Manganese reduces myocardial reperfusion injury on isolated rat heart

It has been shown that reactive oxygen species produced during the early phase of myocardial post-ischemic reperfusion are one of the main causes of reperfusion injury. This observation has led to various antioxidant strategies using many reactive oxygen species scavengers, including manganese complexes. The aim of the present work was to provide a reference study of the effects of manganese itself (MnCl2) on isolated rat hearts submitted to global total normothermic ischemia (30 min) and reperfusion (60 min). McCl2 was administered either during the first 10 min reperfusion (10(-5)M and 10(-4)M) or throughout reperfusion (10(-4)M). After 10 min reperfusion, no functional difference was evidenced between control and manganese-treated groups, whereas high energy phosphate contents were significantly higher in treated groups. MnCl2 10(-4)M enhanced the recovery of developed pressure between 40 and 55 min reperfusion. At the end of reperfusion, hearts treated during the first 10 min reperfusion showed a better metabolic recovery. The group treated throughout reperfusion showed a better metabolic recovery, but a reduced coronary flow and a weak recovery of developed pressure. These results suggest that MnCl2, administered during the early phase of reperfusion, protects against myocardial reperfusion injury. This effect might be mediated by manganese antioxidant properties.     

Factors modifying ischemic injury in the isolated rat heart

The extent of ischemic injury has been studied in the isolated working rat heart utilizing an aortic ball valve that reduces the coronary flow. A number of factors were tested including high heart rate, noradrenaline, acidosis, alkalosis, high afterload, beta-blockade, glucose-insulin-potassium (GIK), palmitate and methylprednisolone. Mechanical performance, myocardial contents of ATP, creatine phosphate, glycogen and lactate and the leakage of creatine phosphokinase (CK) from the myocardium to the perfusion buffer were measured and used for determination of the ischemic injury. Tachycardia, noradrenaline and palmitate are factors that markedly increase the ischemic injury in this preparation. GIK and probably metoprolol decrease the release of CK compared with the controls.     

The sodium-hydrogen exchange system in the heart: its role in ischemic and reperfusion injury and therapeutic implications

OBJECTIVES: To review evidence supporting a role for sodium-hydrogen exchange (Na/H exchange) in mediating myocardial ischemic and reperfusion injury, and to outline clinical implications in terms of the development of novel cardioprotection strategies. DATA SOURCES: Various sources were used including MEDLINE and Reference Update. Only articles written in the English language were used. DATA EXTRACTION: A wide range of publications dealing with cardiac injury and particularly studies involving intracellular pH regulation and Na/H exchange activity. The vast majority of papers cited were published since 1986, with a large percentage appearing within the past five years. DATA SYNTHESIS: Na/H exchange is a major mechanism for restoration of intracellular pH after ischemia, although its activation during both ischemia and reperfusion has been shown to be involved in a paradoxical induction of cell injury. This likely reflects the fact that activation of the exchanger is closely coupled to sodium influx and, as a consequence, to elevation in intracellular calcium concentrations through sodium-calcium exchange. In addition to intracellular acidosis, other factors can stimulate the exchanger, including various autocrine and paracrine factors such as endothelin-1 and activation of alpha 1 adrenergic receptors, both of which likely act through signal transduction processes including activation of protein kinase C. Although at least 5 Na/H exchange isoforms have been identified, it appears that subtype 1, termed NHE-1, is the predominant isoform in the mammalian myocardium. Effective pharmacological inhibitors of Na/H exchange, including those that are NHE-1 specific, have been developed. These have been extensively demonstrated to protect the ischemic and reperfused myocardium, as shown by improved systolic and diastolic function, preservation of cellular ultrastructure and reduced incidence of arrhythmias. Moreover, the salutary effects of these agents have been demonstrated by a variety of experimental models and animal species, suggesting that the role of Na/H exchange in mediating injury is not species-specific. CONCLUSION: Na/H exchange is an important target for pharmacological intervention in attenuation of ischemia- and reperfusion-induced cardiac injury. Coupled with the low potential for toxicity by the agents, Na/H exchange inhibition could emerge as an effective therapeutic strategy in cardiac disorders, particularly involving conditions associated with ischemia and reperfusion.     

