Evidence for enhanced eNOS function in coronary microvessels during the second window of protection

2007 ◽  
Vol 292 (5) ◽  
pp. H2152-H2158 ◽  
Author(s):  
Song-Jung Kim ◽  
Xiaoping Zhang ◽  
Xiaobin Xu ◽  
Alice Chen ◽  
Joaquin B. Gonzalez ◽  
...  
Keyword(s):  
Ace Inhibitors ◽  
Calcium Ionophore ◽  
Left Ventricular ◽  
Wall Thickening ◽  
No Production ◽  
Ionophore A23187 ◽  
Nitrite Production ◽  
Hoe 140 ◽  
Enos Protein ◽  
Second Window Of Protection

Nitric oxide (NO) derived from endothelial NO synthase (NOS) (eNOS) has been identified as a trigger for the second window of protection (SWOP), but its role as a mediator during the SWOP is a matter of debate. Eighteen mongrel dogs were chronically instrumented to measure left ventricular function, coronary blood flow, and wall thickening. Myocardial preconditioning was induced by 10 min coronary artery occlusion. After 24 h of reperfusion (during the SWOP), the hearts were excised. Coronary microvessels were isolated and incubated in presence of 1) the endothelium-dependent agonists carbachol and bradykinin, 2) the calcium ionophore A23187, and 3) the angiotensin-converting enzyme (ACE) inhibitors enalaprilat and ramiprilat. Nitrite, a metabolite of NO, was measured. Under baseline conditions, nitrite production in microvessels from SWOP was 30% higher than that from normal (96 ± 4 vs. 74 ± 3 pmol/mg, P < 0.01, respectively). Nitrite production in response to carbachol, bradykinin, and A23187 was also enhanced in microvessels from SWOP ( P < 0.05). These enhanced responses were abolished by NG-nitro-l-arginine methyl ester (l-NAME) or the endothelial receptor-specific antagonists atropine and HOE-140. The level of eNOS protein in the SWOP myocardium was twofold higher than that in the non-SWOP myocardium. Nitrite production in response to the ACE inhibitors was greater in microvessels from SWOP. These effects were blocked by l-NAME, HOE-140, or dichloroisocoumarin (which inhibits kinin formation). We found that a brief ischemic episode induced delayed, enhanced NO production in coronary microvessels and an upregulation of eNOS protein. These findings suggest that eNOS is a mediator during the SWOP. The ability of ACE inhibitors to enhance NO release during the SWOP points to an additional clinical application for these drugs.

Excessive Nitric Oxide Production of CGD Neutrophils Induces the Down-Regulation of NOS3 and EDN1 Expression in Human Endothelial Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2726-2726
Author(s):  
Akari Utsunomiya ◽  
Miyuki Tsumura ◽  
Norioki Ohno ◽  
Mizuka Miki ◽  
Satoshi Okada ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Healthy Subjects ◽  
Calcium Ionophore ◽  
Calcium Ionophore A23187 ◽  
Cell Contact ◽  
Ros Generation ◽  
No Production ◽  
Ionophore A23187 ◽  
Generation System

