Search Results - (Author, Cooperation:D. Yellon)

2011-06-10

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Adult Stem Cells/*cytology ; Animals ; *Cell Differentiation ; Cellular Reprogramming ; Gene Expression Regulation ; *Heart Injuries ; Mice ; Myocardial Infarction/pathology ; Myocytes, Cardiac/*cytology/metabolism ; Thymosin/metabolism ; WT1 Proteins/genetics/metabolism

0022-2828

Elsevier Journal Backfiles on ScienceDirect 1907 - 2002

Medicine

Electronic Resource

0022-2828

Elsevier Journal Backfiles on ScienceDirect 1907 - 2002

Medicine

Electronic Resource

0022-2828

Elsevier Journal Backfiles on ScienceDirect 1907 - 2002

Medicine

Electronic Resource

0022-2828

Elsevier Journal Backfiles on ScienceDirect 1907 - 2002

Medicine

Electronic Resource

1420-9071

Heat stress ; hsp70 ; stress proteins ; oxidative stress ; ischaemia/reperfusion

Springer Online Journal Archives 1860-2000

Biology

Medicine

Abstract Numerous reports suggest that stress protein accumulation confers protection in various mammalian tissues against differing stresses. The purpose of this article is to review the evidence that stress proteins, in particular hsp70, are able to alter the resistance of the heart to subsequent ischaemic and non-ischaemic injury and to discuss the possible physiological basis for this apparent protection. The possible, though unlikely involvement of heat stress proteins in classical ischaemic preconditioning is addressed as is the possibility of their involvement in a delayed second window of protection.

Electronic Resource

1573-7241

infarct size limitation ; coronary collateral flow ; verapamil ; myocardial ischemia ; salvage index

Springer Online Journal Archives 1860-2000

Medicine

Summary Studies were undertaken to determine whether cardioprotection afforded by verapamil could be sustained in the dog heart during permanent coronary artery occlusion. In 48 dogs a coronary artery was occluded for 24 or 48 hours using a closed-chest embolization procedure. Dogs were assigned to either untreated control or to verapamil-treated (200 μg/kh, intravenous bolus within 5 minutes after coronary occlusion and then 5 μg/kg/min as a continuous intravenous infusion for 24 or 48 hours) groups. After 24 or 48 hours of permanent coronary occlusion, tissue necrosis was evaluated using tetrazolium staining and was related to the major baseline predictors of infarct size including anatomic risk zone (radiolabeled microsphere autoradiography) and coronary collateral flow. The correlation between infarct size and subepicardial coronary collateral flow was calculated in untreated control dogs (r=−0.91 and -0.80 for 24 and 48 hour controls, respectively); analysis of covariance indicated that verapamil treatment shifted this relation downward in both the 24- and 48-hour drug treatment groups. The equation of this regression was used to calculate the size of the infarct that would have occurred in treated dogs if drug treatment had not been initiated. The ratio of observed and calculated infarct size provides a “salvage index.” In conclusion, verapamil was able to limit the extent of tissue necrosis and this cardioprotection appears to be sustained during 48 hours of permanent coronary occlusion.

Electronic Resource

1573-7241

Springer Online Journal Archives 1860-2000

Medicine

Electronic Resource

1573-7241

left ventricular hypertrophy ; ischemia-reperfusion ; reperfusion arrhythmias ; ventricular fibrillation ; diltiazem

Springer Online Journal Archives 1860-2000

Medicine

Summary The ability of the calcium antagonist diltiazem to protect against reperfusion-induced arrhythmias in hypertrophied myocardium was studied. Hearts from normotensive and DOCA-salt hypertensive rats were Langendorff perfused and subjected to 10 minutes of stabilization, 10 minutes of left coronary artery occlusion, and 5 minutes of reperfusion. The incidence and duration of ventricular tachycardia (VT) and ventricular fibrillation (VF) during reperfusion were determined and the effects of diltiazem or vehicle (given as a single bolus 3 minutes before coronary artery occlusion) were assessed in hypertrophied and normal hearts. In vehicle-treated (control) hypertrophied hearts, VF incidence was 91% compared with 67% in normal hearts, and the median duration of VF was 272 seconds (mean 207.4±32.3) compared with 27 seconds (mean 110.6±36.6; p〈0.05), respectively, suggesting that reperfusion VF is more severe in hypertrophied hearts. In normal hearts, diltiazem 18 µg reduced VT incidence from 92% to 55%, reduced VF from 67% to 27%, and sustained VF from 42% to 9%. In hypertrophied hearts, 18 µg diltiazem reduced the VT incidence from 100% to 58%, reduced VF from 91% to 25% (p〈0.01), and sustained VF from 82% to 8% (p〈0.01). Median VF duration in this group was reduced to 0 seconds (p〈0.05; mean 24.7±22.6). Diltiazem did not significantly affect heart rate or coronary flow rate decreases during ischemia. However, developed tension, at the onset of ischemia, was lower in diltiazem-treated groups than in the control groups. We suggest that the attenuation by diltiazem of reperfusion-induced arrhythmias observed in this model was related to an energy-sparing effect during ischemia. This study shows that diltiazem administered acutely before the onset of ischemia attenuates reperfusion-induced arrhythmias in the hypertrophied myocardium, despite its greater susceptibility to reperfusion-induced arrhythmias.

