Human recombinant erythropoietin alters the flow-dependent vasodilatation of in vitro perfused rat mesenteric arteries with unbalanced endothelial endothelin-1 / nitric oxide ratio

2011 ◽  
Vol 89 (6) ◽  
pp. 435-443 ◽  
Author(s):  
Tlili Barhoumi ◽  
Isabelle Jallat ◽  
Alain Berthelot ◽  
Pascal Laurant
Keyword(s):  
Nitric Oxide ◽  
Shear Stress ◽  
Inhibitory Effect ◽  
Mesenteric Arteries ◽  
Recombinant Erythropoietin ◽  
Resistance Arteries ◽  
Vascular Effects ◽  
Human Recombinant Erythropoietin ◽  
Endothelin 1

Chronic use of human recombinant erythropoietin (r-HuEPO) is accompanied by serious vascular side effects related to the rise in blood viscosity and shear stress. We investigated the direct effects of r-HuEPO on endothelium and nitric oxide (NO)-dependent vasodilatation induced by shear stress of cannulated and pressurized rat mesenteric resistance arteries. Intravascular flow was increased in the presence or absence of the NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME; 10−4 mol/L). In the presence of r-HuEPO, the flow-dependent vasodilatation was attenuated, while L-NAME completely inhibited it. The association of r-HuEPO and L-NAME caused a vasoconstriction in response to the rise in intravascular flow. Bosentan (10−5 mol/L), an inhibitor of endothelin-1 (ET-1) receptors, corrected the attenuated vasodilatation observed with r-HuEPO and inhibited the vasoconstriction induced by flow in the presence of r-HuEPO and L-NAME. r-HuEPO and L-NAME exacerbated ET-1 vasoconstriction. At shear stress values of 2 and 14 dyn/cm2 (1 dyn = 10–5 N), cultured EA.hy926 endothelial cells incubated with r-HuEPO, L-NAME, or both released greater ET-1 than untreated cells. In conclusion, r-HuEPO diminishes flow-induced vasodilatation. This inhibitory effect seems to implicate ET-1 release. NO withdrawal exacerbates the vascular effects of ET-1 in the presence of r-HuEPO. These findings support the importance of a balanced endothelial ET-1:NO ratio to avoid the vasopressor effects of r-HuEPO.

scholarly journals Epithelial Na+ channel differentially contributes to shear stress-mediated vascular responsiveness in carotid and mesenteric arteries from mice

2018 ◽  
Vol 314 (5) ◽  
pp. H1022-H1032 ◽  
Author(s):  
Zoe Ashley ◽  
Sama Mugloo ◽  
Fiona J. McDonald ◽  
Martin Fronius
Keyword(s):  
Nitric Oxide ◽  
Shear Stress ◽  
Nitric Oxide Synthase ◽  
Signaling Pathways ◽  
Endothelial Nitric Oxide Synthase ◽  
Mesenteric Arteries ◽  
Intraluminal Pressure ◽  
Resistance Arteries ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

A potential “new player” in arteries for mediating shear stress responses is the epithelial Na+ channel (ENaC). The contribution of ENaC as shear sensor in intact arteries, and particularly different types of arteries (conduit and resistance), is unknown. We investigated the role of ENaC in both conduit (carotid) and resistance (third-order mesenteric) arteries isolated from C57Bl/6J mice. Vessel characteristics were determined at baseline (60 mmHg, no flow) and in response to increased intraluminal pressure and shear stress using a pressure myograph. These protocols were performed in the absence and presence of the ENaC inhibitor amiloride (10 µM) and after inhibition of endothelial nitric oxide synthase (eNOS) by Nω-nitro-l-arginine methyl ester (l-NAME; 100 µM). Under no-flow conditions, amiloride increased internal and external diameters of carotid (13 ± 2%, P < 0.05) but not mesenteric (0.5 ± 0.9%, P > 0.05) arteries. In response to increased intraluminal pressure, amiloride had no effect on the internal diameter of either type of artery. However, amiloride affected the stress-strain curves of mesenteric arteries. With increased shear stress, ENaC-dependent effects were observed in both arteries. In carotid arteries, amiloride augmented flow-mediated dilation (9.2 ± 5.3%) compared with control (no amiloride, 6.2 ± 3.3%, P < 0.05). In mesenteric arteries, amiloride induced a flow-mediated constriction (−11.5 ± 6.6%) compared with control (−2.2 ± 4.5%, P < 0.05). l-NAME mimicked the effect of ENaC inhibition and prevented further amiloride effects in both types of arteries. These observations indicate that ENaC contributes to shear sensing in conduit and resistance arteries. ENaC-mediated effects were associated with NO production but may involve different (artery-dependent) downstream signaling pathways. NEW & NOTEWORTHY The epithelial Na+ channel (ENaC) contributes to shear sensing in conduit and resistance arteries. In conduit arteries ENaC has a role as a vasoconstrictor, whereas in resistance arteries ENaC contributes to vasodilation. Interaction of ENaC with endothelial nitric oxide synthase/nitric oxide signaling to mediate the effects is supported; however, cross talk with other shear stress-dependent signaling pathways cannot be excluded. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/different-roles-of-enac-in-carotid-and-mesenteric-arteries/ .

