Nitric oxide production is maintained in exercising swine with chronic left ventricular dysfunction

2002 ◽  
Vol 282 (6) ◽  
pp. H2198-H2209 ◽  
Author(s):  
David B. Haitsma ◽  
Daphne Merkus ◽  
Jefrey Vermeulen ◽  
Pieter D. Verdouw ◽  
Dirk J. Duncker
Keyword(s):  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Endothelial Dysfunction ◽  
Vascular Tone ◽  
Tissue Perfusion ◽  
Selective Inhibition ◽  
Left Ventricular ◽  
No Synthase ◽  
Lv Dysfunction ◽  
Pulmonary Vasodilator

Left ventricular (LV) dysfunction caused by myocardial infarction (MI) is accompanied by endothelial dysfunction, most notably a loss of nitric oxide (NO) availability. We tested the hypothesis that endothelial dysfunction contributes to impaired tissue perfusion during increased metabolic demands as produced by exercise, and we determined the contribution of NO to regulation of regional systemic, pulmonary, and coronary vasomotor tone in exercising swine with LV dysfunction produced by a 2- to 3-wk-old MI. LV dysfunction resulted in blunted systemic and coronary vasodilator responses to ATP, whereas the responses to nitroprusside were maintained. Exercise resulted in blunted systemic and pulmonary vasodilator responses in MI that resembled the vasodilator responses in normal (N) swine following blockade of NO synthase with N ω-nitro-l-arginine (l-NNA, 20 mg/kg iv). However, l-NNA resulted in similar decreases in systemic (43 ± 3% in N swine and 49 ± 4% in MI swine), pulmonary (45 ± 5% in N swine and 49 ± 4% in MI swine), and coronary (28 ± 4% in N and 35 ± 3% in MI) vascular conductances in N and MI swine under resting conditions; similar effects were observed during treadmill exercise. Selective inhibition of inducible NO synthase with aminoguanidine (20 mg/kg iv) had no effect on vascular tone in MI. These findings indicate that while agonist-induced vasodilation is already blunted early after myocardial infarction, the contribution of endothelial NO synthase-derived NO to regulation of vascular tone under basal conditions and during exercise is maintained.

Abstract 14119: Contrasting Effects of Exercise Training After Acute Myocardial Infarction versus Aortic Stenosis Depend Critically on the Regulation of Endothelial Nitric Oxide Synthase

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yanti Octavia ◽  
Elza D van Deel ◽  
Monique de Waard ◽  
Martine de Boer ◽  
Dirk J Duncker
Keyword(s):  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Exercise Training ◽  
Wheel Running ◽  
Left Ventricular ◽  
Lv Function ◽  
Enhanced Chemiluminescence ◽  
Lv Dysfunction ◽  
Enos Uncoupling ◽  
Endothelial Nitric Oxide

Introduction: The cardiovascular benefits of exercise training (EX) are widely appreciated. Previously we found that the cardiac effects of EX critically depend on the underlying cause of heart disease. Hypothesis: The underlying etiology determines how EX affects the endothelial nitric oxide (NO) synthase (eNOS)-mediated balance between NO and superoxide (O2-). Methods: Mice were subjected to sham surgery, myocardial infarction (MI) or transverse aortic constriction (TAC), and subsequently exposed to 8 weeks of voluntary wheel running or sedentary housing. Left ventricular (LV) function was assessed by echocardiography and hemodynamic measurements; fibrosis by Picro-sirius Red staining; peroxynitrite (ONOO-) and O2- production by luminol- and lucigenin-enhanced chemiluminescence respectively, with or without the NOS inhibitor L-NAME; eNOS uncoupling and eNOS S-glutathionylation by western blot and coimmunoprecipitation, respectively; cardiac NO by the Griess reaction. Results: EX ameliorated LV dysfunction and fibrosis in MI but not TAC (Table 1). Strikingly, O2- generation was blunted by EX in MI, but exacerbated by EX in TAC, which was largely NOS-dependent. Accordingly, eNOS uncoupling and eNOS S-glutathionylation were corrected by EX in MI but aggravated in TAC mice. In parallel, ONOO- levels was attenuated by EX in MI but aggravated by EX in TAC. Cardiac NO levels were reduced in MI and TAC and normalized by EX in MI. Conclusions: The contrasting effects of EX in MI vs TAC can be explained by the highly divergent effects of EX on eNOS regulation, resulting in blunted vs aggravated oxidative stress by EX in MI vs TAC.

