P J Simpson

Concordia University–Ann Arbor, Ann Arbor, Michigan, United States

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Publications (25)142.49 Total impact

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    ABSTRACT: Coronary artery rethrombosis can complicate initially effective thrombolytic therapy. Platelets interacting with injured vascular endothelium in a region along the coronary artery with reduced luminal cross-sectional area contribute to rethrombosis. The purpose of this study was to investigate the potential of the F(ab')2 fragment of the murine monoclonal antibody 7E3 [7E3 F(ab')2] to prevent rethrombosis after intracoronary clot lysis with recombinant tissue-type plasminogen activator (rt-PA) in an experimental model. The 7E3 F(ab')2 binds to the platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), thereby preventing platelet-fibrinogen interaction and intravascular thrombus formation. Experimental coronary artery thrombosis was produced in the anesthetized dog by application of direct anodal current to the intimal surface of the left circumflex coronary artery in the region of an external stenosis. Lysis of the established intracoronary thrombus was achieved with the intravenous administration of rt-PA (25 mg) after which the animals were randomized into two groups. Group 1 (n = 10) served as the control, receiving the saline diluent, and group 2 (n = 9) received 7E3 F(ab')2, given as a single intravenous injection (0.8 mg/kg). The times required for occlusive thrombus formation, rt-PA-induced thrombolysis, and rethrombosis (if it occurred) were similar in the animals treated with saline and those treated with 7E3 F(ab')2. The initial left circumflex coronary artery blood flow was similar in both groups but decreased to a negligible level in group 1. In group 2, left circumflex coronary artery blood flow declined modestly (24 +/- 2 to 10 +/- 2 ml/min). Rethrombosis occurred in all animals in group 1 but in only two of nine animals in group 2 (p less than 0.05). Oscillations in coronary blood flow preceded rethrombosis in group 1, whereas 7E3 F(ab')2 stabilized left circumflex coronary artery blood flow patterns during the course of teh experimental protocol (5.2 +/- 0.9 vs. 0.7 +/- 0.4 oscillations, respectively; p less than 0.05). Thrombus mass recovered from the left circumflex coronary artery at the conclusion of each experiment was greater in group 1 as compared with group 2 (7.0 +/- 2.3 vs. 1.5 +/- 0.7 mg, respectively; p less than 0.05). The area of left ventricle at risk for infarction was similar in both groups but infarct size, infarction/at risk assessed histochemically, was larger in group 1 than group 2 (35 +/- 9% vs. 6 +/- 4%, respectively; p less than 0.05). Platelet aggregation induced by ADP and arachidonic acid was similar at baseline for all of the animals.(ABSTRACT TRUNCATED AT 400 WORDS)
    Circulation 03/1990; 81(2):617-27. · 15.20 Impact Factor
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    ABSTRACT: Pentobarbital anesthetized dogs were subjected to 90 minutes of left circumflex coronary artery (LCCA) occlusion followed by 72 hours of reperfusion. Control or anti-Mo1 (904) F(ab')2 fragments of monoclonal antibodies were administered intravenously at a dose of 1 mg/kg beginning 45 minutes after occlusion and at a dose of 0.5 mg/kg at 12, 24, 36, and 48 hours after reperfusion. Myocardial infarct size expressed as a percentage of the area at risk (IN/AR) measured postmortem after 72 hours of reperfusion was significantly reduced by 904 F(ab')2 (21.6 +/- 2.8%, n = 8) compared with control F(ab')2 (37.4 +/- 5.8%, n = 8; p less than 0.025). There were no significant differences between groups in heart rate, mean arterial blood pressure, rate-pressure product, or LCCA blood flow that could account for a reduced infarct size. Regional myocardial blood flow (RMBF) was determined with 15-microns radiolabeled microspheres. Transmural blood flows (ml/min/g) within the region of myocardium at risk were not statistically different between treatment groups. Infarct size in both groups was related to regional myocardial blood flow, and the relation was shifted downward in the group treated with the anti-Mo1 F(ab')2 antibody (analysis of covariance, p = 0.01). Thus, anti-Mo1 F(ab')2 produces a sustained limitation of myocardial infarct size compared with controls under similar hemodynamic conditions and a similar degree of myocardial ischemia as determined by RMBF. These data suggest that inhibition of neutrophil adhesive interactions (as suggested by the inhibitory effect of anti-Mo1 on canine neutrophil aggregation) may be an effective mechanism for protection against myocardial injury secondary to myocardial ischemia and reperfusion.
