Endothelium-derived Hyperpolarizing Factor Research Articles

Tofacitinib improved peripheral endothelial dysfunction and brain-derived neurotrophic factor levels in the rat adjuvant-induced arthritis model.

This study aimed to explore the effect of Tofacitinib on endothelial dysfunction and cerebral levels of brain-derived neurotrophic factor (BDNF) in the adjuvant-induced arthritis (AIA) rat model. Tofacitinib (10 mg/kg twice a day) or vehicle was administered from the first signs of inflammation. Arthritis scores were daily monitored while other parameters including endothelial function assessed from aortic rings, radiographic scores, blood pressure, heart rate, circulating levels of triglycerides, cholesterol, and interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), IL-17A, and cerebral BDNF levels were determined after 3 weeks of treatment. A group of non-AIA rats served as controls. In AIA rats, as compared with vehicle, Tofacitinib significantly reduced arthritis and radiographic scores, decreased total cholesterol and low-density lipoprotein cholesterol (LDL-C), but changed neither blood pressure nor heart rate and proinflammatory cytokines levels. It also fully restored acetylcholine (Ach)-induced relaxation (p < 0.05) through increased nitric oxide (NO) synthase activity, reduced BH4 deficiency and O2 -° production, decreased cyclo-oxygenase-2 (COX-2)/arginase activities, and enhanced endothelium-derived hyperpolarizing factor (EDHF) production. These effects translated into a decrease in atherogenic index and an elevation of BDNF levels in the prefrontal cortex (p < 0.05) and hippocampus (p < 0.001). The present study identified Tofacitinib as an efficient therapeutic option to reduce cardiovascular risk and improve BDNF-dependent cognition in arthritis.

Reduced Function of Endothelial Nitric Oxide and Hyperpolarization in Artery Grafts with Poor Runoff

BackgroundThe endothelium regulates vascular tonus by releasing nitric oxide (endothelium-derived nitric oxide, EDNO) and hyperpolarizing factor (endothelium-derived hyperpolarizing factor, EDHF). In vein grafts with poor runoff, lack of function of these factors causes severe intimal hyperplasia. This study evaluated how the functions of EDNO and EDHF are altered in artery grafts under poor runoff conditions. Materials and MethodsThe right common carotid arteries of rabbits were excised and implanted in their original positions as autogenous grafts under normal runoff conditions (“nonoccluded grafts”) or poor runoff conditions (“poor runoff grafts”). Histochemical changes, acetylcholine (ACh)-induced effects on endothelium-dependent relaxation and smooth muscle cell (SMC) hyperpolarization were examined. ResultsBoth artery graft types displayed negligible intimal hyperplasia. In the absence and presence of an EDNO synthase inhibitor, ACh-induced relaxation was lower in grafts with poor runoff than in nonoccluded grafts. Furthermore, ACh-induced but not nonreceptor agonist A23187-induced SMC hyperpolarization was lower in the poor runoff graft group than in the nonoccluded graft group. ConclusionsUnlike in those in vein grafts, the functions of EDNO and EDHF in autogenous carotid artery grafts under poor runoff conditions were reduced but partly maintained. In such artery grafts, intimal hyperplasia caused by surgical operation was not present. These results may explain some of the mechanisms underlying the improved patency of artery grafts compared with vein grafts.

Calcitonin Gene Related Peptide, Adrenomedullin, and Adrenomedullin 2 Function in Uterine Artery During Human Pregnancy.

Calcitonin gene-related peptide (CGRP) and its family members adrenomedullin (ADM) and adrenomedullin 2 (ADM2; also known as intermedin) support vascular adaptions in rat pregnancy. This study aimed to assess the relaxation response of uterine artery (UA) for CGRP, ADM, and ADM2 in nonpregnant and pregnant women and identify the involved mechanisms. (1) Segments of UA from nonpregnant women that were precontracted with U46619 (1μM) in vitro are insensitive to the hypotensive effects of CGRP, ADM, and ADM2; (2) CGRP, ADM, and ADM2 (0.1-100nM) dose dependently relax UA segments from pregnant women with efficacy for CGRP > ADM = ADM2; (3) the relaxation responses to CGRP, ADM, and ADM2 are differentially affected by the inhibitors of nitric oxide (NO) synthase (L-NAME), adenylyl cyclase (SQ22536), apamin, and charybdotoxin; (4) UA smooth muscle cells (UASMC) express mRNA for calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein (RAMP)1 and RAMP2 but not RAMP3; (5) receptor heterodimer comprising CRLR/RAMP1 and CRLR/RAMP2 but not CRLR/RAMP3 is present in UA; (6) soluble fms-like tyrosine kinase (sFLT-1) and TNF-α treatment decrease the expression of RAMP1 mRNA (P < 0.05) in UASMC; and (7) sFLT-1 treatment impairs the association of CRLR with all 3 peptides while TNF-α inhibits the interaction of CGRP but not ADM or ADM2 with CRLR in UASMC (P < 0.05). Relaxation sensitivity of UA for CGRP, ADM, and ADM2 is increased during pregnancy via peptide-specific involvement of NO system and endothelium-derived hyperpolarizing factors; vascular disruptors such as sFLT-1 and TNFα adversely impact their receptor system in UASMC.

