Left Ventricular Subendocardium Research Articles

β2-Adrenergic receptor stimulation in vivo induces apoptosis in the rat heart and soleus muscle

High doses of the beta2-adrenergic receptor (AR) agonist clenbuterol can induce necrotic myocyte death in the heart and slow-twitch skeletal muscle of the rat. However, it is not known whether this agent can also induce myocyte apoptosis and whether this would occur at a lower dose than previously reported for myocyte necrosis. Male Wistar rats were given single subcutaneous injections of clenbuterol. Immunohistochemistry was used to detect myocyte-specific apoptosis (detected on cryosections via a caspase 3 antibody and confirmed with annexin V, single-strand DNA labeling, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling). Myocyte apoptosis was first detected at 2 h and peaked 4 h after clenbuterol administration. The lowest dose of clenbuterol to induce cardiomyocyte apoptosis was 1 microg/kg, with peak apoptosis (0.35 +/- 0.05%; P < 0.05) occurring in response to 5 mg/kg. In the soleus, peak apoptosis (5.8 +/- 2%; P < 0.05) was induced by the lower dose of 10 microg/kg. Cardiomyocyte apoptosis was detected throughout the ventricles, atria, and papillary muscles. However, this damage was most abundant in the left ventricular subendocardium at a point 1.6 mm, that is, approximately one-quarter of the way, from the apex toward the base. beta-AR antagonism (involving propranolol, bisoprolol, or ICI 118551) or reserpine was used to show that clenbuterol-induced myocardial apoptosis was mediated through neuromodulation of the sympathetic system and the cardiomyocyte beta1-AR, whereas in the soleus direct stimulation of the myocyte beta2-AR was involved. These data show that, when administered in vivo, beta2-AR stimulation by clenbuterol is detrimental to cardiac and skeletal muscles even at low doses, by inducing apoptosis through beta1- and beta2-AR, respectively.

Alterations in Myofilament Function Contribute to Left Ventricular Dysfunction in Pigs Early After Myocardial Infarction

Myocardial infarction (MI) initiates cardiac remodeling, depresses pump function, and predisposes to heart failure. This study was designed to identify early alterations in Ca2+ handling and myofilament proteins, which may contribute to contractile dysfunction and reduced beta-adrenergic responsiveness in postinfarct remodeled myocardium. Protein composition and contractile function of skinned cardiomyocytes were studied in remote, noninfarcted left ventricular (LV) subendocardium from pigs 3 weeks after MI caused by permanent left circumflex artery (LCx) ligation and in sham-operated pigs. LCx ligation induced a 19% increase in LV weight, a 69% increase in LV end-diastolic area, and a decrease in ejection fraction from 54+/-5% to 35+/-4% (all P<0.05), whereas cardiac responsiveness to exercise-induced increases in circulating noradrenaline levels was blunted. Endogenous protein kinase A (PKA) was significantly reduced in remote myocardium of MI animals, and a negative correlation (R=0.62; P<0.05) was found between cAMP levels and LV weight-to-body weight ratio. Furthermore, SERCA2a expression was 23% lower after MI compared with sham. Maximal isometric force generated by isolated skinned myocytes was significantly lower after MI than in sham (15.4+/-1.5 versus 19.2+/-0.9 kN/m2; P<0.05), which might be attributable to a small degree of troponin I (TnI) degradation observed in remodeled postinfarct myocardium. An increase in Ca2+ sensitivity of force (pCa50) was observed after MI compared with sham (DeltapCa50=0.17), which was abolished by incubating myocytes with exogenous PKA, indicating that the increased Ca2+ sensitivity resulted from reduced TnI phosphorylation. In conclusion, remodeling of noninfarcted pig myocardium is associated with decreased SERCA2a and myofilament function, which may contribute to depressed LV function. The full text of this article is available online at http://circres.ahajournals.org.