    Circulation 02/1990; 81(1):226-37. · 15.20 Impact Factor
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    ABSTRACT: To determine if inhibition of leukocyte adhesion and aggregation could improve postischemic ventricular dysfunction ("stunning"), a monoclonal antibody (904) that binds to the adhesion-promoting Mo1 glycoprotein on the cell surface of leukocytes was administered intravenously (0.5 mg/kg) to open-chest dogs before a 15-minute coronary occlusion. Ultrasonic crystals placed in ischemic and control myocardium were used to measure systolic wall thickening during a 15-minute occlusion of the left anterior descending artery and for 3 hours after reperfusion. Myocardial blood flow was measured with tracer-labeled microspheres before occlusion, after 10 minutes of occlusion, 3 minutes of reperfusion, and at 1 and 3 hours after reperfusion. Six animals receiving anti-Mo1 antibody had antibody excess demonstrated with immunofluorescence techniques at 5 minutes and 3 hours of reperfusion; this finding indicated saturation of binding sites. Five animals served as controls and received an antibody (murine immunoglobulin G) that does not influence neutrophils. The two groups did not differ hemodynamically during ischemia and reperfusion. Risk areas and myocardial blood flow were also not significantly different between the two groups. The main parameter used to define regional myocardial stunning, percentage systolic wall thickening in the ischemic/reperfused area, did not differ significantly between the two groups. Specimens from nonischemic myocardium were compared with ischemic specimens for myeloperoxidase content. There were no significant differences within or between groups. These data indicate that the anti-Mo1 monoclonal antibody (904) is not effective in improving the profound myocardial dysfunction that persists for 3 hours of reperfusion after 15 minutes of ischemia.
    Circulation Research 11/1989; 65(4):1112-24. · 11.86 Impact Factor
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    J K Mickelson, P J Simpson, B R Lucchesi
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    ABSTRACT: Streptokinase is an effective thrombolytic agent which, with early restoration of coronary blood flow, has the potential for limiting infarct size. Distinct from thrombolysis, we studied the effects of streptokinase on reperfusion coronary blood flow and infarct size. Open-chest anesthetized canines underwent a 90 minute snare occlusion of the left circumflex coronary artery followed by release and reperfusion through a critical stenosis for 6 hours. The animals were assigned randomly to two groups. Intracoronary streptokinase [group 1 (n = 8): 6000 IU/kg in 3 ml of saline] or saline [group 2 (n = 8): 3 ml of saline] was infused at 0.05 ml/min for 60 minutes beginning 30 minutes before reperfusion. Coronary blood flow was stable in group 1 during reperfusion, while in group 2 it fell during 6 hours of reperfusion (30 +/- 4 ml/min to 18 +/- 2 ml/min, P = 0.05). The ST-segment elevation on the limb lead II electrocardiogram 15 minutes after coronary artery occlusion was similar in both groups (group 1: 3.9 +/- 0.6 mV, group 2: 2.3 +/- 0.5 mV), suggesting the extent of myocardial ischemia was also similar in both groups. The infarct sizes were similar when expressed both as a percent of the total left ventricular mass [(IZ/LV) group 1: 17 +/- 2.5%, group 2: 17.5 +/- 2.5%] or as a percent of the area at risk of infarction [(IZ/AR) group 1: 39 +/- 6%, group 2: 39 +/- 5%]. In both groups, the mass of left ventricle dependent on the blood flow distribution of the left circumflex coronary artery was similar when compared to total left ventricular mass [(AR/LV) group 1: 41 +/- 3%, group 2: 44 +/- 4%]. These results demonstrate that streptokinase maintains reperfusion coronary blood flow through a critical stenosis at a rate similar to baseline levels. Despite the fact that coronary blood flow remained stable with streptokinase during reperfusion, infarct size was not limited after 90 minutes of fixed coronary artery occlusion in this canine model of myocardial injury.
    International Journal of Cardiology 07/1989; 23(3):373-84. · 6.18 Impact Factor
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    ABSTRACT: Streptokinase is an effective thrombolytic agent which, with early restoration of coronary blood flow, has the potential for limiting infarct size. Distinct from thrombolysis, we studied the effects of streptokinase on reperfusion coronary blood flow and infarct size. Open-chest anesthetized canines underwent a 90 minute snare occlusion of the left circumflex coronary artery followed by release and reperfusion through a critical stenosis for 6 hours. The animals were assigned randomly to two groups. Intracoronary streptokinase [group 1 (n = 8): 6000 IU/kg in 3 ml of saline] or saline [group 2 (n = 8): 3 ml of saline] was infused at 0.05 ml/min for 60 minutes beginning 30 minutes before reperfusion. Coronary blood flow was stable in group 1 during reperfusion, while in group 2 it fell during 6 hours of reperfusion (30 ± 4 ml/min to 18 ± 2 ml/min, P = 0.05). The ST-segment elevation on the limb lead II electrocardiogram 15 minutes after coronary artery occlusion was similar in both groups (group 1: 3.9 ± 0.6 mV, group 2: 2.3 ± 0.5 mV), suggesting the extent of myocardial ischemia was also similar in both groups. The infarct sizes were similar when expressed both as a percent of the total left ventricular mass [() group 1: 17 ± 2.5%, group 2: 17.5 ± 2.5%] or as a percent of the area at risk of infarction [() group 1: 39 ± 6%, group 2: 39 ± 5%]. In both groups, the mass of left ventricle dependent on the blood flow distribution of the left circumflex coronary artery was similar when compared to total left ventricular mass [() group 1: 41 ± 3%, group 2: 44 ± 4%]. These results demonstrate that streptokinase maintains reperfusion coronary blood flow through a critical stenosis at a rate similar to baseline levels. Despite the fact that coronary blood flow remained stable with streptokinase during reperfusion, infarct size was not limited after 90 minutes of fixed coronary artery occlusion in this canine model of myocardial injury.