Abstract Introduction: Chronic granulomatous disease (CGD) is an inherited immunodeficiency due to a mutation in genes that encode the subunits of NADPH oxidase of phagocytes. Phagocytes of CGD can not generate the reactive oxidative species (ROS), whereas nitric oxide (NO) production of CGD phagocytes is increased in response to calcium ionophore, A23187, compared with that of phagocytes from healthy subjects. Recently, X-linked CGD (X-CGD) patients showed lower oxidative stress and higher flow-mediated dilation, suggesting that endothelial cell function is affected by NO production of phagocytes. We studied the effects of NO on the regulation of endothelial gene expression related to dilator and constrictive effect of blood vessels, such as NOS3 and EDN1 using neutrophils from X-CGD patients. Methods: Eighteen X-CGD patients and 18 age-matched healthy male subjects were enrolled in this study from 2009 to 2013. NO production of phagocytes was assessed by flow cytometry using DAF2/DA fluorescent probe. Human umbilical vein endothelial cells (HUVECs) were co-cultured with human neutrophils of X-CGD or healthy subjects in response to calcium ionophore,A23187 without cell to cell contact using the Transwell-permeable support systems. The expression of endothelial NOS3 and EDN1 mRNA gene in HUVECs were quantified by real-time PCR. Results: Neutrophils of X-CGD patients showed significantly higher production of NO in response to A23187 for 30 to 60 minutes than those of normal subjects detected by flow cytometric analyses. NO concentration artificially generated by NO donor was significantly decreased by ROS produced by xanthine and xanthine oxidase. Similarly, neutrophils from healthy subjects, but not from X-CGD stimulated with A23187 induced the decrease in the concentration of NO. These results strongly suggest that the lack of ROS generation in CGD neutrophils leads to the increase of NO production in response to A23187. HUVECs were incubated with NO generation system, ROS generation system alone or with both systems. The expression of NOS3 and EDN1 was significantly decreased depending on the concentration of extracellular NO. In contrast, both NOS3 and EDN1 expression was significantly up-regulated under the ROS generation system without NO. Next, HUVECs were incubated by X-CGD neutrophils or by control neutrophils with or without A23187 for 30 minutes using the wells divided by membrane (0.45μm) to prevent cell to cell contact. Both NOS3 and EDN1 expression of HUVECs incubated with X-CGD neutrophils was significantly down-regulated under A23187 stimulation compared with normal neutrophils (112±117 vs. 34.5±39.9, n=8, p<0.05, 0.94± 0.24 vs. 0.61±0.24, n=5, p<0.05, respectively). Conclusion: This study demonstrated that the stimulated X-CGD neutrophils induced the decreased endothelial NOS3 and EDN1 gene expression through the excessive generation of NO due to the lack of ROS production. These findings suggest that ROS generated by phagocytes may modulate arterial tone affecting the amount of NO, a potent vasodilator molecule produced by endothelial cells. Disclosures No relevant conflicts of interest to declare.

Effects of a stabilized endothelium-derived relaxing factor on the coronary vasculature in awake dogs

1989 ◽  
Vol 257 (6) ◽  
pp. H1895-H1899
Author(s):  
A. Chu ◽  
F. R. Cobb ◽  
P. O. Hagen ◽  
J. J. Murray
Keyword(s):  
Endothelial Cells ◽  
Biological Effects ◽  
Calcium Ionophore ◽  
Left Ventricular ◽  
Ionophore A23187 ◽  
Relaxing Factor ◽  
Endothelium Derived Relaxing Factor ◽  
Distal Flow

The effects of a partially purified endothelium-derived relaxing factor (EDRF) stabilized by acidification from cultured bovine aortic endothelial cells stimulated with the calcium ionophore A23187 on coronary and peripheral vasculature were examined in five awake dogs. The dogs were chronically instrumented with miniature arterial dimension crystals and Doppler flow probes. Intracoronary or intra-arterial infusions of this EDRF induced a rapid (less than 15 s) significant increase in the proximal vessel diameter (P less than 0.02). The duration of proximal dilation response to this EDRF persisted up to 6 min, whereas the smaller changes in distal flow were more transient (less than 1 min). Similar but more pronounced changes in the proximal arterial dilation and distal flow occurred with infusion of nitroglycerin (0.4 mg). No vasoactive changes were observed during infusions of the control vehicle. The vasodilatory effects to this EDRF occurred in the absence of changes in aortic and left ventricular pressure, rate of pressure development (dP/dt), and heart rate. These data demonstrate that infusion of this partially purified relaxing factor from cultured endothelial cells causes vasodilation in vivo with a vasoactive profile similar to nitroglycerin. The biological effects of this EDRF persist significantly longer than the extreme lability of EDRF at neutral pH (approximately 6 s), consistent with its in vitro effects. Despite the demonstration of rapid inactivation of EDRF in vitro by hemoglobin, high oxygen tension, and plasma, the study shows that this EDRF can have significant in vivo vasoactive effects.

