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Biomedical subjects

K Przyklenk

Publications and source records attributed to K Przyklenk.

At least 91 records · Page 5Linked to original sources
PubMed1989

Early treatment with deferoxamine limits myocardial ischemic/reperfusion injury.

Oxygen-derived free radicals (the superoxide anion O2- and hydroxyl radical.OH) have been implicated in myocardial injury associated with coronary artery occlusion followed by reperfusion. Transition metals (such as iron or copper) are needed to catalyze the formation of the .OH radical and subsequent .OH-mediated lipid peroxidation, yet the role of these transition metals in the pathogenesis of myocyte necrosis remains undefined. To address this issue, 21 dogs underwent 2 h of coronary artery occlusion and 4 h of reperfusion. Each animal was randomly assigned into 1 of 3 treatment groups: 7 received the iron chelator deferoxamine beginning 30 min preocclusion, 7 received deferoxamine beginning 5 min prior to reperfusion, while 7 dogs served as saline controls. Deferoxamine effectively chelated free iron in both treatment groups (total urine iron content averaged 42 +/- 16, 662 +/- 177 and 803 +/- 2.5 micrograms in control, pretreated, and deferoxamine at reperfusion groups respectively; p less than 0.05), but had no significant effect on in vivo area at risk (AR), hemodynamic parameters, collateral blood flow during occlusion, or myocardial blood flow following reperfusion. Area of necrosis (AN) in dogs pretreated with deferoxamine (34.6 +/- 3.7% of the AR; p less than 0.05) was significantly smaller than that observed in the saline control group (55.4 +/- 4.7% of the AR). Deferoxamine administered at the time of reperfusion, however, had no significant effect on infarct size (AN/AR = 54.3 +/- 8.7%, p = NS vs. controls). Thus, early treatment with the iron chelator deferoxamine acutely reduced the extent of myocyte necrosis produced by 2 h of transient coronary artery occlusion in the canine model.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Relationships between structure and effects of ACE inhibitors: comparative effects in myocardial ischaemic/reperfusion injury.

1. Coronary artery reperfusion has become the treatment of choice for evolving myocardial infarction. 2. While there is no question that timely restoration of coronary blood flow is essential for the salvage of ischaemic myocardium, coronary reperfusion has also been associated with potentially deleterious consequences. Specifically, the viable tissue salvaged by reperfusion remains 'stunned'--i.e., exhibits prolonged abnormalities in contractile function--for hours to days following reflow. Furthermore, it has been suggested that reperfusion per se may lethally injure some myocytes that were only reversibly injured prior to restoration of blood flow. 3. ACE inhibitors such as captopril and enalapril have been shown to reduce indices of myocardial injury (infarct size, creatine kinase release) and enhance contractile function of stunned myocardium in experimental models of coronary occlusion followed by reperfusion. These effects of ACE inhibitors have largely been attributed to the reduction in myocardial O2-demand and increase in myocardial blood flow associated with blunting of angiotensin II formation. 4. Recent studies suggest that the effects of some ACE inhibitors--particularly captopril--may not solely be explained on the basis of ACE inhibition. In fact, sulphydryl (-SH) containing ACE inhibitors such as captopril appear to act as scavengers of oxygen-derived free radical species thought to be important in the pathogenesis of both postischaemic contractile dysfunction and ischaemia/reperfusion induced myocyte necrosis. 5. Thus, -SH containing ACE inhibitors--which both inhibit ACE and scavenge cytotoxic free radicals--may offer a suitable form of treatment for myocardial ischaemia/reperfusion injury.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Deleterious effects of oxygen radicals in ischemia/reperfusion. Resolved and unresolved issues.