Increase in left ventricular torsion‐to‐shortening ratio in children with valvular aortic stenosis

Perfusion of left ventricular (LV) subendocardium in valvular aortic stenosis (AS) patients is impaired. It was expected that this may lead to a reduction of subendocardial fiber contraction and, consequently, to an increase of LV torsion per amount of ejection. Using MR tagging (MRT), it was investigated whether the torsion-to-shortening ratio (TSR) is elevated in valvular AS patients. Six asymptomatic children with valvular AS were investigated using echo Doppler, ECG, exercise test, and MRT. LV torsion and natural strain of the inner diameter were determined from measured tag displacements in two short-axis slices of the LV. In all AS patients TSR was approximately 40% increased (0.62 +/- 0.04 rad; mean +/- SD) as compared to pediatric (0.44 +/- 0.08 rad; n=5) and adult controls (0.46 +/- 0.08 rad; n=9), indicating subendocardial contractile dysfunction. With other techniques hitherto used this type of dysfunction could not be detected.

Characterisation of isoprenaline myotoxicity on slow-twitch skeletal versus cardiac muscle

Background: Elevated catecholamines are known to be cardiotoxic, but their potential injurious effects on skeletal muscles are largely unknown. We have investigated whether isoprenaline induces in vivo myocyte necrosis in rat soleus muscle, and characterised the time-course, dose–response, spatial distribution and adrenoceptor involvement of its myotoxicity, in comparison with effects on cardiomyocytes in the same animals. Material and methods: Myocyte necrosis in response to subcutaneous isoprenaline was detected in vivo using a monoclonal anti-myosin antibody. Secondary immunoperoxidase staining (in vitro) facilitated the localisation of the damage and quantitative image analysis. Results: Using this sensitive technique we report a novel observation that isoprenaline induces significant myocyte necrosis (5–10%) in the soleus muscle. This toxic damage was initiated at lower doses of isoprenaline than in the myocardium (1 vs. 10 μg kg −1 s.c.), and peaked earlier (at 12 vs. 18 h post injection). Damage was distributed throughout the soleus muscle, whereas cardiomyocyte necrosis was most marked in left ventricular subendocardium where it was approximately 10 and three times greater than in the subepicardium and atria, respectively. Using selective adrenoceptor (AR) antagonism, we found that isoprenaline myotoxicity was mediated via β 2-AR in the soleus and via β 1-AR in the myocardium. Conclusion: The results show that the myopathic effects of isoprenaline are not confined to the heart. The involvement of skeletal muscle with different characteristics and mechanisms may have important implications in elucidating and treating the generalised myopathic processes seen in heart failure patients who have elevated levels of circulating catecholamines.

Site of the Arrhythmogenic Focus and Cardiac Vulnerability to Ventricular Fibrillation

The aim of this study was to test the hypothesis that a subendocardial arrhythmogenic focus makes the heart more susceptible to VF due to electrical interaction with the Purkinje network. Monofocal ventricular tachycardia (mVT) was created by injecting 5-microg aconitine into the left ventricular subepicardium (EPI-mVT, n = 8) or subendocardium (ENDO-mVT, n = 13) in anesthetized dogs. Despite the similar cycle length of mVT, the incidence of VF was significantly different between EPI-mVT and ENDO-mVT (100 [8/8] vs 46% [6/13], P <0.05). VF was invariably preceded by hemodynamic deterioration. Three-dimensional cardiac mapping (n = 10, 221 +/- 11 recording sites) revealed that VF was triggered solely by focal firing unrelated to the primary arrhythmogenic focus in both mVT models. No interaction between the primary focus and adjacent endocardial tissue was indicated. These results suggest that the proximity of the arrhythmogenic focus to the Purkinje network has little role in cardiac vulnerability to VF, and that progression of mVT to VF is largely caused by sporadic focal firing regardless of the site of the arrhythmogenic focus in the present animal model.

Age-associated Changes in Function, Structure and Mitochondrial Genetic and Enzymatic Abnormalities in the Fischer 344×Brown Norway F1Hybrid Rat Heart

