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Query: UNIPROT:P06889 (Mol)
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The left anterior descending coronary artery was occluded for 22.5, 45, 90, 180, and 360 mins in anesthesized open-chest dogs and pigs and thereafter reperfused for 30 min. Myocardial oxygen consumption was varied in dogs by cholinergic stimulation (bradycardia) and by cutting of the right and left vagus nerve (tachycardia). Regional myocardial blood flow was measured with radioactive tracer microspheres at the end of the occlusion period and 5 and 30 min after reflow. Tissue content of adenine nucleotides and of phosphocreatine were determined in the subendo- and subepicardium of transmural biopsies at the end of reflow. Infarct size was determined with nitrobluetetrazolium and compared with risk region size. Porcine hearts developed infarcts sooner. Those canines with a high MVO2 due to tachycardia had larger infarcts than those with bradycardia and resembled infarct development in the pig. The evolution of infarcts with time depended strongly on collateral flow which was significantly higher in canine hearts. Higher collateral flow and lower MVO2 in one group of canine hearts also resulted in better preserved tissue ATP. The fall in tissue ATP with time after coronary occlusion was compared with the O2-supply via collateral flow during occlusion. Assuming that the oxygen entering ischemic myocardium was used for ADP phosphorylation, we could estimate the degree of ATP-"overspending". Overspending was highest in low-flow ischemia and it correlated well with the speed of infarction. The ATP-data are best explained by the phosphocreatine energy shuttle model and by assuming slow access of cytosolic ATP to the ATP-splitting sites at the myofibrils. In conclusion, we postulate that both collateral flow as well as myocardial oxygen consumption before and during occlusion determine infarct size.
J Mol Cell Cardiol 1987 Jan
PMID:Influence of collateral blood flow and of variations in MVO2 on tissue-ATP content in ischemic and infarcted myocardium. 356 Feb 36

The major electrophysiological changes during the first 10 min of myocardial ischemia caused by complete obstruction of a coronary artery are a reduction in membrane potential, a decrease in action potential amplitude and upstroke velocity, and a prolongation of recovery of excitability following an action potential. Conduction velocity in the direction parallel to the long axis of myocardial fibers (VL) and in the transverse direction (VT) in normal myocardium are in the order of 40 cm/s and 20 cm/s respectively. During ischemia, conduction velocity decreases and lowest values for VL are in the order of 20 cm/s, for VT around 10 cm/s, before the ischemic tissue becomes inexcitable. Calculated dimensions of a possible re-entrant circuit in acutely ischemic myocardium (the product of refractory period and conduction velocity) are in the order of 7 to 8 cm. Re-entrant circuits of such dimensions were indeed demonstrated by simultaneous recording of 125 extracellular potentials from the epicardial surface of the ventricles during spontaneously occurring ventricular arrhythmias after coronary occlusion. Previous studies provided evidence that premature ventricular depolarization which initiate re-entry originated in the subendocardium, and the present experiments confirmed this. Destruction of the subendocardium of isolated, Langendorff perfused canine hearts, including the Purkinje system, by intracavitary application of phenol, did not, however, abolish ectopic activity during either ischemia or reperfusion, although the nature of the arrhythmias during ischemia was different from those in intact hearts. Coupling intervals of ectopic beats were longer in phenol-treated hearts than in intact hearts, but the site of origin of initial ectopic beats leading to ventricular tachycardia could not be determined. Re-entrant circuits with revolution times in the order of 340 to 400 ms accounted for the slow tachycardias observed in phenol-treated hearts. In contrast to intact hearts, these tachycardias never degenerated into ventricular fibrillation, indicating that an intact Purkinje system may be a necessary requirement for ventricular fibrillation to occur during acute, regional myocardial ischemia.
J Mol Cell Cardiol 1986 Apr
PMID:Electrophysiological basis for arrhythmias caused by acute ischemia. Role of the subendocardium. 371 46

