Biomedical subjects

P J Simpson

Publications and source records attributed to P J Simpson.

At least 19 recordsLinked to original sources

PubMed1992

Inhibition of granulocyte cAMP-phosphodiesterase by rolipram in vivo is not sufficient to protect the canine myocardium from reperfusion injury.

The purpose of this study was to determine whether the selective type IV cAMP-phosphodiesterase inhibitor rolipram could reduce the reperfusion injury that occurs during myocardial infarction in the anesthetized dog. This question was tested in pentobarbital-anesthetized dogs subject to 90 min of regional myocardial ischemia and 5 h of reperfusion. Dogs were treated with 1 mg/kg of rolipram (i.v., 15 min before reperfusion) followed by a 1 mg/kg/h infusion over the duration of the 5 h of reperfusion. Rolipram was tested in vitro for efficacy in inhibition of isolated human neutrophil superoxide generation. Rolipram produced significant inhibition of superoxide production over the concentration range of 0.1-100 microM rolipram when neutrophils were stimulated with a 10(-7) M concentration of the chemotactic peptide f-Met-Leu-Phe. Rolipram significantly inhibited superoxide generation from human and canine granulocytes in whole blood stimulated by zymosan. Therapeutic concentrations of rolipram in the blood of dogs were achieved during the course of the experiments with a plasma concentration of 0.761 +/- 0.095 micrograms/ml (2.76 +/- 0.34 microM) at the time of reperfusion, and 0.574 +/- 0.098 micrograms/ml (2.08 +/- 0.36 microM) at the end of the reperfusion period. The relative severity of myocardial ischemia between the two treatment groups was similar as assessed with radiolabeled microsphere measurement of myocardial blood flow. Transmural myocardial blood flows were not significantly different between the two groups after coronary occlusion (control, 0.05 +/- 0.01 ml/min/g, n = 6, vs. rolipram, 0.18 +/- 0.07 ml/min/g, n = 6; p = 0.48).(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1992

Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion in murine skin by systemic effects of ultraviolet irradiation.

Systemic effects of UVB irradiation (280-320 nm) have been shown to prevent subsequent chemical tumorigenesis induced by an initiation-promotion protocol. The present investigation was designed to determine whether initiation or promotion is prevented by UV irradiation. Groups of 25 B6D2F1/J mice received 12 weeks of intermittent dorsal UVB radiation treatments administered before, or 3 weeks after, initiation with a single application of 7,12-dimethylbenz[a]anthracene on the ventral skin. All mice were promoted ventrally with 5 micrograms 12-O-tetradecanoylphorbol-13-acetate (TPA) applied three times weekly throughout the experiment. UV irradiation consisted of five 30-min exposures per week to a bank of 6 Westinghouse FS40 sunlamps. UV irradiation applied before or after initiation resulted in a decrease of 18-16 tumors per group of 25 mice, for a reduction of 61 and 50%, respectively, at 24 weeks after the first TPA treatment. Thus, prevention of tumor development was similar whether the UV influence was present or not during initiation. This finding suggests that the UV prevention of promotion could account for UV inhibition of skin tumors induced by an initiation-promotion regimen. Consistent with this concept, pretreatment of mice with dorsal UVB radiation was found to reduce DNA synthesis after exposure to TPA by 46%, although it did not decrease tritiated benzo[a]pyrene binding to DNA, in ventral epidermis. Thus, UVB irradiation systemically reduced TPA-induced tumor promotion in murine skin.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1991

Speech audiometry: digitization effects and the non-equivalence of isophonemic word lists.

Phonetically balanced word lists have many applications, including the field of audiometric testing, as equivalent test material. An experiment designed to assess the effects of digitizing parameters on speech intelligibility has shown, following detailed analysis, that the lists show a degree of non-equivalence. The reasons for this are explored and questions asked about the fundamental principles involved in describing speech forms. Other approaches to this kind of assessment are discussed.

Adult↗

PubMed1991

The role of serotonin (5HT2) receptor blockade in myocardial reperfusion injury: effects of LY53857 in a canine model of myocardial infarction.