    International Journal of Cardiology. 06/1989; 23(3):373–384.
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    ABSTRACT: Interactions between platelets with injured vascular endothelium contribute to thrombotic occlusion. A murine monoclonal antibody [7E3 F(ab′)2] to the platelet receptor complex was used to inhibit platelet aggregation in an experimental model of coronary artery thrombosis. Prevention of thrombotic occlusion by 7E3 F(ab′)2 (0.8 mg/kg bolus i.v.) was studied in dogs with direct current induced intimal injury (100 μA for 5 h) and critical stenosis of the left circumflex coronary artery (LCCA). Baseline LCCA blood flow (CBF) was similar in 7E3 F(ab′)2 and control groups, but decreased in the controls [24 ± 2 ml/min to 0 ± 0 ml/min, n = 13 (mean ±s.e.m.)] due to thrombotic occlusion in each case (time to thrombosis 136 ± 15 min). In the group treated with 7E3 F(ab′)2, CBF did not change significantly (27 ± 3 ml/min to 22 ± 3 ml/min, n = 6) and thrombotic occlusion did not occur during the 5-h observation period in which intimal injury was produced in the LCCA (P < 0.001). Oscillations in CBF preceded thrombosis in the control group, but did not occur with 7E3 F(ab′)2 treatment (2.2 ± 0.7 vs. 0 ± 0, P < 0.05). The thrombus mass recovered from the LCCA 30 min after occlusion was 8.8 ± 1.3 mg in the controls compared to 2.2 ± 1.2 mg determined 5 h after administration of 7E3 F(ab′)2 (P < 0.05). When studied ex vivo, before the administration of the test agents, platelets from both groups of dogs aggregated in response to ADP and arachidonic acid. However, after treatment, the ex vivo aggregation of platelets from 7E3 F(ab′)2 animals was inhibited whereas platelets from the control animals continued to aggregate ex vivo throughout the period of the experimental protocol (P < 0.05). The labeling of platelets with 111indium showed accumulation of radio-activity within the thrombus and upon the vascular endothelium which was less in 7E3 F(ab′)2 treated dogs as compared to the control group (P < 0.05). The murine monoclonal antibody 7E3 F(ab′)2 did not affect hemodynamic values or the circulating platelet count during the experimental protocol. In conclusion, antibody to platelet receptors: (1) prevented thrombotic LCCA occlusion, (2) inhibited ex vivo platelet aggregation, (3) minimized platelet deposition on injured vascular endothelium and within formed thrombi, and (4) stabilized CBF during 5 h of continuous direct currrent induced intimal injury of the LCCA.
    Journal of Molecular and Cellular Cardiology 05/1989; · 5.15 Impact Factor
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    ABSTRACT: The cardio-protective effects of neutrophil depletion or inhibition of neutrophil activation early in the course of myocardial reperfusion has been established. Whether these treatments would be effective during extended periods of reperfusion has not been ascertained. Open-chest anesthetized dogs were subjected to left circumflex artery (LCX) occlusion for 90 minutes followed by 72 hours of reperfusion. Dogs were randomized into one of four groups: 1) control; 2) Ilo-2 (iloprost 100 ng/kg/min administered via the left atrium beginning 10 minutes after LCX occlusion and continuing 2 hours into reperfusion); 3) Ilo-48 (iloprost 100 ng/kg/min administered as above until 1 hour after reperfusion then 25 ng/kg/min for 48 hours of reperfusion; or 4) antibody (neutrophil antibody administered before occlusion and 1/2 hourly for 2 hours of reperfusion and then every 24 hours). Myocardial infarct size, as a percentage of the area at risk assessed after 72 hours of reperfusion, was significantly smaller in the antibody-treated group (32.1 +/- 5.0% mean +/- SEM) or Ilo-48 (22.6 +/- 4.0%) treatment group compared with control (48.7 +/- 5.6%) or Ilo-2 (57.6 +/- 5.2%) groups. Regional myocardial blood flow studies demonstrated that all groups developed similar degrees of ischemia. The iloprost-treated groups had lower mean arterial blood pressures during occlusion and reperfusion than groups 1 and 4 (p less than 0.05). Circulating neutrophil counts were increased in groups 1 and 2 at 24 and 48 hours after reperfusion compared to groups 3 and 4 (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
    Circulation Research 01/1989; 63(6):1070-9. · 11.86 Impact Factor