Oxygen free radicals are known to be generated during periods of ischemia followed by reperfusion. There is still some controversy, however, concerning the use of electron paramagnetic resonance spectroscopy to accurately detect and identify the free radical species that are formed. There is no doubt that oxygen radicals are deleterious to the myocardium; free radicals cause left ventricular dysfunction and structural damage to myocytes and endothelial cells in both in vitro and in vivo preparations. Potential sources of these cytotoxic oxygen species include the xanthine oxidase pathway, activated neutrophils, mitochondria, and arachidonate metabolism, yet the crucial source of free radicals in the setting of ischemia and reperfusion is unresolved. There is little doubt that oxygen radicals play a role in the phenomenon of stunned myocardium induced by brief periods of ischemia followed by reperfusion; numerous studies have consistently observed that pretreatment with free radical scavengers and antioxidants enhances contractile function of stunned, postischemic tissue. Whether oxygen free radical scavengers administered only during reperfusion enhance recovery of stunned myocardium in models of brief ischemia remains to be determined. In models of prolonged ischemia (2 hours) followed by reperfusion, we have not observed a beneficial effect of scavengers on stunned myocardium. The issue of whether oxygen free radical scavengers are capable of reducing so-called irreversible or lethal reperfusion injury remains, in our opinion, unresolved. Although some studies have observed that agents such as superoxide dismutase and catalase reduce infarct size in ischemia and reperfusion models, many others have reported negative results. Additional studies will be needed to resolve this ongoing controversy. Oxygen free radicals may also contribute to reperfusion-induced arrhythmias in rodent heart preparations; however, less data are available in other animal models. The concept of reperfusion injury should not be considered a deterrent to reperfusion for the treatment of acute myocardial infarcts in the clinical setting. Thrombolytic therapy reduces myocardial infarct size, enhances recovery of left ventricular function, and improves survival. Whether incremental beneficial effects on these parameters will be obtained when oxygen radical-scavenging agents are used as adjuvant therapy to thrombolysis in patients remains to be determined.

Animals↗
PubMed1989

"Reperfusion injury" by oxygen-derived free radicals? Effect of superoxide dismutase plus catalase, given at the time of reperfusion, on myocardial infarct size, contractile function, coronary microvasculature, and regional myocardial blood flow.

Do oxygen-derived free radicals, generated at the time of reperfusion, lethally injure viable, previously ischemic myocardium, damage vascular endothelium, and impair recovery of postischemic contractile function? To address these issues, 23 anesthetized open-chest dogs underwent 2 hours of left anterior descending coronary artery occlusion followed by 4 hours of reperfusion. Immediately prior to reflow, each dog was randomized to receive either the free radical scavenging agents superoxide dismutase (SOD) + catalase, or saline alone. SOD + catalase had no significant beneficial effect on infarct size measured by triphenyltetrazolium staining: area of necrosis averaged 38.5 +/- 6.1% vs. 46.3 +/- 6.2% of the area at risk in treated compared with control animals respectively (p = NS). Furthermore, infusion of SOD + catalase did not alter contractile function of the viable subepicardium: mean segment shortening (measured using sonomicrometry) at 4 hours postreperfusion was -23 +/- 5% of baseline, preocclusion values in controls dogs and -24 +/- 9% of preocclusion values in animals that received the scavenging agents. However, SOD + catalase treatment preserved the endocardial microvasculature (assessed by semiquantitative electron microscopic analysis) and enhanced regional myocardial blood flow after reperfusion. Specifically, mean score for microvascular injury was 0.41 +/- 0.14 vs. 0.10 +/- 0.08 (p less than 0.05) in control compared with SOD + catalase treated groups, and blood flow averaged 0.56 +/- 0.11 vs. 1.27 +/- 0.33 ml/min/g tissue (p less than 0.05), respectively, in the previously ischemic endocardium at 2 hours postreflow. Thus, SOD + catalase given at the time of reperfusion had no acute beneficial effect on either the extent of myocyte necrosis or postischemic contractile function in this canine model. SOD + catalase did, however, attenuate both endocardial vascular injury and the "low reflow" phenomenon. These data suggest that microvascular injury and low reflow following prolonged (2 hour) but transient coronary occlusion may be mediated by oxygen-derived free radicals generated at the time of reperfusion.

Animals↗
PubMed1988

Effect of verapamil on postischemic "stunned" myocardium: importance of the timing of treatment.