The potential protective effects of serotonin receptor antagonism during the process of acute myocardial infarction were studied in anesthetized male dogs, which were subjected to a 90-min left circumflex coronary artery occlusion followed by 5 h of reperfusion. Either vehicle (0.9% NaCl) or the serotonin (5HT2) receptor antagonist LY53857 was infused i.v. at a dose of 0.5 mg/kg, followed by a constant infusion of 2 mg/kg/min beginning 5 min before left circumflex coronary artery occlusion and continuing throughout the duration of the ischemia and subsequent reperfusion. Verification of functional 5HT2 receptor antagonism in the circulating blood of the LY53857-treated dogs was monitored throughout the experiments by periodic assessment of ex vivo platelet reactivity to exogenous serotonin. After 5 h of reperfusion, the hearts were excised and analyzed utilizing histochemical staining with triphenyltetrazolium, which demarcates myocardial infarct size and anatomical area of myocardium at risk of infarction. There was not a significant reduction of infarct size with LY53857 treatment: control infarct/area at risk = 38.6 +/- 4.7%, n = 9 LY53857 infarct/area at risk = 33.4 +/- 3.8%, n = 6. Similarly, when myocardial infarct size was analyzed as a function of myocardial collateral blood flow, there were no significant effects of drug treatment on the relationship between collateral blood flow and infarct size. The effects of 5HT on neutrophil activation were determined by measuring the potential ability of 5HT to enhance the chemotactic peptide-induced production of superoxide. 5HT did not activate human neutrophils in vitro and LY53857 had no effect on neutrophil superoxide production.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Therapeutic defibrination with ancrod does not protect canine myocardium from reperfusion injury.

The purpose of this study was to determine whether normal fibrinogen contributes to the development of myocardial reperfusion injury by acting as a substrate in vivo for neutrophil adhesion. This was tested in a dog model of acute myocardial infarction that used pentobarbital anesthetized dogs subjected to 90 min regional myocardial ischemia and 5 h reperfusion. Dogs were treated with 1 unit/kg Ancrod (venom from the Malayan pit viper, Agkistrodon rhodostoma) or vehicle i.v. 60 min after left circumflex coronary artery occlusion. Therapeutic defibrination was verified in Ancrod-treated dogs by measurements of clottable fibrinogen, alpha-2 antiplasmin and plasminogen, by the activated partial thromboplastin time and by immunoelectrophoresis. Fibrinogen was depleted to below detectable limits of the assay (less than 0.05 mg/ml) after treatment with Ancrod. The defibrination effect was accomplished by the expected activation of the fibrinolytic system: alpha-2 antiplasmin was decreased by 10% and plasminogen activity was decreased by 30% with Ancrod treatment. There were no measureable differences between the two treatment groups in heart rate, mean arterial blood pressure, rate pressure product or circumflex coronary blood flow throughout the 90 min of regional ischemia or during the 5 h of reperfusion. The relative severity of ischemia between the two treatment groups was similar when assessed with radiolabeled microsphere measurement of myocardial blood flow. The accumulation of neutrophils (measured by myeloperoxidase activity) within the myocardium after reperfusion was not reduced by prior depletion of fibrinogen.(ABSTRACT TRUNCATED AT 250 WORDS)

Ancrod↗

PubMed1991

Characterization of LY233569 on 5-lipoxygenase and reperfusion injury of ischemic myocardium.