Electronic Resource

1435-1803

nifedipine ; coronary embolized dog ; limitation of infarct size

Springer Online Journal Archives 1860-2000

Medicine

Summary We studied the ability of nifedipine, a calcium antagonist, to limit infarct size in the closed chest, coronary embolized dog. Immediately after embolization141Ce labelled microspheres were administered into the left ventricle. Myocardium not receiving microspheres was considered to be the region at risk. The nifedipine group (10 dogs) received a bolus (16 μg/kg i.v. over 8 minutes as a loading dose) followed by continuous infusion (1,000 μg/24 hours) 10 min after embolization. The control group (9 dogs) received an equal volume of saline. Twenty-four hours after embolization the dogs were sacrificed, the heart sectioned into 4-mm slices and the slices were stained with tetrazolium to reveal the infarct. The region at risk was determined by autoradiography of the microspheres in the heart slices. Infarct and risk zone volume were determined by planimetric methods. The nifedipine group had a significantly smaller infarct volume to risk zone voluem ratio than the control group (38.7±4.7% vs. 79.5±4.3%, p〈0.001). We conclude that nifedipine produces a sustained limitation of infarct size following permanent occlusion of a dog's coronary artery.

Electronic Resource

1435-1803

Cardioprotection ; ischaemia ; ischaemic preconditioning ; second window of protection

Springer Online Journal Archives 1860-2000

Medicine

Electronic Resource

1435-1803

Heat stress ; ischaemia ; hsp70 ; cardiac myocytes

Springer Online Journal Archives 1860-2000

Medicine

Abstract Primary rat cardiocytes were subjected to either thermal “preconditioning” for 30 min at 43°C or 20 min metabolic “preconditioning” (10 mM deoxyglucose, 20 mM lactate, pH 6.5). Eighteen hours later cells were analysed either for hsp 70i expression or subjected to a subsequent lethal heat stress or simulated ischaemia (10 mM deoxyglucose, 20 mM lactate, 0.75 mM sodium dithionite, 12 mM potassium chloride, pH 6.5) for 2 hours and assessed for survival by trypan blue exclusion. Hsp 70i was induced over 100 fold by thermal “preconditioning” and 30 fold by metabolic “preconditioning” (p〈0.001, p〈0.05), hsp 90 was induced 2.71 fold and 2.24 fold (p〈0.001, p〈0.001) by thermal and metabolic “preconditioning” respectively, while hsp 60 was not induced by either treatment. Preconditioned cultures had improved survival against subsequent lethal heat stress or simulated ischaemia: Thermal “preconditioning” reduced death from 69.22% to 52.46% upon subsequent “lethal” heat stress and from 49.13% to 36.66% upon subsequent “lethal” simulated ischaemia. Metabolic “preconditioning” reduced cell death from 51.29% to 33.8% against subsequent “lethal” heat stress, and from 69.09% to 55.61% upon subsequent “lethal” simulated ischaemia. A second marker of cell death, the release of lactate dehydrogenase activity into the culture media, was reduced to 65% and 60% of control values for thermally preconditioned cells subjected to “lethal” heat or “lethal” simulated ischaemia respectively. Metabolically “preconditioned” cells demonstrated lactate dehydrogenase activity of 59% and 51% that of control values, when subjected to “lethal” heat or “lethal” simulated “ischaemia” respectively.