The diabetic heart is more sensitive to ischemic injury

A review of the literature on the impact of dental care on the incidence of dental caries in children and adults suggests that the effect is small. Dental services were relatively unimportant in explaining the recent decline in caries in 5- and 12-year-olds. An important contribution of the dental services to the decline in caries was a change in the diagnostic and treatment criteria. The role of dentistry in reducing dental caries may lie mainly in the non-personal health services. Knowledge of the life history and patterns of caries attack rates within populations and individuals could be used as a benchmark against which interventions can be assessed. Different teeth and tooth sites are affected differentially at different levels of dental caries. This truism may appear obvious but it is not used to evaluate the effectiveness and quality of dental treatment. A working rule is that "As caries prevalence falls, the least susceptible sites (proximal and smooth surfaces) reduce by the greatest proportion, while the most susceptible sites (occlusal) reduce by the smallest proportion." There is a specific relationship between the mean DMFT and mean DMFS, and the percentage of caries-free subjects and the frequency distribution of subjects with different levels of caries. Further more, the best predictor of caries at older ages is DMFT at a younger age. Caries levels follow trend lines for each level of caries. As the mean DMFT declines so post-eruptive time increases for initiation of caries and the progression rates of caries through enamel decreases. This is true regardless of the presence of fluoride.     

The role of the endogenous opioid system in regulation of the nonspecific resistance of the myocardium to reperfusion injury in rats

Under conditions of postischemic reperfusion, significance of endogenous opioid receptors' agonists for regulation of the myocardial contractility becomes enhanced. The sigma-receptor blocking contributes to a decrease in postischemic contracture and preservation of the cardiac cell membrane integrity. In sigma-receptor blockade, reoxygenation contracture does not appear. Preliminary mu-receptor blocking leads to an almost complete restitution of the heart contractility and decreases sarcolemma damage during postischemic period.     

Effects of nimodipine on acute cerebral ischemia and reperfusion injury of rats

AIM: To study the effect of nimodipine (Nim) on ischemic cerebral damage. METHODS: The four-vessel occlusion method was performed on rats. Monoamines were measured by fluorospectrophotometry. RESULTS: Intraperitoneal injection of Nim 0.75 and 1.5 mg.kg-1 quickened the recovery of EEG changes to 19 +/- 3 and 17 +/- 4 min (P < 0.01), respectively. Nim reduced the decreases of monoamines (NE, DA, 5-HT, and 5-HIAA) contents after 30-min cerebral ischemia and 1-h reperfusion. CONCLUSION: Nim protects the brain from ischemic damage.     

Increased oxidant resistance of alveolar macrophages isolated from rats repeatedly exposed to cadmium aerosols

This study investigated potential mechanisms of oxidant resistance in alveolar macrophages (AM) isolated from Lewis rats exposed repeatedly to cadmium aerosols. Macrophages from Cd-adapted animals significantly greater resistance to oxidant-induced cytotoxicity than control cells when challenged with hydrogen peroxide in vitro. Elevations in glutathione peroxidase and glutathione reductase activities were associated with increased oxidant tolerance but catalase activity was unchanged. Metallothionein (MT) expression (protein and mRNA) was dramatically up-regulated in response to in vivo Cd exposure. A study using immunocytochemistry and in situ hybridization techniques revealed significantly heterogeneity in the expression of metallothionein by AMs. The percentage of AMs positive for MT (protein and mRNA) and the degree of MT expression within individual cells increased in response to additional Cd exposures. A putative state of activation was suggested by differences in size and number of inclusion bodies in macrophages from Cd-adapted animals and by secretion of a cytokine with interleukin-1-like characteristics. In summary, AMs from Cd-adapted animals are distinguished from control cells with respect to: (1) increased oxidant resistance, (2) secretion of cytokines, (3) elevations in enzymes associated with glutathione metabolism, and (4) up-regulation in metallothionein expression.     

Effect of captopril cardioplegia on renin-angiotensin system, prostaglandins, free radicals and electrolytes in the isolated hypothermic ischemic and reperfusion rabbit hearts