This study was designed to examine whether diltiazem, a calcium channel-blocker, inhibits the cardiac ultrastructural alterations induced by coronary occlusion with or without reperfusion, in dogs anesthetized with pentobarbital. The left anterior descending coronary artery (LAD) was completely occluded for 60 min with or without reperfusion (induced by release of occlusion) for 20 min. Coronary occlusion increased ST segment in the ischemic area, and also produced typical ultrastructural alterations including decreased glycogen granules, destruction of mitochondria, and margination of the nuclear chromatin, especially in the subendocardium. Reperfusion of the ischemic area resulted in more severe alterations of the myocardial ultrastructure, including many myofibrillar contraction bands. Diltiazem was injected intravenously at the dose of 200 micrograms/kg (bolus injection) 20 min before LAD occlusion, and was then infused intravenously at the rate of 80 micrograms/kg/min for 10 min starting at the beginning of LAD occlusion, the total dose being 1 mg/kg. Diltiazem decreased heart rate and diastolic blood pressure, inhibited the increase in ST segment, and also inhibited the ultrastructural alterations induced by coronary occlusion, regardless of reperfusion. A bolus injection of diltiazem alone (200 micrograms/kg), however, did not inhibit markedly the ultrastructural alterations induced by coronary occlusion, regardless of reperfusion. It is concluded that the large dose of diltiazem (1 mg/kg) protects the myocardium from ischemic injury.
J Mol Cell Cardiol 1986 Apr
PMID:Protective effect of diltiazem on ultrastructural alterations induced by coronary occlusion and reperfusion in dog hearts. 371 50

Studies in cats suggest alpha-adrenergic contributions to arrhythmias during myocardial ischemia and reperfusion. The validity of this concept in other species, however, remains uncertain. Thus, 106 chloralose-anesthetized open-chest dogs undergoing a 25 min coronary artery occlusion followed by reperfusion received saline (n = 52), prazosin (1 mg/kg, n = 26), phentolamine (5 mg/kg, n = 18), or phentolamine (same dose) + propranolol (1 mg/kg, n = 10). Alpha-blockade was confirmed by alpha-agonist dose-response studies. In phentolamine-treated dogs, arterial pressure and heart rate were kept constant to prevent exacerbation of ischemia. Control and treated groups were comparable with respect to variables known to affect arrhythmias, such as size of occluded and reperfused vascular beds, coronary collateral flow, severity of ischemia estimated from intramyocardial CO2 tension, and peak reactive hyperemia. During coronary occlusion, the number of single premature ventricular complexes was reduced by phentolamine (P less than 0.01), but not by prazosin or phentolamine + propranolol; no treatment affected the total number of couplets, ventricular tachycardia episodes and ventricular ectopic complexes, or the incidence of ventricular tachycardia and ventricular fibrillation. During coronary reperfusion, arrhythmias did not differ in control and treated groups. Thus, selective alpha 1-(prazosin), nonselective alpha 1- and alpha 2-(phentolamine), and combined alpha- and beta-blockade (phentolamine + propranolol) failed to attenuate complex arrhythmias induced by acute myocardial ischemia and reperfusion. Alpha-adrenergic mechanisms appear unimportant in the genesis of these arrhythmias in the canine model.
J Mol Cell Cardiol 1984 Dec
PMID:Effect of alpha-adrenergic blockade on arrhythmias induced by acute myocardial ischemia and reperfusion in the dog. 615 73

Scanning electron microscopy and transmission electron microscopy were used together with tannic acid and ruthenium-red staining to examine connective tissue damage caused by acute myocardial ischemia for 20, 40 and 120 min in pig hearts. The microsphere blood flow technique revealed that blood flow was approximately 0.02 ml/min/g in inner, middle and outer thirds of the ischemic zone. After 20 min of occlusion of the left anterior descending coronary artery, the collagen network and microfilaments became irregularly arranged. After 40 min of occlusion, ruthenium-red positive glycoprotein material around the collagen fibrils and elastin began to disappear. After 2 h occlusion, the collagen fibrils and microfilaments had separated from the basement membrane. Collagen fibrils, elastic fibers, and microfilaments were broken down and were found in decreased quantities. These results have revealed that the connective tissue remains intact during the first 20 min of coronary occlusion despite zero blood flow and mild cellular changes but does undergo prominent alterations after 40 min of occlusion.
J Mol Cell Cardiol 1983 Apr
PMID:Connective tissue changes in early ischemia of porcine myocardium: an ultrastructural study. 687 83

