P1: CHOLINERGIC RECEPTOR FUNCTION IN CARDIAC ISCHEMIC PRECONDITIONING

Purpose of StudyCardiac acetylcholine (ACh) signaling is protective, but the role of ACh in ischemic preconditioning (IPC) remains largely unknown. We studied the effect of selective alpha-7 nicotinic ACh receptor (a7nAChR) antagonism by methyllycaconitine (MLA) on the functional benefits of IPC and the effects of this on mitochondrial complexity and inner mitochondrial membrane potential (ψM).Methods UsedMale Sprague Dawley rats (n=17, 322±17 g) were heparinized and anesthetized with 80 mg/kg pentobarbital IP, and their hearts excised and perfused at constant pressure with a non-circulating Langendorff apparatus. Left ventricular (LV) pressure (LVDP) and heart rate (HR) were continually measured with a fluid filled latex balloon attached to a pressure transducer. Treatment groups were: ischemia-reperfusion (IR)(n=6): 20 min. perfusion, 30 min. of global ischemia, 45 min. of reperfusion; IPC (n=5): 10 min. perfusion, 3 min. ischemia with 2 min. reperfusion repeated 3 times prior to IR protocol, IPC+MLA (n=6): 6 min. perfusion, 4 min. of infusion of MLA at 233 nM, IPC with MLA during reperfusion periods, then IR. Mitochondria were isolated from the LV free wall, stained for ψM and for size, and examined by Flow Cytometry with a BD LSRFortessa. Controls (C) (n=4) were freshly excised hearts from similar animals with identical anesthesia.Summary of ResultsIPC increased LV work product (LVDP times HR) as a percent of pre-ischemia (%P) during reperfusion compared to IR control, and this effect was attenuated by MLA pretreatment (IR=24.1±4.5%P, IPC=49.8±2.8%P, IPC+MLA=33.8±3.5%P, p<0.01). IPC reduced end diastolic pressure from IR levels, and this was partially prevented by MLA treatment (IR=78.8±7.7 mm Hg, IPC=18.8±6.6 mm Hg, IPC+MLA=46.3±8.6 mm Hg, p<0.05). IPC maintained mitochondrial structural complexity compared to IR (C=65±6% of total mitochondria, IPC=61±5%, IR=32±4%, p<0.01). MLA reduced the effect of IPC on ψM in intact mitochondria to IR levels (IR=67±10% of intact population, IPC=88±3%, IPC+MLA=71±4%, p<0.01).ConclusionsSignaling through the a7nAChR is necessary for the effect of IPC on maintaining ψM and cardiac contractile function after IR injury.

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Reperfusion at reduced flow rates enhances postischemic contractile recovery of perfused heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.268.6.h2384 ◽

1995 ◽

Vol 268 (6) ◽

pp. H2384-H2395 ◽

Cited By ~ 4

Author(s):

S. Takeo ◽

J. X. Liu ◽

K. Tanonaka ◽

Y. Nasa ◽

K. Yabe ◽

...

Keyword(s):

Flow Rate ◽

Diastolic Pressure ◽

Contractile Function ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Cardiac Contractile Function ◽

