Myocardial contractile function and vulnerability to ischemia ex vivo can be worsened by prior experimental ischemic stroke in rats

Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally based molecular mechanism in cardiovascular biology is poorly understood. We hypothesized that the circadian clock within the cardiomyocyte influences diurnal variations in myocardial biology. We, therefore, generated a cardiomyocyte-specific circadian clock mutant (CCM) mouse to test this hypothesis. At 12 wk of age, CCM mice exhibit normal myocardial contractile function in vivo, as assessed by echocardiography. Radiotelemetry studies reveal attenuation of heart rate diurnal variations and bradycardia in CCM mice (in the absence of conduction system abnormalities). Reduced heart rate persisted in CCM hearts perfused ex vivo in the working mode, highlighting the intrinsic nature of this phenotype. Wild-type, but not CCM, hearts exhibited a marked diurnal variation in responsiveness to an elevation in workload (80 mmHg plus 1 μM epinephrine) ex vivo, with a greater increase in cardiac power and efficiency during the dark (active) phase vs. the light (inactive) phase. Moreover, myocardial oxygen consumption and fatty acid oxidation rates were increased, whereas cardiac efficiency was decreased, in CCM hearts. These observations were associated with no alterations in mitochondrial content or structure and modest mitochondrial dysfunction in CCM hearts. Gene expression microarray analysis identified 548 and 176 genes in atria and ventricles, respectively, whose normal diurnal expression patterns were altered in CCM mice. These studies suggest that the cardiomyocyte circadian clock influences myocardial contractile function, metabolism, and gene expression.

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Abstract 293: Inhibition of Nitric Oxide Synthase Decreases Myocardial Injury Following Hemorrhagic Shock and Resuscitation in Rat Model

Circulation ◽

10.1161/circ.130.suppl_2.293 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Mona Soliman

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Hemorrhagic Shock ◽

Contractile Function ◽

Ex Vivo ◽

Left Ventricular ◽

Arterial Blood ◽

Myocardial Contractile ◽

Oxide Synthase

Resuscitation following hemorrhagic shock result in myocardial contractile dysfunction and injury. We examined the protective effects of non-selective inhibitor of nitric oxide synthase N(G)-nitro-L-arginine methylester (L-NAME) on myocardial contractile function in the isolated perfused hearts, after ex vivo as well as in vivo treatment with L-NAME and resuscitation following one hour of hemorrhagic shock.Male Sprague Dawley rats (300-350 gm) were assigned to 2 sets of experimental protocols: ex vivo and in vivo treatment and resuscitation. Each set has 3 experimental groups (n= 6 per group): normotensive (N), hemorrhagic shock and resuscitation (HS-R) and hemorrhagic shock rats treated with L-NAME and resuscitated (HS- L-NAME-R). Rats were hemorrhaged over 60 min to reach a mean arterial blood pressure of 40 mmHg. In the ex vivo group, hearts were harvested and ex vivo treated and resuscitated by perfused in the Langendorff System. In the L-NAME treated group, L-NAME was added for the first 5 min . Cardiac function was measured Left ventricular generated pressure and +dP/dt were calculated. In the in vivo group, rats were treated with L-NAME intra-arterially after 60 min hemorrhagic shock. Resuscitation was performed in vivo by the reinfusion of the shed blood for 30 min to restore normo-tension. Inhibition of nitric oxide synthase using L-NAME before resuscitation in ex vivo treated and resuscitated isolated hearts and in in vivo treated and resuscitated rats following hemorrhagic shock improved myocardial contractile function. Left ventricular generated pressure and + dP/dt max was significantly higher in L-NAME treated rats compared to the untreated group.Treatment with L-NAME improved left ventricular generated pressure following hemorrhagic shock in the ex vivo as well as the in vivo treated and resuscitated rats. The results indicate that L-NAME protects the myocardium against dysfunction by inhibiting NOS.