Mild (not harmful) stress may initiate an adaptive mechanism, protecting the heart from harmful consequences of a more severe stress. There are at least three known types of cardiac adaptation to stress, such as: a) the gradually developing, long lasting adaptation to chronic mechanical overload, leading to cardiac hypertrophy, later to cardiomyopathy and heart failure, b) the rapidly developing adaptation to moderate stress initiated by 'preconditioning' brief coronary occlusion(s) or brief periods of rapid cardiac pacing, protecting for less than 1 h against consequences of a subsequent, severe stress, c) the later appearing, more prolonged cardio-protective adaptation, described by us in 1983, induced by various forms of more severe but not injurious stimuli, such as an optimal dose of prostacyclin or its stable analogues; or a series of brief periods of rapid pacings. This form of cardiac adaptation to stress protects for 24-48 h against consequences of a more severe stress such as: 1. myocardial ischaemia; 2. early and late postocclusion and reperfusion arrhythmias; 3. early morphologic changes secondary to ischaemia and reperfusion; 4. ischaemia induced myocardial loss of K+ and accumulation of Na+ and Ca++; 5. it may increase the tolerance to the toxic effects of cardiac glycosides. A reduced response to beta-adrenergic stimuli and a concomitant increase in activity and amount of PDE I and IV was shown by us earlier.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Biochem
PMID:On the mechanism and possible therapeutic application of delayed adaptation of the heart to stress situations. 749 39

Current methods of experimental infarct size measurement require tissue analysis several hours after the ischemic event. Electron microscopy identifies irreversibly injured myocytes early after ischemia, but cannot be used to measure myocardial infarct size. Horseradish peroxidase (HRP), a tracer protein that permeates the disrupted sarcolemma of injured myocytes, was used to determine infarct size. New Zealand White rabbits (n = 15) were subjected to 30 min coronary artery occlusion and 24 h reperfusion. Prior to euthanasia, HRP was administered intravenously. The hearts were excised, perfused with triphenyl tetrazolium chloride (TTC), and perfusion fixed. A frozen section was cut from left ventricular slices, and the brown HRP reaction product was developed with 3,3'-diaminobenzidine tetrahydrochloride and H2O2. The areas delineated by intramyocyte HRP (as a percent of the left ventricle) closely correlated with infarct size determined by conventional hematoxylin-eosin (H&E) stain and TTC (means +/- S.E.M.): 29.5 +/- 3.0% vs 27.6 +/- 2.9% vs 28.6 +/- 2.6%, respectively. The coefficient of correlation between HRP and H&E was 0.94. This method was tested for early infarct detection in rabbits subjected to 30 min coronary occlusion followed by intravenous injection of HRP and sacrifice. HRP-delineated infarcts measured 21.4 +/- 3.7% of the left ventricle, and electron microscopic examination from ischemic and non-ischemic areas was used to confirm that cells containing HRP were irreversibly injured. Thus, HRP can be used to accurately measure myocardial infarct size in experimental coronary artery occlusion and reperfusion in infarcts as early as 30 min after coronary occlusion or following 24 h of reperfusion.
J Mol Cell Cardiol 1993 Apr
PMID:Early detection and measurement of experimental myocardial infarcts with horseradish peroxidase. 768 52

There are several factors besides brief episodes of total coronary occlusion which can provide sufficient stress to result in a preconditioning-like effect on the size of a myocardial infarction. Partial coronary artery stenosis, hypoxia, stretch, catecholamines, rapid pacing, and certain pharmacologic therapies may provide preconditioning stimuli. These same factors as well as mechanical complications in which a coronary artery is briefly occluded or stenosed prior to a subsequent coronary occlusion may lead to inadvertent preconditioning and confound the results of experimental cardiology studies.
J Mol Cell Cardiol 1995 Feb
PMID:Preconditioning stimuli and inadvertent preconditioning. 777 79