Endothelium-Derived Hyperpolarizing Factor (EDHF) Mediates Acetylsalicylic Acid (Aspirin) Vasodilation of Pregnant Rat Mesenteric Arteries.

Acetylsalicylic acid (aspirin) exhibits a broad range of activities, including analgesic, antipyretic, and antiplatelet properties. Recent clinical studies also recommend aspirin prophylaxis in women with a high risk of pre-eclampsia, a major complication of pregnancy characterized by hypertension. We investigated the effect of aspirin on mesenteric resistance arteries and found outdiscovered the molecular mechanism underlying this action. Aspirin (10−12–10−6 M) was tested on pregnant rat mesenteric resistance arteries by a pressurized arteriography. Aspirin was investigated in the presence of several inhibitors of: (a) nitric oxide synthase (L-NAME 2 × 10−4 M); (b) cyclooxygenase (Indomethacin, 10−5 M); (c) Ca2+-activated K+ channels (Kca): small conductance (SKca, Apamin, 10−7 M), intermediate conductance (IKca, TRAM34, 10−5 M), and big conductance (BKca, paxilline, 10−5 M); and (d) endothelial-derived hyperpolarizing factor (high KCl, 80 mM). Aspirin caused a concentration-dependent vasodilation. Aspirin-vasodilation was abolished by removal of endothelium or by high KCl. Furthermore, preincubation with either apamin plus TRAM-34 or paxillin significantly attenuated aspirin vasodilation (p < 0.05). For the first time, we showed that aspirin induced endothelium-dependent vasodilation in mesenteric resistance arteries through the endothelial-derived hyperpolarizing factor (EDHF) and calcium-activated potassium channels. By activating this molecular mechanism, aspirin may lower peripheral vascular resistance and be beneficial in pregnancies complicated by hypertension.

The Transient Receptor Potential Vanilloid 4 Channel and Cardiovascular Disease Risk Factors.

Vascular endothelial cells regulate arterial tone through the release of nitric oxide and other diffusible factors such as prostacyclin and endothelium derived hyperpolarizing factors. Alongside these diffusible factors, contact-mediated electrical propagation from endothelial cells to smooth muscle cells via myoendothelial gap junctions, termed endothelium-dependent hyperpolarization (EDH), plays a critical role in endothelium-dependent vasodilation in certain vascular beds. A rise in intracellular Ca2+ concentration in endothelial cells is a prerequisite for both the production of diffusible factors and the generation of EDH, and Ca2+ influx through the endothelial transient receptor potential vanilloid 4 (TRPV4) ion channel, a nonselective cation channel of the TRP family, plays a critical role in this process in various vascular beds. Emerging evidence suggests that the dysregulation of endothelial TRPV4 channels underpins endothelial dysfunction associated with cardiovascular disease (CVD) risk factors, including hypertension, obesity, diabetes, and aging. Because endothelial dysfunction is a precursor to CVD, a better understanding of the mechanisms underlying impaired TRPV4 channels could lead to novel therapeutic strategies for CVD prevention. In this mini review, we present the current knowledge of the pathophysiological changes in endothelial TRPV4 channels associated with CVD risk factors, and then explore the underlying mechanisms involved.

Endothelium-dependent contraction: The non-classical action of endothelial prostacyclin, its underlying mechanisms, and implications.