The effect of captopril cardioplegia on ischemic and reperfusion myocardium after 3 hours of hypothermic (13 +/- 1 C) arrest and 35 minutes of reperfusion was studied in the isolated working rabbit heart. In comparison with the control group, captopril cardioplegia reduced the content of angiotensin II (381 +/- 56 vs 507 +/- 84 pg/g wt of the control group, P < 0.01) and MDA (50.0 +/- 9.2 vs 85.1 +/- 16.1 pmol/mg pr, P < 0.01) in the reperfusion myocardium; augmented the renin activity of ischemic (1050 +/- 353 vs 669 +/- 301 pg/g wt/h, P < 0.05) and reperfusion myocardium (1261 +/- 421 vs 498 +/- 353 pg/g wt/h, P < 0.01) increased the 6-K-PGF1 alpha/TXB2 ratio in the reperfusion myocardium (by 48.1% of the control group). Meanwhile, captopril cardioplegia could also decrease the content of calcium (0.027 +/- 0.015 vs 0.045 +/- 0.014 microM/mg pr, P < 0.05) and sodium (0.54 +/- 0.26 vs 0.82 +/- 0.15 microM/mg pr, P < 0.05) in the reperfusion myocardium, but had no effect on the potassium content. The results show that the protective effect of captopril on hypothermic myocardium may be related to the free radical scavenging action, inhibition of angiotensin II production, improvement of PGI2/TXA2 ratio and decrease of calcium and sodium overload in the myocardium.     

Blocking of classical complement pathway inhibits endothelial adhesion molecule expression and preserves ischemic myocardium from reperfusion injury

Myocardial injury after ischemia (I) and reperfusion (R) is related to leukocyte activation with subsequent release of cytokines and oxygen-derived free radicals as well as complement activation. In our study, the cardioprotective effects of exogenous C1 esterase inhibitor (C1 INH) were examined in a rat model of myocardial I + R (i.e., 20 min + 24 hr or 48 hr). The C1 INH (10, 50 and 100 U/kg) administered 2 min before reperfusion significantly attenuated myocardial injury after 24 hr of R compared to vehicle treated rats (P < .001). Further, cardiac myeloperoxidase activity (i.e., a marker of PMN [polymorphonuclear leukocyte] accumulation) in the ischemic area was significantly reduced after C1 INH treatment compared to vehicle treated animals (0.81 +/- 0.1, 0.34 +/- 0.13, 0.13 +/- 0.1 vs. 1.44 +/- 0.3 U/100 mg tissue, P < .001). In addition, C1 INH (100 U/kg) significantly attenuated myocardial injury and neutrophil infiltration even after 48 hr of reperfusion compared to vehicle treatment. Immunohistochemical analysis of ischemic-reperfused myocardial tissue demonstrated activation of classical complement pathway by deposition of C1q on cardiac myocytes and cardiac vessels. In addition, expression of the endothelial adhesion molecules P-selectin and intercellular adhesion molecule 1 (ICAM-1) was observed after reperfusion of the ischemic myocardium. In this regard, C1 INH administration abolished expression of P-selectin and ICAM-1 on the cardiac vasculature after myocardial ischemia and reperfusion. Blocking the classical complement pathway by exogenous C1 INH appears to be an effective means to preserve ischemic myocardium from injury after 24 and 48 hr of reperfusion. The mechanisms of this cardioprotective effect appears to be due to blocking of complement activation and reduced endothelial adhesion molecule expression with subsequent reduced PMN-endothelium interaction, resulting in diminished cardiac necrosis.     

Venous blood return to the heart in focal myocardial ishemia and its effect on the degree of ischemic injury and the size of the ischemic area

It was established in experiments on 14 dogs that the acute character of ischemic damage to the myocardium and the size of the zone of ischemia in occlusion of the coronary artery diminish against the background of reduced venous return to the heart. The reduction in the ischemic area occurs for the most part because of a decrease of the border-line and neutral zones.     

Staged reperfusion preserves the coronary flow reserve, especially in the regions not severely damaged by ischemic injury in the canine heart

The objective of this study was to determine the effects of staged reperfusion on the progressive reduction in coronary blood flow (CBF) and coronary flow reserve during reperfusion and on the infarct size in the canine heart. Fifteen dogs underwent 90 min of left circumflex coronary artery occlusion and 3 hr of reperfusion. In the abrupt reperfusion group, the occluder was released completely at the initiation of reperfusion. In the staged reperfusion group, CBF was maintained at 20% of preocclusion values for 10 min after initiation of reperfusion, then gradually released, and completely released 20 min after initiation of reperfusion. There was no significant difference in CBF between the staged (n = seven) and abrupt (n = eight) groups after 3 hr of reperfusion. The repayment of flow debt in the staged reperfusion group was significantly greater than in the abrupt reperfusion group after 3 hr of reperfusion (260+/-120% vs 100+/-60%, staged vs abrupt at 3 hr, p < 0.03). The ratio of peak reactive hyperemic flow to resting flow in the staged reperfusion group was significantly greater than in the abrupt reperfusion group throughout the reperfusion phase (4.4+/-1.0 vs 2.6+/-0.6 at 3 hr, p < 0.001), and had returned to the preocclusion values after 3 hr of reperfusion. This preservation of the coronary flow reserve in the staged reperfusion group was observed in the epicardium (4.1+/-0.6 vs 2.8+/-0.7, staged vs abrupt at 3 hr, p < 0.01), but not in the endocardium or midmyocardium. Infarct size did not differ significantly between the two groups. Staged reperfusion in this study did not appear to attenuate the reduction of CBF, or to reduce infarct size, however preserved the coronary flow reserve, especially in the regions not severely damaged by ischemic injury.     

