Reduced Efficacy of Volatile Anesthetic Preconditioning with Advanced Age in Isolated Rat Myocardium

2004 ◽  
Vol 100 (3) ◽  
pp. 589-597 ◽  
Author(s):  
Roman Sniecinski ◽  
Hong Liu
Keyword(s):  
Young Adult ◽  
Ischemic Preconditioning ◽  
Age Groups ◽  
Left Ventricular ◽  
Aged Rats ◽  
Middle Aged ◽  
Beneficial Effects ◽  
Anesthetic Preconditioning ◽  
Intracellular Ca ◽  
Developed Pressure

Background Ischemic preconditioning and anesthetic preconditioning (APC) are reported to decrease myocardial infarct size during ischemia-reperfusion injury. However, the beneficial effects of ischemic preconditioning have been shown to decrease with advancing age. Although the mechanisms of ischemic preconditioning and APC are thought to be similar, it is not known whether the beneficial effects of APC are also reduced in the aged myocardium. Methods Male Fischer 344 rats of three age groups (2-4, 10-12, and 20-24 months) were used. Hearts were Langendorff perfused. Six hearts in each age group were pretreated with 10 min of sevoflurane and a 5-min washout before 25 min of ischemia and 60 min of reperfusion. Six control hearts in each age group received no treatment before ischemia. Nuclear magnetic resonance was used to measure intracellular Na, intracellular Ca, and intracellular pH, respectively. Left ventricular developed pressure, creatine kinase, and infarct size were measured. Results Ischemia decreases intracellular pH and increases intracellular Na and intracellular Ca in all age groups. APC blunts the pH decreases in young adult and middle-aged rats, but not in aged rats. APC decreased intracellular Na and intracellular Ca accumulation during ischemia in young adult and middle-aged hearts. APC improved adenosine triphosphate recovery in young rats but not in aged rats. Creatine kinase and infarct sizes were significantly reduced and left ventricular developed pressure was improved with APC in the young adult and middle-aged groups but not the aged group. Conclusions The benefits of APC are significantly reduced with advanced age in an isolated rat heart model.

Local delivery of PKCε-activating peptide mimics ischemic preconditioning in aged hearts through GSK-3β but not F1-ATPase inactivation

2007 ◽  
Vol 293 (4) ◽  
pp. H2056-H2063 ◽  
Author(s):  
Donna H. Korzick ◽  
John C. Kostyak ◽  
J. Craig Hunter ◽  
Kurt W. Saupe
Keyword(s):  
Ischemic Preconditioning ◽  
Local Delivery ◽  
Left Ventricular ◽  
Aged Rats ◽  
Adult Rats ◽  
Gsk 3Β ◽  
Developed Pressure ◽  
Sb 216763 ◽  
First Time ◽  
Perfused Hearts

In adult heart, selective PKCε activation limits ischemia (I)-reperfusion (R) damage and mimics the protection associated with ischemic preconditioning. We sought to determine whether local delivery of PKCε activator peptide ψε-receptor for activated C-kinase (ψε-RACK) is sufficient to produce a similarly protected phenotype in aged hearts. Langendorff-perfused hearts isolated from adult (5 mo; n = 9) and aged (24 mo; n = 9) male Fisher 344 rats were perfused with ψε-RACK conjugated to Tat (500 nM) or Tat only (500 nM) for 10 min before global 31-min ischemia. Western blotting was used to measure mitochondrial targeting of PKCε, PKCδ, phospho (p)-GSK-3β (Ser9) and GSK-3β in hearts snap-frozen during I. Recovery of left ventricular developed pressure was significantly improved by ψε-RACK ( P < 0.01) and infarct size reduced in 24-mo rats vs. age-matched controls (60% vs. 34%; P < 0.01). Mitochondrial PKCε levels were 30% greater during I with ψε-RACK in aged vs. control rats ( P < 0.01). Interestingly, mitochondrial GSK-3β levels were threefold greater in aged vs. adult rats during I, and ψε-RACK prevented this increase ( P < 0.01). Mitochondrial p-GSK-3β levels were also greater in aged rats after ψε-RACK ( P < 0.01), and subsequent inhibition of GSK-3β with SB-216763 (3 μM) before I/R elicited protection similar to that of ψε-RACK ( n = 3/group). Mitochondrial proteomic analysis further identified group differences in the F1-ATPase β-subunit, and coimmunoprecipitation studies revealed a novel interaction with PKCε. F1-ATPase-PKCε association was affected by ψε-RACK in adult but not aged rats. Our results provide evidence, for the first time, for PKCε-mediated protection in aged rat heart after I/R and suggest a central role for mitochondrial GSK-3β but not F1-ATPase as a potential target of PKCε to limit I/R damage with aging.

