment of ACh responses in PD OVX rats may, in part, result from the elevated contractile responses to PE, loss of contribution of endothelium-dependent hyperpolarization (EDH) to vasorelaxation, and a decreased sensitivity of MA to nitric oxide (NO), and 2) the basis for the protective effects of E2 may be partly attributed to the elevation of the NO contribution to vasorelaxation and its interaction with MA as well as potential improvement of insulin signaling. Here, we provide the first evidence of the role of E2 in protecting MA from early vascular dysfunction in prediabetic female rats.

The predominance of endothelium-derived relaxing factors and beta-adrenergic receptor pathways in strong vasorelaxation induced by 4-hydroxybenzaldehyde in the rat aorta.

4-hydroxybenzaldehyde (4HB), known as ρ-hydroxybenzaldehyde, is commonly present in traditional Chinese medicine herb, most frequently used for hypertension treatment. This research aims to determine the potency of 4HB's vasorelaxant action. In the study, the vasodilation effect of 4HB was evaluated using in vitro isolated rat aortic rings assay. The aortic rings were pre-incubated with respective antagonists before being pre-contracted with phenylephrine (PE) and challenged with various concentrations of 4HB for mechanistic action studies. Rmax (maximal vasodilation) and pEC50 (negative logarithm of half-maximal effective concentration) values of each experiment were determined for comparison purposes. 4HB caused vasodilation on endothelium-intact aortic rings which pre-contracted with PE (pEC50 = 3.53±0.05, Rmax = 100.95±4.25%) or potassium chloride (pEC50 = 2.96±0.13, Rmax = 72.13±4.93%). The vasodilation effect of 4HB was significantly decreased in the absence of an endothelium (pEC50 = 2.21±0.25, Rmax = 47.96±4.16%). The atropine, 4-aminopyridine, Nω-nitro-L-arginine methyl ester, glibenclamide, and propranolol significantly reduced the vasorelaxation effect of 4HB. Besides that, 4HB blocked the voltage-operated calcium channel (VOCC) and regulated the intracellular Ca2+ release from the sarcoplasmic reticulum (SR) in the aortic ring. Thus, the results indicated that 4HB exerted its vasodilatory effect via cGMP and β2 pathways, M3-dependent PLC/IP3 pathways, and potassium and calcium channels.

Antihypertensive Effects of IGTGIPGIW Peptide Purified from Hippocampus abdominalis: p-eNOS and p-AKT Stimulation in EA.hy926 Cells and Lowering of Blood Pressure in SHR Model.

The aim of this study was to assess the potential hypertensive effects of the IGTGIPGIW peptide purified from Hippocampus abdominalis alcalase hydrolysate (HA) for application in the functional food industry. We investigated the antihypertensive effects of IGTGIPGIW in vitro by assessing nitric oxide production in EA.hy926 endothelial cells, which is a major factor affecting vasorelaxation. The potential vasorelaxation effect was evaluated using 4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate, a fluorescent stain. IGTGIPGIW significantly increased the expression of endothelial-derived relaxing factors, including endothelial nitric oxide synthase and protein kinase B, in EA.hy926 cells. Furthermore, oral administration of IGTGIPGIW significantly lowered the systolic blood pressure (183.60 ± 1.34 mmHg) and rapidly recovered the diastolic blood pressure (143.50 ± 5.55 mmHg) in the spontaneously hypertensive rat model in vivo. Our results demonstrate the antihypertensive activity of the IGTGIPGIW peptide purified from H. abdominalis and indicate its suitability for application in the functional food industry.

Endothelium-dependent vasorelaxant effects of praeruptorin a in isolated rat thoracic aorta