Effect of oligosaccharides on rejection and reperfusion injury after lung transplantation

PURPOSE: We developed two models that are modifications of our original poly(2-hydroxyethyl methacrylate) (PHEMA) core-and-skirt keratoprosthesis. In these keratoprostheses, the mechanical strength of the skirt has been considerably increased with divinyl glycol (DVG) as a cross-linking agent during polymerization. In one (KPro I), methyl methacrylate (MMA) was added as comonomer to increase cell adhesion, and in the other (KPro II), HEMA was polymerized with DVG without comonomer. The aim of this study was to evaluate the process of healing and biocolonization and to ascertain whether KPro I demonstrates better ingrowth than the mechanically stronger KPro II, after implantation in rabbit eyes. METHODS: Ten rabbits were used for each model and studied at five predetermined end points up to 26 weeks. The device was implanted as a full-thickness keratoprosthesis covered with a conjunctival flap. RESULTS: Neither prosthesis demonstrated extrusion or retroprosthetic membrane formation. There was no significant difference between the two types of prosthesis with respect to tissue ingrowth and surrounding tissue melting. Histologically, inflammation was not severe, but calcification was seen in most specimens. Evidence of biodegradation of the prosthesis also was seen. CONCLUSION: In our original keratoprosthesis, fibrovascular invasion had occurred into the prosthetic skirt, but wound dehiscence and low mechanical strength resulted in an unfavorable outcome. In this series, the mechanical properties were improved, and KPro II was stronger than KPro I. Therefore KPro II would be the preferred polymer combination for surgical manipulation. However, biodegradation and calcification require further investigation into the degree and significance of these adverse reactions.     

Ischemic preconditional protection of ischemia reperfusion injury on isolated hearts of ground squirrel and rat

The protective effects of ischemic preconditioning on ischemia-reperfusion injury was investigated using isolated Langendorff perfusing hearts from ground squirrel and rat. In Preconditioning I group hearts were first perfused with Krebs-Henseleit solution for 10 min to establish a steady state, then stopped for 15 min to establish global ischemia, and finally followed by 10 min ischemia and 10 min reperfusion. In Preconditioning II group there were three cycles of 5 min ischemia + 5 min reperfusion after 10 min equilibration and then the final 10 min ischemia and 10 min reperfusion were followed. It was found that in group I during the final 10 min ischemia period there was remarkable augmentation of CK release from both animal's hearts. But in group II CK release decreased markedly during the same ischemic period. CK release during final 10 min reperfusion period also decreased significantly in group II in comparison with group I. The incidence of arrhythmias occurred in both animal's hearts was markedly reduced in group II rather than group I. In conclusion, short episode ischemic preconditioning protect subsequent ischemia-reperfusion injury on isolated hearts from ground squirrel and rat.     

Redox transformations of spin probes during interaction with isolated myocardium in ischemic and reperfusion conditions

It has been shown, that a certain part of spin labels TEMPO, TEMPAMINE or TEMPOL undergoes redox-transformations during the perfusion of rat isolated working hearts. The kinetic parameters of the redox-transformations depend on the duration of the ischemia period.     

