Vasodilator Factors Research Articles

Lipoic acid antagonizes paraquat-induced vascular endothelial dysfunction by suppressing mitochondrial reactive oxidative stress.

Paraquat (PQ) is a widely used herbicide in the agricultural field. The lack of an effective antidote is the significant cause of high mortality in PQ poisoning. Here, we investigate the antagonistic effects of alpha lipoic acid (α-LA), a naturally existing antioxidant, on PQ toxicity in human microvascular endothelial cells (HMEC-1). All the doses of 250, 500 and 1000 μM α-LA significantly inhibited 1000 μM PQ-induced cytotoxicity in HMEC-1 cells. α-LA pretreatment remarkably diminished the damage to cell migration ability, recovered the declined levels of the vasodilator factor nitric oxide (NO), elevated the expression level of endothelial nitric oxide synthases (eNOS), and inhibited the upregulated expression of vasoconstrictor factor endothelin-1 (ET-1). Moreover, α-LA pretreatment inhibited reactive oxygen species (ROS) generation, suppressed the damage to the mitochondrial membrane potential (ΔΨ m) and mitigated the inhibition of adenosine triphosphate (ATP) production in HMEC-1 cells. These results suggested that α-LA could alleviate PQ-induced endothelial dysfunction by suppressing oxidative stress. In summary, our present study provides novel insight into the protective effects and pharmacological potential of α-LA against PQ toxicity in microvascular endothelial cells.

Effect of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on the regulation of vascular endothelial cell function

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) belong to polyunsaturated fatty acids from the group n-3 (n-3 PUFA), and their main source are marine fishes. Many epidemiological studies have shown that high intake of these kinds of fishes is strictly associated with a reduced risk of cardiovascular diseases. DHA and EPA inhibit the development of inflammation, change the function and regulation of molecules that are also vascular biomarkers. They are vasodilating and vasoconstriction factors by controlling the production of nitric oxide (NO) and endothelin 1 (ET-1) in endothelial cells. They also contribute to antiatherosclerotic protection by regulating the expression of the oxidized low density lipoprotein (oxLDL) receptor, plasminogen activator inhibitor-1 (PAI-1), thromboxane A2 (TXA2) receptor and adhesion molecules: intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion protein 1 (VCAM-1) as well as monocyte chemoattractant protein 1 (MCP-1). Studies indicate that DHA and EPA regulate toll-like receptor 4 (TLR4) activation and impair nuclear factor-κB (NF-κB) signaling pathway activation. They show anti-inflammatory effects by affecting free fatty acid receptor 4 (FFAR4). However, efficacy as well as the mechanisms of action of these acids in the prevention of cardiovascular disease are still not fully understood. Therefore, the aim of this study was to assess the effect of DHA and EPA on endothelial cells of blood vessels and to review the latest research on their potential in the prevention of cardiovascular diseases.

P716Role of EDRFs in aortic and mesenteric arterial function of the UC Davis Type 2 Diabetic Mellitus (UCD-T2DM) male rats