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    ABSTRACT: The thrombolytic efficacy of recombinant single-chain urokinase-type plasminogen activator (rscu-PA) was studied in an open-chest canine model of coronary artery thrombosis. Dogs (n=16) were anesthetized, a left thoracotomy performed, and a two cm segment of the left circumflex coronary artery was isolated and instrumented with an electromagnetic flow probe, an intracoronary stimulation electrode, and an adjustable mechanical occluder. Anodal direct current (100 μA) was applied to the stimulation electrode until thrombosis occurred (n=14). After 30 min of thrombotic occlusion, rscu-PA was administered intravenously. Dogs were sacrificed either 6 h after thrombolysis or 6.5 h after initiation of rscu-PA when thrombolysis did not occur. In group A (30–50 μg/kg bolus rscu-PA + 20–40 μg/kg/min infusion rscu-PA for 30 min, n=5) thrombolysis occurred in one case (20%) and this artery reoccluded. In group B (250 μg/kg bolus rscu-PA + 25 μg/kg/min infusion rscu-PA for 30 min, n=6) all reperfused and only one reoccluded (16.6%). In group C (200 μg/kg bolus rscu-PA + 100 μg/kg/min rscu-PA infusion for 30 min, n=2) both reperfused and neither reoccluded. Infarct size, determined as a percentage of left ventricle, was smaller when thrombolysis was followed by persistent reperfusion (n=7), than when reperfusion did not occur (n=4): 16.9 ± 3.7% vs 31.3 ± 2.2%, respectively (mean ±SEM, p<0.02). If thrombolysis was followed by reocclusion, infarct size was 27.0 ± 10.0%. In this study thrombolysis occurred when changes in prothrombin time, partial thromboplastin time, fibrinogen and fibrin split products were suggestive of systemic finbrinogenolysis. In conclusion, effective thrombolysis with rscu-PA appears to limit infarct size and to be accompanied by evidence of systemic fibrinolysis.
    Thrombosis Research 08/1988; · 3.13 Impact Factor
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    ABSTRACT: Coronary artery reperfusion established by thrombolytic agents early in the evolution of an acute myocardial infarction is known to result in the salvage of otherwise jeopardized heart muscle. Recently, experimental evidence has suggested that reactive products of oxygen are formed as a result of reperfusion and can increase the amount of myocardial tissue that becomes irreversibly damaged. The purpose of the present study was to determine if the thrombolytic agent, streptokinase, could serve to scavenge reactive species of oxygen, thereby protecting the myocardium by a mechanism independent of its ability to lyse an occlusive thrombus. Rabbit isolated hearts were perfused at a constant rate with Krebs-Henseleit buffer (25 ml/min, 31[degrees]C, pH 7.4) using a modified Langendorff method. Changes in the permeability of the coronary vascular bed were determined with '"1-labeled albumin added to the perfusion buffer. An intraventricular fluid-filled latex balloon connected to a pressure transducer maintained the left ventricle in an isovolumic state and was used to detect changes in myocardial contractility throughout the study protocol. Electrolysis of the oxygenated Krebs-Henseleit perfusion buffer with a 20 mA direct current for 2 min, delivered with a stainless-steel anode (proximal) and a platinum cathode (distal), resulted in the generation of reactive products of oxygen. Perfusion of the isolated heart with buffer containing the products of electrolysis resulted in an increase in mean coronary artery perfusion pressure, from 48 +/- 3 to 121 +/-6 mm Hg [mean +/- SEM (n = 17)]. and an increase in the left ventricular end-diastolic pressure, from 10 +/- 1 to 54 +/- 6 mm Hg. The addition of streptokinase (150 U/ml) or heparin (20 U/ml) to the perfusion medium attenuated the observed increase in coronary artery perfusion pressure from 42 +/- 3 to 73 +/- 9 mm Hg (n = 9) or from 43 +/- 2 to 98 +/- 9 mm Hg (n = 9), respectively. In addition, streptokinase prevented the increase in the left ventricular end-diastolic pressure (11 +/- I to 36 +/- 5 mm Hg, n = 9) and preserved left ventricular function as determined by the pressure-volume relationship. Myocardial accumulation of l25I-la-beled albumin after exposure of the heart to the reactive products of oxygen was attenuated by the addition of streptokinase or heparin to the buffer solution. The data suggest that streptokinase and, to a lesser extent, heparin may preserve myocardial and coronary vascular function by scavenging reactive oxygen species. (C) Lippincott-Raven Publishers.