Electronic Resource

1435-1803

Cardioprotection ; infarction ; ischemia ; ischemic preconditioning ; second window of protection

Springer Online Journal Archives 1860-2000

Medicine

Abstract The delayed phase (‘second window’) of protection induced by ischemic preconditioning in rabbit heart is observed as enhanced resilience to infarction 24 hours after repetitive brief cycles of ischemia. Here we provide a fuller physiological characterisation of this phenomenon in the open-chest rabbit model, examining temporal characteristics and dose-dependency of this adaptation. For examination of the timecourse of delayed protection, rabbits were pretreated with four 5 minute coronary artery occlusions (PC) or sham operation (SHAM). Twenty four, 48, 72 or 96 hours later, infarct size after 30 min coronary occlusion and 120 minutes reperfusion was assessed with TTC staining and expressed as a percentage of myocardial risk volume (I/R). I/R was reduced at 24 hours (SHAM 48.1±3.9% v PC31.4±3.0%, P〈0.01), 48 hours (SHAM 41.9±3.0% v PC 19.6±6.3%, P〈0.01), and 72 hours (SHAM 39.8±3.4% v PC 17.2±2.5%, P〈0.01). No protection was observed 96 hours after preconditioning (SHAM 35.0±4.8% v PC 36.9±3.8%). In a further study, animals were pretreated with one, two or four 5 minute coronary occlusions (1×5 PC, 2×5 PC, 4×5 PC) and subjected to the infarction protocol 48 hours later. I/R was 44.5±4.3% in SHAM, 24.8±4.4% in 1×5 PC (P〈0.01), 27.4±2.9% in 2×5 PC (P〈0.05) and 24.4±4.8 in 4×5 PC (P〈0.01). Delayed protection in this rabbit model is prolonged, extending between 24 and 72 hours after the preconditioning stimulus. The threshold for eliciting the second window of protection in this model is as low as one 5 minute coronary occlusion.

Electronic Resource

1435-1803

Key words Cardioprotection – infarction – ischemia – ischemic preconditioning – second window of protection

Springer Online Journal Archives 1860-2000

Medicine

Abstract The delayed phase (‘second window’) of protection induced by ischemic preconditioning in rabbit heart is observed as enhanced resilience to infarction 24 hours after repetitive brief cycles of ischemia. Here we provide a fuller physiological characterisation of this phenomenon in the open-chest rabbit model, examining temporal characteristics and dose-dependency of this adaptation. For examination of the timecourse of delayed protection, rabbits were pretreated with four 5 minute coronary artery occlusions (OC) or sham operation (SHAM). Twenty four, 48, 72 or 96 hours later, infarct size after 30 min coronary occlusion and 120 minutes reperfusion was assessed with TTC staining and expressed as a percentage of myocardial risk volume (I/R). I/R was reduced at 24 hours (SHAM 48.1 ± 3.9% v PC 31.4 ± 3.0%, P 〈 0.01), 48 hours (SHAM 41.9 ± 3.0% v PC 19.6 ± 6.3%, P 〈 0.01), and 72 hours (SHAM 39.8 ± 3.4% v PC 17.2 ± 2.5%, P 〈 0.01). No protection was observed 96 hours after preconditioning (SHAM 35.0 ± 4.8% v PC 36.9 ± 3.8%). In a further study, animals were pretreated with one, two or four 5 minute coronary occlusions ( 1 × 5 PC, 2 × 5 PC, 4 × 5 PC) and subjected to the infarction protocol 48 hours later. I/R was 44.5 ± 4.3 % in SHAM, 24.8 ± 4.4% in 1 × 5 PC (P 〈 0.01), 27.4 ± 2.9 % in 2 × 5 PC (P 〈 0.05) and 24.4 ± 4.8 in 4 × 5 PC (P 〈 0.01). delayed protection in this rabbit model is prolonged, extending between 24 and 72 hours after the preconditioning stimulus. The threshold for eliciting the second window of protection in this model is as low as one 5 minute coronary occlusion.

Electronic Resource

1435-1803

Adenosine triphosphate (ATP) ; creatine phosphate (CP) ; contractile recovery ; rat heart ; contractile failure