Timely administration of verapamil has been shown to reduce indexes of ischemic injury in experimental models of prolonged coronary artery occlusion, yet its effect on contractile function of reversibly injured (that is, "stunned") myocardium remains unknown. The objective of the present study was to determine whether verapamil--administered either 30 min before coronary artery occlusion, at the time of reperfusion or 30 min after reperfusion--could attenuate the regional contractile dysfunction and alterations in high energy phosphate metabolism produced by 15 min of transient coronary artery occlusion in anesthetized, open chest dogs. All treatment groups exhibited passive systolic bulging during occlusion. In the control dogs receiving saline solution, segment shortening in the previously ischemic tissue averaged only 31 +/- 8% of normal baseline values after 3 h of reperfusion. In addition, endocardial adenosine triphosphate (ATP) stores were depleted by -8.7 +/- 0.8 nmol/mg cardiac protein to 26.5 +/- 1.1 nmol/mg protein, and endocardial creatine phosphate content increased by 9.6 +/- 4.3 nmol/mg cardiac protein over normal values. Pretreatment with verapamil essentially ablated the phenomenon of postischemic stunning: segment shortening was restored to 115 +/- 8% of normal after 3 h of reflow (p less than 0.01 versus control), endocardial ATP stores were partially preserved (30.6 +/- 1.2 nmol/mg protein; p less than 0.05 versus control) and creatine phosphate overshoot was blunted (endocardial creatine phosphate content decreased by -5.6 +/- 2.9 nmol/mg protein; p less than 0.05 versus control). Verapamil administered at or after reperfusion also attenuated postischemic contractile dysfunction: segment shortening for both groups recovered to 65 +/- 9% of baseline at 3 h after reperfusion (p less than 0.05 versus control). Verapamil given at or after reperfusion had no beneficial effect, however, on high energy phosphate stores. Thus, even when treatment was "delayed," that is, initiated at or after reperfusion, administration of verapamil significantly increased contractile function of the postischemic stunned myocardium.

Adenosine Triphosphate↗
PubMed1988

Oxygen-derived free radicals and 'stunned myocardium'.

A brief, transient period of coronary artery occlusion (less than 20 minutes in duration) followed by reperfusion does not result in irreversible myocyte injury or death, yet the regional contractile function and high energy phosphate content of the previously ischemic tissue remains depressed or 'stunned' for hours to days following reperfusion. It has been suggested that this prolonged postischemic dysfunction of viable, previously ischemic myocardium may be a consequence of oxygen-derived free radicals generated during occlusion or at the time of reperfusion. Recent evidence demonstrates that free radical scavenging agents such as superoxide dismutase (SOD) + catalase, N-2-mercaptopropionylglycine, and allopurinol, administered prior to coronary artery occlusion, significantly enhance recovery of regional contractile function of the stunned, previously ischemic tissue. This improved contractile function was not, however, accompanied by improvements in high energy phosphate metabolism: infusion of SOD + catalase did not preserve ATP stores in the previously ischemic tissue. These data support the hypothesis that oxygen-derived free radicals contribute, at least in part, to the phenomenon of the stunned myocardium. The source or mechanisms of free radical production in the setting of brief, transient ischemia, however, remains to be elucidated.

Adenosine Triphosphate↗
PubMed1987

Effect of myocyte necrosis on strength, strain, and stiffness of isolated myocardial strips.

Cardiac rupture accounts for 8% to 10% of patient deaths after acute myocardial infarction, suggesting that myocyte necrosis weakens the ventricular wall in the initial days after occlusion. To test this theory, permanent occlusion of the left anterior descending coronary artery was performed in dogs. Twenty-four hours after occlusion, the tensile strength, strain at rupture, and stiffness of necrotic epicardium, midmyocardium, endocardium, subepicardium, and the visceral pericardium (VP) were quantified and compared with those of noninfarcted cardiac tissue. The relationship between tensile strength, stiffness, and collagen content was also examined. These material properties did not differ between necrotic and normal myocardium in any of the layers, indicating that myocyte necrosis, per se, does not weaken the myocardium. In both necrotic and normal tissue, marked transmural heterogeneity was observed; tensile strength of the endo- and epicardium (21.3 +/- 3.3 and 21.3 +/- 3.2 gm/mm2) was significantly greater (p less than 0.01) than that of the midmyocardium (4.0 +/- 0.3 gm/mm2) and subepicardium (5.0 +/- 0.5 gm/mm2), whereas the VP was substantially stronger (greater than 100 gm/mm2) than any myocardial layer. Similar results were obtained for stiffness. In contrast, strain at rupture did not vary significantly among myocardial layers and ranged from 0.40 +/- 0.03 (VP) to 0.53 +/- 0.03 (endocardium). Both tensile strength and stiffness of the myocardial layers were found to correlate directly with their collagen content: the higher the hydroxyproline concentration, the greater the tensile strength (r = 0.83). These results support the concept that the collagen fibroskeleton is an important determinant of the material properties of the myocardium. As myocyte necrosis, per se, did not affect tensile strength, we tentatively conclude that cardiac rupture may be a consequence of a defect or weakness in the collagenous framework of the heart.