    Journal of Cardiovascular Pharmacology 07/1988; 12(2). · 2.38 Impact Factor
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    ABSTRACT: Myocardial injury was produced in separated groups of anesthetized rabbits by occlusion of the left circumflex coronary artery for 1 h followed by reperfusion for 2, 4, or 6 h after release of the occlusive ligature. The ischemically-injured and reperfused hearts subsequently were isolated and perfused using a modified Langendorff apparatus. Platelet-activating factor in the form of AGEPC (1-0-hexadecyl-2-acetyl-sn-glyceryl-phosphorylcholine), 40 nmol in 1 ml, was infused above the coronary ostia over 15 s. Thromboxane B2 (TxB2- and peptidoleukotrienes (LT) were measured in the lymphatic effluent from the heart. Noninfarcted hearts (isolated hearts and sham-operated animals) served as procedural controls and lyso-GEPC (1-0-hexa-decyl-2-0-lyso-sn-glyceryl-phosphorylcholine), 40 nmol in 1 ml, served as the agonist control. After the infusion of AGEPC in the infarcted hearts, coronary perfusion pressure and left ventricular end-diastolic pressure increased while left ventricular peak systolic pressure decreased. The observed changes coincided with TxB2 peak release at 1 min and LT peak release at 2 min. The longer post-ischemic reperfusion time was associated with increasingly greater changes in these parameters. In hearts isolated after 6 h of reperfusion, the functional changes and the appearance of TxB2 and LT in response to the administration of AGEPC reached a significant level (ANOVA) with respect to those base-line values and the values obtained with hearts from sham-operated animals. Minimal changes occurred in noninfarcted hearts or with the administration of the biologically inactive phospholipid, lyso-GEPC. Histologic evaluation of cardiac tissue showed a progressive time-dependent migratory increase of leukocytes from the intra- and perivascular areas toward the region of infarcted myocardium. Platelet aggregates were seen in the intravascular spaces. The data are consistent with the suggestion that the infiltrating leukocytes and platelets may serve as a source for the synthesis and release of TxB2 and LT in acutely infarcted hearts upon exposure to AGEPC. If it is possible for AGEPEC to be synthesized and released from vascular endothelial or inflammatory cells leading to the formation of thromboxane A2 and LT from reperfused myocardium, then these substances may participate in increasing coronary artery resistance and in the development of myocardial dysfunction during the evolution of an acute myocardial infarction and especially during the phase of perfusion.
    Journal of Molecular and Cellular Cardiology 07/1988; · 5.15 Impact Factor
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    ABSTRACT: In the present study, dogs were pretreated with intravenous digoxin, 0.0125 mg/kg/day, for 6 to 7 consecutive days to achieve clinically relevant serum concentrations; untreated animals were used as control subjects. After pretreatment, nine digoxin-pretreated dogs and nine control dogs were anesthetized and subjected to a 60-minute occlusion of the left circumflex coronary artery, followed by 6 hours of reperfusion. Anatomic myocardial infarct size, expressed as a percentage of the areas at risk of infarction and as a percentage of the total left ventricle were: 20.2 +/- 3.3% control vs 35.4 +/- 6.2% digoxin-pretreated (p less than 0.05) and 8.6 +/- 1.3% control vs 14.7 +/- 2.5% digoxin-pretreated (p less than 0.05), respectively (2.04 +/- 0.37 ng/ml serum digoxin). Regional myocardial blood flow in the nonischemic and ischemic zones tended to be lower in digoxin-pretreated than in control animals at baseline testing and were significantly reduced in the anterior subendocardial sites of digoxin-pretreated dogs during ischemia and reperfusion. These data suggest that an exacerbation or enhancement of myocardial ischemia-reperfusion injury may occur in the presence of clinically observable serum digoxin concentrations.
    American Heart Journal 07/1988; 115(6):1171-82. · 4.50 Impact Factor
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    ABSTRACT: A monoclonal antibody (904) that binds to a leukocyte cell adhesion-promoting glycoprotein, (Mo1; CD11b/CD18) was administered (1 mg/kg, iv.) to open chest anesthetized dogs 45 min after the induction of regional myocardial ischemia. Ischemia was produced by occluding the left circumflex coronary artery (LCX) for 90 min and then reperfusing for 6 h. There was no difference between control and antibody treated groups with respect to arterial blood pressure, heart rate, or LCX blood flow. Administration of antibody produced no observable effect on circulating neutrophil counts, suggesting that antibody-bound neutrophils were not cleared from the circulation. The mean size of myocardial infarct expressed as percentage of the area at risk of infarction that resulted was reduced by 46% with anti-Mo1 treatment (25.8 +/- 4.7%, n = 8) compared to control (47.6 +/- 5.7%, n = 8; P less than 0.01). The area at risk of infarction was similar between groups. Circulating (serum) antibody excess was confirmed in all 8 anti-Mo1 treated dogs by immunofluorescence analysis. Analysis of ST segment elevation on the electrocardiogram as an indicator of the severity of ischemia suggests that the anti-Mo1 reduces infarct size independent of the severity of ischemia. An additional group of dogs (n = 5) was tested with a control monoclonal antibody of the same subtype (murine IgG1) and was found to produce no significant reduction in myocardial infarct size. Accumulation of neutrophils within the myocardium was significantly attenuated with 904 treatment when analyzed by histological methods. These data demonstrate that administration of anti-Mo1 monoclonal antibody after the induction of regional myocardial ischemia results in reduced myocardial reperfusion injury as measured by ultimate infarct size.