scholarly journals TRPV4-mediated endothelial Ca2+ influx and vasodilation in response to shear stress

2010 ◽  
Vol 298 (2) ◽  
pp. H466-H476 ◽  
Author(s):  
Suelhem A. Mendoza ◽  
Juan Fang ◽  
David D. Gutterman ◽  
David A. Wilcox ◽  
Aaron H. Bubolz ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Shear Stress ◽  
Transient Receptor Potential ◽  
Mesenteric Arteries ◽  
Flow Mediated Dilation ◽  
Potential Candidate ◽  
Resistance Arteries ◽  
Small Resistance ◽  
Trpv4 Channel

The transient receptor potential vallinoid type 4 (TRPV4) channel has been implicated in the endothelial shear response and flow-mediated dilation, although the precise functions of this channel remain poorly understood. In the present study, we investigated the role of TRPV4 in shear stress-induced endothelial Ca2+ entry and the potential link between this signaling response and relaxation of small resistance arteries. Using immunohistochemical analysis and RT-PCR, we detected strong expression of TRPV4 protein and mRNA in the endothelium in situ and endothelial cells freshly isolated from mouse small mesenteric arteries. The selective TRPV4 agonist GSK1016790A increased endothelial Ca2+ and induced potent relaxation of small mesenteric arteries from wild-type (WT) but not TRPV4−/− mice. Luminal flow elicited endothelium-dependent relaxations that involved both nitric oxide and EDHFs. Both nitric oxide and EDHF components of flow-mediated relaxation were markedly reduced in TRPV4−/− mice compared with WT controls. Using a fura-2/Mn2+ quenching assay, shear was observed to produce rapid Ca2+ influx in endothelial cells, which was markedly inhibited by the TRPV4 channel blocker ruthenium red and TRPV4-specific short interfering RNA. Flow elicited a similar TRPV4-mediated Ca2+ entry in HEK-293 cells transfected with TRPV4 channels but not in nontransfected cells. Collectively, these data indicate that TRPV4 may be a potential candidate of mechanosensitive channels in endothelial cells through which the shear stimulus is transduced into Ca2+ signaling, leading to the release of endothelial relaxing factors and flow-mediated dilation of small resistance arteries.

Carbon monoxide induces vasodilation and nitric oxide release but suppresses endothelial NOS

1999 ◽  
Vol 277 (6) ◽  
pp. F882-F889 ◽  
Author(s):  
Christian Thorup ◽  
Caroline L. Jones ◽  
Steven S. Gross ◽  
Leon C. Moore ◽  
Michael S. Goligorsky
Keyword(s):  
Nitric Oxide ◽  
Carbon Monoxide ◽  
Feedback Regulation ◽  
No Production ◽  
Resistance Arteries ◽  
Vascular Effects ◽  
Nitric Oxide Release ◽  
In Vitro Measurements ◽  
No Release