Animals↗
PubMed1987

Differential effects of reperfusion on incidence of ventricular arrhythmias and recovery of ventricular function at 4 days following coronary occlusion.

To determine the influence of coronary reperfusion on ventricular arrhythmias and ventricular function at 4 days post occlusion, anesthetized dogs randomly received no occlusion (sham), permanent occlusion, or 1-, 2-, 3-, 4-, or 6-hour occlusions of the left anterior descending coronary artery, followed by reperfusion. An ambulatory ECG was recorded between 78 and 96 hours. The total runs of ventricular tachycardia were 1 +/- 0 (sham), 155 +/- 101 (1 hour), 66 +/- 32 (2 hours), 56 +/- 35 (3 hours), 167 +/- 68 (4 hours), 942 +/- 618 (6 hours), and 1422 +/- 486 (permanent occlusion); the runs of ventricular tachycardia were significantly less in the combined 1- to 4-hour groups (93 +/- 24) compared to the 6-hour and permanent occlusion groups (1282 +/- 384; p less than 0.006). Similar results were obtained for the number of hours in which ventricular tachycardia or frequent ventricular premature beats occurred. At 96 hours, improvement in percent systolic wall thickening of the ischemic myocardium assessed by two-dimensional echocardiography was seen in the group reperfused at 1 hour (p less than 0.01). Similar results were obtained for the reduction in degrees of wall circumference showing systolic thinning. In summary, at 4 days post occlusion in a dog model, spontaneous ventricular arrhythmias are reduced by reperfusion within 4 hours, while return of ventricular function is only improved by reperfusion within approximately 1 hour of coronary occlusion.

Animals↗
PubMed1987

Coronary reperfusion following experimental myocardial infarction.

Numerous studies have shown that early coronary reperfusion is feasible in the setting of evolving acute myocardial infarction in man. While early reperfusion reduces myocardial infarct size, there are potentially deleterious consequences of reperfusion. The concept of "reperfusion injury", oxygen-free radical damage, no reflow phenomenon, and stunned myocardium are discussed.

Animals↗
PubMed1986

Capillary anastomoses between the left anterior descending and circumflex circulations in the canine heart: possible importance during coronary artery occlusion.

The mammalian coronary microcirculation is a complex network of anastomosing vessels. Previous studies have documented the presence of anatomoses between capillaries originating from a common artery; however, the existence of anastomotic vessels connecting different arteries remains a subject of controversy. The objective of the current study was to determine the extent of anastomotic connections between the left anterior descending (LAD) and circumflex (Cx) beds at the capillary level in the canine heart. Red phthalo pigment (Dupont: Wilmington, Del.) was perfused in vitro, at 120 mm Hg, into the LAD bed, while blue pigment was perfused simultaneously, under the same pressure, into the Cx. Capillary anastomoses between the LAD and Cx were confirmed histologically by the consistent presence of vessels at the junction of the two perfusion fields filled with both colors of pigment. In normal dog hearts, 21.9 +/- 2.8% (mean +/- SEM) of vessels at the junction of the LAD and Cx were perfused by both arterial trees; the percentage capillary anastomoses did not vary significantly with location, apex to base, in the hearts. In addition, the proportion of capillary anastomoses was not altered by either 1 or 6 hr of coronary artery occlusion followed by reperfusion (21.3 +/- 2.8% and 22.5 +/- 2.6%, respectively), or by postmortem cautery of the epicardial collateral vessels (21.8 +/- 5.1%). To assess the potential functional role of these capillary interconnections, regional blood flow at the outer margin of the LAD bed, measured during LAD occlusion by injection of radioactive microspheres, was considered as a function of percentage capillary anastomoses. There was a positive correlation (r = 0.87) between the proportion of anastomoses between the two circulations and blood flow at the outermost edge of the LAD bed, while the LAD was occluded. These results suggest that the anastomoses between the LAD and Cx beds in canine hearts could be important in maintaining blood flow at the extreme outer edge of the perfusion field, if flow through one of the arteries is impaired.