Testosterone-augmented contractile responses to α1- and β1-adrenoceptor stimulation are associated with increased activities of RyR, SERCA, and NCX in the heart

2009 ◽  
Vol 296 (4) ◽  
pp. C766-C782 ◽  
Author(s):  
Sharon Tsang ◽  
Stanley S. C. Wong ◽  
Song Wu ◽  
Gennadi M. Kravtsov ◽  
Tak-Ming Wong
Keyword(s):  
Ventricular Myocytes ◽  
Left Ventricular ◽  
Contractile Responses ◽  
Adrenoceptor Antagonist ◽  
Cardiac Contractile ◽  
Plasmic Reticulum ◽  
Adrenoceptor Agonist ◽  
Intracellular Ca ◽  
Developed Pressure ◽  
Stimulation Of

We hypothesized that testosterone at physiological levels enhances cardiac contractile responses to stimulation of both α1- and β1-adrenoceptors by increasing Ca2+ release from the sarcoplasmic reticulum (SR) and speedier removal of Ca2+ from cytosol via Ca2+-regulatory proteins. We first determined the left ventricular developed pressure, velocity of contraction and relaxation, and heart rate in perfused hearts isolated from control rats, orchiectomized rats, and orchiectomized rats without and with testosterone replacement (200 μg/100 g body wt) in the presence of norepinephrine (10−7 M), the α1-adrenoceptor agonist phenylephrine (10−6 M), or the nonselective β-adrenoceptor agonist isoprenaline (10−7 M) in the presence of 5 × 10−7 M ICI-118,551, a β2-adrenoceptor antagonist. Next, we determined the amplitudes of intracellular Ca2+ concentration transients induced by electrical stimulation or caffeine, which represent, respectively, Ca2+ release via the ryanodine receptor (RyR) or releasable Ca2+ in the SR, in ventricular myocytes isolated from the three groups of rats. We also measured 45Ca2+ release via the RyR. We then determined the time to 50% decay of both transients, which represents, respectively, Ca2+ reuptake by sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and removal via the sarcolemmal Na+/Ca2+ exchanger (NCX). We correlated Ca2+ removal from the cytosol with activities of SERCA and its regulator phospholamban as well as NCX. The results showed that testosterone at physiological levels enhanced positive inotropic and lusitropic responses to stimulation of α1- and β1-adrenoceptors via the androgen receptor. The increased contractility and speedier relaxation were associated with increased Ca2+ release via the RyR and faster Ca2+ removal out of the cytosol via SERCA and NCX.

scholarly journals Sex-related effects on diabetes-induced alterations in calcium release in the rat heart

2007 ◽  
Vol 293 (6) ◽  
pp. H3584-H3592 ◽  
Author(s):  
Nazmi Yaras ◽  
Erkan Tuncay ◽  
Nuhan Purali ◽  
Babur Sahinoglu ◽  
Guy Vassort ◽  
...  
Keyword(s):  
Calcium Release ◽  
Binding Protein ◽  
Ryanodine Receptors ◽  
Left Ventricular ◽  
Adult Rats ◽  
Fk506 Binding Protein ◽  
Pressure Development ◽  
Spatiotemporal Parameters ◽  
Intracellular Ca ◽  
Developed Pressure

The present study was designed to determine whether the properties of local Ca2+ release and its related regulatory mechanisms might provide insight into the role of sex differences in heart functions of control and streptozotocin-induced diabetic adult rats. Left ventricular developed pressure, the rates of pressure development and decay (±dP/d t), basal intracellular Ca2+ level ([Ca2+]i), and spatiotemporal parameters of [Ca2+]i transients were found to be similar in male and female control rats. However, spatiotemporal parameters of Ca2+ sparks in cardiomyocytes isolated from control females were significantly larger and slower than those in control males. Diabetes reduced left ventricular developed pressure to a lower extent in females than in males, and the diabetes-induced depressions in both +dP/d t and −dP/d t were less in females than in males. Diabetes elicited a smaller reduction in the amplitude of [Ca2+]i transients in females than in males, a smaller reduction in sarcoplasmic reticulum-Ca2+ load, and less increase in basal [Ca2+]i. Similarly, the elementary Ca2+ events and their control proteins were clearly different in both sexes, and these differences were more marked in diabetes. Diabetes-induced depression of the Ca2+ spark amplitude was significantly less in females than in matched males. Levels of cardiac ryanodine receptors (RyR2) and FK506-binding protein 12.6 in control females were significantly higher than those shown in control males. Diabetes induced less RyR2 phosphorylation and FK506-binding protein 12.6 unbinding in females. Moreover, total and free sulfhydryl groups were significantly less reduced, and PKC levels were less increased, in diabetic females than in diabetic males. The present data related to local Ca2+ release and its related proteins describe some of the mechanisms that may underlie sex-related differences accounting for females to have less frequent development of cardiac diseases.