    Journal of Clinical Investigation 03/1988; 81(2):624-9. · 12.81 Impact Factor
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    ABSTRACT: The ability of prostaglandin E1 (PGE1) to reduce myocardial infarct size in an anesthetized open-chest canine model of regional myocardial ischemia and reperfusion was investigated. Administration of PGE1 (100 ng/kg/min into the left atrium) to dogs beginning 10 min after left circumflex coronary artery (LCCA) occlusion and continuing up to 2 hr of reperfusion resulted in a 43% reduction in infarct size expressed as a percentage of the area at risk: control infarct, 44.3 +/- 3.2%, n = 15; PGE1, 27.3 +/- 3.2%, n = 19, P less than .0005. Regional myocardial blood flow (measured with tracer-labeled microspheres in six dogs from each group) was similar between treatment groups at base line, 5 min after LCCA occlusion, 80 min after LCCA occlusion and 1 hr after LCCA reperfusion. In another group of anesthetized dogs, PGE1 was tested for its ability to decrease neutrophil migration into skin lesions. PGE1 at the same concentration that reduced infarct size, decreased the number of neutrophils (assessed by myeloperoxidase activity) that accumulated in skin lesions after intradermal injection of C5a by 63%. In addition, PGE1 inhibited the production of superoxide anion in vitro by zymosan-stimulated canine neutrophils in a concentration-dependent manner. Thus, PGE1 reduces myocardial infarct size and inhibits neutrophil function in vitro and in vivo. These data suggest that the reduction in infarct size by PGE1 may be due to multiple mechanisms including: 1) inhibition of neutrophil migration and activation at the site of tissue injury or 2) reduction in blood pressure which reduces myocardial oxygen demand.
    Journal of Pharmacology and Experimental Therapeutics 03/1988; 244(2):619-24. · 3.89 Impact Factor
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    ABSTRACT: There is increasing evidence that activated neutrophils cause myocardial injury during reperfusion of ischemic myocardium. This study was performed to assess the effect of Ci-922, an inhibitor of neutrophil activation, in a canine preparation of myocardial infarction. Dogs received 15-min infusions of CI-922 1 mg/kg or 5% dextrose beginning 30 min before occlusion of the left circumflex coronary artery. After occlusion for 90 min and reperfusion for 6 h, infarct size was determined by ex vivo perfusion of the left circumflex coronary artery with triphenyltetrazolium chloride. The percentage of the area at risk infarcted was: control, 42 +/- 5; and CI-922, 23 +/- 4 (p less than 0.05 vs. control). There were no significant inter-group differences in heart rate or mean arterial pressure, and CI-922 did not enhance collateral blood flow to the ischemic bed. After incubation with CI-922 (100 microM), production of superoxide anions by canine neutrophils activated by opsonized zymosam decreased from 3.5 +/- 0.2 to 2.0 +/- 0.4 nmol/10 min/10(6) cells (p less than 0.05). Thus, inhibition of neutrophil-mediated damage may explain the cardioprotective effect of CI-922.
    Journal of Cardiovascular Pharmacology 02/1988; 12(5):608-14. · 2.38 Impact Factor
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    ABSTRACT: This study was performed to evaluate the effects of superoxide dismutase, a scavenger of superoxide anions, on leukocyte accumulation and myocardial injury in a canine preparation of myocardial infarction. Dogs underwent occlusion of the left circumflex coronary artery for 90 min, followed by a reperfusion for 6 or 24 h. The dogs received either saline or superoxide dismutase (5 mg/kg), beginning 15 min before coronary occlusion and ending 15 min after coronary reflow. Myocardial infarct size, expressed as a percentage of the area at risk, was significantly less in superoxide-dismutase-treated dogs that underwent reperfusion for 6 h, 17.5 +/- 1.7, or 24 h, 25.8 +/- 3.6, compared to saline-treated dogs that underwent reperfusion for 6 h, 42.7 +/- 4.4 (p less than 0.05), or 24 h, 53.0 +/- 6.1 (p less than 0.05). The differences in infarct size were not due to differences in myocardial oxygen demand. Superoxide dismutase had no effect on regional myocardial perfusion of the ischemic bed. Accumulation of 111indium (In)-labeled autologous leukocytes within the area at risk was similar in control and superoxide-dismutase-treated dogs (p greater than 0.05). The results suggest that oxygen radicals play a role in the extent of injury due to regional myocardial ischemia followed by reperfusion, and the protective effect of free radical scavengers may be sustained beyond the expected plasma half-life of the administered agent.