Abstract Several studies have shown vascular dysfunction in diabetic rats, however, there is no data on the vascular function of UC Davis type 2 diabetes Mellitus (UCD-T2DM) rats. UCD-T2DM is a novel but validated model of type 2 diabetes (T2D) which more closely resembles the pathophysiology of diabetes in humans. The aim of this study was to determine whether aortic or mesenteric arterial function were altered in UCD-T2DM male rats. Specifically, we determined the responses to endothelium-dependent vasodilator and vasoconstrictor in this model. We also studied the relative contribution of endothelium-derived relaxing factors (EDRFs) in modulating vascular reactivity of aorta or mesenteric artery (MA) in UCD-T2DM male rats. Endothelium-dependent vasodilation (EDV) to acetylcholine (ACh) was measured in rat aorta or MA pre-contracted with phenylephrine (PE). Particularly, EDV to ACh were measured before and after pretreatment with indomethacin (indo, cyclooxygenase inhibitor), ODQ (soluble guanylate cyclase inhibitor), L-NNA (nitric oxide synthase (NOS) inhibitor), TRAM-34 (IKca blocker), or Apamin (SKca blocker). Constrictor response curves to PE were also generated in both aorta and MA. Furthermore, the protein expression of IK channels were determined using Western blotting. We demonstrated that EDV to ACh was impaired in MA, while potentiated in the aortic rings of UCD-T2DM rats. In diabetic MA, the importance of endothelium-derived hyperpolarizing factor (EDHF) in ACh-induced relaxation was decreased, while the contribution of nitric oxide (NO) was enhanced. On the other hand, in diabetic aorta, the relative contribution of EDHF in relaxation responses to ACh was significantly enhanced (as measured by ACh response which was insensitive to indo, ODQ and L-NNA). The incubation of aorta or MA with TRAM-34 blunted the relaxation responses to ACh in both control and diabetic groups. However, the inhibitory effects of TRAM 34 on ACh responses were more prominent in arteries taken from UCD-T2DM groups compared to those in controls. By contrast, ACh responses were not affected following incubation of aorta or MA with Apamin in either control or diabetic groups suggesting that SKca channels plays no role in EDHF-mediated relaxation in either vascular beds. Accordingly, the IKca expression level was significantly higher in aortic rings of diabetic group than in the controls. The responsiveness to PE was significantly enhanced in the aortic rings of diabetic group, whereas in MA, diabetes did not alter the contractile responses to PE. These data suggest that in MA of UCD-T2DM rats, the predisposition to vascular injury may be due to a shift away from EDHF, initially the major vasodilatory factor, toward a greater reliance on NO. However, in aorta, despite elevated contractile responses, ACh responses were enhanced. Increased contribution of NO-independent factors specifically IKca channel plays a role in potentiated responses to ACh in this model. Acknowledgement/Funding NIHLBI

Triiodothyronine Reduces Vascular Dysfunction Associated with Hypertension by Attenuating Protein Kinase G/Vasodilator-Stimulated Phosphoprotein Signaling.

Vascular dysfunction associated with hypertension comprises hypercontractility and impaired vasodilation. We have previously demonstrated that triiodothyronine (T3), the active form of thyroid hormone, has vasodilatory effects acting through rapid onset mechanisms. In the present study, we examined whether T3 mitigates vascular dysfunction associated with hypertension. To test the direct effects of T3 in hypertensive vessels, aortas from female Dahl salt-sensitive (Dahl SS) rats fed a high-salt diet (8% NaCl, HS group) and their age-matched controls fed a standard low-salt diet (0.3% NaCl, LS group) for 16 weeks were isolated and used in ex vivo vascular reactivity studies. We confirmed that the HS group exhibited a higher systolic blood pressure in comparison with the control LS group and displayed aortic remodeling. Aortas from both groups were pretreated with T3 (0.1 μM) for 30 minutes at 37°C in a 5% CO2 incubator before functional vascular studies. T3 treatment significantly attenuated hypercontractility and improved impaired endothelium-dependent vasodilation in aortas from the HS group. These vascular improvements in response to T3 were accompanied by increased phosphorylation of vasodilator-stimulated phosphoprotein (VASP) at serine 239, a vasodilatory factor of the cGMP-dependent protein kinase (PKG)/VASP signaling pathway in vascular smooth muscle cells. Moreover, increased production of reactive oxygen species in aortas from the HS group were significantly reduced by T3, suggesting a potential antioxidant effect of T3 in the vasculature. These results demonstrate that T3 can mitigate hypertension-related vascular dysfunction through the VASP signaling pathway and by reducing vascular ROS production. SIGNIFICANCE STATEMENT: This study demonstrates that triiodothyronine (T3) directly acts on vascular tone and has a beneficial effect in hypertension-induced vascular dysfunction. T3 augmented vasodilation and diminished vasoconstriction in blood vessels from hypertensive rats in association with activation of the protein kinase G/vasodilator-stimulated phosphoprotein signaling pathway that activates vascular relaxation and exerted an antioxidant effect. Collectively, these results show that T3 is a potential vasoprotective agent with rapid action on hypertension-related vascular dysfunction.

Shear stress-induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure.