Endothelial nitric oxide synthase increases in left atria of dogs with pacing-induced heart failure

1998 ◽  
Vol 275 (6) ◽  
pp. H1971-H1978 ◽  
Author(s):  
Fadi H. Khadour ◽  
Darryl W. O’Brien ◽  
Yuling Fu ◽  
Paul W. Armstrong ◽  
Richard Schulz
Keyword(s):  
Heart Failure ◽  
Cardiac Tissue ◽  
Left Ventricular ◽  
No Production ◽  
Ventricular Activity ◽  
Plasma Nitrate ◽  
Oxide Synthase ◽  
Nos Isoforms ◽  
Endothelial Nitric Oxide ◽  
Enos Protein

In congestive heart failure (CHF) the alterations in cardiac NO synthase (NOS) isoforms activity and expression are incompletely documented and the chamber specificity of these changes is unknown. We studied plasma nitrate-nitrite ([Formula: see text]), atrial, and ventricular NOS activities and protein expression (Western blot and densitometric analysis) in nonpaced control dogs and in dogs paced for 2 or 21 days into CHF. Plasma [Formula: see text] rose significantly after 7 and 21 days of pacing, whereas creatinine levels remained unchanged. In control dogs Ca2+-dependent NOS activity in left atria was double that of right or left ventricular activity. In paced animals the activity increased only in the atria after 21 but not 2 days of pacing. Levels of endothelial NOS (eNOS) protein were enhanced in the left atria but not ventricles after 21 days of pacing because of a greater quantity of the 150-kDa but not the 135-kDa eNOS. Ca2+-independent NOS activity was undetectable in any cardiac tissue. The specific upregulation of eNOS in the left atria suggests that NO production may be enhanced to counterbalance hypertrophy that develops during pacing-induced CHF.

Growth factors and the primary cilium in BALB/c 3T3 cells

1987 ◽  
Vol 45 ◽  
pp. 830-831
Author(s):  
R. W. Tucker ◽  
N. S. More ◽  
S. Jayaraman
Keyword(s):  
Growth Factors ◽  
Primary Cilium ◽  
Cultured Cells ◽  
Morphological Changes ◽  
Calcium Ionophore ◽  
Growth Stimulation ◽  
Calcium Ionophore A23187 ◽  
Ionophore A23187 ◽  
3T3 Cells ◽  
Microtubule Depolymerization

The mechanisms by which polypeptide growth factors Induce DNA synthesis in cultured cells is not understood, but morphological changes Induced by growth factors have been used as clues to Intracellular messengers responsible for growth stimulation. One such morphological change has been the transient disappearance of the primary cilium, a “9 + 0” cilium formed by the perinuclear centriole in interphase cells. Since calcium ionophore A23187 also produced both mitogenesis and ciliary changes, microtubule depolymerization might explain ciliary disappearance monitored by indirect immunofluorescence with anti-tubulin antibody. However, complete resorption and subsequent reformation of the primary cilium occurs at mitosis, and might also account for ciliary disappearance induced by growth factors. To settle this issue, we investigated the ultrastructure of the primary cilium using serial thin-section electron microscopy of quiescent BALB/c 3T3 cells before and after stimulation with serum.

Assessment of Myocardial Viability in Persistent Defects on Thallium-201 SPECT after Reinjection Using Gradient-Echo MRI

1996 ◽  
Vol 35 (05) ◽  
pp. 146-152 ◽  
Author(s):  
A. Kögler ◽  
H.-A. Schmitt ◽  
D. Emrich ◽  
H. Kreuzer ◽  
D. L. Munz ◽  
...  
Keyword(s):  
Wall Thickness ◽  
Myocardial Viability ◽  
Cardiac Cycle ◽  
Single Photon ◽  
Contractile Function ◽  
Left Ventricular ◽  
Wall Thickening ◽  
Gradient Echo ◽  
Systolic Wall Thickening

SummaryThis prospective study assessed myocardial viability in 30 patients with coronary heart disease and persistent defects despite reinjection on TI-201 single-photon computed tomography (SPECT). In each patient, three observers graded TI-201 uptake in 7 left ventricular wall segments. Gradient-echo magnetic resonance imaging in the region of the persistent defect generated 12 to 16 short axis views representing a cardiac cycle. A total of 120 segments were analyzed. Mean end-diastolic wall thickness and systolic wall thickening (± SD) was 11.5 ± 2.7 mm and 5.8 ± 3.9 mm in 48 segments with normal TI-201 uptake, 10.1 ± 3.4 mm and 3.7 ± 3.1 mm in 31 with reversible lesions, 11.3 ± 2.8 mm and 3.3 ± 1.9 mm in 10 with mild persistent defects, 9.2 ± 2.9 mm and 3.2 ±2.2 mm in 15 with moderate persistent defects, 5.8 ± 1.7 mm and 1.3 ± 1.4 mm in 16 with severe persistent defects, respectively. Significant differences in mean end-diastolic wall thickness (p <0.0005) and systolic wall thickening (p <0.005) were found only between segments with severe persistent defects and all other groups, but not among the other groups. On follow-up in 11 patients after revascularization, 6 segments with mild-to-moderate persistent defects showed improvement in mean systolic wall thickening that was not seen in 6 other segments with severe persistent defects. These data indicate that most myocardial segments with mild and moderate persistent TI-201 defects after reinjection still contain viable tissue. Segments with severe persistent defects, however, represent predominantly nonviable myocardium without contractile function.