Triphenyltetrazolium Chloride ◽

Perfused Heart ◽

Flow Rates ◽

Reduced Flow

The effects of reperfusion at reduced flow rates on postischemic cardiac contractile function were examined in perfused rat hearts. Isolated hearts were subjected to 35-min ischemia followed by reperfusion at the preischemic flow rate (9.0 ml.g-1.min-1; ordinary flow rate) or at reduced flow rates (0.9-8.1 ml.g-1.min-1). Reperfusion at ordinary flow rate did not generate any left ventricular developed pressure (LVDP), whereas reperfusion at reduced flow rates (0.9-7.2 ml.g-1.min-1) elicited 13-57% of initial contractile force at reperfusion's end; optimal recovery occurred at 3.6 ml.g-1.min-1 (reduced flow rate). Reduced flow rate reperfusion attenuated ischemia-reperfusion-induced increase in left ventricular end-diastolic pressure (LVEDP) and perfusion pressure (PP), alteration in tissue Na+, K+, Ca2+, and Mg2+, release of creatine kinase and ATP metabolites, and development of triphenyltetrazolium chloride-unstained areas. Enhanced postischemic LVDP recovery was inversely related to higher coronary PP at the initial stage (4 min) of reperfusion (r = -0.763). The benefit of reduced flow rate reperfusion could not be attributed to rate of calcium delivery to the heart, formation of oxygen free radicals in myocardium, endothelium-dependent coronary artery dilation, or LVDEP reduction. Enhancement of postischemic LVDP recovery was associated with attenuation of ischemia-reperfusion-induced increases in myocardial sodium and calcium; failure of postischemic LVDP recovery was accompanied by an increase. Reduction in sodium and calcium overload may underlie the beneficial effects of reduced flow rate reperfusion in ischemic-reperfused heart.

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AT1-receptor blockade enhances ischemic preconditioning in hypertrophied rat myocardium

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.277.6.h2482 ◽

1999 ◽

Vol 277 (6) ◽

pp. H2482-H2487 ◽

Cited By ~ 3

Author(s):

Karyn L. Butler ◽

Alice H. Huang ◽

Judith K. Gwathmey

Keyword(s):

Ischemic Preconditioning ◽

Contractile Function ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Heart Weight ◽

Rat Myocardium ◽

Sprague Dawley ◽

Isolated Hearts ◽

Sd Rats ◽

Developed Pressure

The purpose of this study was to determine whether ischemic preconditioning protects contractile function in hypertrophied rat myocardium from ischemia-reperfusion (I/R) injury. Male salt-sensitive rats were fed a high-salt diet for 2 wk to induce myocardial hypertrophy. Nonhypertrophied hearts were obtained from age-matched Sprague-Dawley (SD) rats fed a regular diet. Heart weight-to-body weight ratios were higher in salt-sensitive rats than in SD rats (6.9 ± 0.2 vs. 4.7 ± 0.2 g/kg, P < 0.01). A second group of salt-sensitive and SD rats was administered losartan (10 mg ⋅ kg−1 ⋅ day−1), an AT1-receptor blocker, for 1 wk before the study. Isolated hearts were preconditioned with transient ischemia before global I/R. After I/R, preconditioned hypertrophied hearts exhibited greater recovery of left ventricular developed pressure compared with that of preconditioned normal hearts (73 ± 8 vs. 18 ± 8%, P < 0.01). Left ventricular developed pressure was further enhanced by losartan in both hypertrophied and normal myocardium (99 ± 5 vs. 73 ± 8%, P < 0.05 and 97 ± 15 vs. 18 ± 8%, P < 0.01). Hypertrophied rat myocardium can be protected from I/R-induced contractile dysfunction by ischemic preconditioning. Losartan improves the ischemic tolerance of normal and hypertrophied myocardium.

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Role of endogenous testosterone in myocardial proinflammatory and proapoptotic signaling after acute ischemia-reperfusion

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00784.2004 ◽

2005 ◽

Vol 288 (1) ◽

pp. H221-H226 ◽

Cited By ~ 70

Author(s):

Meijing Wang ◽

Ben M. Tsai ◽

Ajay Kher ◽

Lauren B. Baker ◽

G. Mathenge Wairiuko ◽

...