Hypertension is a primary risk factor for cardiovascular diseases including myocardial infarction and stroke. Major determinants of blood pressure are vasodilatory factors such as nitric oxide (NO) released from the endothelium under the influence of fluid shear stress exerted by the flowing blood. Several endothelial signaling processes mediating fluid shear stress-induced formation and release of vasodilatory factors have been described. It is, however, still poorly understood how fluid shear stress induces these endothelial responses. Here we show that the endothelial mechanosensitive cation channel PIEZO1 mediated fluid shear stress-induced release of adrenomedullin, which in turn activated its Gs-coupled receptor. The subsequent increase in cAMP levels promoted the phosphorylation of endothelial NO synthase (eNOS) at serine 633 through protein kinase A (PKA), leading to the activation of the enzyme. This Gs/PKA-mediated pathway synergized with the AKT-mediated pathways leading to eNOS phosphorylation at serine 1177. Mice with endothelium-specific deficiency of adrenomedullin, the adrenomedullin receptor, or Gαs showed reduced flow-induced eNOS activation and vasodilation and developed hypertension. Our data identify fluid shear stress-induced PIEZO1 activation as a central regulator of endothelial adrenomedullin release and establish the adrenomedullin receptor and subsequent Gs-mediated formation of cAMP as a critical endothelial mechanosignaling pathway regulating basal endothelial NO formation, vascular tone, and blood pressure.

Mechanisms of TRPV4 channel activation in human arteriolar endothelial cells: A structure‐activity study with arachidonic acid and analogs

Previous studies from our group indicated that arachidonic acid (AA) induces dilation of human coronary arterioles (HCAs) through the activation of endothelial TRPV4 channels followed by the release of vasodilator factors or endothelial hyperpolarization. In addition, TRPV4‐mediated vasodilatory response to flow is augmented in HCAs from subjects with coronary artery disease (CAD), a condition associated with a change of vasodilators from nitric oxide to hydrogen peroxide. However, the mechanisms of TRPV4 activation by AA and its role in the regulation of TRPV4 function under normal conditions remain to be elucidated. In this study, we examined the structure‐activity relationships of AA and its congeners in human adipose arterioles from subjects without CAD (non‐CAD). Adipose arterioles (~150 μm ID), isolated from non‐CAD human subjects, were cannulated and pressurized at 60 mmHg for videomicroscopic measurement of vessel diameters. In adipose arterioles pre‐constricted with endothelin‐1, AA (10−11 to 10−6 M) elicited a potent concentration‐dependent dilation (maximal dilation: 84±3%, logEC50: −8.2, n=6), and this response was largely blocked by HC‐067047 (10−6 M), a TRPV4 antagonist (17±3%, n=6). Compared with AA (C20:4ω6), vasodilator effect of AA analog homo‐γ‐linolenic acid (HGLA, C20:3ω6; 10−11 to 10−6 M) was less potent (maximal dilation: 44±8%, logEC50: −7.2, n=6) but the dilation was also largely abolished by HC‐067047 (6±3%, n=4). These HC067047‐inhibitable vasodilator effects of AA and HGLA were similar as those in HCAs from CAD subjects shown previously (maximal dilation: 84±5% and 40±5%, logEC50: −8.3 and −6.8, n=5 and 3, respectively). In adipose arterioles, another AA analog 5,8,11,14‐eicosatetraynoic acid (ETYA, 10−11 to 10−6 M) demonstrated greatly reduced response (maximal dilation: 19±3%, logEC50: −7.1, n=3), which was eliminated by HC‐067047 (5±2%, n=3). Pretreatment of adipose arterioles with ETYA (10−5 M) decreased vasodilation responses to AA (25±2%, n=5). Vessel denudation markedly reduced vasodilatory responses to AA (10−11 to 10−6 M) (maximal dilation: 33±5%, n=4) as well as to HGLA (10−11 to 10−6 M) (maximal dilation: 13±3%, n=4), confirming the endothelium‐dependent effects of AA and analogs. The dilation to the smooth muscle relaxant sodium nitroprusside (10−10 to 10−4 M) was not affected by HC‐067047 (maximal dilation: 100±0% vs. 99.8±1%, n=2). Together, these data provide evidence that AA activates endothelial TRPV4 to induce comparable dilation in non‐CAD human arterioles. AA congeners also activate TRPV4 channels, however, but they exhibit reduced vasodilatory responses and can antagonize arachidonic‐acid‐induced TRPV4‐mediated vasodilation, suggesting a potential role of specific cis‐double bonds and/or their position for AA‐induced TRPV4 activation. Future studies will examine whether the mechanisms of TRPV4 activation involve potential binding of AA to the channel protein or indirect effect through AA metabolites.Support or Funding InformationThis work was supported by R01‐HL 096647This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Vasoactive intestinal peptide shapes first-trimester placenta trophoblast, vascular, and immune cell cooperation.