Abstract 067: Long-Term Ivabradine Treatment Does Not Preserve Myocardial Perfusion and Coronary Reserve in Middle-Aged Rats with Large Myocardial Infarction

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Eduard I Dedkov ◽  
Yevgen Bogatyryov ◽  
Daniela McCooey ◽  
Lance P Christensen ◽  
Robert J Tomanek
Keyword(s):  
Myocardial Perfusion ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Coronary Perfusion ◽  
Free Wall ◽  
Aged Rats ◽  
Middle Aged ◽  
Perfusion Reserve ◽  
Coronary Conductance

Background: We have previously shown that 1-month treatment with ivabradine (IVA), the selective cardiac pacemaker I f current inhibitor, preserved myocardial perfusion and coronary perfusion reserve in post-MI middle-aged rats. However, the persistence of this cardioprotective effect after a prolonged period of IVA treatment remains to be determined. Methods: Acute MI was induced in 12-month-old male Sprague-Dawley rats by left coronary artery ligation. Twenty four hours later, the rats with a confirmed large transmural MI (>50% of the left ventricular (LV) free wall) were randomly assigned in two experimental groups. In a first group, rats were treated with IVA i.p. via osmotic pumps in a dose of 10.5 mg/kg/day for 3 months (MI+IVA). In a second group, rats received placebo treatment (5% dextrose) during the same time period (MI). Sham-operated rats served as an age-matched control. At the end of experimental period, myocardial perfusion (baseline and maximal coronary conductance per 100g of tissue) and coronary perfusion reserve (fold increase between baseline and maximal coronary conductance) were determined in non-infarcted LV free wall and interventricular septum by using the neutron-activated stable isotope-labeled microsphere technique. Results: During 3 months of IVA treatment, heart rate in MI+IVA rats was consistently reduced compared to untreated MI rats by mean of 30.6%. Nevertheless, we found that the infarct size and the extent of LV remodeling were relatively comparable between MI and MI+IVA rats three months after surgery. Moreover, the levels of baseline and maximal coronary conductance were similar in LV free wall and septum between two experimental groups. Consequently, IVA-treated rats revealed no difference in coronary perfusion reserve as compared to untreated post-MI animals (2.22±0.46 vs. 2.59±0.41 in LV free wall and 2.30±0.59 vs. 2.68±0.44 in septum, respectively). However, the rats of both post-MI groups had markedly reduced levels of maximal coronary blood flow as compared to non-infarcted controls (p≤0.01). Conclusion: Our data demonstrate that long-term IVA treatment does not provide sustainable improvement in LV myocardial perfusion and coronary perfusion reserve in middle-aged rats following large MI.

Protective effects of adenosine in the perfused rat heart: changes in metabolism and intracellular ion homeostasis

1993 ◽  
Vol 264 (4) ◽  
pp. C986-C994 ◽  
Author(s):  
T. A. Fralix ◽  
E. Murphy ◽  
R. E. London ◽  
C. Steenbergen
Keyword(s):  
Cell Injury ◽  
Recovery Of Function ◽  
Ion Homeostasis ◽  
High Energy ◽  
Left Ventricular ◽  
Protective Effects ◽  
Intracellular Ca ◽  
Developed Pressure ◽  
High Energy Phosphate Metabolism ◽  
Glycolytic Rate