Keyword(s):

P38 Mapk ◽

Functional Recovery ◽

Caspase 3 ◽

Diastolic Pressure ◽

Contractile Function ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Acute Ischemia ◽

Caspase 1 ◽

Tnf Α

Myocardial ischemia is the leading cause of death in both men and women; however, very little information exists regarding the effect of testosterone on the response of myocardium to acute ischemic injury. We hypothesized that testosterone may exert deleterious effects on myocardial inflammatory cytokine production, p38 MAPK activation, apoptotic signaling, and myocardial functional recovery after acute ischemia-reperfusion (I/R). To study this, isolated, perfused rat hearts (Langendorff) from adult males, castrated males, and males treated with a testosterone receptor blocker (flutamide) were subjected to 25 min of ischemia followed by 40 min of reperfusion. Myocardial contractile function (left ventricular developed pressure, left ventricular end-diastolic pressure, positive and negative first derivative of pressure) was continuously recorded. After reperfusion, hearts were analyzed for expression of tissue TNF-α, IL-1β, and IL-6 (ELISA) and activation of p38 MAPK, caspase-1, caspase-3, caspase-11, and Bcl-2 (Western blot). All indices of postischemic myocardial functional recovery were significantly higher in castrated males or flutamide-treated males compared with untreated males. After I/R, castrated male and flutamide-treated male hearts had decreased TNF-α, IL-1β, and IL-6; decreased activated p38 MAPK; decreased caspase-1, caspase-3, and caspase-11; and increased Bcl-2 expression compared with untreated males. These results show that blocking the testosterone receptor (flutamide) or depleting testosterone (castration) in normal males improves myocardial function after I/R. These effects may be attributed to the proinflammatory and/or the proapoptotic properties of endogenous testosterone. Further understanding may allow therapeutic manipulation of sex hormone signaling mechanisms in the treatment of acute I/R.

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Lipid peroxidation contributes to cardiac deficits after ischemia and reperfusion of the small bowel

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1993.264.5.h1686 ◽

1993 ◽

Vol 264 (5) ◽

pp. H1686-H1692 ◽

Cited By ~ 2

Author(s):

J. W. Horton ◽

D. J. White

Keyword(s):

Lipid Peroxidation ◽

Contractile Function ◽

Ischemia Reperfusion ◽

Left Ventricular Pressure ◽

Left Ventricular ◽

Cardiac Contractile Function ◽

Langendorff Preparation ◽

Cardiac Contractile ◽

Intestinal Ischemia Reperfusion

Our previous studies showed that intestinal ischemia-reperfusion (IR) impairs cardiac contractile function. The present study examined the contribution of oxygen free radicals and lipid peroxidation of cardiac cell membrane to cardiac dysfunction after intestinal IR in a rat model of superior mesenteric artery (SMA) occlusion (atraumatic clip for 20 min) and collateral arcade ligation. Controls were sham operated (group 1, n = 25). In group 2, 30 rats with SMA occlusion were killed 3-4 h after reperfusion without treatment. Aminosteroid (U-74389F), a pharmacological agent known to inhibit lipid peroxidation of membranes, was given 1 min before occlusion of the SMA (group 3, n = 19). All rats were killed 3-4 h after reperfusion of the ischemic intestine, and the hearts were harvested for in vitro assessment of cardiac function (Langendorff preparation). Cardiac contractile depression occurred in the untreated group as indicated by a fall in left ventricular pressure (from 76 +/- 3 to 64 +/- 3 mmHg, P = 0.01), maximum +dP/dt (from 1,830 +/- 60 to 1,577 +/- 64 mmHg/s, P = 0.05), and maximum -dP/dt (from 1,260 +/- 50 to 950 +/- 60 mmHg/s, P = 0.005). Lipid peroxidation of cardiac membranes occurred after untreated IR as indicated by the rise in cardiac malondialdehyde levels (MDA) (from 0.203 +/- 0.046 to 0.501 +/- 0.044 nM/mg protein, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

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Glibenclamide improves postischemic recovery of myocardial contractile function in trained and sedentary rats

Journal of Applied Physiology ◽

10.1152/jappl.2001.91.4.1545 ◽

2001 ◽

Vol 91 (4) ◽

pp. 1545-1554 ◽

Cited By ~ 18

Author(s):

Korinne N. Jew ◽

Russell L. Moore

Keyword(s):