    Journal of Cardiovascular Pharmacology 02/1988; 11(1):36-44. · 2.38 Impact Factor
  • P J Simpson, B R Lucchesi
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    ABSTRACT: There is a growing body of evidence for the role of free radicals in mediating myocardial tissue injury during myocardial ischemia and in particular during the phase of myocardial reoxygenation. Associated with myocardial ischemia and reperfusion is the generation of oxygen-derived free radicals from a variety of sources that include the mitochondrial electron transport chain; the biosynthesis of prostaglandins; the enzyme xanthine oxidase; and circulating elements in the blood, with the polymorphonuclear neutrophil assuming a primary focus of attention. Experimental studies have shown that free radical scavengers (e.g., N-[2-mercaptopropionyl]glycine) and enzymes that scavenge or degrade reactive species of oxygen (superoxide dismutase or catalase) can reduce the mass of myocardial tissue that undergoes irreversible injury. Additionally allopurinol, which inhibits the enzyme xanthine oxidase, reduces ultimate infarct size, putatively by reducing the xanthine oxidase generation of superoxide anion. Neutrophils that enter the ischemically injured myocardium under the influence of chemotactic attraction and activation of the complement system generate and release highly reactive and cytotoxic oxygen derivatives that are destructive to the vascular endothelium and to the cardiac myocytes. Studies have documented that neutrophil depletion or suppression of neutrophil function (ibuprofen, nafazatrom, BW 755C, or more recently with prostacyclin or iloprost) results in a significant salvage of myocardial tissue that is subjected to a period of regional ischemia followed by reperfusion. Our current understanding of the events associated with myocardial ischemia suggests that within the ischemic myocardial region or area at risk, there is a population of cells that are reversibly injured and that reperfusion within a specified period (less than 3 hours) of time is capable of restoring the majority of the jeopardized cells to a normal status, but that the act of reperfusion itself will lead to the sudden demise of a fraction of the cells because of the cytotoxic effects of reactive species of oxygen derived from one or more of the sources indicated above. The efforts to minimize the amount of tissue that undergoes cell death as a result of myocardial ischemia demand that early reperfusion be established. However, the reintroduction of molecular oxygen and the circulating elements of the blood will be associated with an "explosive" and self-limited destruction of some of the myocardial cells in the area at risk.(ABSTRACT TRUNCATED AT 400 WORDS)
    Journal of Laboratory and Clinical Medicine 08/1987; 110(1):13-30. · 2.62 Impact Factor
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    ABSTRACT: A dog with severe recurrent bacterial infections, impaired pus formation, delayed wound healing, and severe persistent leukocytosis was the result of a mother-son mating. Assessment of leukocyte function revealed profound abnormalities in adherence-dependent activities including impaired granulocyte adhesion to glass/plastic surfaces or nylon wool, decreased granulocyte aggregation and chemotaxis, and diminished lymphocyte blastogenesis, but normal neutrophil oxidative activity, serum immunoglobulin, and complement levels. By immunofluorescence analysis, CD11b and CD18 monoclonal antibodies specific for the 155-kd alpha polypeptide of Mo1 (gp 155, 94) and the 94 kd beta peptide common to Mo1, LFA-1 (gp 170, 94), and Leu M5 (p 150, 94) (surface molecules that promote leukocyte adhesion) failed to bind to unstimulated and A23187 calcium ionophore-stimulated granulocytes or mononuclear cells of the affected dog as compared with strong specific binding to canine control cells. The Mo1 glycoproteins were only barely detectable by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of immunoprecipitates from lysates of 125I surface-labeled neutrophils from the affected dog as compared with intense bands seen with canine control cell precipitates. We conclude that this dog has a severe leukocyte surface glycoprotein deficiency syndrome that is similar, if not identical, to that recently recognized in humans. Dogs with deficiency of leukocyte Mo1, LFA-1, and Leu M5 expression may represent a useful animal model to characterize further the molecular basis for an inherited disorder in leukocyte effector function.