Although commonly thought to produce prostacyclin (prostaglandin I2 ; PGI2 ) that evokes vasodilatation and protects vessels from the development of diseases, the endothelial cyclooxygenase (COX)-mediated metabolism has also been found to release substance(s) called endothelium-derived contracting factor(s) (EDCF) that causes endothelium-dependent contraction and implicates in endothelial dysfunction of disease conditions. Various mechanisms have been proposed for the process; however, the major endothelial COX metabolite PGI2 , which has been classically considered to activate the I prostanoid receptor (IP) that mediates vasodilatation and opposes the effects of thromboxane (Tx) A2 produced by COX in platelets, emerges as a major EDCF in health and disease conditions. Our recent studies from genetically altered mice further suggest that vasomotor reactions to PGI2 are collectively modulated by IP, the vasoconstrictor Tx-prostanoid receptor (TP; the prototype receptor of TxA2 ) and E prostanoid receptor-3 (EP3; a vasoconstrictor receptor of PGE2 ) although with differences in potency and efficacy; a contraction to PGI2 reflects activities of TP and/or EP3 outweighing that of the concurrently activated IP. Here, we discuss the history of endothelium-dependent contraction, evidences that support the above hypothesis, proposed mechanisms for the varied reactions to endothelial PGI2 synthesis as well as the relation of its dilator activity to the effect of another NO-independent vasodilator mechanism, the endothelium-derived hyperpolarizing factor. Also, we address the possible pathological and therapeutic implications as well as questions remaining to be resolved or limitations of our above findings obtained from genetically altered mouse models.

Vasodilation and blood pressure-lowering effect mediated by 5,6-EEQ lactone in 5/6 nephrectomy hypertensive rats

Microvascular dysfunction is a key contributor to vascular hypertension, one of the most common chronic diseases in the world. Microvascular dysfunction leads to the loss of nitric oxide-mediated endothelial dilation and the subsequent compensatory function of endothelium-derived hyperpolarizing (EDH) factors in the regulation of vascular tone. Previously, we showed that lactone metabolite derived from arachidonic acid induces endothelial-dependent vasodilation in isolated human microvessels. Based on structural similarities, we hypothesize that additional lactone metabolites formed from eicosapentaenoic fatty acid (EPA) may bear EDH properties. AimTo elucidate the vasodilatory and blood pressure (BP)-reducing characteristics of the 5,6-EEQ (5,6-epoxyeicosatetraenoic acids) lactone (EPA-L) in hypertensive 5/6 nephrectomy (5/6Nx) rats. Methods5/6Nx hypertensive rats intravenously administrated with EPA-L for five days. BP, blood and urine chemistry, and kidney function were detected and analyzed. Vascular dilation was detected using a pressure myograph with or without Ca2+ − activated K+ (KCa) endothelial channel inhibitors. KCNN3 and KCNN4 gene expression (mRNA) detected in mesenteric arteries from 5/6Nx and NT rats. ResultsEPA-L administration to 5/6Nx rats significantly (p < 0.05) reduced BP and heart rate without affecting kidney function. 5/6Nx rat mesenteric arterioles exhibited a lower dilation response to acetylcholine (10-7 mol/l) than normotensive (NT) vessels, while EPA-L administration restored the vessel relaxation response. The EPA-L-driven relaxation of mesenteric arteries was significantly reduced by pretreatment with TRAM-34 and apamin. However, KCa channel expression did not significantly differ between 5/6Nx and NT mesenteric arteries. ConclusionEPA-L reduces BP by improving microvessel dilation involving calcium-dependent potassium endothelial channels.

Endothelium-derived hydrogen sulfide acts as a hyperpolarizing factor and exerts neuroprotective effects via activation of large-conductance Ca2+ -activated K+ channels.

Endothelium-derived hyperpolarizing factor (EDHF) has been suggested as a therapeutic target for vascular protection against ischaemic brain injury. However, the molecular entity of EDHF and its action on neurons remains unclear. This study was undertaken to demonstrate whether the hydrogen sulfide (H2 S) acts as EDHF and exerts neuroprotective effect via large-conductance Ca2+ -activated K+ (BKCa /KCa 1.1) channels. The whole-cell patch-clamp technology was used to record the changes of BKCa currents in rat neurons induced by EDHF. The cerebral ischaemia/reperfusion model of mice and oxygen-glucose deprivation/reoxygenation (OGD/R) model of neurons were used to explore the neuroprotection of EDHF by activating BKCa channels in these neurons. Increases of BKCa currents and membrane hyperpolarization in hippocampal neurons induced by EDHF could be markedly inhibited by BKCa channel inhibitor iberiotoxin or endothelial H2 S synthase inhibitor propargylglycine. The H2 S donor, NaHS-induced BKCa current and membrane hyperpolarization in neurons were also inhibited by iberiotoxin, suggesting that H2 S acts as EDHF and activates the neuronal BKCa channels. Besides, we found that the protective effect of endothelium-derived H2 S against mice cerebral ischaemia/reperfusion injury was disrupted by iberiotoxin. Importantly, the inhibitory effect of NaHS or BKCa channel opener on OGD/R-induced neuron injury and the increment of intracellular Ca2+ level could be inhibited by iberiotoxin but enhanced by co-application with L-type but not T-type calcium channel inhibitor. Endothelium-derived H2 S acts as EDHF and exerts neuroprotective effects via activating the BKCa channels and then inhibiting the T-type calcium channels in hippocampal neurons.