We hypothesized that cardiac aging in the rat involves mitochondrial genetic damage and mitochondrial enzymatic dysfunction of individual cardiomyocytes as has been demonstrated previously only in primate myocardium. Myocardium from Fischer 344 × Brown Norway F1hybrid rats of ages 5, 18 and 36–38 months was examined for mitochondrial genetic and enzymatic abnormalities. In-vivo hemodynamic measurements revealed age-related changes of left ventricular function while histological evaluation demonstrated an increase in percent area fibrosis from 7%±5 in the 5-month-old hearts to 38%±2 in the subendocardium of the left ventricle of 38-month-old rats. Mitochondrial genomes lacking 8000 to 9000 bp of primary sequence were detected in tissue homogenates from right and left ventricular myocardium and the abundance of these deleted genomes increased with age. In-situ histochemical staining of serial cryomicrotome sections of myocardial tissue revealed individual cardiomyocytes displaying abnormal, primarily absent, activities of cytochrome c oxidase and succinate dehydrogenase. The area density of histochemically-abnormal cardiomyocytes increased from 0.05 per mm2to 0.3 per mm2between 5 and 36–38 months of age in the left ventricle, and they were localized primarily to the left ventricular subendocardium. The presence of age-related mitochondrial genetic and enzymatic abnormalities in the Fischer 344×Brown Norway F1hybrid rat heart suggests the role of mitochondrial dysfunction, secondary to mtDNA mutations, in age-related cardiomyocyte loss and subsequent cardiac aging.

Distribution of a persistent sodium current across the ventricular wall in guinea pigs.

A tetrodotoxin-sensitive persistent sodium current, I(pNa), was found in guinea pig ventricular myocytes by whole-cell patch clamping. This current was characterized in cells derived from the basal left ventricular subendocardium, midmyocardium, and subepicardium. Midmyocardial cells show a statistically significant (P<0.05) smaller I(pNa) than subendocardial and subepicardial myocytes. There was no significant difference in I(pNa) current density between subepicardial and subendocardial cells. Computer modeling studies support a role of this current in the dispersion of action potential duration across the ventricular wall.

Improvement in the Capillarity of the Left Ventricular Wall of Stroke-Prone Spontaneously Hypertensive Rats Following Angiotensin Ii Receptor Blockade

The effect of the angiotensin II type 1 receptor blockade, candesartan cilexetil (TCV116), on the capillarity of the innermost region of the left ventricular subendocardium were studied in stroke-prone spontaneously hypertensive rats (SHRSP). The rats were fed for 32 days on chow that contained TCV1 16, the average dose being 0.96mg/kg/day. Compared with values from control SHRSP, the systolic blood pressure, left ventricular weight and cross-sectional area of cardiomyocytes decreased. A significant increase in the total capillary density was coupled with a decrease of capillary domain areas in all capillary portions. The proportion of venular capillary portions, which was low in control SHRSP, increased significantly, suggesting neoangiogenesis of capillaries. The results indicate that AT1-receptor blockade caused regression of the hypertrophied cardiomyocytes and improved capillarity of the left ventricular wall.

Microheterogeneity of regional myocardial blood flows within the rabbit left ventricular subendocardium evaluated by a molecular flow tracer

Microheterogeneity of regional myocardial blood flows within the rabbit left ventricular subendocardium evaluated by a molecular flow tracer

Myocyte hypertrophy and capillarization in spontaneously hypertensive stroke-prone rats.

Stroke-prone spontaneously hypertensive rats (SHRSP) are liable to suffer a stroke between 25 and 40 weeks of age. Left ventricular capillarity was studied in 40-week-old SHRSP to clarify the effects of hypertrophic changes in cardiomyocytes on oxygen transport capacity within the tissue. The innermost region of the left ventricular subendocardium at the level of the maximum diameter of the heart was investigated. Methods for sectioning and differential staining of arteriolar, intermediate and venular capillaries, and measurements for determining capillarity parameters were as previously described. Total capillary density decreased, while capillary domain areas increased along the whole capillary pathway. These changes in SHRSP seemed unfavorable for oxygen supply to ventricular tissues. To minimize the effects of the adverse changes, the ratio of the capillary to myocyte number increased markedly. The proportion of arteriolar capillaries increased and the venular proportion decreased.

Functional and ultrastructural alterations of canine myocardium subjected to very brief coronary occlusions.

The effects of very brief and recurrent coronary occlusions on myocardial regional shortening and its ultrastructure have been analysed. Ultrasonic crystals were implanted in the left ventricular subendocardium of 23 anaesthetized dogs with the thorax open, to measure the shortening fractions of an ischaemic and a control segment. Twenty 2 min total occlusions were provoked in the left anterior descending coronary artery, with 3 min recovery intervals (reperfusion) between occlusions. The shortening fraction decreased progressively with each occlusion, reaching a value 18.9% lower than the basal after the last ischaemic episode (P < 0.05); 32.3% after 4 h of reperfusion (P < 0.01), and 28.6% after 24 h (P < 0.01). Qualitative and quantitative ultrastructural analysis showed an increase in the mitochondrial volume of the ischaemic tissue (158% vs control, P < 0.001) with significant damage to the cell components (7.7-fold increases vs control mitochondria). These results show that when the myocardium is subjected to very brief and repeated coronary occlusions, there is progressive deterioration of systolic function with structural alterations, mainly at the mitochondrial level. These modifications are still observable 24 h after the end of ischaemic stimulation and could be the cause of transitory and/or chronic systolic dysfunctions in the absence of previous heart attack.