scholarly journals Vitamin D Is a Regulator of Endothelial Nitric Oxide Synthase and Arterial Stiffness in Mice

2014 ◽  
Vol 28 (1) ◽  
pp. 53-64 ◽  
Author(s):  
Olena Andrukhova ◽  
Svetlana Slavic ◽  
Ute Zeitz ◽  
Sabine C. Riesen ◽  
Monika S. Heppelmann ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vitamin D ◽  
Endothelial Dysfunction ◽  
Arterial Stiffness ◽  
Epidemiological Data ◽  
Vitamin D Insufficiency ◽  
Left Ventricular ◽  
No Synthase ◽  
Mutant Mice ◽  
Endothelial No Synthase

Abstract The vitamin D hormone 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] is essential for the preservation of serum calcium and phosphate levels but may also be important for the regulation of cardiovascular function. Epidemiological data in humans have shown that vitamin D insufficiency is associated with hypertension, left ventricular hypertrophy, increased arterial stiffness, and endothelial dysfunction in normal subjects and in patients with chronic kidney disease and type 2 diabetes. However, the pathophysiological mechanisms underlying these associations remain largely unexplained. In this study, we aimed to decipher the mechanisms by which 1,25(OH)2D3 may regulate systemic vascular tone and cardiac function, using mice carrying a mutant, functionally inactive vitamin D receptor (VDR). To normalize calcium homeostasis in VDR mutant mice, we fed the mice lifelong with the so-called rescue diet enriched with calcium, phosphate, and lactose. Here, we report that VDR mutant mice are characterized by lower bioavailability of the vasodilator nitric oxide (NO) due to reduced expression of the key NO synthesizing enzyme, endothelial NO synthase, leading to endothelial dysfunction, increased arterial stiffness, increased aortic impedance, structural remodeling of the aorta, and impaired systolic and diastolic heart function at later ages, independent of changes in the renin-angiotensin system. We further demonstrate that 1,25(OH)2D3 is a direct transcriptional regulator of endothelial NO synthase. Our data demonstrate the importance of intact VDR signaling in the preservation of vascular function and may provide a mechanistic explanation for epidemiological data in humans showing that vitamin D insufficiency is associated with hypertension and endothelial dysfunction.

scholarly journals Effect of cardiosphere-derived cells on segmental myocardial function after myocardial infarction: ALLSTAR randomised clinical trial

Open Heart ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. e001614
Author(s):  
Mohammad R Ostovaneh ◽  
Raj R Makkar ◽  
Bharath Ambale-Venkatesh ◽  
Deborah Ascheim ◽  
Tarun Chakravarty ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Clinical Trial ◽  
Myocardial Function ◽  
Randomised Clinical Trial ◽  
Scar Tissue ◽  
Left Ventricular ◽  
Lv Function ◽  
Cardiac Events ◽  
Lv Dysfunction ◽  
Registration Number