Increased concentrations of intracellular H+, Na+, and Ca2+ have been observed during ischemia, and these ionic alterations have been correlated with several indexes of cell injury in a number of studies. Recently, adenosine was proposed to play a role in ischemic preconditioning, since adenosine antagonists block the protective effects of these brief intermittent periods of ischemia and reflow. In this study we evaluated the protective effects of adenosine (20 microM) on high-energy phosphate metabolism, H+ and Ca2+ accumulation, and glycolytic rate during 30 min of no-flow ischemia. Adenosine was observed to slow the onset of contracture (7.0 +/- 0.9 min) and to improve left ventricular developed pressure (62 +/- 7% of initial) during reperfusion compared with untreated hearts (5.0 +/- 0.6 min and 18 +/- 5%, respectively). Intracellular Ca accumulation at the end of 30 min of ischemia was higher in the untreated (2,835 +/- 465 nM) than in the adenosine-treated (2,064 +/- 533 nM) hearts, while intracellular pH fell more in the untreated (5.85 +/- 0.17) than in the adenosine-treated hearts (6.27 +/- 0.16). Glycolytic rate and the rate of ATP decline were significantly attenuated in the adenosine-treated hearts during ischemia. Thus adenosine treatment slowed the rate of metabolism and delayed the accumulation of H+ and Ca2+ during ischemia, resulting in better recovery of function upon reflow.

Lipoxygenase metabolism of arachidonic acid in ischemic preconditioning and PKC-induced protection in heart

1999 ◽  
Vol 276 (6) ◽  
pp. H2094-H2101 ◽  
Author(s):  
Weina Chen ◽  
Wayne Glasgow ◽  
Elizabeth Murphy ◽  
Charles Steenbergen
Keyword(s):  
Arachidonic Acid ◽  
Protective Effect ◽  
Ischemic Preconditioning ◽  
Rabbit Heart ◽  
Left Ventricular ◽  
Arachidonic Acid Metabolism ◽  
Developed Pressure ◽  
12 Lipoxygenase ◽  
Hydroperoxyeicosatetraenoic Acid ◽  
Pkc Activation

We tested the hypothesis that activation of the 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism contributes to the protective effect of protein kinase C (PKC) activation and ischemic preconditioning (PC), and we report, in perfused rat heart, that both PC and the PKC activator 1,2-dioctanoyl- sn-glycerol (DOG) confer a similar protective effect and stimulate a comparable accumulation of 12-LO metabolites. The 12-LO product, 12( S)-hydroxyeicosatetraenoic acid [12( S)-HETE], was increased in DOG-treated (22.8 ± 4.4 ng/g wet wt) and PC hearts (26.8 ± 5.5 ng/g wet wt) compared with control (13.8 ± 2.1 ng/g wet wt, P < 0.05), and this increase was blocked by 12-LO or PKC inhibitors. Both DOG pretreatment and PC improved recovery of left ventricular developed pressure (LVDP) nearly twofold after 20 min of ischemia; this improvement was blocked by 12-LO inhibitors and was mimicked by infusion of 12-hydroperoxyeicosatetraenoic acid [12( S)-HpETE; 67 ± 6% recovery of LVDP vs. 35 ± 3% for untreated hearts]. Also, the protection afforded by 12( S)-HpETE, as well as by PC, was attenuated by the K+-channel blocker 5-hydroxydecanoate, suggesting that the downstream mechanisms of 12( S)-HpETE-mediated protection are similar to PC. Furthermore, PC stimulates 12-LO metabolism in perfused rabbit heart, and 12-LO inhibition blocks PC-induced cardioprotection. Thus the data suggest that 12-LO metabolism plays an important role in cardioprotection.

Late-onset renal hypertension in old rats alters myocardial microvessels

1990 ◽  
Vol 259 (6) ◽  
pp. H1681-H1687 ◽  
Author(s):  
R. J. Tomanek ◽  
M. R. Aydelotte ◽  
C. A. Butters
Keyword(s):  
Late Onset ◽  
Renal Hypertension ◽  
Age Groups ◽  
Left Ventricular ◽  
Numerical Density ◽  
Middle Aged ◽  
Absolute Increase ◽  
The Mean ◽  
Microvascular Alterations ◽  
O2 Supply