Capillarity in left ventricular subendocardium in STZ-induced daibetic rats

Capillarity in left ventricular subendocardium in STZ-induced daibetic rats

Gradients of transgene expression directed by the human myoglobin promoter in the developing mouse heart.

Prior studies using transient transfection assays in cultured avian and murine skeletal myotubes indicate that the proximal 2-kb segment of the 5' flanking region of the human myoglobin gene contains transcriptional control elements sufficient to direct muscle-specific and developmentally regulated expression of reporter genes. To examine the function of the human myoglobin gene promoter during development of skeletal and cardiac myocytes in the intact animal, a 2.0-kb myoglobin gene upstream fragment was fused to an Escherichia coli lacZ reporter gene and injected into fertilized mouse oocytes. beta-Galactosidase (beta-gal) activity was detected selectively in cardiac and skeletal myocytes of fetal and adult transgenic mice. A distinctive spatial pattern of myoglobin promoter activity was observed in fetal hearts: beta-gal staining was more pronounced within the left ventricular subendocardium than within the subepicardium and was essentially undetectable in the ventricular trabeculae or atria. Expression of endogenous myoglobin mRNA and protein, assessed by in situ hybridization and immunohistochemistry, demonstrated a similar spatial pattern. In contrast, hearts from adult transgenic mice demonstrated essentially homogeneous expression of beta-gal and of endogenous myoglobin mRNA and protein throughout the myocardium, including the trabeculae and atria. These data indicate that the 2.0-kb upstream region of the human myoglobin gene includes cis-acting regulatory elements sufficient to direct transgene expression during murine cardiac development that is myocyte-specific and responsive to positional cues in a similar manner to the endogenous myoglobin gene.

Flow support catheter for prolonged maintenance of coronary blood flow

A newly designed flow support catheter with a supporting wire mesh cage which can be expanded into a tubular configuration and then readily reduced was evaluated in mongrel dogs. Regional myocardial blood flow (RMBF) was measured using the radioactive microsphere technique in the area of both balloon-denuded instrumented and control non-instrumented coronary arteries following placement of either a fixed-wire or a higher profile rapid exchange flow support catheter. At 5, 20, and 180 min following delivery and expansion of either device, RMBF was not significantly different in left ventricular subepicardium and subendocardium perfused by the instrumented vs. the control coronary arteries. Angiography demonstrated widely patent instrumented arteries in 15/18 dogs; in no dog was side branch occlusion observed. Significant cage thrombus deposition was seen angiographically in 3 animals causing temporary total coronary occlusion in 1. Following reduction and removal of the flow support catheter, vessel patency was present in all dogs. The flow support catheter is an effective endovascular stenting device capable of providing structural arterial support, while simultaneously maintaining distal coronary blood flow. It is envisioned that the primary application of this catheter will be to enable primary salvage of vessels acutely injured during coronary angioplasty, by "tacking up" intimal flaps for an extended period. It may also provide a bridge to emergency surgical revascularization.

Left ventricular beta 1 and beta 2 adrenoceptor mRNA expression in normal and volume overloaded human heart.