The vascular effects of carbon monoxide (CO) resemble those of nitric oxide (NO), but it is unknown whether the two messengers converge or exhibit reciprocal feedback regulation. These questions were examined in microdissected perfused renal resistance arteries (RRA) studied using NO-sensitive microelectrodes. Perfusion of RRA with buffers containing increasing concentrations of CO resulted in a biphasic release of NO. The NO response peaked at 100 nM CO and then declined to virtually zero at 10 μM. When a series of 50-s pulses of 100 nM CO were applied repeatedly (150-s interval), the amplitude of consecutive NO responses was diminished. NO release from RRA showed dependence on l-arginine but notd-arginine, and the responses to CO were inhibited by pretreatment with NG-nitro-l-arginine methyl ester (l-NAME), an inhibitor of NO synthases (NOS). CO (100 nM) also suppressed NO release induced by 100 μM carbachol, a potent agonist for endothelial NOS (eNOS). RRA from rats in which endogenous CO production from inducible HO was elevated (cobalt chloride 12 h prior to study) also showed suppressed responses to carbachol. Furthermore, responses consistent with these findings were obtained in juxtamedullary afferent arterioles perfused in vitro, where the vasodilatory response to CO was biphasic and the response to acetylcholine was blunted. Collectively, these data suggest that the CO-induced NO release could be attributed to either stimulation of eNOS or to NO displacement from a cellular storage pool. To address this, direct in vitro measurements with an NO-selective electrode of NO production by recombinant eNOS revealed that CO dose-dependently inhibits NO synthesis. Together, the above data demonstrate that, whereas high levels of CO inhibit NOS activity and NO generation, lower concentrations of CO induce release of NO from a large intracellular pool and, therefore, may mimic the vascular effects of NO.

The Action of Sevoflurane on Vascular Smooth Muscle of Isolated Mesenteric Resistance Arteries (Part 1)

2000 ◽  
Vol 92 (5) ◽  
pp. 1426-1440 ◽  
Author(s):  
Kaoru Izumi ◽  
Takashi Akata ◽  
Shosuke Takahashi
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Potassium Chloride ◽  
Contractile Response ◽  
Isometric Force ◽  
Direct Action ◽  
Mesenteric Arteries ◽  
Systemic Resistance ◽  
Resistance Arteries ◽  
Endothelin 1

Background The direct action of sevoflurane on systemic resistance arteries is not fully understood. Methods Isometric force was recorded in isolated rat small mesenteric arteries. Results Sevoflurane (2-5%) enhanced contractile response to norepinephrine only in the presence of endothelium, but inhibited it in its absence. Sevoflurane still enhanced the norepinephrine response after inhibitions of the nitric oxide, endothelium-derived hyperpolarizing factor, cyclooxygenase and lipoxygenase pathways, or after blockade of either endothelin-1 ET-1), angiotensin-II, or sevotonin receptors. Sevoflurane (3-5%) inhibited contractile response to potassium chloride only in the absence of endothelium but did not influence it in its presence. In the endothelium-intact strips, inhibition of the norepinephrine response, which was enhanced during application of sevoflurane, was observed after washout of sevoflurane and persisted for approximately 15 min. In the endothelium-denuded strips, the inhibition of norepinephrine response was similarly prolonged after washout of sevoflurane. However, no significant inhibitions of potassium chloride response were observed after washout of sevoflurane in both the endothelium-intact and the endothelium-denuded strips. Conclusions The action of sevoflurane on norepinephrine contractile response consists of endothelium-dependent vasoconstricting and endothelium-independent vasodilating components. In the presence of endothelium, the former predominates over the latter, enhancing the norepinephrine response. The endothelium-independent component persisted after washout of sevoflurane, leading to prolonged inhibition of the norepinephrine response. The mechanisms behind the sevoflurane-induced inhibition of norepinephrine response are at least in part different from those behind its inhibition of potassium chloride response. Nitric oxide, endothelium-derived hyperpolarizing factor, cyclooxygenase products, lipoxygenase products, endothelin-1, angiotensin-II, and serotonin are not involved in the vasoconstricting action. (Key words: Halogenated volatile anesthetics; sympathetic nervous system; systemic hypotension; vascular endothelium.)