Inhibition of Platelet Aggregation by Ethanol in Vitro Shows Specificity for Aggregating Agent Used and Is Influenced by Platelet Lipid Composition

1982 ◽  
Vol 48 (01) ◽  
pp. 049-053 ◽  
Author(s):  
C G Fenn ◽  
J M Littleton
Keyword(s):  
Platelet Aggregation ◽  
Lipid Composition ◽  
Saturated Fatty Acids ◽  
Calcium Ionophore ◽  
Cholesterol Content ◽  
Membrane Lipid ◽  
Calcium Ionophore A23187 ◽  
Ionophore A23187 ◽  
Increased Sensitivity

SummaryEthanol at physiologically tolerable concentrations inhibited platelet aggregation in vitro in a relatively specific way, which may be influenced by platelet membrane lipid composition. Aggregation to collagen, calcium ionophore A23187 and thrombin (low doses) were often markedly inhibited by ethanol, adrenaline and ADP responses were little affected, and aggregation to exogenous arachidonic acid was actually potentiated by ethanol. Aggregation to collagen, thrombin and A23187 was inhibited more by ethanol in platelets enriched with saturated fatty acids than in those enriched with unsaturated fats. Platelets enriched with cholesterol showed increased sensitivity to ADP, arachidonate and adrenaline but this increase in cholesterol content did not appear to influence the inhibition by ethanol of platelet responses. The results suggest that ethanol may inhibit aggregation by an effect on membrane fluidity and/or calcium mobilization resulting in decreased activity of a membrane-bound phospholipase.

scholarly journals Isolated Left Ventricular Noncompaction in a Case of Sotos Syndrome: A Casual or Causal Link?

2011 ◽  
Vol 2011 ◽  
pp. 1-3 ◽  
Author(s):  
Patrizia Saccucci ◽  
Federica Papetti ◽  
Roberta Martinoli ◽  
Alessandro Dofcaci ◽  
Ursula Tuderti ◽  
...  
Keyword(s):  
Physical Examination ◽  
Causal Link ◽  
Left Ventricular ◽  
Wall Thickening ◽  
Ventricular Wall ◽  
Sotos Syndrome ◽  
Left Ventricular Noncompaction ◽  
Ventricular Noncompaction ◽  
Cardiac Evaluation ◽  
Chromosome 5Q35

A 16-year-old boy affected by Sotos syndrome was referred to our clinic for cardiac evaluation in order to play noncompetitive sport. Physical examination was negative for major cardiac abnormalities and rest electrocardiogram detected only minor repolarization anomalies. Transthoracic echocardiography showed left ventricular wall thickening and apical trabeculations with deep intertrabecular recesses, fulfilling criteria for isolated left ventricular noncompaction (ILVNC). Some sporadic forms of ILVNC are reported to be caused by a mutation on CSX gene, mapping on chromosome 5q35. To our knowledge, this is the first report of a patient affected simultaneously by Sotos syndrome and ILVNC.

scholarly journals Association arterial stiffness reduction with improved left ventricular longitudinal and torsional deformation after 3 years of antihypertensive treatment

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Tzortzis ◽  
I Ikonomidis ◽  
H Triantafyllidi ◽  
J Thymis ◽  
A Frogoudaki ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Arterial Stiffness ◽  
Ace Inhibitors ◽  
Antihypertensive Treatment ◽  
Left Ventricular ◽  
Torsional Deformation ◽  
Flow Reserve ◽  
Stiffness Reduction ◽  
Arterial Blood ◽  
Lv Mass

