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Masato Tani
Nippon rinsho. Japanese journal of clinical medicine 05/2004; 62 Suppl 4:107-16.
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ABSTRACT: Ischemic preconditioning (PC) improves post-ischemic function, and heat shock (HS) mimics delayed PC in young animals. However, PC is not protective and the consequences of HS are not known in the aging hearts. This report examines the efficacy of HS and its synergy with PC in the middle-aged rat hearts. Hearts from 12- or 50-week-old rats were subjected to PC before 25 min ischemia followed by 30 min reperfusion 48 h after HS. HS induced HS proteins (HSP) in both age groups but that PC and HS translocated PKC-alpha and -delta only in young rats. The beneficial effects of HS and PC were additive and enhanced protein kinase C (PKC) translocation in young rats. However, neither HS alone nor in combination with PC conferred any functional advantage or accelerated PKC translocation in old rats. Similarly neither HS alone nor in combination with PC restore PC effects in old rats with impaired PKC activation, despite the induction of HSP, indicating that induction of HSP is insufficient for cytoprotection.
Experimental Gerontology 04/2003; 38(3):299-306. · 3.74 Impact Factor
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ABSTRACT: Opioids confer biphasic (early and late) cardioprotection against myocardial infarction by opening mitochondrial ATP-sensitive K(+) channels. It is unknown whether cyclooxygenase-2 (COX-2), which mediates ischemia-induced late preconditioning, also mediates opioid-induced cardioprotection. Isolated perfused rat hearts were subjected to 20 min of global ischemia followed by 20 min of reperfusion. BW-373U86 (BW), a delta-opioid receptor agonist, was administered 1, 12, or 24 h before death. Recovery of left ventricular developed pressure (LVDP) after ischemia-reperfusion improved when BW was administered 1 or 24 h before ischemia (control: 57 +/- 8, BW 1 h: 75 +/- 5, BW 24 h: 85 +/- 6%) but not when it was administered 12 h before (60 +/- 5%). Levels of 6-keto-PGF(1alpha) (a stable metabolite of PGI(2)) in coronary effluent after 20 min of reperfusion were higher with 24-h BW pretreatment than in controls (1,053 +/- 92 vs. 724 +/- 81 pg/ml), whereas 6-keto-PGF(1alpha) levels at baseline did not differ. Administration of a selective COX-2 inhibitor, NS-398, abolished the late phase of cardioprotection (recovery of LVDP, 53 +/- 8%) and attenuated the increase in PGI(2) (706 +/- 138 pg/ml) but did not block the early phase of cardioprotection. The selective COX-1 inhibitor SC-560 did not affect either phase of protection. Western immunoblotting revealed upregulation of PGI(2) synthase protein 24 h after BW administration without changes in COX-1 and COX-2 protein levels. In conclusion, the late (but not the early) phase of delta-opioid receptor-induced preconditioning is mediated by COX-2. A functional coupling between COX-2 and upregulated PGI(2) synthase appears to underlie this cardioprotective phenomenon in the rat.
AJP Heart and Circulatory Physiology 01/2003; 283(6):H2534-43. · 3.71 Impact Factor
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ABSTRACT: Hypoxic preconditioning (HP) does not improve post-ischemic function in the hearts of aging rats secondary to failure of protein kinase C (PKC) activation, but the effect of heat shock (HS) or preconditioning has not been studied. We studied whether HS increases tolerance to ischemia and whether its combination with HP would restore the cardioprotective effect in aging rat hearts. HS was performed in 12- and 50-week-old rats. Hearts were isolated and subjected to HP by 10 min hypoxic perfusion before 25 min ischemia followed by 30 min reperfusion 48 h after HS. Both HP and HS improved recovery of left ventricular function with translocation of PKC-delta from the cytosol to the nuclear fraction and induction of heat shock proteins, HSP27, HSP70, and alphaB-crystallin. The combination of HS and HP enhanced the translocation of PKC-delta in young rats, resulting in further improvement in functional recovery. In older rats, HP translocated PKC-delta from the membrane to the cytosol fraction, but did not improve functional recovery, although the combination of HS with HP induced HS proteins and translocated PKC-delta from the cytosol to the nuclear fraction. HS provided cardioprotection and had additive effects to HP with additional PKC-delta activation in young rats. However, in hearts from aging rats, HS alone was not cardioprotective, nor was its combination with HP, despite the induction of HS proteins and the activation of PKC-delta, resulting in its translocation to the nuclear fraction.