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Effect of alkali therapy with NaHCO3 or THAM on cardiac contractility

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1996.270.5.r955 ◽

1996 ◽

Vol 270 (5) ◽

pp. R955-R962

Author(s):

C. D. Mazer ◽

B. Naser ◽

K. S. Kamel

Keyword(s):

Myocardial Ischemia ◽

Contractile Function ◽

Venous Blood ◽

Systolic Pressure ◽

Ischemic Myocardium ◽

Stroke Work ◽

Length Relationship ◽

Alkali Therapy ◽

Myocardial Contractile ◽

The Impact

We examined the impact of alkali therapy on myocardial contractility in a model of myocardial ischemia in dogs using direct measurements of myocardial contractile function. Myocardial ischemia in the left anterior descending (LAD) artery territory was induced using a perfusion circuit from the internal carotid artery to the LAD artery. Myocardial contractile function was assessed using sonomicrometry for measurement of percent systolic shortening (%SS), preload recruitable stroke work (PRSW) slope, and end-systolic pressure-length relationship (ESPLR) area. Because the blood flow in LAD artery was diminished by approximately 70%, there was a significant decrease in O2 delivery and uptake by the ischemic myocardium. Ischemia led to a significant fall in LAD regional contractile function with %SS decreasing from 15 +/- 2 to 7 +/- 2%, PRSW slope from 82 +/- 10 to 37 +/- 5 mmHg, and ESPLR area from 121 +/- 2 to 48 +/- 14 mmHg.mm (P < 0.05). In six dogs, the intracoronary administration of NaHCO(3) resulted in a significant increase in pH in LAD arterial and venous blood. There was, however, no significant increase in %SS (6 +/- 2), PRSW slope (43 +/- 10 mmHg), or ESPLR area (60 +/- 13 mmHg.mm). Since administration of NaHCO(3) resulted in a significant increase in PCO2 in LAD arterial and venous blood, similar experiments were carried out in five dogs, but with the intracoronary infusion of the amine buffer THAM [tris(hydroxymethyl)aminomethane (Tris) buffer; 2-amino-2-hydroxyl-1,3-propandiol] instead of NaHCO3. Although administration of THAM resulted in a significant increase in pH and a significant decrease in PCO2, in both LAD arterial and venous blood, there was no significant improvement in any of the parameters used to assess myocardial contractile function. In conclusion, administration of alkali (NaHCO3 or THAM) does not enhance the contractile function of the ischemic myocardium.

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Restoring Perivascular Adipose Tissue Function in Obesity Using Exercise

Cardiovascular Drugs and Therapy ◽

10.1007/s10557-020-07136-0 ◽

2021 ◽

Author(s):

Sophie N Saxton ◽

Lauren K Toms ◽

Robert G Aldous ◽

Sarah B Withers ◽

Jacqueline Ohanian ◽

...

Keyword(s):

Adipose Tissue ◽

Contractile Function ◽

Ex Vivo ◽

Vascular Complications ◽

Electrical Field Stimulation ◽

Organic Cation Transporter ◽

Nervous Stimulation ◽

Perivascular Adipose Tissue ◽

Contractile Effect ◽

Organic Cation Transporter 3

AbstractPurposePerivascular adipose tissue (PVAT) exerts an anti-contractile effect which is vital in regulating vascular tone. This effect is mediated via sympathetic nervous stimulation of PVAT by a mechanism which involves noradrenaline uptake through organic cation transporter 3 (OCT3) and β3-adrenoceptor-mediated adiponectin release. In obesity, autonomic dysfunction occurs, which may result in a loss of PVAT function and subsequent vascular disease. Accordingly, we have investigated abnormalities in obese PVAT, and the potential for exercise in restoring function.MethodsVascular contractility to electrical field stimulation (EFS) was assessed ex vivo in the presence of pharmacological tools in ±PVAT vessels from obese and exercised obese mice. Immunohistochemistry was used to detect changes in expression of β3-adrenoceptors, OCT3 and tumour necrosis factor-α (TNFα) in PVAT.ResultsHigh fat feeding induced hypertension, hyperglycaemia, and hyperinsulinaemia, which was reversed using exercise, independent of weight loss. Obesity induced a loss of the PVAT anti-contractile effect, which could not be restored via β3-adrenoceptor activation. Moreover, adiponectin no longer exerts vasodilation. Additionally, exercise reversed PVAT dysfunction in obesity by reducing inflammation of PVAT and increasing β3-adrenoceptor and OCT3 expression, which were downregulated in obesity. Furthermore, the vasodilator effects of adiponectin were restored.ConclusionLoss of neutrally mediated PVAT anti-contractile function in obesity will contribute to the development of hypertension and type II diabetes. Exercise training will restore function and treat the vascular complications of obesity.