Extravillous trophoblast (EVT) cells are responsible for decidual stromal invasion, vascular transformation, and the recruitment and functional modulation of maternal leukocytes in the first-trimester pregnant uterus. An early disruption of EVT function leads to placental insufficiency underlying pregnancy complications such as preeclampsia and fetal growth restriction. Vasoactive intestinal peptide (VIP) is a vasodilating and immune modulatory factor synthesized by trophoblast cells. However, its role in first-trimester placenta has not been explored. Here, we tested the hypothesis that VIP is involved in first-trimester EVT outgrowth, spiral artery remodelling, balancing angiogenesis, and maintenance of immune homeostasis. First-trimester placental tissue (five to nineweeks of gestation) was collected, and was used for EVT outgrowth experiments, immunofluorescence, isolation of decidual natural killer (dNK) cells and decidual macrophages (dMA), and functional assays. Peripheral blood monocytes were differentiated with GM-CSF and used for angiogenesis assays. In decidua basalis, VIP+ EVT were observed sprouting from cell columns and lining spiral arterioles. EVT migrating from placental explants were also VIP+. VIP increased EVT outgrowth and IL-10 release, whereas it decreased pro-inflammatory cytokine production in EVT, dNK cells, and dMA. VIP disrupted endothelial cell networks, both directly and indirectly via an effect on macrophages. The results suggest that VIP assists the progress of EVT invasion and vessel remodelling in first-trimester placental bed in an immunologically "silent" milieu. The effects of VIP in the present ex vivo human placental model endorse its potential as a therapeutic candidate for deep placentation disorders.

Selective BMP-9 Inhibition Partially Protects Against Experimental Pulmonary Hypertension.

Although many familial cases of pulmonary arterial hypertension exhibit an autosomal dominant mode of inheritance with the majority having mutations in essential constituents of the BMP (bone morphogenetic protein) signaling, the specific contribution of the long-term loss of signal transduction triggered by the BMPR2 (type 2 BMP receptor) remains poorly characterized. To investigate the role of BMP9, the main ligand of ALK1 (Activin receptor-like kinase 1)/BMPR2 heterocomplexes, in pulmonary hypertension. The absence of BMP9 in Bmp9-/- mice and its inhibition in C57BL/6 mice using neutralizing anti-BMP9 antibodies substantially prevent against chronic hypoxia-induced pulmonary hypertension judged by right ventricular systolic pressure measurement, right ventricular hypertrophy, and pulmonary distal arterial muscularization. In agreement with these observations, we found that the BMP9/BMP10 ligand trap ALK1ECD administered in monocrotaline or Sugen/hypoxia (SuHx) rats substantially attenuate proliferation of pulmonary vascular cells, inflammatory cell infiltration, and regresses established pulmonary hypertension in rats. Our data obtained in human pulmonary endothelial cells derived from controls and pulmonary arterial hypertension patients indicate that BMP9 can affect the balance between endothelin-1, apelin, and adrenomedullin. We reproduced these in vitro observations in mice chronically exposed to hypoxia, with Bmp9-/- mice exhibiting lower mRNA levels of the vasoconstrictor peptide ET-1 (endothelin-1) and higher levels of the 2 potent vasodilator factors apelin and ADM (adrenomedullin) compared with Bmp9+/+ littermates. Taken together, our data indicate that the loss of BMP9, by deletion or inhibition, has beneficial effects against pulmonary hypertension onset and progression.