Endothelium-Dependent Hyperpolarization: The Evolution of Myoendothelial Microdomains.

Endothelium-derived hyperpolarizing factor (EDHF) was envisaged as a chemical entity causing vasodilation by hyperpolarizing vascular smooth muscle (VSM) cells and distinct from nitric oxide (NO) ([aka endothelium-derived relaxing factor (EDRF)]) and prostacyclin. The search for an identity for EDHF unraveled the complexity of signaling within small arteries. Hyperpolarization originates within endothelial cells (ECs), spreading to the VSM by 2 branches, 1 chemical and 1 electrical, with the relative contribution varying with artery location, branch order, and prevailing profile of VSM activation. Chemical signals vary likewise and can involve potassium ion, lipid mediators, and hydrogen peroxide, whereas electrical signaling depends on physical contacts formed by homocellular and heterocellular (myoendothelial; MEJ) gap junctions, both able to conduct hyperpolarizing current. The discovery that chemical and electrical signals each arise within ECs resulted in an evolution of the single EDHF concept into the more inclusive, EDH signaling. Recognition of the importance of MEJs and particularly the fact they can support bidirectional signaling also informed the discovery that Ca2+ signals can pass from VSM to ECs during vasoconstriction. This signaling activates negative feedback mediated by NO and EDH forming a myoendothelial feedback circuit, which may also be responsible for basal or constitutive release of NO and EDH activity. The MEJs are housed in endothelial projections, and another spin-off from investigating EDH signaling was the discovery these fine structures contain clusters of signaling proteins to regulate both hyperpolarization and NO release. So, these tiny membrane bridges serve as a signaling superhighway or infobahn, which controls vasoreactivity by responding to signals flowing back and forth between the endothelium and VSM. By allowing bidirectional signaling, MEJs enable sinusoidal vasomotion, co-ordinated cycles of widespread vasoconstriction/vasodilation that optimize time-averaged blood flow. Cardiovascular disease disrupts EC signaling and as a result vasomotion changes to vasospasm.

Adipose Stromal Vascular Fraction Restores Coronary Microvascular Flow‐Mediated Dilation in Aging Female Rats via Enhanced Peroxynitrite Signaling

Introduction Coronary Microvascular Disease (CMD) presents in a majority of aging post-menopausal women and is defined by hyperconstricted tone. CMD can lead to chronic ischemia exacerbated by reduced perfusion with aging. Flow-mediated dilation (FMD) primarily regulates vascular patency via endothelial shear stress, but the signaling mechanism of FMD alters throughout the lifespan from vasoprotective nitric oxide (NO) in youth to the less efficacious hydrogen peroxide (H2O2) in advancing age. Reactive Oxygen Species (ROS), including H2O2, suppress NO, cause cellular damage and are pro-atherogenic. Adipose Stromal Vascular Fraction (SVF) is a heterogenous cell population that has antioxidant and regenerative properties. We hypothesize that coronary microvascular FMD is reduced with age, but aged rats treated with SVF (OSVF) will exhibit restored FMD via increased NO and decreased ROS at baseline and with flow. Methods Isolated coronary microvessels from young (4 months), old (24 months), or OSVF (tail vein injection 4 weeks prior to sacrifice at 24 months) from female Fischer 344 rats were assessed via pressure myography. FMD was assessed at flow rates of 5, 10, 15, 20, and 25 μL/min at physiologic pressure (45 mmHg) and temperature (37°C). Mean Fluorescence Intensity (MFI) of NO, H2O2, superoxide (O2-), peroxynitrite (ONOO-) and antioxidant glutathione (GSH) were assessed via intraluminally-infused fluorescence dyes (2,3-diaminonapthalene, mitopy1, mitosox, biotracker 515, and SEMKUR-IM, respectively) at baseline and during flow at 10 and 25 μL/min. Results Percent relaxation to intraluminal flow (FMD) is reduced with aging and restored to youthful levels by SVF (Figure 1a). At baseline, H2O2 and ONOO- MFI are significantly increased with aging compared to young and OSVF (p = < .001, .01 vs. young, < .001, .024 vs. OSVF). O2- MFI is reduced at baseline in OSVF compared to aging alone (p = .004). NO and GSH MFI are significantly reduced at baseline with aging (p = .01, < .001) and increased slightly (non-significant) with OSVF. Intraluminal flow preferentially increases MFI of NO in youth, H2O2 in aging, and ONOO- in OSVF. These data correspond functionally as FMD was significantly attenuated in youth via L-NAME inhibition of NO production, inhibited in OSVF via uric acid scavenging of ONOO-, but was unaffected by reducing H2O2 signaling via catalase in aging controls (Figure 1b-d). Conclusions FMD is abrogated with aging, contributing to CMD hyperconstriction associated with increased ROS and loss of NO and GSH. FMD can be restored with therapeutic SVF associated with increased ONOO- signaling in response to intraluminal flow. Although ONOO- is considered a ROS, it could be considered a NO reservoir inducing FMD as a NO donor since O2- and NO combine to form ONOO-. Alternatively, ONOO- can elicit FMD as an Endothelium-Derived Hyperpolarizing Factor. Future directions will differentiate between these alternative mechanisms. SVF represents a plausible future clinical direction to alleviate vascular oxidative stress and restore microvascular patency and perfusion.