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Protective Effects of Estradiol on Myocardial Contractile Function Following Hemorrhagic Shock and Resuscitation in Rats

Chinese Medical Journal ◽

10.4103/0366-6999.163390 ◽

2015 ◽

Vol 128 (17) ◽

pp. 2360-2364 ◽

Cited By ~ 3

Author(s):

Mona Soliman

Keyword(s):

Hemorrhagic Shock ◽

Contractile Function ◽

Protective Effects ◽

Myocardial Contractile

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Treatment of type 2 diabetic db/db mice with a novel PPARγ agonist improves cardiac metabolism but not contractile function

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00329.2003 ◽

2004 ◽

Vol 286 (3) ◽

pp. E449-E455 ◽

Cited By ~ 70

Author(s):

Andrew N. Carley ◽

Lisa M. Semeniuk ◽

Yakhin Shimoni ◽

Ellen Aasum ◽

Terje S. Larsen ◽

...

Keyword(s):

Contractile Function ◽

Ex Vivo ◽

Metabolic Changes ◽

Pparγ Agonist ◽

Perfused Hearts ◽

Type 2 Diabetic ◽

Contractile Performance ◽

Exogenous Substrates

Hearts from insulin-resistant type 2 diabetic db/db mice exhibit features of a diabetic cardiomyopathy with altered metabolism of exogenous substrates and reduced contractile performance. Therefore, the effect of chronic oral administration of 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (COOH), a novel ligand for peroxisome proliferator-activated receptor-γ that produces insulin sensitization, to db/db mice (30 mg/kg for 6 wk) on cardiac function was assessed. COOH treatment reduced blood glucose from 27 mM in untreated db/db mice to a normal level of 10 mM. Insulin-stimulated glucose uptake was enhanced in cardiomyocytes from COOH-treated db/db hearts. Working perfused hearts from COOH-treated db/db mice demonstrated metabolic changes with enhanced glucose oxidation and decreased palmitate oxidation. However, COOH treatment did not improve contractile performance assessed with ex vivo perfused hearts and in vivo by echocardiography. The reduced outward K+ currents in diabetic cardiomyocytes were still attenuated after COOH. Metabolic changes in COOH-treated db/db hearts are most likely indirect, secondary to changes in supply of exogenous substrates in vivo and insulin sensitization.

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Stress-induced opening of the permeability transition pore in the dystrophin-deficient heart is attenuated by acute treatment with sildenafil

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00522.2010 ◽

2011 ◽

Vol 300 (1) ◽

pp. H144-H153 ◽

Cited By ~ 41

Author(s):

Alexis Ascah ◽

Maya Khairallah ◽

Frédéric Daussin ◽

Céline Bourcier-Lucas ◽

Richard Godin ◽

...

Keyword(s):