Contractile Function ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Treadmill Running ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Diastolic Stiffness ◽

Pressure Development ◽

Increased Sensitivity ◽

Developed Pressure

In this study, we sought to determine whether there was any evidence for the idea that cardiac ATP-sensitive K+ (KATP) channels play a role in the training-induced increase in the resistance of the heart to ischemia-reperfusion (I/R) injury. To do so, the effects of training and an KATP channel blocker, glibenclamide (Glib), on the recovery of left ventricular (LV) contractile function after 45 min of ischemia and 45 min of reperfusion were examined. Female Sprague-Dawley rats were sedentary (Sed; n = 18) or were trained (Tr; n = 17) for >20 wk by treadmill running, and the hearts from these animals used in a Langendorff-perfused isovolumic LV preparation to assess contractile function. A significant increase in the amount of 72-kDa class of heat shock protein was observed in hearts isolated from Tr rats. The I/R protocol elicited significant and substantial decrements in LV developed pressure (LVDP), minimum pressure (MP), rate of pressure development, and rate of pressure decline and elevations in myocardial Ca2+ content in both Sed and Tr hearts. In addition, I/R elicited a significant increase in LV diastolic stiffness in Sed, but not Tr, hearts. When administered in the perfusate, Glib (1 μM) elicited a normalization of all indexes of LV contractile function and reductions in myocardial Ca2+content in both Sed and Tr hearts. Training increased the functional sensitivity of the heart to Glib because LVDP and MP values normalized more quickly with Glib treatment in the Tr than the Sed group. The increased sensitivity of Tr hearts to Glib is a novel finding that may implicate a role for cardiac KATP channels in the training-induced protection of the heart from I/R injury.

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Direct cardiac versus systemic effects of inorganic nitrite on human left ventricular function

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00081.2021 ◽

2021 ◽

Author(s):

Kevin O'Gallagher ◽

Ana R Cabaco ◽

Matthew Ryan ◽

Ali Roomi ◽

Haotian Gu ◽

...

Keyword(s):

Diastolic Function ◽

Sodium Nitrite ◽

Diastolic Pressure ◽

Contractile Function ◽

Systolic Function ◽

Left Ventricular ◽

Lv Function ◽

Cardiac Contractile Function ◽

Lv Systolic Function ◽

Lv Diastolic Function

Background Inorganic nitrite generates nitric oxide (NO) in vivo and is considered a potential therapy in settings where endogenous NO bioactivity is reduced and left ventricular (LV) function impaired. However, the effects of nitrite on human cardiac contractile function, and the extent to which these are direct or indirect, are unclear. Methods and Results We studied 40 patients undergoing diagnostic cardiac catheterisation who had normal LV systolic function and were not found to have obstructive coronary disease. They received either an intracoronary sodium nitrite infusion (8.7-26 mmol/min, n=20) or an intravenous sodium nitrite infusion (50 mg/kg/min, n=20). LV pressure-volume relations were recorded. The primary end point was LV end-diastolic pressure (LVEDP) while secondary end points included indices of LV systolic and diastolic function. Intracoronary nitrite infusion induced a significant reduction in LVEDP, LV end-diastolic pressure-volume relationship (EDPVR) and the time to LV end-systole (LVEST) but had no significant effect on measures of LV systolic function or systemic haemodynamics. Intravenous nitrite infusion induced greater effects, with significant decreases in LVEDP, EDPVR, LVEST, LV dP/dtmin, tau, and mean arterial pressure. Conclusions These results indicate that inorganic nitrite has modest direct effects on human LV diastolic function, independent of LV loading conditions and without affecting LV systolic properties. The systemic administration of nitrite has larger effects on LV diastolic function which are related to reduction in both preload and afterload. These effects of inorganic nitrite indicate a favourable profile for conditions characterized by LV diastolic dysfunction, e.g. heart failure with preserved ejection fraction.