Nitric oxide-dependent pulmonary vasodilation in polycythemic rats

2000 ◽  
Vol 279 (5) ◽  
pp. H2382-H2389 ◽  
Author(s):  
Benjimen R. Walker ◽  
Thomas C. Resta ◽  
Leif D. Nelin
Keyword(s):  
Nitric Oxide ◽  
Shear Stress ◽  
Treated Group ◽  
Vehicle Group ◽  
Recombinant Erythropoietin ◽  
Enos Expression ◽  
Human Recombinant Erythropoietin ◽  
Pulmonary Vasodilation ◽  
Isolated Lungs ◽  
Nitrite Nitrate

Polycythemia causes increased vascular production of nitric oxide (NO), most likely secondary to an effect of elevated vascular shear stress to enhance expression of endothelial nitric oxide synthase (eNOS). Because both polycythemia and increased eNOS expression are associated with chronic hypoxia-induced pulmonary hypertension, experiments were performed to test the hypothesis that increased hematocrit leads to upregulation of pulmonary eNOS and enhanced vascular production of NO independent of hypoxia. Rats were administered human recombinant erythropoietin (rEpo; 48 U/day) or vehicle for 2 wk. At the time of study, hematocrit was significantly greater in the rEpo-treated group than in the vehicle group (65.8 ± 0.7% vs. 45.1 ± 0.5%), although mean pulmonary artery pressure did not differ between treatments. Experiments on isolated, saline-perfused lungs demonstrated similar vasodilatory responses to the endothelium-derived NO-dependent agonist ionomycin in each group. Additional experiments showed that the vasoconstrictor response to the thromboxane mimetic U-46619 was diminished at lower doses in lungs from the rEpo group compared with the vehicle group. However, perfusate nitrite/nitrate concentration after 90 min of perfusion in isolated lungs was not different between groups. Additionally, no difference was detected between groups in lung eNOS levels by Western blot. We conclude that the predicted increase in shear stress associated with polycythemia does not result in altered pulmonary eNOS expression.

Regulation of nitric oxide andbcl-2 expression by shear stress in human osteoarthritic chondrocytes in vitro

2003 ◽  
Vol 90 (1) ◽  
pp. 80-86 ◽  
Author(s):  
Mel S. Lee ◽  
Michael C.D. Trindade ◽  
Takashi Ikenoue ◽  
Stuart B. Goodman ◽  
David J. Schurman ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Shear Stress ◽  
Osteoarthritic Chondrocytes

Simulated microgravity alters rat mesenteric artery vasoconstrictor dynamics through an intracellular Ca2+ release mechanism

2008 ◽  
Vol 294 (5) ◽  
pp. R1577-R1585 ◽  
Author(s):  
Patrick N. Colleran ◽  
Bradley J. Behnke ◽  
M. Keith Wilkerson ◽  
Anthony J. Donato ◽  
Michael D. Delp
Keyword(s):  
Temporal Dynamics ◽  
Orthostatic Intolerance ◽  
Mesenteric Arteries ◽  
Release Mechanism ◽  
Resistance Arteries ◽  
Receptor Mrna ◽  
Cardiovascular Deconditioning ◽  
Rat Mesenteric Artery ◽  
Mrna And Protein Expression

Previous work has shown that orthostatic hypotension associated with cardiovascular deconditioning results from inadequate peripheral vasoconstriction. We used the hindlimb-unloaded (HU) rat in this study as a model to induce cardiovascular deconditioning. The purpose of this study was to test the hypothesis that 14 days of HU diminishes vasoconstrictor responsiveness of mesenteric resistance arteries. Mesenteric resistance arteries from control ( n = 43) and HU ( n = 44) rats were isolated, cannulated, and pressurized to 108 cm H2O for in vitro experimentation. Myogenic (intralumenal pressure ranging from 30 to 180 cm H2O), KCl (2–100 mM), norepinephrine (NE, 10−9–10−4 M) and caffeine (1–20 mM) induced vasoconstriction, as well as the temporal dynamics of vasoconstriction to NE, were determined. The active myogenic and passive pressure responses were unaltered by HU when pressures remained within physiological range. However, vasoconstrictor responses to KCl, NE, and caffeine were diminished by HU, as well as the rate of constriction to NE (C, 14.8 ± 3.6 μm/s vs. HU 7.6 ± 1.8 μm/s). Expression of sarcoplasmic reticulum Ca2+ATPase 2 and ryanodine 3 receptor mRNA was unaffected by HU, while ryanodine 2 receptor mRNA and protein expression were diminished in mesenteric arteries from HU rats. These data suggest that HU-induced and microgravity-associated orthostatic intolerance may be due, in part, to an attenuated vasoconstrictor responsiveness of mesenteric resistance arteries resulting from a diminished ryanodine 2 receptor Ca2+ release mechanism.