Mitochondrial Permeability Transition ◽

Contractile Function ◽

Ex Vivo ◽

Ischemia Reperfusion ◽

Clinical Signs ◽

Permeability Transition Pore ◽

Permeability Transition ◽

Mdx Mice ◽

Uptake Velocity ◽

Ptp Opening

Susceptibility of cardiomyocytes to stress-induced damage has been implicated in the development of cardiomyopathy in Duchenne muscular dystrophy, a disease caused by the lack of the cytoskeletal protein dystrophin in which heart failure is frequent. However, the factors underlying the disease progression are unclear and treatments are limited. Here, we tested the hypothesis of a greater susceptibility to the opening of the mitochondrial permeability transition pore (PTP) in hearts from young dystrophic ( mdx) mice (before the development of overt cardiomyopathy) when subjected to a stress protocol and determined whether the prevention of a PTP opening is involved in the cardioprotective effect of sildenafil, which we have previously reported in mdx mice. Using the 2-deoxy-[3H]glucose method to quantify the PTP opening in ex vivo perfused hearts, we demonstrate that when compared with those of controls, the hearts from young mdx mice subjected to ischemia-reperfusion (I/R) display an excessive PTP opening as well as enhanced activation of cell death signaling, mitochondrial oxidative stress, cardiomyocyte damage, and poorer recovery of contractile function. Functional analyses in permeabilized cardiac fibers from nonischemic hearts revealed that in vitro mitochondria from mdx hearts display normal respiratory function and reactive oxygen species handling, but enhanced Ca2+ uptake velocity and premature opening of the PTP, which may predispose to I/R-induced injury. The administration of a single dose of sildenafil to mdx mice before I/R prevented excessive PTP opening and its downstream consequences and reduced tissue Ca2+ levels. Furthermore, mitochondrial Ca2+ uptake velocity was reduced following sildenafil treatment. In conclusion, beyond our documentation that an increased susceptibility to the opening of the mitochondrial PTP in the mdx heart occurs well before clinical signs of overt cardiomyopathy, our results demonstrate that sildenafil, which is already administered in other pediatric populations and is reported safe and well tolerated, provides efficient protection against this deleterious event, likely by reducing cellular Ca2+ loading and mitochondrial Ca2+ uptake.

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Glucose-6-Phosphate Dehydrogenase and NADPH Redox Regulates Cardiac Myocyte L-Type Calcium Channel Activity and Myocardial Contractile Function

PLoS ONE ◽

10.1371/journal.pone.0045365 ◽

2012 ◽

Vol 7 (10) ◽

pp. e45365 ◽

Cited By ~ 17

Author(s):

Dhwajbahadur K. Rawat ◽

Peter Hecker ◽

Makino Watanabe ◽

Sukrutha Chettimada ◽

Richard J. Levy ◽

...

Keyword(s):

Calcium Channel ◽

Cardiac Myocyte ◽

Contractile Function ◽

Channel Activity ◽

Myocardial Contractile ◽

Glucose 6 Phosphate Dehydrogenase

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Viscerosomatic interaction induced by myocardial ischemia in conscious dogs

Journal of Applied Physiology ◽

10.1152/japplphysiol.00495.2006 ◽

2007 ◽

Vol 103 (2) ◽

pp. 511-517 ◽

Cited By ~ 2

Author(s):

Patricia A. Gwirtz ◽

Jerry Dickey ◽

David Vick ◽

Maurice A. Williams ◽

Brian Foresman

Keyword(s):

Myocardial Ischemia ◽

Contractile Function ◽

Muscle Tone ◽

Muscle Tension ◽

Left Ventricular ◽

Diagnostic Potential ◽

Myocardial Contractile ◽

Muscle Groups ◽

The Right ◽

Somatic Response

Studies tested the hypothesis that myocardial ischemia induces increased paraspinal muscular tone localized to the T2–T5 region that can be detected by palpatory means. This is consistent with theories of manual medicine suggesting that disturbances in visceral organ physiology can cause increases in skeletal muscle tone in specific muscle groups. Clinical studies in manual and traditional medicine suggest this phenomenon occurs during episodes of myocardial ischemia and may have diagnostic potential. However, there is little direct evidence of a cardiac-somatic mechanism to explain these findings. Chronically instrumented dogs [12 neurally intact and 3 following selective left ventricular (LV) sympathectomy] were examined before, during, and after myocardial ischemia. Circumflex blood flow (CBF), left ventricular contractile function, electromyographic (EMG) analysis, and blinded manual palpatory assessments (MPA) of tissue over the transverse spinal processes at segments T2–T5 and T11–T12 (control) were performed. Myocardial ischemia was associated with a decrease in myocardial contractile function and an increase in heart rate. MPA revealed increases in muscle tension and texture/firmness during ischemia in the T2–T5 segments on the left, but not on the right or in control segments. EMG demonstrated increased amplitude for the T4–T5 segments. After LV sympathectomy, MPA and EMG evidence of increased muscle tone were absent. In conclusion, myocardial ischemia is associated with significant increased paraspinal muscle tone localized to the left side T4–T5 myotomes in neurally intact dogs. LV sympathectomy eliminates the somatic response, suggesting that sympathetic neural traffic between the heart and somatic musculature may function as the mechanism for the interaction.

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