Paying the Toll for Inflammation

Paying the Toll for Inflammation

Enoxaparin prevents fibrin accumulation in liver tissues and attenuates methotrexate-induced liver injury in rats.

Methotrexate (MTX) is a widely used drug for treatment of many malignant, rheumatic, and autoimmune diseases. However, hepatotoxicity remains one of the most serious side effects of MTX. The extrinsic coagulation pathway is activated after tissue injury through the release of tissue factor (TF) which activates a cascade of clotting factors including prothrombin and fibrinogen. Liver sinusoidal endothelial cells express endothelial nitric oxide synthase (eNOS) as a source for nitric oxide (NO) that serves as vasodilator and antithrombotic factor. In the current study, we tested the possible role of coagulation system activation in MTX-induced hepatotoxicity. Our results showed that single-dose administration of MTX significantly altered rat liver functions with concurrent turbulence in redox status. Immunofluorescence staining showed accumulation of fibrin in the periportal hepatocytes and downregulation of eNOS expression in hepatic endothelial and sinusoidal cells following MTX treatment. Moreover, MTX administration increased the expression of inducible nitric oxide synthase (iNOS) and NOSTRIN (eNOS traffic inducer) in the hepatic sinusoids. On the other hand, pre-treatment with enoxaparin rescued against MTX-induced liver injury with subsequent amelioration of liver redox status. Furthermore, it significantly prevented the effect of MTX on the expression of fibrin, iNOS, eNOS, and NOSTRIN. We concluded that liver tissue aggregation of the coagulation product, fibrin, may play a crucial role in the pathogenesis of MTX-induced liver injury.

Effects of different doses of ticagrelor on platelet aggregation and endothelial function in diabetic patients with stable coronary artery disease

We performed this study to observe the effects of different doses of ticagrelor and standard-dose clopidogrel on platelet reactivity and endothelial function in diabetic patients with stable coronary artery disease (CAD). Sixty type 2 diabetic patients were assigned to one-quarter standard-dose ticagrelor, half standard-dose ticagrelor, standard-dose ticagrelor and standard-dose clopidogrel groups. Light transmission aggregometry (LTA) and VerifyNow assay were used to measure platelet function. Endothelial function was assessed by measurement of flow-mediated vasodilation (FMD) and plasma von Willebrand factor (VWF) levels were detected. Enzyme-linked immunosorbent assay (ELISA) examined the Interleukin-8(IL-8) and IL-10. The results suggested that the one-quarter dose (34.0%± 14.7%), half-dose (26.9%± 11.6%) and standard-dose (17.3%± 10.3%) ticagrelor showed lower platelet aggregation rate than clopidogrel (52.8%± 18.3%; P ＜0.0001). PRU values in three ticagrelor groups were lower than that in clopidogrel group (102 (76–184)；75 (33–88)；38 (11–52) versus 194 (138–271) and；P ＜0.0001). FMD levels were higher in ticagrelor groups compared with baseline levels while lower in clopidogrel group after treatment. However, no significant differences were found in the percentage increase in the FMD between ticagrelor groups and clopidogrel group. The levels of VWF after treatment were lower than the baseline levels, but there was no statistically significant difference between ticagrelor group and clopidogrel group after treatment. The concentration of IL-8 and IL-10 were decreased in patients with half and standard-dose ticagrelor group. In conclusion, one-quarter standard-dose ticagrelor produced similar inhibitory effects on platelet aggregation as standard-dose clopidogrel in diabetic patients with stable CAD. The half standard-dose ticagrelor had a similar inhibitory effect on platelet inhibition as standard-dose ticagrelor, which was stronger than that of clopidogrel. Moreover, the half-dose ticagrelor had equal protection of endothelial function and inhibition of inflammatory factor as standard-dose ticagrelor.

Nitrate-Rich Fruit and Vegetable Supplement Reduces Blood Pressure in Normotensive Healthy Young Males without Significantly Altering Flow-Mediated Vasodilation: A Randomized, Double-Blinded, Controlled Trial.