Role of Transient Receptor Potential Vanilloid 4 in Vascular Function.

Transient receptor potential vanilloid 4 (TRPV4) channels are widely expressed in systemic tissues and can be activated by many stimuli. TRPV4, a Ca2+-permeable cation channel, plays an important role in the vasculature and is implicated in the regulation of cardiovascular homeostasis processes such as blood pressure, vascular remodeling, and pulmonary hypertension and edema. Within the vasculature, TRPV4 channels are expressed in smooth muscle cells, endothelial cells, and perivascular nerves. The activation of endothelial TRPV4 contributes to vasodilation involving nitric oxide, prostacyclin, and endothelial-derived hyperpolarizing factor pathways. TRPV4 activation also can directly cause vascular smooth muscle cell hyperpolarization and vasodilation. In addition, TRPV4 activation can evoke constriction in some specific vascular beds or under some pathological conditions. TRPV4 participates in the control of vascular permeability and vascular damage, particularly in the lung capillary endothelial barrier and lung injury. It also participates in vascular remodeling regulation mainly by controlling vasculogenesis and arteriogenesis. This review examines the role of TRPV4 in vascular function, particularly in vascular dilation and constriction, vascular permeability, vascular remodeling, and vascular damage, along with possible mechanisms, and discusses the possibility of targeting TRPV4 for therapy.

The Role of K+, Ca2+ channels, Some Endothelium Hyperpolarizing Factors in Taurine Induced Vasorelaxation in Rats Aorta

The current study included the relaxant effect of taurine on rat’s aortic rings and the mechanism behind this relaxation. Taurine produced a potent spasmolytic effect on aortic rings at concentrations from zero to 80 mM. The results of K+ channel subtypes using specific blockers indicated that the Kv channel has a considerable role in taurine-induced relaxation, while KATP has a limited role, Exposure of aortic rings to combinations of two K+ blockers showed that KCa, Kv, and KIR play important role in taurine mediated relaxation. The endothelium-derived hyperpolarizing factors used showed responses to a variable extent in taurine mediated relaxation; since NO and cGMP played a major role whereas PGS played a minor role in taurine mediated relaxation. Finally, the results also indicated that taurine-mediated relaxation is endothelium-dependent.

The Role of K+, Ca2+ channels and Endothelial Hyperpolarizing Factors in Vasorelaxation Induced by Tribulus terrestris

The present study focused on the relaxant effect of themethanolic extract (ME) of Tribulus terristris on rats’ thoracic aortae and included the study of underlying vasorelaxation mechanisms. The methanolic extract produced concentration-dependent relaxation in rats’ aorta. The methanolic extract produced concentration-dependent relaxation in the aortic rings. The use of different K+ channel blockers (BaCl2, 4-AP, GLIB, and TEA) indicated that Kv, KATP, KIR, and KCa and L-type Ca channels played no role in the methanolic extractinduced relaxation. However, with respect to endothelium-derived hyperpolarizing factors, PGI2 and sGC produced a mild inhibition in the relaxation response to ME while NO produced no effect at all.&#x0D; Based on the novel results of the current study, it can be concluded that T. terrestris methanolic extract (ME) mediated relaxation in isolated rat aortic tissues in a concentration-dependent manner. Moreover, we discovered that ME-mediated relaxation is endothelium-dependent and that potassium and calcium ion channels play no role in this relaxation with a limited role of PGI2 and sGC.