Animals↗
PubMed1986

Salvage of ischaemic myocardium by reperfusion: importance of collateral blood flow and myocardial oxygen demand during occlusion.

Early reperfusion after coronary artery occlusion is used to treat acute myocardial infarction, but the factors that determine whether salvage of ischaemic myocardium actually occurs remain poorly defined. Differences in collateral blood flow to the region at risk, and haemodynamic variables during occlusion, may contribute to uncertainty as to the time beyond which reperfusion no longer reduces infarct size. To clarify this issue, open chest anaesthetised dogs underwent 1, 2, 3, 4, or 6 hours of left anterior descending coronary artery occlusion followed by reperfusion or permanent occlusion (n = 8 per group). Microspheres were injected before occlusion and 15 minutes after occlusion for regional myocardial blood flow determination, and heart rate and arterial blood pressure were measured before occlusion and 10 minutes and 30 minutes after occlusion. At 96 hours after occlusion haemodynamic variables were again measured; the animals were then killed, and occluded bed size was determined by in vitro dye perfusion. The area of necrosis was quantified from histological sections and expressed as a percentage of occluded bed size (AN/OB). If duration of occlusion is considered alone, reperfusion beyond two hours did not salvage ischaemic myocardium in this model. If the results for occlusion equal to and greater than two hours are combined, the mean area of necrosis (27(2)%) was significantly greater than that produced by one hour of occlusion followed by reperfusion (10(4)%). For the animals undergoing occlusion for two or more hours or permanent occlusion, collateral blood flow significantly influenced the area of necrosis. When epicardial flow during occlusion was high (greater than 0.30 ml X min-1 X g-1 tissue) 13 out of 14 dogs undergoing occlusion for two or more hours or permanent occlusion developed small (AN/OB less than 27%) infarcts (mean AN/OB 17(2)%). In contrast, when epicardial collateral flow was low (less than 0.30 ml X min-1 X g-1) 14 out of 23 animals had large (AN/OB greater than 27%) infarcts (mean AN/OB 34(3)%). For the 23 dogs in which epicardial flow was low, heart rate during occlusion significantly influenced infarct size: the 14 dogs that developed large infarcts (AN/OB greater than 27%) had a higher mean heart rate (152(6) beats X min-1) than the nine that developed small infarcts (AN/OB less than 27%) (130(5) beats X min-1; p less than 0.025). Thus reperfusion at one hour after occlusion salvaged ischaemic myocardium.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Superoxide dismutase plus catalase improve contractile function in the canine model of the "stunned myocardium".

Fifteen minutes of coronary occlusion followed by reperfusion does not result in myocardial necrosis; however, the contractile function and high energy phosphate content of the previously ischemic myocardium remains depressed or "stunned" for several hours to days after reperfusion. Oxygen-derived free radicals have been implicated in ischemia and reperfusion-induced injury in a variety of tissues. We wished to determine whether administration of free radical scavengers superoxide dismutase plus catalase before and during occlusion, and throughout reperfusion, could attenuate the "stunning" produced by 15 minutes of left anterior descending coronary artery occlusion in anesthetized, open-chest dogs. Segment shortening in the previously ischemic zone recovered to within only +/- 10% of preinfusion values in the control group during 3 hours of reperfusion, while, in the treated dogs, segment shortening returned to a maximum of 56 +/- 16% of preinfusion at 1 1/2 hours post-reperfusion (P less than 0.0003 compared to controls). Similarly, superoxide dismutase + catalase-treated dogs exhibited improved wall thickening during reperfusion (+30% to +70% of preinfusion values), compared to controls (0% to +10%). However, this improvement in contractile function in the treated group was not accompanied by increased adenosine triphosphate stores in the previously ischemic zone (31.8 +/- 0.8 vs. 28.2 +/- 2.2 nmol/mg protein for control vs. treated groups). Infusion of superoxide dismutase + catalase did not influence blood flow during occlusion or reperfusion. However, the treated group did exhibit a significant decrease in blood pressure during reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1985

Effects of exercise frequency, intensity, and duration on revascularization in the transition zone of infarcted rat hearts.