Nitric oxide (NO) is a primary vasodilatory factor released from endothelial cells of the peripheral vasculature. NO production is stimulated through enzymatic-dependent mechanisms via NO synthase and from dietary intake of nitrate-containing foods or supplements. We evaluated the efficacy of a nitrate-rich fruit and vegetable liquid supplement (FVS, AMPED NOx, Isagenix International LLC) versus a juice low in nitrates (prune juice, PRU) on circulating nitrates/nitrites as well as cardiovascular parameters in 45 healthy normotensive men (18–40 y). Blood pressure, flow-mediated dilation (FMD), and plasma nitrates and nitrites were measured at baseline and after two weeks of supplementation (2 oz/d). Subjects also completed questionnaires on sleep quality and mood since these measures have been associated with endothelial function. In contrast to PRU, FVS significantly increased plasma nitrates and nitrites (+67%, p < 0.001) and decreased diastolic blood pressure (−9%, p=0.029) after two weeks. The change in FMD for FVS supplementation versus PRU supplementation was not significant (+2% vs. −9%, respectively, p=0.145). Changes in sleep quality or total mood state did not differ between groups after the 2-week study. Thus, the nitrate-rich FVS supplement increased plasma NO and reduced diastolic blood pressure in young normotensive men, but increased plasma NO was not associated with improvements in FMD, mood, or sleep. This trial is registered with ClinicalTrials.gov NCT03486145.

Bonus Effects of Antidiabetic Drugs: Possible Beneficial Effects on Endothelial Dysfunction, Vascular Inflammation and Atherosclerosis.

Diabetes currently affects more than 400 million people worldwide. This metabolic disorder causes various micro- and macrovascular complications that accelerate atherosclerosis and yet trigger other cardiovascular diseases. The characteristic frame of hyperglycaemia, hyperinsulinaemia and hyperlipidaemia in diabetes increases several inflammatory mediators leading to endothelial dysfunction and pro-atherosclerotic processes. This MiniReview summarizes evidence that antidiabetic drugs have effects beyond lowering glycaemic levels. In experimental studies, antidiabetic drugs reduce the vascular production and release of pro-inflammatory cytokines, the recruitment, infiltration and activation of immune cells and pro-inflammatory mediators, thus decreasing vascular inflammatory responses; they also re-establish vascular redox homeostasis by reducing oxidative stress and balancing the release of vasoconstrictor and vasodilator factors, hence contributing to the improvement of endothelial function. These effects are associated with a reduction in vascular remodelling due to decreased matrix metalloproteinases expression/activity, reduced inflammatory processes and vascular wall fibrosis. In clinical studies, antidiabetic drugs also reduce the production and release of pro-inflammatory, pro-atherosclerotic and pro-oxidative mediators and improve flow-mediated dilatation, indicating beneficial effects on endothelial function. These bonus effects of antidiabetic drugs may delay and/or reduce the installation and development of the atherosclerotic disease, decrease cardiovascular risk and possibly impact mortality risk, life expectancy and quality.

Vascular dysfunction of postural tachycardia syndrome in children.

Postural orthostatic tachycardia syndrome (POTS) is a form of orthostatic intolerance, and its incidence in children is approximately 6.8% [1]. The pathogenesis of POTS is complex with multiple, overlapping, interacting pathophysiological mechanisms. Although the specific pathogenic mechanism has remained perplexing, with the discovery of various gasotransmitters and biological peptides, the vascular dysfunction has aroused overwhelming attention. On the basis of searching in a wide range of recent original literatures, we reviewed the pathogenesis of vascular dysfunction in children with POTS. The flow-mediated vasodilation of POTS patients was greater than that of healthy controls, and the vasodilator factors were increased in patients with POTS under basal condition or under a standing position, while the vasoconstriction factors were reduced. Vascular dysfunction, as one of pathogenesis in pediatric POTS patients, affects the occurrence and development of diseases through a variety of factors.

Endothelium-Dependent Hyperpolarization (EDH) in Hypertension: The Role of Endothelial Ion Channels.