BackgroundMost cell therapy trials failed to show an improvement in global left ventricular (LV) function measures after myocardial infarction (MI). Myocardial segments are heterogeneously impacted by MI. Global LV function indices are not able to detect the small treatment effects on segmental myocardial function which may have prognostic implications for cardiac events. We aimed to test the efficacy of allogeneic cardiosphere-derived cells (CDCs) for improving regional myocardial function and contractility.MethodsIn this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF <45% and 15% or greater LV scar size were randomised in 2:1 ratio to receive intracoronary infusion of allogenic CDCs or placebo, respectively. Change in segmental myocardial circumferential strain (Ecc) by MRI from baseline to 6 months was compared between CDCs and placebo groups.ResultsIn total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3 (10.8) and 108 (87.1%) men). Segmental Ecc improvement was significantly greater in patients receiving CDC (−0.5% (4.0)) compared with placebo (0.2% (3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of −0.7% (3.5) in patients receiving CDC vs 0.04% (3.7) in the placebo group, p=0.04).ConclusionsIn patients with post-MI LV dysfunction, CDC administration resulted in improved segmental myocardial function. Our findings highlight the importance of segmental myocardial function indices as an endpoint in future clinical trials of patients with post-MI.Trial registration numberNCT01458405.

Regulation of components of the brain and cardiac renin-angiotensin systems by 17β-estradiol after myocardial infarction in female rats

2006 ◽  
Vol 291 (1) ◽  
pp. R155-R162 ◽  
Author(s):  
Stephanie A. Dean ◽  
Junhui Tan ◽  
Roselyn White ◽  
Edward R. O’Brien ◽  
Frans H. H. Leenen
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricular ◽  
Female Rats ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Brain Nuclei ◽  
Renin Angiotensin ◽  
Lv Dysfunction ◽  
17Β Estradiol ◽  
The Brain

The present study tested the hypothesis that 17β-estradiol (E2) inhibits increases in angiotensin-converting enzyme (ACE) and ANG II type 1 receptor (AT1R) in the brain and heart after myocardial infarction (MI) and, thereby, inhibits development of left ventricular (LV) dysfunction after MI. Age-matched female Wistar rats were treated as follows: 1) no surgery (ovary intact), 2) ovariectomy + subcutaneous vehicle treatment (OVX + Veh), or 3) OVX + subcutaneous administration of a high dose of E2 (OVX + high-E2). After 2 wk, rats were randomly assigned to coronary artery ligation (MI) and sham operation groups and studied after 3 wk. E2 status did not affect LV function in sham rats. At 2–3 wk after MI, impairment of LV function was similar across MI groups, as measured by echocardiography and direct LV catheterization. LV ACE mRNA abundance and activity were increased severalfold in all MI groups compared with respective sham animals and to similar levels across MI groups. In most brain nuclei, ACE and AT1R densities increased after MI. Unexpectedly, compared with the respective sham groups the relative increase was clearest (20–40%) in OVX + high-E2 MI rats, somewhat less (10–15%) in ovary-intact MI rats, and least (<10–15%) in OVX + Veh MI rats. However, because in the sham group brain ACE and AT1R densities increased in the OVX + Veh rats and decreased in the OVX + high-E2 rats compared with the ovary-intact rats, actual ACE and AT1R densities in most brain nuclei were modestly higher (<20%) in OVX + Veh MI rats than in the other two MI groups. Thus E2 does not inhibit upregulation of ACE in the LV after MI and amplifies the percent increases in ACE and AT1R densities in brain nuclei after MI, despite E2-induced downregulation in sham rats. Consistent with these minor variations in the tissue renin-angiotensin system, during the initial post-MI phase, E2 appears not to enhance or hinder the development of LV dysfunction.

Abstract 814: Atorvastatin Attenuates Oxidative Stress And Improves Neuronal Nitric Oxide Synthase In The Brain Stem Of Heart Failure Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Joseph Francis ◽  
Li Yu ◽  
Anuradha Guggilam ◽  
Srinivas Sriramula ◽  
Irving H Zucker
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Brain Stem ◽  
Mrna Expression ◽  
Natriuretic Peptide ◽  
Left Ventricular ◽  
Neuronal Nos ◽  
The Brain