Regulation of human placental fetal vessel tone: role of nitric oxide

1995 ◽  
Vol 7 (6) ◽  
pp. 1407 ◽  
Author(s):  
RG King ◽  
NM Gude ◽  
Iulio JL Di ◽  
SP Brennecke
Keyword(s):  
Nitric Oxide ◽  
Perfusion Pressure ◽  
Factors Affecting ◽  
Endothelin 1 ◽  
Calcium Dependent ◽  
Fetal Vessel ◽  
Nitric Oxide Inhibitors ◽  
Vessel Resistance ◽  
Endothelin 3

Factors affecting fetal vessel resistance have been studied in vitro in bilaterally perfused lobules of human placentae. Potent and efficacious constrictors in this preparation (in order of potency) include endothelin-1 > the thromboxane mimetic U46619 > endothelin-3 > prostaglandin F2 alpha. Inhibitors of eicosanoid synthesis did not affect fetal vessel basal perfusion pressure, nor did they potentiate the effects of the vasoconstrictor U46619. In contrast, the nitric oxide inhibitors N omega-nitro-L-arginine (NOLA), haemoglobin and methylene blue all increased fetal vessel basal perfusion pressure and also increased U46619-induced constriction. Similarly, NOLA markedly potentiated the constrictor effects of endothelin-1, angiotensin II, 5-hydroxytryptamine and bradykinin. These studies therefore provide evidence that NO is important in the maintenance of low basal fetal vessel impedance and also reduces the effects of a number of vasoconstrictor autacoids. Nitric oxide synthase (NOS) activity of human placental homogenates has been measured and shown to be mainly calcium-dependent. Human placental NOS activity was not affected by labour state but was reduced in pre-eclampsia. No evidence was found that in pre-eclampsia raised concentrations of the endogenous NOS inhibitor asymmetric dimethylarginine were responsible for the reduced placental NOS activity. Hence, these studies provide evidence that NO is an important endogenous dilator of the fetal vessels of the human placenta and that reduced NOS activity could contribute to the pathogenesis and/or effects of pre-eclampsia.

Physiological fluid shear stress causes downregulation of endothelin-1 mRNA in bovine aortic endothelium

1992 ◽  
Vol 263 (2) ◽  
pp. C389-C396 ◽  
Author(s):  
A. Malek ◽  
S. Izumo
Keyword(s):  
Shear Stress ◽  
Fluid Shear Stress ◽  
Fluid Velocity ◽  
Low Frequency ◽  
Turbulent Shear ◽  
Specific Response ◽  
Dependent Manner ◽  
Fluid Shear ◽  
Endothelin 1

We report here that the level of endothelin-1 (ET-1) mRNA from bovine aortic endothelial cells grown in vitro is rapidly (within 1 h of exposure) and significantly (fivefold) decreased in response to fluid shear stress of physiological magnitude. The downregulation of ET-1 mRNA occurs in a dose-dependent manner that exhibits saturation above 15 dyn/cm2. The decrease is complete prior to detectable changes in endothelial cell shape and is maintained throughout and following alignment in the direction of blood flow. Peptide levels of ET-1 secreted into the media are also reduced in response to fluid shear stress. Cyclical stretch experiments demonstrated no changes in ET-1 mRNA, while increasing media viscosity with dextran showed that the downregulation is a specific response to shear stress and not to fluid velocity. Although both pulsatile and turbulent shear stress of equal time-average magnitude elicited the same decrease in ET-1 mRNA as steady laminar shear (15 dyn/cm2), low-frequency reversing shear stress did not result in any change. These results show that the magnitude as well as the dynamic character of fluid shear stress can modulate expression of ET-1 in vascular endothelium.

Sign in / Sign up

Export Citation Format

Share Document