Previous studies have demonstrated that transforming growth factor-beta (TGF-beta) can accelerate wound healing, inhibit free radical formation and limit myocardial ischemia/reperfusion injury in a variety of experimental models. However, it is unknown whether exogenous TGF-beta 1 can attenuate the prolonged contractile dysfunction that is observed after a brief, reversible ischemic insult (myocardial stunning). Thus, open-chest dogs undergoing a 15-min left anterior descending coronary artery occlusion and 4 h of reperfusion were given TGF-beta 1 as an intravenous bolus (250 micrograms) at 24 h and again at 1 h before coronary occlusion (n = 5). Control dogs (n = 7) received equivalent amounts of vehicle. The two groups were similar with respect to occluded bed size, collateral blood flow and rate-pressure product. Fundamental physiological parameters, such as body temperature, arterial pH, PO2 and hematocrit, were within normal limits throughout the experiment. In control dogs, regional myocardial function (assessed as systolic thickening fraction) remained depressed throughout the 4 h reperfusion period, indicating severe myocardial stunning. TGF-beta 1 did not produce any significant improvement in the recovery of regional function; 4 h after reperfusion, paradoxical systolic thinning was still present in both treated and control groups, with thickening fraction being -22.5 +/- 6.1% and -31.0 +/- 5.3% of baseline, respectively (P = N.S.). These results demonstrate that a large dose of TGF-beta 1 given before ischemia fails to attenuate myocardial stunning in the open-chest dog, suggesting that this growth factor does not exert protective effects in the setting of reversible myocardial ischemia/reperfusion injury.
J Mol Cell Cardiol 1993 Apr
PMID:Effect of transforming growth factor-beta 1 on myocardial stunning in the intact dog. 834 Sep 31

The aim of this study was: (1) to elucidate in more detail the relationship between stress protein expression and brief periods of ischaemia and reperfusion, such as occur during early (classical) ischaemic preconditioning (PC) in the rabbit myocardium; (2) to determine whether stress protein expression is affected by adenosine receptor modulation, since adenosine is a mediator of the preconditioning response. We have studied the expression of the 60 kDa (hsp60); 70 kDa (hsp70-inducible and constitutive isoforms) and 27 kDa (hsp27) stress proteins and the mitochondrial ATP-synthase beta-subunit using Northern blotting. Hsp60, hsp70 and hsp27 expression were also determined at the protein level by Western blotting. Total RNA and proteins were prepared from frozen samples of ischaemic left ventricle and non-ischaemic right ventricle rabbit myocardium after the following treatments (1) sham-operated; (2) 15 min stabilization + 5 min coronary occlusion + 10 min reperfusion (PC); (3) PC + 30 min coronary occlusion (I); (4) PC + 30 min coronary occlusion + 2 h reperfusion (I/R) (5) the adenosine receptor antagonist 8-(p-sulpho-phenyl) theophyline (SPT) given 5 min prior to PC; (6) the adenosine receptor agonist 2-chlorocyclopentyl-N6-adenosine (CCPA) given in place of PC. A transient, approximately two-fold elevation in hsp60 mRNA occurred following 5 min coronary occlusion + 10 min reperfusion (PC) which was stable during a subsequent 30 min ischaemia (I), but returned to baseline during the second (2 h) reperfusion (I/R). An inducible hsp70 mRNA species appeared within 10 min of the second (30 min) coronary occlusion (I) which continued to increase to high levels during the second (2 h) reperfusion (I/R). Hsp27 mRNA expression was not altered following PC or subsequent ischaemia and reperfusion (I/R). ATP synthase beta-subunit mRNA did not change during PC or I but decreased during the subsequent 2 h reperfusion (I/R). Western blot analysis showed no change in left ventricle ischaemic zone hsp60, hsp70i/hsc70 or hsp27 protein during PC compared to an approximately two-fold elevation of hsp70i 24 h following whole body heat stress or 24 h following 4 x 5 min coronary occlusion (as reported by Marber et al., 1993). However, hsp70i, hsp60 and hsp27 showed significant decreases in immunodetectable protein following subsequent ischaemia and reperfusion (I/R). SPT inhibited the increase in hsp60 mRNA following PC (P < or = 0.05), but had no effect on hsp70, hsp27 or ATP-synthase mRNA levels. Therefore, differential expression of mRNAs for hsp60 and hsp70 occurred following ischaemia and reperfusion, with hsp70 mRNA expression involving a significant reperfusion-dependent component. CCPA had no effect on expression of mRNAs for hsp60, hsp70, hsp27 or ATP-synthase. We conclude that the early phase of adenosine receptor-dependent preconditioning in the rabbit heart is not mediated via stress protein expression. However, brief ischaemia and reperfusion resulted in differential changes in individual stress protein gene expression which may be due to different physiological and/or biochemical components of ischaemia and reperfusion in the heart. In addition, partial dependence of hsp60 expression on adenosine receptor modulation was observed.
J Mol Cell Cardiol 1995 Oct
PMID:Differential stress protein mRNA expression during early ischaemic preconditioning in the rabbit heart and its relationship to adenosine receptor function. 857 30


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