Abstract Background We investigated the effects of antihypertensive treatment on vascular function, longitudinal and torsional deformation in hypertensives. Methods In 200 untreated patients with arterial hypertension (age 52.5±11.6 years, 56% females), we measured at baseline and after a 3-year of antihypertensive treatment (160 received ACEi± diuretics and 40 CCBs± diuretics): a) 24h ambulatory blood pressure b) Carotid-femoral pulse wave velocity (PWV) b) Coronary flow reserve (CFR), LV mass index (LVMI), the global longitudinal strain (GLS) and diastolic (LongSRSE) strain rate, peak twisting (Tw-deg) and untwisting at mitral valve opening (UtwMVO), at peak E (UtwE) and at the end of the E wave (UtwendE) of the mitral inflow as well as twisting (TwVel-deg/sec) velocity using speckle tracking imaging. We calculated the % change of LV untwisting as difference between peakTw and UtwMVO, UtwpeakE and UtwendE. Results Compared to baseline, there was an improvement of GLS (−19.9±3.4 vs. −18.7±3.1%), LongSRS (−1.08±0.22 vs. −0.98±0.26 1/s), LongSRE (1.09±0.36 vs. 0.99±0.31 1/s), peak Tw (16.2±5.1 vs. 18.7±5.9 deg), Tw velocity, and the %LV untwisting (31.04±19.28 vs 26.02±15.69% at MVO, 60.04±19.78 vs 53.96±19.76% at peakE and 79.98±14.24 vs 75.90±17.01% at endE) post-treatment. In parallel, CFR (2.72±0.61 vs. 2.55±0.64), PWV (10.34±1.93 vs. 11.2±2.08 m/s) and LVMI were improved (p&lt;0.01 for all comparisons). By ANOVA, the interaction term between changes of all the above parameters and antihypertensive treatment (ACE inhibitors vs calcium channel blockers) was not significant (p&gt;0.05). By multivariate analysis, the reduction of 24h meanBP and PWV independently determined the respective improvement of GLS (b=0.478 and b=0.248 respectively), LongS (b=0.428 and b=0.201 respectively) as well as Twisting (b=0.449 and b=0.294 respectively) after adjusting for changes in LV mass, CFR and atherosclerotic risk factors (p&lt;0.05). Conclusions Long-term optimal blood pressure control with ACE inhibitors and CCBs improves LV longitudinal and torsional mechanics in hypertensives in parallel with arterial stiffness and blood pressure. This improvement in LV deformation and twisting was independently related to changes in arterial blood pressure and arterial stiffness. Funding Acknowledgement Type of funding source: None

Effects of glucocorticoids on prostaglandin formation by human amnion

1990 ◽  
Vol 68 (6) ◽  
pp. 671-676 ◽  
Author(s):  
William Gibb ◽  
Jean-Claude Lavoie
Keyword(s):  
Calcium Ionophore ◽  
Inhibitory Effect ◽  
Calcium Ionophore A23187 ◽  
Ionophore A23187 ◽  
Isolated Cells ◽  
Stimulatory Action ◽  
Human Amnion ◽  
Human Labor ◽  
Epidermal Growth

The human amnion may be an important source of prostaglandins involved in the onset of human labor and therefore it is important to define the factors that regulate their formation in this tissue. In the present study we demonstrate that glucocorticoids inhibit prostaglandin production by freshly isolated amnion cells. The inhibitory action of the glucocorticoids, however, changes to a stimulatory action when the cells are maintained in primary culture for a few days. For both inhibition and stimulation, concentrations of 10−8 M dexamethasone or greater were required to give significant effects, and estradiol and progesterone had no effect on the prostaglandin output of the cells. Epidermal growth factor (EGF), which has previously been found to stimulate prostaglandin output by confluent amnion cells, did not alter prostaglandin output of cells initially placed in culture. Furthermore, the stimulatory action of EGF and dexamethasone appeared additive. The calcium ionophore A23187 stimulated prostaglandin output in freshly isolated cells and accentuated the inhibitory effect of dexamethasone. These studies indicate that prostaglandin formation by human amnion during pregnancy could be regulated by glucocorticoids. These steroids are easily available to the amnion by way of cortisone conversion to Cortisol by the maternal decidua. The results also indicate that amnion is capable of responding to glucocorticoids in both a stimulatory and inhibitory fashion and whether one or both actions are of importance in vivo is a question that is as yet unresolved.Key words: prostaglandins, amnion, fetal membranes, glucocorticoids, labor, pregnancy.

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