In the rat model of chronic myocardial infarction the border or "transition zone," extending 225-525 micron from the margin of the scar, is supplied by significantly fewer capillaries and characterized by an altered capillary-fiber geometry when compared with healthy rat myocardium. Four weeks of daily voluntary running can, under certain conditions, promote capillary growth and a shift in capillary-fiber geometry, such that a normal capillary supply is restored to the transition zone. However, the importance of exercise frequency, intensity, and duration for capillary growth in the transition zone has not been determined. One week after surgical occlusion of the left coronary artery, rats were divided into four groups following different protocols of voluntary exercise (running): A (2 h/day, 6 days/week for 4 weeks), B (2 h/day, 3 days/week for 4 weeks), C (2 h/day, 6 days/week for 2 weeks, followed by 2 weeks sedentary), and D (2 h/day, 6 days/week for 2 weeks). Significant improvements in capillary supply to the transition zone were associated with voluntary exercise, three separate factors being of importance. (i) An intermediate total distance run; rats that ran 5-10 km in the month restored a normal number of capillaries and a normal capillary-fiber geometry in the transition zone, whereas rats that ran either less than 5 or greater than 10 km showed no significant improvements. (ii) A balance between exercise frequency and mean distance run per 2-h exercise period; rats in group B (3 days/week) had to run twice the daily distance of those in group A (6 days/week) to obtain the same improvement in capillary supply.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Can exercise promote revascularization in the transition zone of infarcted rat hearts?

A border or transition zone, comprising muscle fibers supplied by fewer capillaries than normal, and characterized by an altered capillary--fiber geometry, is present as long as 5 weeks following coronary artery occlusion in the rat. This zone, which extends 225-525 microns laterally from the margin of the necrosis, may be at risk of becoming hypoxic, especially under conditions of increased oxygen demand. Our objective was to determine whether exercise can stimulate capillary growth in this transition zone. Myocardial infarcts were induced in rats by ligating the left coronary artery, midway between its origin and the apex of the heart. After a 1-week recovery period, the animals underwent 4 weeks of voluntary exercise, 2 h/day, 6 days/week. Rats which had run a total distance of 5-10 km during the month had both a normal number of capillaries and normal capillary--fiber geometry in the transition zone. In contrast, rats that ran either less than 5 km or more than 10 km during the 4 weeks showed no significant improvement in the number of capillaries or capillary--fiber geometry within the border zone. Thus, under certain conditions, exercise can promote revascularization in the transition zone of infarcted rat hearts.

Animals↗
PubMed1983

Microvascular evidence for a transition zone around a chronic myocardial infarct in the rat.

Muscle fibers in the transition zone of an infarcted heart are thought to be potentially ischemic during the first 6-9 h following coronary artery occlusion. However, the long-term fate of the muscle fibers at the margin of the necrosis is uncertain. Ischemia implies reduced oxygenation, possibly owing to a reduced capillary supply; thus our objective was to determine whether a region of reduced microvascular supply exists at the margin of a necrosis produced by chronic coronary artery occlusion. Five variables were used to quantitate the capillary supply in the transition zone: C/F (capillary to fiber) ratio, Vf (number of vessels around a fiber), Fv (number of fibers surrounding a vessel), capillary density, and fiber diameter. Infarcts were induced in young male rats by ligating the left coronary artery midway between its origin and the apex of the heart. Five weeks later, the capillary supply in the transition zone was significantly below control values, i.e., significant reductions in C/F, Vf, and Fv were found. This region of reduced capillary supply extended 225-525 microns laterally from the edge of the necrosis. Thus, a narrow transition zone, defined as a region of viable muscle fibers with a subnormal microvascular supply, exists as long as 5 weeks following coronary artery occlusion in the rat.

Animals↗