Upon stimulation with agonists and shear stress, the vascular endothelium of different vessels selectively releases several vasodilator factors such as nitric oxide and prostacyclin. In addition, vascular endothelial cells of many vessels regulate the contractility of the vascular smooth muscle cells through the generation of endothelium-dependent hyperpolarization (EDH). There is a general consensus that the opening of small- and intermediate-conductance Ca2+-activated K+ channels (SKCa and IKCa) is the initial mechanistic step for the generation of EDH. In animal models and humans, EDH and EDH-mediated relaxations are impaired during hypertension, and anti-hypertensive treatments restore such impairments. However, the underlying mechanisms of reduced EDH and its improvement by lowering blood pressure are poorly understood. Emerging evidence suggests that alterations of endothelial ion channels such as SKCa channels, inward rectifier K+ channels, Ca2+-activated Cl− channels, and transient receptor potential vanilloid type 4 channels contribute to the impaired EDH during hypertension. In this review, we attempt to summarize the accumulating evidence regarding the pathophysiological role of endothelial ion channels, focusing on their relationship with EDH during hypertension.

The Yin and Yang of endothelium-derived vasodilator factors.

The Yin and Yang of endothelium-derived vasodilator factors.

The Role of Vasodilator Receptors of Renin-angiotensin System on Nitric Oxide Formation and Kidney Circulation after Angiotensin II Infusion in Renal Ischemia/Reperfusion Rats.

Background:Nitric oxide (NO) as a vasodilator factor has renoprotective effect against renal ischemia. The balance between angiotensin II (Ang II) and NO can affect kidney homeostasis. The aim of this study was to determine NO alteration in response to renin–Ang system vasodilator receptors antagonists (PD123319; Ang II type 2 receptor antagonist and A779; Mas receptor antagonist) in renal ischemia/reperfusion injury (IRI) in rats.Materials and Methods:Sixty-three Wistar male and female rats were used. Animals from each gender were divided into four groups received saline, Ang II, PD123319 + Ang II, and A779 + Ang II after renal IRI. Renal IRI induced with an adjustable hook. Blood pressure and renal blood flow (RBF) measured continuously. The nitrite levels were measured in serum, kidney, and urine samples.Results:In female rats, the serum and kidney nitrite levels increased significantly by Ang II (P < 0.05) and decreased significantly (P < 0.05) when PD123319 was accompanied with Ang II. Such observation was not seen in male. Ang II decreased RBF significantly in all groups (P < 0.05), while PD + Ang II group showed significant decrease in RBF in comparison with the other groups in female rats (P < 0.05).Conclusion:Males show more sensibility to Ang II infusion; in fact, it is suggested that there is gender dimorphism in the Ang II and NO production associated with vasodilator receptors.

Seawater acclimation affects cardiac output and adrenergic control of blood pressure in rainbow trout (Oncorhynchus mykiss)-implications for salinity variations now and in the future.

Greater salinity variations resulting from ongoing climate change requires consideration in conservation management as this may impact on the performance of aquatic organisms. Euryhaline fish exhibit osmoregulatory flexibility and can exploit a wide range of salinities. In seawater (SW), they drink and absorb water in the intestine, which is associated with increased gastrointestinal blood flow. Yet, detailed information on other cardiovascular changes and their control across salinities is scant. Such knowledge is fundamental to understand how fish are affected during migrations between environments with different salinities, as well as by increased future salinity variability. We used rainbow trout (Oncorhynchus mykiss) as a euryhaline model species and determined dorsal aortic blood pressure, cardiac output and systemic vascular resistance in vivo after chronic freshwater-or SW-acclimation. We also assessed α-adrenergic control of blood pressure using pharmacological tools. Dorsal aortic blood pressure and systemic vascular resistance were reduced, whereas cardiac output increased in SW. α-Adrenergic stimulation with phenylephrine caused similar dose-dependent increases in resistance and pressure across salinities, indicating unaltered α-adrenoceptor sensitivity. α-Adrenergic blockade with prazosin decreased resistance and pressure across salinities, but the absolute reduction in resistance was smaller in SW. Yet, both pressure and resistance after prazosin remained consistently lower in SW. This shows that SW-acclimation lowers systemic resistance through reduced vascular α-adrenergic tone, along with other unknown vasodilating factors. The marked changes in adrenergic regulation of the vasculature across salinities discovered here may have implications for cardiovascular and aerobic performance of fishes, with possible impacts on fitness-related traits like digestion and exercise capacity. Moreover, the evolution of more complex circulatory control systems in teleost fishes compared with elasmobranchs and cyclostomes may have been an important factor in the evolution of euryhalinity, and may provide euryhaline teleosts with competitive advantages in more variable salinity environments of the future.