The Vascular Effects of Isolated Isoflavones-A Focus on the Determinants of Blood Pressure Regulation.

Simple SummaryIsoflavones are naturally-occurring phytoestrogens, highly prevalent in soybeans, and known to improve cardiovascular health in populations with a high isoflavone dietary intake. Most clinical studies have assessed the impact of dietary intake or supplementation with mixtures of isoflavones, with few studies dedicated to the effects of isolated compounds (i.e., genistein, daidzein, glycitein, formononetin, biochanin A, and equol). This paper reviews the main actions of isolated isoflavones on the vasculature, with particular focus on the determinants of blood pressure regulation. Isoflavones evoke relaxation of different vascular beds by acting on several signaling pathways in the endothelium, where they potentiate the release of important vasorelaxant mediators, and in vascular smooth muscle cells, where relaxation is attained mainly through hyperpolarization. Some of these effects are attributed to their ability to modulate estrogen receptors. These vascular effects occur at plasma concentrations in the micromolar range, attained only through dietary supplementation. This paper highlights isolated isoflavones as potentially suitable alternatives to soy-based foodstuffs and supplements and which could enlarge the current therapeutic arsenal.Isoflavones are phytoestrogen compounds with important biological activities, including improvement of cardiovascular health. This activity is most evident in populations with a high isoflavone dietary intake, essentially from soybean-based products. The major isoflavones known to display the most important cardiovascular effects are genistein, daidzein, glycitein, formononetin, and biochanin A, although the closely related metabolite equol is also relevant. Most clinical studies have been focused on the impact of dietary intake or supplementation with mixtures of compounds, with only a few addressing the effect of isolated compounds. This paper reviews the main actions of isolated isoflavones on the vasculature, with particular focus given to their effect on the determinants of blood pressure regulation. Isoflavones exert vasorelaxation due to a multitude of pathways in different vascular beds. They can act in the endothelium to potentiate the release of NO and endothelium-derived hyperpolarization factors. In the vascular smooth muscle, isoflavones modulate calcium and potassium channels, leading to hyperpolarization and relaxation. Some of these effects are influenced by the binding of isoflavones to estrogen receptors and to the inhibition of specific kinase enzymes. The vasorelaxation effects of isoflavones are mostly obtained with plasma concentrations in the micromolar range, which are only attained through supplementation. This paper highlights isolated isoflavones as potentially suitable alternatives to soy-based foodstuffs and supplements and which could enlarge the current therapeutic arsenal. Nonetheless, more studies are needed to better establish their safety profile and elect the most useful applications.

Роль К+-каналов и сероводорода в регуляции тонуса церебральных артерий нефрэктомированных крыс

Chronic renal failure is widespread. It disrupts the functional state of cerebral arteries, leads to cognitive impairment and an increased risk of ischemic stroke. The study investigated the role of the endothelium-derived hyperpolarizing factor (EDHF) mediated mechanism and H2S in endothelium-dependent dilatation of cerebral arteries in nephrectomized (NE) rats. The study explored the reactions of cerebral arteries with a diameter of 60–80 μm and ˂ 20 μm NE and sham-operated male Wistar rats to acetylcholine (ACh) as well as to ACh acting under an NO synthase inhibitor, cystathionine γ-lyase and blocking of Ca2+-activated K+-channels. The attenuation of ACh-induced dilatation of cerebral arteries in NE rats with L-NAME was lower than in the control group. In the small arteries of the control group of rats, blocking of Ca2+ -activated K+-channels was accompanied by a decrease in ACh-induced dilatation by 11.2 ± 0.7%, in NE rats — by 18.8 ± 1.3%. Inhibition of cystathionine-γ-lyase in small arteries of control rats weakened ACh-induced dilatation by 14 ± 0.9%, in NE rats — by 22.8 ± 1.6%. It was concluded that the impairment of ACh-induced dilatation of arteries in NE rats is caused by a deficiency (bioavailability decrease) of NO. In small arteries, part of endothelium-dependent dilatation is realized through the EDH-type mechanism; in NE rats, the role of this mechanism increases. H2S is involved in endothelium-dependent dilatation of small cerebral arteries in control and NE rats (in the latter, H2S is a more significant vasodilator).