Archiv für Kreislaufforschung 12/2002; 97(6):489-95. · 7.35 Impact Factor
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ABSTRACT: Rat cardiomyocytes were exposed to H2O2 (1–100 μmol/L) for 10 min with washout for 10 min. Intracellular Ca2+ concentration ([Ca2+]i) was measured using fluo-3. [Ca2+]i increased with 100 μmol/L H2O2 and further increased during washout, causing irreversible contracture in one-half of the cells. The increase in [Ca2+]i with 10 μmol/L H2O2 was modest with few cells showing irreversible contracture and attenuated by caffeine, and [Ca2+]i gradually decreased during washout and this decrease was accelerated by a calcium-free solution, while 1 μmol/L H2O2 did not have any effects on [Ca2+]i or cell viability. Ca2+ overload caused during exposure to 100 μmol/L H2O2 was attenuated by caffeine with improved cellular viability but not by chelerythrine, KB-R7943 or nifedipine. With 100 μmol/L
H2O2 calcium-free solution attenuated the increase during exposure and washout while KB-R7943 or chelerythrine partly attenuated
further increase during washout but not improved cell viability, but chelerythrine did not have additional effect on calcium-free
treatment. Catalase abolished the effects of H2O2. We concluded that the increased [Ca2+]i during exposure to 100 μmol/L H2O2 was caused both by release of Ca2+ from the intracellular store sites including the sarcoplasmic reticulum and by influx through route(s) other than the voltage-dependent
Ca2+ channels or Na+/Ca2+ exchanger, although the Na+/Ca2+ exchanger or protein kinase C-mediated mechanism was partly responsible for a further increase during washout.
Archiv für Kreislaufforschung 11/2001; 96(6):623-629. · 7.35 Impact Factor
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ABSTRACT: Some animal studies indicate that ischemic tolerance is decreased in the senescent myocardium. However, the results of cardiac
operations in the elderly are compatible with those performed in middle-aged people. It is important to determine whether
ischemic tolerance may be decreased in middle age. Hearts from young adult (12 weeks old) or the middle-aged (50 weeks old)
Fischer 344 rats were subjected to 15, 20, or 25 minutes of global ischemia followed by reperfusion. The recovery of left
ventricular function and high-energy phosphates was significantly lower in the hearts of middle-aged rats than in those of
the young adult rats after any period of global ischemia. The increase in left ventricular end-diastolic pressure was also
greater in the middle-aged rats, although there were no diferences in these indexes in the two age groups before the induction
of ischemia. The incidence of reperfusion-induced ventricular fibrillation was significantly higher and the release of creatine
kinase in the coronary effluent during reperfusion significantly greater in the middle-aged rats than in the young adult rats.
Results indicate that rat hearts are more vulnerable to ischemia, even in middle age.
12/1997: pages 461-471;
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ABSTRACT: Objectives: We previously reported that a brief period of hypoxic perfusion (BHP) prior to ischemia in rat hearts improved functional recovery upon reperfusion with reduced Ca2+ overload. The present study was designed to determine whether the effect of BHP would be associated with a reduction in reperfusion arrhythmias and a preservation of function of the sarcoplasmic reticulum (SR). Methods: Hearts were subjected to 40 min of global ischemia and 30 min of reperfusion after a 20 min period of oxygenated perfusion (oxygenated group: OG), or a 10 min period of oxygenation and 10 min of hypoxic perfusion (hypoxic group: HG). We evaluated the release of Ca2+ by SR blocked by ryanodine, the recovery of left ventricular function, and the reperfusion induced ventricular tachycardia/fibrillation (VT/VF). Results: Functional recovery improved and the incidence and duration of reperfusion VT/VF were reduced in HG. In HG the uptake of Ca2+ in SR decreased during ischemia, but this decrease was less than that in OG. However, recovery of Ca2+ uptake after reperfusion did not differ between groups. The release of Ca2+ by SR blocked by ryanodine was inhibited in HG throughout the ischemia-reperfusion sequence. Conclusions: Observations suggest that the benefits of BHP on recovery of function and reperfusion arrhythmias were associated with a decrease in release of Ca2+ by SR blocked by ryanodine.