ABSTRACT Praeruptorin A (PA) is a natural coumarin compound from the roots of Radix Peucedani and is commonly used in the treatment of certain respiratory diseases and hypertension. Although previous studies identified relaxant effects of PA on tracheal and arterial preparations, little is known about its vasodilative effects and underlying mechanisms. Here, an organ bath system and tension recording methods were used to prepare and analyze isolated rat thoracic aorta artery rings. Aorta artery rings were pre-contracted with phenylephrine and then incubated with PA, and the possible mechanism of relaxation was investigated by adding inhibitors of nitric oxide synthase (NG-nitro-L-arginine methyl ester, L-NAME), endothelial nitric oxide synthase (L-NG-nitroarginine, L-NNA), cyclooxygenase (indomethacin), guanylyl cyclase (1 H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one, ODQ), and KCa channels (tetraethylammonium, TEA). Our study showed that PA-induced vasodilation was blocked by L-NAME, L-NNA, and ODQ, while CaCl2-induced vasoconstriction was countered by PA. Thus, PA may exert a vasodilatory effect by influencing the amounts of endothelium-derived relaxing factors through endothelial-dependent NO-cGMP and prostacyclin pathways (such as NO and prostacyclin 2). In the rat thoracic aorta, PA reduces vasoconstriction by inhibiting Ca2+ inflow.

Noble Gases Therapy in Cardiocerebrovascular Diseases: The Novel Stars?

Cardiocerebrovascular diseases (CCVDs) are the leading cause of death worldwide; therefore, to deeply explore the pathogenesis of CCVDs and to find the cheap and efficient strategies to prevent and treat CCVDs, these are of great clinical and social significance. The discovery of nitric oxide (NO), as one of the endothelium-derived relaxing factors and its successful utilization in clinical practice for CCVDs, provides new ideas for us to develop drugs for CCVDs: “gas medicine” or “medical gases.” The endogenous gas molecules such as carbon monoxide (CO), hydrogen sulfide (H2S), sulfur dioxide (SO2), methane (CH4), and hydrogen (H2) have essential biological effects on modulating cardiocerebrovascular homeostasis and CCVDs. Moreover, it has been shown that noble gas atoms such as helium (He), neon (Ne), argon (Ar), krypton (Kr), and xenon (Xe) display strong cytoprotective effects and therefore, act as the exogenous pharmacologic preventive and therapeutic agents for CCVDs. Mechanistically, besides the competitive inhibition of N-methyl-D-aspartate (NMDA) receptor in nervous system by xenon, the key and common mechanisms of noble gases are involved in modulation of cell death and inflammatory or immune signals. Moreover, gases interaction and reduction in oxidative stress are emerging as the novel biological mechanisms of noble gases. Therefore, to investigate the precise actions of noble gases on redox signals, gases interaction, different cell death forms, and the emerging field of gasoimmunology, which focus on the effects of gas atoms/molecules on innate immune signaling or immune cells under both the homeostatic and perturbed conditions, these will help us to uncover the mystery of noble gases in modulating CCVDs.

Metabolomics analysis delineates the therapeutic effects of hydroethanolic extract of Cucumis sativus L. seeds on hypertension and isoproterenol-induced myocardial infarction

Cucumis sativus L., widely cultivated as an edible vegetable. Its seeds are well reputed for cardiovascular preventive properties. However, the mechanisms underlying for cardiovascular protection of C. sativus are still unidentified. Therefore, this study utilized a metabolomics approach to investigate putative mechanisms of C. sativus seeds in myocardial infarction (MI) and in vitro models of vasoconstriction, atrium, and invasive blood pressure measurement. Results showed that Cu.EtOH extract showed a vasorelaxant response with potent hypotensive effect in normotensive rats and L-NAME induced hypertension. Cu.EtOH caused a negative inotropic and positive chronotropic effect on the atrium. Cu.EtOH protected the animals from ISO-induced myocardial infarction (MI) interventions in left ventricular thickness, cardiomyocyte hypertrophy, mRNA gene expression, and biochemical assays. The metabolomics data suggested that Cu.EtOH mainly affected amino acid metabolism, BCAA degradation, ketone bodies degradation, and oxidative stress. Our study showed that Cu.EtOH suppressed inflammation with a strong anti-myocardial infarction impact. Additionally, our findings indicated Cu.EtOH reverted the amino acid metabolism, BCAA, and ketone bodies degradation. The findings show the antihypertensive mechanism of Cu.EtOH may include the modulation of endothelium-derived relaxing factor (EDRF) produced from nitric oxide (NO) and is connected with vascular endothelial function. C. sativus seeds, in particular, played a pivotal role in the treatment of myocardial and vascular disorders by enhancing the EDRF mechanism, energy generation, and antioxidant capacity. In summary, our findings showed the mechanistic insights on the therapeutic potential of C. sativus seeds for cardiovascular disorders.