Mechanisms of SGLT2 (Sodium-Glucose Transporter Type 2) Inhibition-Induced Relaxation in Arteries From Human Visceral Adipose Tissue.

As novel drug treatments for diabetes have shown favorable cardiovascular effects, interest has mounted with regard to their possible vascular actions, particularly in relation to visceral adipose tissue perfusion and remodeling in obesity. The present study tested the vasorelaxing effect of the SGLT2 (sodium-glucose transporter type 2) inhibitor canagliflozin in arteries from visceral adipose tissue of either nonobese or obese humans and investigated the underlying mechanisms. Also, the vasorelaxing effect of canagliflozin and the GLP-1 (glucagon-like peptide 1) agonist liraglutide were compared in arteries from obese patients. To these purposes, small arteries (116-734 μm) isolated from visceral adipose tissue were studied ex vivo in a wire myograph. Canagliflozin elicited a higher concentration-dependent vasorelaxation in arterioles from obese than nonobese individuals (P=0.02). The vasorelaxing response to canagliflozin was not modified (P=0.93) by inhibition of nitric oxide synthase (L-NAME) or prostacyclin (indomethacin), or by H2O2 scavenging (catalase); also, canagliflozin-induced relaxation was similar (P=0.23) in endothelium-intact or -denuded arteries precontracted with high potassium concentration, thereby excluding an involvement of endothelium-derived hyperpolarizing factors. The vasorelaxing response to canagliflozin was similar to that elicited by the Na+/H+ exchanger 1 inhibitor BIX (P=0.67), but greater than that to the Na+/Ca++ exchanger inhibitor SEA 0400 (P=0.001), hinting a role of Na+/H+ exchanger inhibition in canagliflozin-induced relaxation. In arterioles from obese patients, the vasorelaxing response to canagliflozin was greater than that to liraglutide (P=0.004). These findings demonstrate that canagliflozin induces endothelium-independent vasorelaxation in arterioles from human visceral adipose tissue, thereby suggesting that SGLT2 inhibition might favorably impact the processes linking visceral adipose burden to vascular disease in obesity.

Endothelium-Derived Hyperpolarizing Factor and Myoendothelial Coupling: The in vivo Perspective.

The endothelium controls vascular tone adopting blood flow to tissue needs. It releases chemical mediators [e.g., nitric oxide (NO), prostaglandins (PG)] and exerts appreciable dilation through smooth muscle hyperpolarization, thus termed endothelium-dependent hyperpolarization (EDH). Initially, EDH was attributed to release of a factor, but later it was suggested that smooth muscle hyperpolarization might be derived from radial spread of an initial endothelial hyperpolarization through heterocellular channels coupling these vascular cells. The channels are indeed present and formed by connexins that enrich in gap junctions (GJ). In vitro data suggest that myoendothelial coupling underlies EDH-type dilations as evidenced by blocking experiments as well as simultaneous, merely identical membrane potential changes in endothelial and smooth muscle cells (SMCs), which is indicative of coupling through ohmic resistors. However, connexin-deficient animals do not display any attenuation of EDH-type dilations in vivo, and endothelial and SMCs exhibit distinct and barely superimposable membrane potential changes exerted by different means in vivo. Even if studied in the exact same artery EDH-type dilation exhibits distinct features in vitro and in vivo: in isometrically mounted vessels, it is rather weak and depends on myoendothelial coupling through connexin40 (Cx40), whereas in vivo as well as in vitro under isobaric conditions it is powerful and independent of myoendothelial coupling through Cx40. It is concluded that EDH-type dilations are distinct and a significant dependence on myoendothelial coupling in vitro does not reflect the situation under physiologic conditions in vivo. Myoendothelial coupling may act as a backup mechanism that is uncovered in the absence of the powerful EDH-type response and possibly reflects a situation in a pathophysiologic environment.

The effectiveness of yoga exercise toward blood pressure and endothelial-derived hyperpolarizing factor (EDHF) level in hypertensive diabetic population