The aim was to determine gene expressions of beta 1 and beta 2 adrenoceptor subtypes (BAR-1, BAR-2) in normal and volume overloaded human heart. Tissue mRNA levels were determined by excess solution hybridisation using 35S-UTP labelled BAR-1 and BAR-2 cRNA probes. Atrium, right and left ventricular subendocardium, and papillary muscle from donor hearts and papillary muscle from patients operated for mitral stenosis and mitral regurgitation were studied. The basal levels of myocardial BAR-1 and BAR-2 mRNA expression were similar to the levels in human adipose tissue that have been reported previously from our laboratory (10-15 amol mRNA.micrograms-1 total nucleic acids). No differences in BAR-1 and BAR-2 mRNA expression were observed between various parts of the normal heart. In papillary muscle, BAR-1 and BAR-2 mRNA levels were 8.8 (SEM 5.1) and 10.2(6.6) amol.micrograms-1 total nucleic acids, respectively. Furthermore, no differences in BAR mRNA expression were observed between myocardium subjected to mitral stenosis as compared to normal myocardium. On the other hand, patients with mitral regurgitation expressed significantly lower levels of both BAR-1 and BAR-2 mRNA, at 4.8(1.0) (p less than 0.05) and 2.6(1.1) (p less than 0.001) amol.micrograms-1 total nucleic acids, respectively. The ratio BAR-1/BAR-2 mRNA was higher (p less than 0.01) in mitral regurgitation than in the normal heart. Myocardium from different parts of the normal human heart, where different pressure work is generated, express similar levels of BAR-1 and BAR-2 mRNA. With volume load a significant decrease in BAR mRNA levels was observed, which was more marked for BAR-2 mRNA. This difference in specific mRNA levels in patients with mitral regurgitation indicates an independent regulation of the expression of these two receptor subtypes.

Myoglobin content and citrate synthase activity in different parts of the normal human heart

Myoglobin (Mb) content and citrate synthase (CS) activity were determined in myocardial samples from nine human brain-dead organ donors with normal hearts. Six regions of each heart were analyzed: right and left atria, right ventricle, left ventricular subepicardium, subendocardium, and anterior papillary muscle. The Mb content was similar, whereas the CS activity was higher in the left than in the right heart at both atrial and ventricular levels. Mb content and CS activity were higher in ventricles than in atria. The subendocardial layer and papillary muscle of the left ventricle had a higher Mb content than the subepicardial layer, whereas CS activity was similar in these three locations. The results suggested a closer relationship between CS activity (oxidative potential) and work load than between Mb content and work load. Mb content may, instead, be related to intramuscular oxygen tension (PO2) on the basis of a comparison between our Mb data and those of others on regional variations in myocardial PO2.

Excitotoxic lesions of the paraventricular hypothalamus: Metabolic and cardiac effects

The excitotoxin, N- methyl- d-aspartic acid (NMDA), was used to lesion cell bodies, but not fibers-of-passage, in the paraventricular hypothalamus. Bilateral injections of NMDA ( 12.6 nmol 100 nl ) were made into the paraventricular hypothalamus in halothane-anesthetized male Sprague-Dawley rats. Water intake, food intake, urine output and body weight were measured daily for 26 days after lesioning. Lesioned rats exhibited a modest, but significant, reduction in the rate of gain of body weight, which was most closely correlated with decreases in food intake. Water intake and urine output were not significantly different among the groups. Resting blood pressure, heart rate and baroreflex sensitivity (using the infusion of phenylephrine method) were similar in conscious animals of both groups, 4–5 weeks after lesioning. Neuronal loss, primarily of parvocellular elements, was evident in the paraventricular hypothalamus and neuronal loss frequently extended into the ventro-medial thalamus adjacent to the paraventricular hypothalamus in NMDA-lesioned rats. In a second experiment, injections of NMDA were given acutely into the paraventricular hypothalamus of halothane-anesthetized rats. Upon recovery from anesthesia, behavioral excitation and increases in blood pressure and heart rate were evident for 1–2 hr. Histological examination of hearts taken 48 hr after injection of NMDA revealed a largely mononuclear inflammatory infiltration, hyperemia and myocardial hemorrhage and focal myocardial necrosis. Inflammatory and degenerative changes were most prominent in the left ventricular subendocardium. The cardiomyopathy possessed similarities with catecholamine-induced myocardial necrosis. The results indicated that NMDA-induced lesions of parvocellular elements of the paraventricular hypothalamus did not cause hyperphagia or obesity or alter the resting systemic circulatory function. However, an inflammatory cardiomyopathy, termed “excitotoxin-induced myocardial necrosis”, was associated with injections of NMDA into the hypothalamus. Excitotoxin-induced myocardial necrosis may complicate any hemodynamic studies performed in rats in which lesions of the CNS have been produced by means of application of excitotoxins.

Atrial natriuretic peptide distribution in fetal and failed adult human hearts.