3-Hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to reduce the incidence of myocardial infarction independent of their lipid-lowering effects. Nitric oxide (NO) in the central nervous system contributes to cardiovascular regulatory mechanisms. Imbalance between nitric oxide (NO) and superoxide anion (O 2 . − ) in the brain may contribute to enhanced sympathetic drive in heart failure (HF). This study was done to determine whether treatment with atorvastatin (ATS) ameliorates the imbalance between NO and O 2 . − production in the brain stem and contributes to improvement of left ventricular (LV) function. Methods and Results: Myocardial infarction (MI) was induced by ligation of the left coronary artery or sham surgery. Subsequently, mice were treated with ATS (10 μg/kg) (MI + ATS), or vehicle (MI + V). After 5 weeks, echocardiography revealed left ventricular dilatation in MI mice. Realtime RT-PCR indicated an increase in the mRNA expression of the LV hypertrophy markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Neuronal NOS (nNOS) and endothelial NOS (eNOS) mRNA expression were significantly reduced, while that of NAD(P)H oxidase subunit (gp91phox) expression was elevated in the brain stem of MI mice. Compared with sham-operated mice, ATS-treated mice showed reduced cardiac dilatation, decreased ANP and BNP in the LV. ATS also reduced gp91phox expression and increased nNOS mRNA expression in the brain stem, while no changes in eNOS and iNOS were observed. Conclusion: These findings suggest that ATS reduces oxidative stress and increases neuronal NOS in the brain stem, and improves left ventricular function in heart failure.

scholarly journals Takotsubo Cardiomyopathy and Non-ST-Segment Elevation Myocardial Infarction: Predictors of Left Ventricular Dysfunction

2017 ◽  
Vol 11 ◽  
pp. 117954681771610
Author(s):  
Andrew Hinojos ◽  
Thomas E Vanhecke ◽  
Susan Enright ◽  
Nathan Elg ◽  
Kristina Gifft ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricular ◽  
Retrospective Case ◽  
St Segment Elevation ◽  
Coronary Syndrome ◽  
Segment Elevation Myocardial Infarction ◽  
Lv Dysfunction ◽  
St Segment ◽  
Artery Disease ◽  
Control Study

Background: Acute coronary syndrome (ACS) from non-ST-segment elevation myocardial infarction (NSTEMI) and Takotsubo (TK) cardiomyopathy present with similar initial clinical features and can result in left ventricular (LV) dysfunction and acute heart failure. Methods: This study was a retrospective case-control study that identified patients aged 18 years and older who presented with ACS and underwent cardiac catheterization. Results: There were a total of 321 patients in the TK group and 1031 patients in the NSTEMI group. There was significantly worse LV dysfunction in the TK group with average ejection fraction (EF) of 44.35% (±15.11%) versus NSTEMI with an average EF of 47.36% (±13.5%) ( P < .001). The presence of TK yielded of an odds ratio (OR) of 2.373 (95% confidence interval [CI]: 1.165-3.618) and presence of peripheral artery disease (PAD) yielded an OR of 2.053 (95% CI: 1.165-3.618). Conclusions: The presence of TK cardiomyopathy and PAD were independent predictors of patients who had LVEF of <35% and elevated B-type natriuretic peptide levels.

scholarly journals P774 Utility of global longitudinal strain to predict post-operative outcomes in non-cardiac surgery

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
C J Park ◽  
L S Tan ◽  
P Huang ◽  
P J Tan ◽  
J H J See
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Surgery ◽  
Risk Stratification ◽  
Longitudinal Strain ◽  
Myocardial Injury ◽  
Global Longitudinal Strain ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Operative Outcomes ◽  
Lv Dysfunction