Regulation of myocardial oxygen delivery in response to graded reductions in hematocrit: role of K+ channels.

This study was designed to identify mechanisms responsible for coronary vasodilation in response to progressive decreases in hematocrit. Isovolemic hemodilution was produced in open-chest, anesthetized swine via concurrent removal of 500ml of arterial blood and the addition of 500ml of 37°C saline or synthetic plasma expander (Hespan, 6% hetastarch in 0.9% sodium chloride). Progressive hemodilution with Hespan resulted in an increase in coronary flow from 0.39±0.05 to 1.63±0.16ml/min/g (P<0.001) as hematocrit was reduced from 32±1 to 10±1% (P<0.001). Overall, coronary flow corresponded with the level of myocardial oxygen consumption, was dependent on arterial pressures≥~60mmHg, and occurred with little/no change in coronary venous PO2. Anemic coronary vasodilation was unaffected by the inhibition of nitric oxide synthase (L-NAME: 25mg/kg iv; P=0.92) or voltage-dependent K+ (K V) channels (4-aminopyridine: 0.3mg/kg iv; P=0.52). However, administration of the K ATP channel antagonist (glibenclamide: 3.6mg/kg iv) resulted in an~40% decrease in coronary blood flow (P<0.001) as hematocrit was reduced to~10%. These reductions in coronary blood flow corresponded with significant reductions in myocardial oxygen delivery at baseline and throughout isovolemic anemia (P<0.001). These data indicate that vasodilator factors produced in response to isovolemic hemodilution converge on vascular smooth muscle glibenclamide-sensitive (K ATP) channels to maintain myocardial oxygen delivery and that this response is not dependent on endothelial-derived nitric oxide production or pathways that mediate dilation via K V channels.

Beet Juice Energy Drink Increases Nitric Oxide Bioavailability and Lowers Blood Pressure in Healthy Men

The peripheral vasculature is important in the regulation of healthy blood pressure as endothelial cells are a source of a variety of vasoactive factors. One of the most important vasodilatory factors released from these cells is nitric oxide (NO). Production of NO is stimulated both through enzymatic‐dependent mechanisms via NO synthase as well as from dietary intake of nitrate‐containing foods or supplements such as beets or green leafy vegetables that increase NO bioavailability. Therefore, we hypothesized supplementation of a normal diet with daily consumption of a 2‐ounce beet juice energy drink (AMPED NOx; Isagenix International LLC) would increase plasma nitrates and affect cardiovascular parameters compared to a placebo drink (prune juice). Healthy male adults aged 18–40y were recruited to participate in this placebo‐controlled, randomized clinical trial as men have a greater risk of developing cardiovascular disease than pre‐menopausal women. Furthermore, women were excluded in the current study as fluctuations in progesterone are known to influence vascular reactivity. Anthropometrics, blood pressure, and fasting blood samples were collected and flow‐mediated vasodilation was measured at baseline and after one and two weeks of supplementation. Subjects also completed questionnaires on sleep quality and mood. No changes in sleep quality, mood or anthropometrics were detected following supplementation with AMPED NOx (n=24 subjects) compared to prune juice placebo (n=24 subjects). In contrast, compared to prune juice AMPED NOx significantly increased plasma nitrates and nitrites (p&lt;0.001) while decreasing both systolic (p=0.015) and diastolic (p=0.015) blood pressures after two weeks of supplementation. There was a weak trend for AMPED NOx to increase FMD as compared to prune juice (p=0.086). The hypotensive effect of the supplement was surprising considering the average systolic and diastolic blood pressure at baseline (116±8 and 64±8 mmHg respectively). In summary, AMPED NOx is a good source of dietary nitrates and an effective strategy to lower blood pressure. Further studies are needed to determine effectiveness in a diseased population.Support or Funding InformationFunding for the study was provided by Isagenix International, LLC.