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ABSTRACT: Objectives: The objective of this study was to determine whether hypoxic preconditioning (HP) could lessen the myocardial increase in [Na+]<SUB>i</SUB>, thus protecting the aging myocardium against ischemia. Background: A decrease in ischemic tolerance with aging is associated with an accelerated increase in [Na+]<SUB>i</SUB> during ischemia. Ischemic preconditioning fails to protect the middle-aged and senescent myocardium against ischemia. Methods: Isolated hearts of young adult (12-week-old), middle-aged (50-week-old) and senescent (100-week-old) Fischer 344 rats were subjected to 25 min of ischemia with or without HP followed by 30 min of reperfusion. Left ventricular (LV) function, myocardial energy metabolites and [Na+]<SUB>i</SUB> were measured. Results: In the older groups, the recovery of LV function and high-energy phosphates (HEPs) was lower with an increased release of creatine kinase (CK) during reperfusion than in the young group. The increased [Na+]<SUB>i</SUB> at the end of ischemia was greater in the former groups than in the young group. HP decreased myocardial glycogen and lessened the increased [Na+]<SUB>i</SUB> in the young group, resulting in an improved recovery of LV function and HEPs, as well as decreased CK release. However, the levels of glycogen before HP in the older groups were higher than in the young group and its levels after HP were similar to that before HP in the young group. HP did not affect the [Na+]<SUB>i</SUB>, exacerbated CK release and inhibited the recovery of LV function and HEPs in the older groups. Conclusions: HP failed to lessen the increased [Na+]<SUB>i</SUB> or to protect the aging hearts, probably due to the preexistence of increased glycogen level.
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ABSTRACT: Objectives: This study is aimed to determine whether loss of preconditioning (IP) effects in the middle-aged hearts (MA) is due to the failure of protein kinase C (PKC) activation and, if so, whether direct activation of mitochondrial ATP-sensitive potassium channels (m-K<SUB>ATP</SUB>) or PKC mimics IP. Background: PKC is a mediator and m-K<SUB>ATP</SUB> may be its downstream effector of IP in young adult hearts (YA), but we have demonstrated that IP is not effective in MA. Methods and results: Isolated hearts from YA (12-week) and MA (50-week) Fischer 344 rats were preconditioned by three cycles of ischemia and reperfusion (5 min each), and the translocation of PKC isoforms and the effects on reperfusion injury were assessed. In some hearts activation of m-K<SUB>ATP</SUB> or PKC by diazoxide or 1,2-dioctanoyl glycerol (DOG) was performed before 25 min of global ischemia/30 min of reperfusion. IP could improve the recovery of LV function and resulted in higher content of ATP after reperfusion in YA but these beneficial effects of IP was not found in MA. The effects of IP in YA were abolished by 5-hydroxydecanoate. In YA but not in MA, immunohistochemical analysis revealed that IP translocated PKC- and from the cytosolic or membrane to the perinuclear region but immunoblotting analysis showed translocation of PKC- , and to the membrane fraction. Pretreatment with diazoxide or DOG mimicked IP and decreased the creatine kinase release in YA. Diazoxide was also effective but effects of DOG were less in MA as compared with in YA. Conclusions: IP is not effective in MA hearts partly due to failure of translocation of PKC isoforms. Moreover, less efficacy of PKC activation by DOG as compared with activities of m-K<SUB>ATP</SUB> by diazoxide in MA may suggest that defect(s) of cell signaling downstream to PKC may also be involved in the loss of IP effects in MA.
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ABSTRACT: While the ischemic tolerance of the myocardium has been reported to decrease with senescence, it is not known when and how this occurs. Our objectives were to determine whether the tolerance to myocardial ischemia in rats decreased before the onset of senescence and whether an increase in myocardial ionic imbalance was associated with an enhanced myocardial injury with aging. Hearts were isolated from Fischer 344 rats categorized as young (12 weeks old), mature adult (24 weeks), middle-aged (50 weeks) or senescent (100 weeks). Hearts were perfused isovolumically by the Langendorff procedure and subjected to 25 min of global ischemia followed by 30 min of reperfusion. In the 50- and 100-week-old rats, the recovery of ventricular function and high-energy phosphate levels was lower and there was increased incidence of ventricular fibrillation after 25 min of global ischemia followed by reperfusion. The release of creatine kinase and lactate dehydrogenase during reperfusion was greater in the 50-and 100-week-old rats than in the 12- and 24-week-old rats, indicating the irreversible myocardial damage due to ischemia-reperfusion increased by middle-age. Intracellular levels of Na+and K+before ischemia were higher in the 50- or 100-week-old rats than in the 12-week-old rats. The increase in intracellular Na+at end of ischemia was greater in the older (50-week-old, 215% of the pre-ischemic value; 100-week-old, 232% of the pre-ischemic value) than in the younger rats (12-week-old, 158% of the pre-ischemic value). Results indicated that the rat heart becomes more vulnerable to ischemia in middle-age. This decrease in ischemic tolerance may be caused by an acceleration of myocardial ionic imbalance with aging.
Journal of Molecular and Cellular Cardiology.