Abstract Background Pre-operative echocardiography is performed in selected groups of patients for cardiac risk stratification prior to surgery. Many parameters, including Left Ventricular Ejection Fraction (LVEF), are assessed during echocardiography. While many studies have cited association between low LVEF and poor operative outcomes such as perioperative myocardial infarction or cardiogenic pulmonary edema, LVEF has limitations such as left ventricular (LV) cavity border tracing, geometric assumptions and inter-observer variability. LVEF may also appear normal in the presence of LV hypertrophy and a small LV cavity size. Studies have described the routine use of global longitudinal strain (GLS) as an alternative measure of ventricular function, with GLS having been reported to be a reliable marker in detecting subclinical LV dysfunction. This adds incremental value in predicting myocardial function and in risk stratification. In fact, some studies have documented GLS being a useful preoperative parameter in predicting postoperative LV dysfunction after cardiac valve surgery. Purpose The aim of this study is to determine the value of GLS in predicting post-operative outcomes in patients undergoing non-cardiac surgeries. Methods This was a retrospective study of all patients who had echocardiography performed for a pre-operative indication from February 2017 to October 2017. These patients were screened for those who had normal LVEF, had undergone subsequent non-cardiac surgery, and had post-operative troponins measured. Medical records were traced for baseline demographics, past medical history and echocardiographic features. GLS evaluation was prospectively performed using TOMTEC-ARENA (TOMTEC Imaging Systems GmbH) by assessors blinded to patient outcomes. Outcomes for major adverse cardiovascular events and mortality up to 1 year post surgery were collected. Post-op myocardial injury was defined as a peak Troponin T value of &gt;30 ng/L or a &gt;20% increment from baseline. Results A total of 42 patients were included. 61.9% (n = 26) were male and mean age was 72.3 years. Only 75.6% of patients were fully independent with activities of daily living and mean creatinine was 153.4μmol/L. Mortality at 1 year was 16.7% (n = 7) and 28.6% (n = 12) were deemed to have post-operative myocardial injury. 1-year mortality was associated with a lower GLS (-23.8% vs -19.2%, p = 0.001). However, GLS was not correlated with post-operative myocardial injury or hospital readmissions. In our study population, only a history of past myocardial infarction predicted post-op myocardial injury (58.3% vs 16.7%, p = 0.019). Conclusion Our study did not demonstrate the utility of GLS in predicting post-operative events, but this is likely because of the small sample size with low event rates. Nevertheless, GLS values did correlate with 1-year mortality and could be a marker of frailty and an increased mortality risk.

Prostanoids suppress the coronary vasoconstrictor influence of endothelin after myocardial infarction

2011 ◽  
Vol 301 (3) ◽  
pp. H1080-H1089 ◽  
Author(s):  
Vincent J. de Beer ◽  
Yannick J. Taverne ◽  
Diederik W. Kuster ◽  
Aref Najafi ◽  
Dirk J. Duncker ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Myocardial Infarction ◽  
Endothelial Dysfunction ◽  
Vasodilator Effect ◽  
Protein Levels ◽  
Cyclooxygenase 1 ◽  
Vasoconstrictor Effect ◽  
Endothelial Control ◽  
Endothelial Nitric Oxide ◽  
Coronary Vasoconstrictor