The distributions of atrial natriuretic peptide (ANP) in human hearts during the developmental stage and in adult pathological states was examined with an antibody specific to human alpha-ANP. With immunoblotting and immunofluorescence methods, we found that a 17-kDa protein, which is a pro ANP, was expressed in human fetal ventricles, in which the numbers of myofibers containing ANP granules were more abundant in the subendocardial region than the subepicardial region. As determined by radioimmunoassay, the content of immunoreactive ANP (per milligram protein) in the developing heart was greatest in the left atrium and occurred decreasingly in the right atrium, right ventricle, and left ventricle, respectively. Because ANP content in the left ventricle declined during the progress of gestation in developing hearts and because it was very low, if ever detectable, in normal adult hearts, ventricular ANP expression appears to be developmentally regulated from the early gestational stage. However, it was reexpressed in the ventricles of patients who had suffered from severe congestive heart failure. In this situation, we found that the ventricular ANP expression was more marked in patients with dilated cardiomyopathy than in patients with severe valvular disease. Interestingly, in the ventricles of patients with dilated cardiomyopathy, ANP contents were higher in the left ventricular free wall than in the right ventricular free wall, although the left ventricular subendocardium contained more ANP than the subepicardium, showing a transmural gradient similar to that expressed in fetal ventricles. Thus, the expression of ANP in human ventricles is developmentally regulated from the early gestational stage, and even adult ventricular myofibers can synthesize ANP during severe congestive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Early loss of myocardial myoglobin detected immunohistochemically following occlusion of the coronary artery in rats

The time course of the loss of myoglobin from the rat ventricular myocardium in the early phase of ischemia was studied with the use of an immunohistochemical technique and an image analyzer. The loss of myoglobin, as an index of myocardial injury, was evident in the left ventricular subendocardium as early as 0.5 hr after occlusion of the left main coronary artery. A clear-cut demarcation of the myoglobin-depleted area helped quantification of the injured areas with an image analyzer. The area with depleted myoglobin became transmural and reached maximum after 2 and 3 hr of occlusion, respectively. Electron microscopic observation of the myoglobin-depleted region revealed amorphous dense bodies in the mitochondria, indicating irreversible damage to the myocardial cells. On the other hand, no irreversible changes could be detected with hematoxylin-eosin stain until 6 hr after the start of the ischemia, and the distinction between the reversible and irreversible areas was unclear. We suggest that depletion of myoglobin from the myocardium serves as a marker for irreversible ischemic injury. Quantitative assessment of the injured areas by immunohistochemical staining for myoglobin together with an image analyzer could be of great value for the evaluation of early ischemic myocardial damage.

Myocardial Protection: Left Ventricular Ultrastructure after Different Forms of Cardiac Arrest

Clinically applied methods of cardioplegia show very different effects on the rapidity of decay of energy-rich phosphates as well as on kind and progression of ultrastructural alterations of the ischemic myocardium. Comparing the methods of cardioplegia according to Kirklin, St. Thomas's Hospital and Bretschneider (solution HTK) with pure ischemia at 25 degrees C (model A) and Kirklin's or St. Thomas's cardioplegia and subsequent 210 min or HTK cardioplegia and 300 min ischemia at 22 degrees C plus 20 min subsequent reperfusion (model B) leads to the following results: Model A: Compared with pure ischemia cardioplegia according to Kirklin and the St. Thomas's Hospital slows down the decay of the left ventricular ATP-concentration by a mean factor of 3 and the progression of structural alterations of the left ventricular subendocardium by a factor of 2. HTK retards the ATP-decay by a factor of 6, the alterations of ultrastructure by a factor of 6.5. St. Thomas's solution, in contrast to all other methods of cardioplegia, at the onset of ischemia already causes a cellular edema of myocytes; the edema increases during ischemia, and at the ATP-concentration of 4 mumol per gram myocardium is more pronounced than with pure ischemia, Kirklin or HTK. After application of Kirklin's solution, in contrast, a cellular edema of capillary endothelia develops during ischemia, which at 4 mumol ATP is more pronounced than with each of the other methods. Model B: After global ischemia until the ATP-concentration of left ventricular myocardium is 4 mumol/g and a subsequent 20 minutes post-ischemic recovery the ultrastructural alterations in principle resemble those occurring during ischemia (model A).(ABSTRACT TRUNCATED AT 250 WORDS)