    Blood 07/1987; 69(6):1622-30. · 9.06 Impact Factor
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    ABSTRACT: The focus of this investigation was to examine the potential beneficial effects of the selective thromboxane synthetase inhibitor CGS 13080 (imidazo [1,5-a] pyridine-5-hexanoic acid) on coronary blood flow after streptokinase-induced thrombolysis. Thrombotic occlusion of the circumflex coronary artery was produced by electrolytic (100 microA anodal current) injury to the intimal surface of the circumflex coronary artery at the site of a noncircumferential stenosis in dogs anesthetized with pentobarbital to have open-chest surgery. Intracoronary streptokinase, 6000 IU/kg in 3 ml saline solution, was infused at 0.05 ml/min for 1 hour, beginning 30 minutes after the formation of an occlusive thrombus. The animals were assigned randomly to two groups. In group I (n = 10) the intravenous infusion of vehicle was begun simultaneously with the intracoronary administration of streptokinase and continued for 2 hours after thrombolysis had been achieved. The animals in group II (n = 10) received intravenous CGS 13080 (1 mg/kg/hr) along with intracoronary streptokinase. Infarct size was assessed by a dual perfusion technique with Evans blue and triphenyltetrazolium stains to demarcate the normally perfused myocardium from the area at risk and the infarct zone within the risk region. The two groups did not differ with respect to baseline coronary blood flow, time to the development of coronary artery thrombotic occlusion, or time to achieve thrombolysis. Oscillations in coronary blood flow were more frequent in group I than in group II (group I, 9 +/- 2.2; group II, 4.4 +/- 0.8 oscillation/min X 100, p less than 0.05 [mean +/- SEM)].(ABSTRACT TRUNCATED AT 250 WORDS)
    American Heart Journal 07/1987; 113(6):1345-52. · 4.50 Impact Factor
  • P J Simpson, J K Mickelson, B R Lucchesi
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    ABSTRACT: Reperfusion of ischemic myocardium is recognized as potentially beneficial because mortality is directly related to infarct size, and the latter is related to the severity and duration of ischemia. However, reperfusion is associated with extension of the injury that is additive to that produced by ischemia alone. The phenomenon of reperfusion injury is caused in large part by oxygen-derived free radicals from both extracellular and intracellular sources. The loci of oxygen-free radical formation include: myocardial sources (mitochondria), vascular endothelial sources (xanthine oxidase and other oxidases), or the inflammatory cellular infiltrate (neutrophils). Experimental studies have shown that free radical scavengers and agents that prevent free radical production can reduce myocardial infarct size in dogs subjected to temporary regional ischemia followed by reperfusion. Superoxide dismutase and catalase, which catalyze the breakdown of superoxide anion and hydrogen peroxide, respectively, limit experimental myocardial infarct size. The free radical scavenging agent N-(2-mercaptopropionyl)glycine (MPG) is reported to be effective in limiting infarct size. The ischemic-reperfused myocardium derives significant protection when experimental animals are pretreated with the xanthine oxidase inhibitor allopurinol. Neutrophils also serve as a significant source of oxygen-derived free radicals at the site of tissue injury. A number of agents have been shown to directly inhibit neutrophil-derived oxygen free radical formation and neutrophil accumulation within the reperfused myocardium. These agents include ibuprofen, nafazatrom, BW755C, prostacyclin, and iloprost. Thus, free radical scavengers and agents that prevent free radical formation can provide significant protection to the ischemic-reperfused myocardium.
    Federation proceedings 06/1987; 46(7):2413-21.
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    ABSTRACT: The prostacyclin analogue iloprost (ZK 36374) inhibits neutrophil activation in vitro, reduces neutrophil accumulation in inflammatory skin lesions, and reduces ultimate infarct size in an anesthetized open-chest canine model of regional ischemia and reperfusion. Iloprost (0.1-100 microM) inhibited the in vitro production of superoxide anion by canine neutrophils in a concentration-dependent manner. Iloprost (100 ng/kg/min i.v.) inhibited C5a-induced neutrophil migration into inflammatory skin lesions as assessed by the neutrophil-specific enzyme marker, myeloperoxidase. The myeloperoxidase activity determined 2 hours after the intradermal administration of C5a in each of the groups was control 13.3 +/- 1.8 units/g tissue (n = 12) and iloprost 6.5 +/- 0.9 units/g (n = 12), p less than 0.01. Iloprost was administered to anesthetized open-chest dogs (100 ng/kg/min) 10 minutes after left circumflex coronary artery (LCCA) occlusion and continued during the 90-minute occlusion period and the first 2 hours of reperfusion. Regional myocardial blood flow was similar between treatment groups at baseline, 5 minutes and 80 minutes after LCCA occlusion, and after 1 hour of reperfusion. Infarct size, assessed 6 hours after reperfusion, was reduced by iloprost treatment: 22.4 +/- 3.1% of the area at risk (n = 15) compared with 42.4 +/- 3.3% of control (n = 13), p less than 0.01. Iloprost treatment reduced the accumulation of neutrophils (measured by myeloperoxidase activity) in the ischemic myocardium at the interface between infarcted and noninfarcted tissue: control (n = 9) 9.0 +/- 1.8 units/g tissue, iloprost (n = 6) 2.0 +/- 0.4 units/g, p less than 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)
    Circulation Research 06/1987; 60(5):666-73. · 11.86 Impact Factor