Springer Online Journal Archives 1860-2000

Medicine

Summary The adenosine triphosphate (ATP) content of isolated Langendorff-perfused rat hearts may be increased by more than 40% above the normal value by a 2-h perfusion with adenosine (15 μmol/l). This metabolic manipulation was used to investigate the hypothetical relationship between total tissue ATP content and ischaemia-induced contractile failure, ischaemic contracture and post-ischaemic functional recovery. Adenosine perfused hearts were submitted to 20 min of normothermic ischaemia and reperfused for 45 min with or without adenosine. Control experiments were performed with adenosine-free preischaemic perfusion. In identically designed experiments the tissue-protective effect of diltiazem (0.5 μmol/l) was determined and compared with the experiments with adenosine. At the end of 120 min of preischaemic perfusion, the ATP content of the adenosine treated hearts was 34.3±1.8 μmol/g dry weight (control=23.6±1.9 μmol/g, p〈0.01). After a period of 20 min of normothermic ischaemia, the ATP content of the adenosine hearts decreased to 13.3± .4 μmol/g, whereas ATP fell to 8.3±1.6 μmol/g in the control hearts. The creatine phosphate (CP) levels of adenosine hearts were significantly lower than those of the control group before ischaemia, but did not show major differences following ischaemia. During ischaemia, the contractile activity measured via an intraventricular balloon catheter, as well as ischaemic contracture did not differ between the adenosine and control hearts. The inclusion of diltiazem into the perfusate significantly delayed the onset of contracture. After 45 min of reperfusion, ATP contents of adenosine and control hearts reached similar values (8.4±2.3 and 8.3±2.9 μmol/g, respectively). Inclusion of adenosine (15 μmol/l in the reperfusion perfusate of the adenosine experiments prevented a further decrease, but did not increase tissue ATP content. CP values of all groups showed a partial recovery upon reperfusion, they did not differ significantly. Contractile recovery was equal in all experimental groups except for the diltiazem treated hearts, which showed during the first 10 min of reperfusion an improved mechanical performance. It is concluded that total tissue ATP is not necessarily a good indicator of functional capabilities under conditions of normothermic ischaemia and reperfusion in the isolated rat heart.

Electronic Resource

1435-1803

Ischaemic preconditioning ; KATP channel openers ; human atrium ; pre-operative nicorandil

Springer Online Journal Archives 1860-2000

Medicine

Abstract The ATP-sensitive potassium channel (KATP channel) has been implicated in the mechanism underlying ischaemic preconditioning protection. This study based on human atrium compared the protective effects of ischaemic preconditioning with pre-operative nicorandil (a KATP channel opener with nitrate actions). We also examined the added effect of ischaemic preconditioning to that of nicorandil on ischaemic protection. The protective effects of other KATP channel openers devoid of nitrate actions were also examined. Atrial trabeculae harvested from patients undergoing routine myocardial revascularisation were divided on the basis of whether patients had been ingesting nicorandil orally preoperatively. Trabeculae were superfused with oxygenated Tyrode's solution and following stabilisation underwent 90 minutes simulated ischaemia followed by 120 minutes reoxygenation (n=6 per group). Atrial trabeculae exposed to nicorandil underwent either no treatment (N), or ischaemic preconditioning (N+PC) using 3 minutes simulated ischaemia and 7 minutes reoxygenation prior to the 90 minutes simulated ischaemia. Similarly trabeculae not exposed to nicorandil underwent either no treatment, controls (C), or ischaemic preconditioning (PC). The experimental endpoint was recovery of contractile function presented as percentage baseline function. Further groups were examined using other KATP channels openers with and without ischaemic preconditioning. In the control group, following 120 minutes reoxygentation the recovery of function reached 28.8±3.5%. In contrast, exposure to nicorandil alone improved recovery of function (55.5%±5.3) to a similar extent as PC (55.3%±2.5) when compared to controls (p〈0.05, ANOVA). The addition of ischaemic preconditioning to nicorandil exposure abolished protection (29.7%±3.1). Findings were confirmed using the other KATP channels openers. Clinically available nicorandil appears to afford ischaemic protection to isolated human atrial muscle. The addition of a short ischaemic episode to nicorandil exposure seems to completely abolish this protection. Although the mechanism underlying this effect remains unknown, we believe that this observation may have clinical implications.

Electronic Resource

1435-1803

FK506 ; cellular ischemia ; immunosuppressant action

Springer Online Journal Archives 1860-2000

Medicine

Abstract Pre-treatment with the immunosuppressant FK506 is shown to protect primary cardiocytes against a subsequent severe thermal or ischaemic stress. This effect is not observed with the related compounds cyclosporin A or rapamycin. It does not involve induction of the FK506 binding, heat inducible protein hsp56 or of the other heat shock proteins. In addition over-expression of hsp56 does not protect cardiac cells from severe stress in contrast to our previous results with hsp70 and hsp90. These results suggest the FK506 is acting via a novel mechanism to protect cardiac cells against cellular ischaemia which may not be related to its immunosuppressant action.

Electronic Resource