Introduction: Diabetes and its complications are the leading causes of premature death worldwide. Diabetes causes complications such as hypertension and an increased risk of cardiovascular diseases. Endothelial dysfunction is the primary pathophysiology that underlies complications of diabetes mellitus. EDHF (Endothelial-Derived Hyperpolarizing Factor) is a relaxing factor that targets current therapy in vascular dysfunction and insulin resistance in obesity and diabetes mellitus. Yoga training is a physical activity that has been shown to play a role in decrease blood pressure, but to our knowledge, there are no studies that prove the effectiveness of yoga in increasing EDHF levels. Therefore, this study aimed to determine the efficacy of yoga to decrease blood pressure and increase EDHF levels in type II diabetes mellitus patients with hypertension.Methods: This research was a randomized control trial that involved 39 hypertensive diabetic respondents and was conducted in Denpasar, Bali, Indonesia. Yoga exercise was carried out two times a week for eight weeks, with a duration of 60 minutes per session. EDHF levels were examined using the ELISA technique.Results: There was a significant difference in systolic, diastolic and EDHF levels after the intervention between the yoga and control groups and large effect size.Conclusion: In conclusion, yoga training effectively reduced blood pressure and prevented endothelial dysfunction by increasing the blood vessel relaxing factor, namely EDHF.

Influence of prostaglandins and endothelial-derived hyperpolarizing factors on brachial and popliteal endothelial-dependent function in young adults.

Heterogeneous flow-mediated dilation (FMD) and low-flow-mediated constriction (L-FMC) responses have been reported between upper- and lower-limb arteries. Radial artery L-FMC, but not FMD, responses are blunted when endothelial-derived hyperpolarizing factors (EDHFs) or prostaglandin production is inhibited in young adults. However, it is unknown if these mechanisms similarly impact endothelial-dependent responses in the brachial (BA) and popliteal (POP) arteries. We tested whether BA- and POP-L-FMC and FMD would be influenced by independent EDHF and prostaglandin inhibition. Eighteen participants (23 ± 3 yr; 6♀) completed three randomized and double-blinded ultrasound assessments following ingestion of an opaque capsule containing maltodextrin (control), 150 mg of fluconazole (EDHF inhibition), or 500 mg of aspirin (prostaglandin inhibition). POP resting diameter was reduced following fluconazole administration (6.13 ± 0.63 mm vs. 6.19 ± 0.65 mm in control, P = 0.03). Compared with control, fluconazole also blunted the relative L-FMC responses in both the BA (-2.1 ± 0.8% vs. -0.8 ± 1.0%, P = 0.001) and POP (-1.7 ± 1.1% vs. -0.8 ± 0.9%, P = 0.009). In contrast, aspirin did not impact either the BA (-1.9 ± 0.7%) or POP-L-FMC (-1.3 ± 0.6%) responses (both, P > 0.35). The FMD response was unchanged following fluconazole or aspirin administration in either artery (both, P > 0.36). Our findings demonstrate that EDHF mediates L-FMC responses in both the brachial and popliteal arteries. Complementary to the nitric oxide-mediated FMD response, L-FMC appears to provide information regarding the EDHF pathway. Future research should uncover if these mechanisms impact older adults and/or patient populations characterized by vascular endothelial dysfunction associated with low aerobic fitness and habitual physical activity levels.NEW & NOTEWORTHY We compared changes in upper- and lower-limb artery endothelial-dependent vasodilatory and vasoconstrictor responses between control, prostaglandin inhibition, and endothelial-derived hyperpolarizing factor inhibition conditions. Neither prostaglandins nor endothelial-derived hyperpolarizing factor influenced flow-mediated dilation responses in either the brachial or popliteal artery. In contrast, endothelial-derived hyperpolarizing factor, but not prostaglandins, reduced resting brachial artery blood flow and shear rate and resting popliteal artery diameter, as well as low-flow-mediated constriction responses in both the popliteal and brachial arteries.

Role of Kinins in Hypertension and Heart Failure.

The kallikrein–kinin system (KKS) is proposed to act as a counter regulatory system against the vasopressor hormonal systems such as the renin-angiotensin system (RAS), aldosterone, and catecholamines. Evidence exists that supports the idea that the KKS is not only critical to blood pressure but may also oppose target organ damage. Kinins are generated from kininogens by tissue and plasma kallikreins. The putative role of kinins in the pathogenesis of hypertension is discussed based on human mutation cases on the KKS or rats with spontaneous mutation in the kininogen gene sequence and mouse models in which the gene expressing only one of the components of the KKS has been deleted or over-expressed. Some of the effects of kinins are mediated via activation of the B2 and/or B1 receptor and downstream signaling such as eicosanoids, nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and/or tissue plasminogen activator (T-PA). The role of kinins in blood pressure regulation at normal or under hypertension conditions remains debatable due to contradictory reports from various laboratories. Nevertheless, published reports are consistent on the protective and mediating roles of kinins against ischemia and cardiac preconditioning; reports also demonstrate the roles of kinins in the cardiovascular protective effects of the angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor blockers (ARBs).