Effect of acetylsalicylic acid on metabolism and contractility in the ischemic reperfused heart

The effect of acetylsalicylic acid (ASA) on high-energy phosphates (adenosine triphosphate: ATP, creatine phosphate: CrP, inorganic phosphate: Pi) and intracellular pH during myocardial ischemia and reperfusion was studied using phosphorus 31-nuclear magnetic resonance (31P-NMR) in the isolated rabbit hearts. Coronary flow, left ventricular systolic developed pressure (LV Dev.P) and left ventricular end-diastolic pressure (LVEDP) were also measured. Langendorff hearts perfused at 37 degrees C with the perfluorochemical emulsion Fluosol-43 were subjected to 15 min and 30 min of zero-flow ischemia and to 15 min of low-flow ischemia (coronary perfusion pressure = 20 mmHg) followed by 65 min of reperfusion (control, Group I). ASA (0.28 mmol/L) was infused either for the entire experimental period from beginning 45 min prior to ischemia (Group II) and infused immediately after reperfusion (Group III). During ischemia, Group II showed a significant suppression of the decrease in the ATP level and pH with both zero-flow and low-flow ischemia compared to those in the other groups, and moreover the increase in Pi and the decrease in CrP in low-flow ischemia were also suppressed. In Group III, the ATP level during reperfusion was significantly higher than that in Group I, but was not significantly different from that in 30 min zero-flow ischemia. In 30 min zero-flow ischemia, Pi, CrP and coronary flow after reperfusion in Group II tended to recover to preischemic values. There were no differences in LV Dev.P among the 3 groups. In conclusion, ASA has a protective effect on myocardial high-energy phosphates during ischemia and reperfusion in rabbit hearts.     

Effect of spinal cord injury on the heart and cardiovascular fitness

The use of various FES protocols to encourage increases in physical activity and to augment physical fitness and reduce heart disease risk is a relatively new, but growing field of investigation. The evidence so far supports its use in improving potential health benefits for patients with SCI. Such benefits may include more efficient and safer cardiac function; greater stimulus for metabolic, cardiovascular, and pulmonary training adaptations; and greater stimulus for skeletal muscle training adaptations. In addition, the availability of relatively inexpensive commercial FES units to elicit muscular contractions, the ease of use of gel-less, reusable electrodes, and the increasing popularity of home and commercial upper body exercise equipment mean that such benefits are likely to be more accessible to the SCI population through increased convenience and decreased cost. The US Department of Health and Human Services has identified those with SCI as a "special population" whose health problems are accentuated, and so need to be specifically addressed. FES presents "a clear opportunity.... For health promotion and disease prevention efforts to improve the health prospects and functional independence of people with disabilities." As a corollary to this, the Centers for Disease Control and Prevention have recommended the development of techniques to prevent or ameliorate secondary disabilities in persons with a SCI. Patients with SCI have an increased susceptibility to cardiac morbidity and mortality in the acute and early stages of their injury. Most of these patients make an excellent adaptation except when confronted with infection or hypoxia. SCI by itself does not promote atherosclerosis; however, in association with multiple secondary conditions related to SCI, along with advancing age, patients with SCI are predisposed to relatively greater risk of heart disease. The epidemiologic significance of this is reflected in demographic studies that indicate an increasing number of SCI patients becoming aged. Currently 71,000 (40%) of the total 179,000 patients with SCI living in the United States are older than 40 years, and 45,000 have injuries sustained more than 20 years earlier. In addition, new injuries in the older population are increasing (currently 11% of all injuries), and some of these new patients with SCI already have pre-existing cardiac disease. Studies have demonstrated that improved lifestyle, physical activity, lipid management, and dietary restrictions can affect major risk factors for coronary artery disease. Therefore an aggressive cardiac prevention program is appropriate for patients with SCI as part of their rehabilitation. At a given submaximal workload, arm exercise is performed at a greater physiologic cost than is leg exercise. At maximal effort, however, physiologic responses are generally greater in leg exercise than arm exercise. Arm exercise is less efficient and less effective than lower body exercise in developing and maintaining both central and peripheral aspects of cardiovascular fitness. The situation is further compounded in SCI because of poor venous return as a result of lower-limb blood pooling, as a result of lack of sympathetic tone, and a diminished or absent venous "muscle pump" in the legs. This latter mechanism perhaps contributes the greatest diminution in the potential for aerobic performance in the SCI population. Obtaining a cardiopulmonary training effect in individuals with SCI is quite possible. Current studies indicate decreases in submaximal HR, respiratory quotient, minute ventilation, and oxygen uptake, with increases in maximal power output, oxygen uptake, minute ventilation, and lactic acid. Individuals with SCI have been shown to benefit from lower limb functional electrical stimulation (FES)-induced exercise. Studies have consistently reported increases in lower limb strength and cycle endurance performance with these protocols, as well as improvements in metabolic and