Myocardial infarction (MI) is associated with endothelial dysfunction resulting in an imbalance in endothelium-derived vasodilators and vasoconstrictors. We have previously shown that despite increased endothelin (ET) plasma levels, the coronary vasoconstrictor effect of endogenous ET is abolished after MI. In normal swine, nitric oxide (NO) and prostanoids modulate the vasoconstrictor effect of ET. In light of the interaction among NO, prostanoids, and ET combined with endothelial dysfunction present after MI, we investigated this interaction in control of coronary vasomotor tone in the remote noninfarcted myocardium after MI. Studies were performed in chronically instrumented swine (18 normal swine; 13 swine with MI) at rest and during treadmill exercise. Furthermore, endothelial nitric oxide synthase (eNOS) and cyclooxygenase protein levels were measured in the anterior (noninfarcted) wall of six normal and six swine with MI. eNOS inhibition with Nω-nitro-l-arginine (l-NNA) and cyclooxygenase inhibition with indomethacin each resulted in coronary vasoconstriction at rest and during exercise, as evidenced by a decrease in coronary venous oxygen levels. The effect of l-NNA was slightly decreased in swine with MI, although eNOS expression was not altered. Conversely, in accordance with the unaltered expression of cyclooxygenase-1 after MI, the effect of indomethacin was similar in normal and MI swine. l-NNA enhanced the vasodilator effect of the ETA/B receptor blocker tezosentan but exclusively during exercise in both normal and MI swine. Interestingly, this effect of l-NNA was blunted in MI compared with normal swine. In contrast, whereas indomethacin increased the vasodilator effect of tezosentan only during exercise in normal swine, indomethacin unmasked a coronary vasodilator effect of tezosentan in MI swine both at rest and during exercise. In conclusion, the present study shows that endothelial control of the coronary vasculature is altered in post-MI remodeled myocardium. Thus the overall vasodilator influences of NO as well as its inhibition of the vasoconstrictor influence of ET on the coronary resistance vessels were reduced after MI. In contrast, while the overall prostanoid vasodilator influence was maintained, its inhibition of ET vasoconstrictor influences was enhanced in post-MI remote myocardium.

Cytochrome P-450 metabolites but not NO, PGI2, and H2O2 contribute to ACh-induced hyperpolarization of pressurized canine coronary microvessels

2003 ◽  
Vol 285 (5) ◽  
pp. H1939-H1948 ◽  
Author(s):  
Mitsuaki Tanaka ◽  
Hiroshi Kanatsuka ◽  
Boon-Hooi Ong ◽  
Toshinori Tanikawa ◽  
Akira Uruno ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Membrane Potential ◽  
Fluorescence Intensity ◽  
Vascular Tone ◽  
Endothelial Damage ◽  
No Synthase ◽  
Internal Diameter ◽  
Physiological Salt Solution ◽  
Cytochrome P 450 ◽  
Large Coronary Arteries

The endothelium-dependent hyperpolarization of cells has a crucial role in regulating vascular tone, especially in microvessels. Nitric oxide (NO) and prostacyclin (PGI2), in addition to endothelium-derived hyperpolarizing factor (EDHF), have been reported to hyperpolarize vascular smooth muscle in several organs. Studies have reported the hyperpolarizing effects of these factors are increased by a stretch in large coronary arteries. EDHF has not yet been identified and cytochrome P-450 metabolites and H2O2 are candidates for EDHF. With the use of the membrane potential-sensitive fluorescent dye bis-(1,3-dibutylbarbituric acid)trimethione oxonol [DiBAC4(3)], we examined whether NO, PGI2, cytochrome P-450 metabolites, and H2O2 contribute to ACh-induced hyperpolarization in pressurized coronary microvessels. Canine coronary arterial microvessels (60–356 μm internal diameter) were cannulated and pressurized at 60 cmH2O in a vessel chamber perfused with physiological salt solution containing DiBAC4(3). Fluorescence intensity and diameter were measured on a computer. There was a linear correlation between changes in the fluorescence intensity and membrane potential. ACh significantly decreased the fluorescence intensity (hyperpolarization) of the microvessels without any inhibitors. Endothelial damage caused by air perfusion abolished the ACh-induced decrease in fluorescence intensity. The inhibitors of NO synthase and cyclooxygenase did not affect the ACh-induced decreases in the fluorescence intensity. The addition of 17-octadecynoic acid, a cytochrome P-450 monooxygenase inhibitor, to those inhibitors significantly attenuated the ACh-induced decreases in fluorescence intensity, whereas catalase, an enzyme that dismutates H2O2 to form water and oxygen, did not. Furthermore, catalase did not affect the vasodilation produced by ACh. These results indicate that NO and PGI2 do not contribute to the ACh-induced hyperpolarization and that the cytochrome P-450 metabolites but not H2O2 are involved in EDHF-mediated hyperpolarization in canine coronary arterial microvessels.

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