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Abstract 2316: Ranolazine, a Late Sodium Current Inhibitor, as an Adjunct to Cardioplegia Further Reduces Contracture during Ischemia and Reperfusion

Circulation ◽

10.1161/circ.118.suppl_18.s_705-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Hyosook Hwang ◽

Joseph M Arcidi ◽

Sharon L Hale ◽

Boris Z Simkhovich ◽

Luiz Belardinelli ◽

...

Keyword(s):

Therapeutic Potential ◽

Diastolic Pressure ◽

Contractile Function ◽

Sodium Current ◽

Protective Role ◽

Pressure Curve ◽

Sprague Dawley ◽

Cardiac Contractile Function ◽

Antianginal Agent ◽

Developed Pressure

Although cardioplegia (CP) protects myocardium during ischemic cardiac arrest, cardioplegic preservation can be suboptimal for increasingly complex cardiac surgical patients. Ranolazine (Ran), a novel antianginal agent, was recently shown to mitigate ischemia-induced Ca 2+ overload via its inhibitory effects on the late Na + current, but the benefit of Ran during cardioplegic arrest is not known. The purpose of the study was to investigate the therapeutic potential of Ran as an adjunct to CP. Hearts isolated from female Sprague-Dawley rats were Langendorff-perfused and exposed to normothermic global ischemia for 40 min followed by 30-min reperfusion (I/R). Three groups were studied: control buffer (n = 10); crystalloid CP (Fremes, n = 12); CP supplemented with Ran (n = 12). CP was bolus-injected with or without Ran at the time of ischemia. End-diastolic pressure (EDP), developed pressure, dP/dt min , and dP/dt max were measured throughout the study. CP significantly delayed onset of ischemic contracture (defined as a time to 20 mmHg of EDP), compared to control (25 ± 2 min in CP alone vs. 12 ± 1 min in control, p < 0.05). Ran added to CP further delayed the time to contracture (34 ± 2 min in Ran, p < 0.05 compared to CP alone). Consistent with these findings, the area under the diastolic pressure curve during the entire period of ischemia was significantly smaller in CP + Ran versus CP alone (p < 0.05). I/R caused dramatic elevations in EDP during reperfusion. CP lessened the extent of the reperfusion contracture (32 ± 3 mmHg in CP alone vs. 76 ± 3 mmHg in control, p < 0.05). Addition of Ran to CP further lessened the contracture (17 ± 2 mmHg in Ran, p < 0.05 compared to CP alone). I/R severely depressed systolic cardiac contractile function. The impairment in contractile function was significantly reduced by CP, as well as CP + Ran, but there was no statistical difference between the two groups. While CP alone reduced the onset of cardiac contracture in this model of I/R, addition of Ran to CP further enhanced the cardioprotection. These results suggest the potential therapeutic efficacy of Ran as an adjunct to CP and further support the protective role of late Na + current inhibition.

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Effects of exercise training on contractile function in myocardial trabeculae after ischemia-reperfusion

Journal of Applied Physiology ◽

10.1152/japplphysiol.00850.2004 ◽

2005 ◽

Vol 99 (1) ◽

pp. 230-236 ◽

Cited By ~ 10

Author(s):

Hyosook Hwang ◽

Peter J. Reiser ◽

George E. Billman

Keyword(s):

Exercise Training ◽

Diastolic Pressure ◽

Contractile Function ◽

Isometric Force ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Aerobic Exercise Training ◽