We tested the hypothesis that late-onset hypertension in middle-aged (15 mo) and senescent (24 mo) rats would adversely affect the coronary microvasculature. Morphometric analyses were performed on coronary capillaries and arterioles from rats with one-kidney, figure-8 renal wrap hypertension of 3-mo duration. Compared with control rats, wall-to-lumen ratios of arterioles with lumen diameters less than 25 microns were higher in the two hypertensive groups by approximately 30%; larger arterioles did not show consistent intergroup differences. A comparison of the two control groups revealed that wall-to-lumen ratio of arterioles with lumen diameters less than 50 microns tended to be greater in the senescent rats. Capillary numerical density was markedly reduced in the hypertensive animals of both age groups and caused an increase in the mean Krough cylinder radius and in the mean capillary domain. The latter increased by 28-63%; the largest increment occurred in the endomyocardium of the senescent group. A trend toward increased heterogeneity of capillary spacing was also noted in the hypertensive rats. The observed microvascular alterations occurred in the absence of an absolute increase in left ventricular mass but in the presence of cardiocyte hypertrophy. Thus the decrements in capillary numerical density are not only due to inadequate growth but reflect an absolute reduction in the number of these vessels associated with cardiocyte loss. It is concluded that late-onset hypertension in middle-aged and senescent rats is characterized by left ventricular wall remodeling that includes microvascular alterations that would be expected to limit maximal myocardial flow and O2 supply to the cardiocyte.

Effect of aging on tracheal mucociliary clearance in beagle dogs

1987 ◽  
Vol 62 (3) ◽  
pp. 1331-1334 ◽  
Author(s):  
S. L. Whaley ◽  
B. A. Muggenburg ◽  
F. A. Seiler ◽  
R. K. Wolff
Keyword(s):  
Young Adult ◽  
Gamma Camera ◽  
Mucociliary Clearance ◽  
Age Groups ◽  
Beagle Dogs ◽  
Velocity Measurements ◽  
Middle Aged ◽  
Age Related ◽  
Age Related Changes ◽  
Made In

Tracheal mucous velocity measurements were made in 24 beagle dogs in five age groups, using a gamma camera to detect movement of instilled 99mTc-macroaggregated albumin. Age groups were defined as immature (9–10 mo), young adult (2.8–3.0 yr), middle aged (6.7–6.9 yr), mature (9.6–9.8 yr), and aged dogs (13.6–16.2 yr). Mean velocities were 3.6 +/- 0.4 (SE) mm/min in the immature dogs, 9.7 +/- 0.6 mm/min in the young adults, 6.9 +/- 0.5 mm/min in the middle-aged dogs, 3.5 +/- 0.8 mm/min in the mature dogs, and 2.9 +/- 0.5 mm/min in the aged dogs. Tracheal mucous velocity was significantly (P less than 0.05) greater in the young adult and middle-aged groups compared with the immature, mature, and aged dogs. This pattern of age-related changes was noted to be similar to age-related changes described for certain pulmonary function measurements.

Cardiac protection by mitoKATP channels is dependent on Akt translocation from cytosol to mitochondria during late preconditioning

2006 ◽  
Vol 290 (6) ◽  
pp. H2402-H2408 ◽  
Author(s):  
Nauman Ahmad ◽  
Yigang Wang ◽  
Khawaja Husnain Haider ◽  
Boyu Wang ◽  
Zeeshan Pasha ◽  
...  
Keyword(s):  
Cardiac Tissue ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Phosphatidylinositol 3 Kinase ◽  
Akt Phosphorylation ◽  
Beneficial Effects ◽  
Late Preconditioning ◽  
Phosphorylated Akt ◽  
Developed Pressure ◽  
Mitokatp Channels

This investigation elucidates the Akt/mitochondrial ATP-sensitive K+ (mitoKATP) channel signaling pathway in late pharmacological preconditioning, using the mitoKATP channel openers BMS-191095 (BMS) and diazoxide (DE). BMS (1 mg/kg ip) and DE (7 mg/kg ip) alone or BMS plus wortmannin (WTN, 15 μg/kg ip), an inhibitor of phosphatidylinositol 3-kinase, and BMS plus 5-hydroxydecanoic acid (5-HD, 5 mg/kg ip), an inhibitor of mitoKATP channels, were administered to male mice. Twenty-four hours later, hearts were isolated and subjected to 40 min of ischemia and 120 min of reperfusion via Langendorff's apparatus. Both BMS and DE reduced left ventricular end-diastolic pressure and increased left ventricular developed pressure as well as reduced LDH release. Coadministration of BMS and WTN abolished the beneficial effects of BMS on cardiac function. Moreover, BMS and DE accelerated Akt phosphorylation in cardiac tissue as determined by Western blot analysis and also significantly reduced apoptosis compared with ischemic control. WTN significantly suppressed BMS-induced Akt phosphorylation, whereas 5-HD had no effect on Akt phosphorylation in cytosol, and the effect of BMS on apoptosis was abolished. It is concluded that the cardioprotective effect by mitoKATP channels is attributed to the translocation of phosphorylated Akt from cytosol to mitochondria.

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