Protective Effects ◽

Shortening Velocity ◽

Cross Sectional

Potential protective effects of aerobic exercise training on the myocardium, before an ischemic event, are not completely understood. The purpose of the study was to investigate the effects of exercise training on contractile function after ischemia-reperfusion (Langendorff preparation with 15-min global ischemia/30-min reperfusion). Trabeculae were isolated from the left ventricles of both sedentary control and 10- to 12-wk treadmill exercise-trained rats. The maximal normalized isometric force (force/cross-sectional area; Po/CSA) and shortening velocity ( Vo) in isolated, skinned ventricular trabeculae were measured using the slack test. Ischemia-reperfusion induced significant contractile dysfunction in hearts from both sedentary and trained animals; left ventricular developed pressure (LVDP) and maximal rates of pressure development and relaxation (±dP/d tmax) decreased, whereas end-diastolic pressure (EDP) increased. However, this dysfunction (as expressed as percent change from the last 5 min before ischemia) was attenuated in trained myocardium [LVDP: sedentary −60.8 ± 6.4% (32.0 ± 5.5 mmHg) vs. trained −15.6 ± 8.6% (64.9 ± 6.6 mmHg); +dP/d tmax: sedentary −54.1 ± 4.7% (1,058.7 ± 124.2 mmHg/s) vs. trained −16.7 ± 8.4% (1,931.9 ± 188.3 mmHg/s); −dP/d tmax: sedentary −44.4 ± 2.5% (−829.3 ± 52.0 mmHg/s) vs. trained −17.9 ± 7.2% (−1,341.3 ± 142.8 mmHg/s); EDP: sedentary 539.5 ± 147.6%; (41.3 ± 6.0 mmHg) vs. trained 71.6 ± 30.6%; 11.4 ± 1.2 mmHg]. There was an average 26% increase in Po/CSA in trained trabeculae compared with sedentary controls, and this increase was not affected by ischemia-reperfusion. Ischemia-reperfusion reduced V0 by 39% in both control and trained trabeculae. The relative amount of the β-isoform of myosin heavy chain (MHC-β) was twofold greater in trained trabeculae as well as in the ventricular free walls. Despite a possible increase in the economy in the trained heart, presumed from a greater amount of MHC-β, ischemia-reperfusion reduced Vo, to a similar extent in both control and trained animals. Nevertheless, the trained myocardium appears to have a greater maximum force-generating ability that may, at least partially, compensate for reduced contractile function induced by a brief period of ischemia.

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Energy-linked functional alterations in experimental cardiomyopathies

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1991.261.4.l39 ◽

1991 ◽

Vol 261 (4) ◽

pp. L39-L44 ◽

Cited By ~ 1

Author(s):

V. I. Kapelko ◽

V. I. Veksler ◽

M. I. Popovich ◽

R. Ventura-Clapier

Keyword(s):

Diastolic Pressure ◽

Contractile Function ◽

High Energy ◽

Left Ventricular ◽

High Energy Phosphates ◽

Phosphate Content ◽

High Energy Phosphate ◽

Cardiac Contractile Function ◽

Myocardial Stiffness ◽

Cardiac Contractile

Changes in high-energy phosphate content and cardiac contractile function of isolated rat hearts as well as changes in Ca2+ sensitivity and mitochondrial respiration of myocardial skinned fibers were assessed in hereditary cardiomyopathies and in cardiomyopathies induced by chronic treatment with adriamycin or norepinephrine, by autoimmunization, by diabetes, or by creatine deficiency. The sum of ATP and phosphocreatine contents as well as cardiac output at standard load conditions was substantially lower in almost all groups. The common features of cardiac pump failure were mild bradycardia, elevated left ventricular (LV) diastolic pressure, and stiffness that limited cardiac contractile adaptation to volume or resistance loads. The LV diastolic stiffness at maximal functional load was inversely correlated with high-energy phosphate content. Increased myofibrillar sensitivity to Ca2+ and defective function of mitochondrial creatine kinase were found in skinned myocardial fibers. These results suggested that both increased myofibrillar Ca2+ sensitivity and energy deficiency within myofibrils may contribute to increased myocardial stiffness. Increased stiffness limits LV filling but facilitates pressure development, which partly compensates for decreased contractility of cardiomyopathic hearts. cardiac contractile function; high-energy phosphates; isolated heart; myocardial stiffness

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