LY233569 produced concentration-dependent inhibition of isolated guinea pig 5-lipoxygenase (5-LPO) and 5-LPO activity of human polymorphonuclear leukocytes in vitro; IC50 values were 0.4 and 0.1 microM, respectively. LY233569 also inhibited (IC50 approximately 1.8 microM) zymosan-stimulated production of leukotriene B4 in canine whole blood but had little or no concomitant effect on the production of thromboxane B2. Concentrations of LY233569 as high as 10 microM did not inhibit production or scavenge superoxide from activated human neutrophils. In normal anesthetized dogs, infusion of LY233569 (0.11 mg/kg/min, i.v.) for 6 hr produced persistent inhibition (approximately 80%) of leukotriene B4 production in blood challenged ex vivo with zymosan; the plasma concentration (approximately 4 microM) of LY233569 was consistent with in vitro data illustrating selective and maximal inhibition of 5-LPO. In subsequent experiments, myocardial infarct size was measured after 1 hr of occlusion of the circumflex coronary artery and 5 hr of reperfusion. Continuous infusion of LY233569 (0.11 mg/kg/min, i.v.) had little or no effect on base-line systolic arterial pressure, cardiac rate and the pressure rate product when compared with time-related changes observed in control dogs. LY233569 infusion also did not alter the degree of ST-segment deviation or the intensity and duration of cardiac arrhythmias associated with coronary artery occlusion and reperfusion. Resultant myocardial infarct sizes were 45 +/- 5% of the left ventricle placed at risk in control dogs and 43 +/- 4% in dogs given LY233569. Myeloperoxidase activity of infarcted myocardium did not differ between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Sustained limitation of myocardial reperfusion injury by a monoclonal antibody that alters leukocyte function.

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.

Animals↗

PubMed1990

Antiplatelet antibody [7E3 F(ab')2] prevents rethrombosis after recombinant tissue-type plasminogen activator-induced coronary artery thrombolysis in a canine model.

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)

Animals↗

PubMed1990

Antagonism of leukotriene B4 receptors does not limit canine myocardial infarct size.

Injection of leukotriene (LT)B4 (0.1-3 micrograms/kg i.v.) in normal anesthetized dogs produced dose-related leukopenia that was accompanied by arterial hypotension and tachycardia at higher tested doses. LTD4 (0.1-3 micrograms/kg i.v.), in contrast, increased arterial blood pressure, lowered cardiac rate and produced little change in arterial blood leukocyte count. Continuous infusion of LY255283 [(1-(5-ethyl-2-hydroxy-4-(6-methyl-6-(1H-tetrazol-5-yl)- heptyloxy)phenyl)ethanone] (0.33 mg/kg/min i.v.), a selective LTB4 receptor antagonist, resulted in near complete inhibition of leukopenic, hypotensive and tachycardic responses to LTB4 (3 micrograms/kg i.v.) challenge over a 6-hr test period. Persistent antagonism of canine LTB4 receptors was associated with high circulating levels of LY255283 that were bound extensively to plasma proteins. In subsequent experiments, myocardial infarct size was measured following 1 hr of occlusion of the circumflex coronary artery and 5 hr of reperfusion in control dogs infused with vehicle, and in dogs receiving LY255283 (0.33 mg/kg/min i.v.). Drug and vehicle were infused continuously beginning 15 min before coronary artery occlusion. LY255283 treatment essentially did not alter base-line cardiovascular parameters or myocardial oxygen demand when alterations were compared to time-related changes observed in control dogs. LY255283 infusion also did not alter the degree of myocardial ischemia or the intensity and duration of cardiac arrhythmias associated with coronary artery occlusion and reperfusion. Resultant infarct sizes were 43 +/- 5% of the left ventricle placed at risk in control dogs and 32 +/- 5% in dogs given LY255283; this difference was not statistically significant. The extent of left ventricle placed at risk was similar between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

von Willebrand factor biosynthesis and partitioning between constitutive and regulated pathways of secretion after thrombin stimulation.

The major part of von Willebrand factor (vWf) synthesized in cultured endothelial cells is secreted constitutively without stimulation and consists of all multimeric forms of vWf. In contrast, stimulation with secretagogues such as thrombin results in the release of vWf from the storage pool, the Weibel-Palade bodies which contain only the largest, most biologically potent multimeric forms of vWf. We wished to determine whether the signal for release of vWf might also function as a signal for replenishment of the vWf by enhancing de novo biosynthesis and if replenishment of the vWf storage pool involved a diversion of newly synthesized vWf from the constitutive pathway to the regulated pathway. vWf mRNA and protein levels in unstimulated human umbilical vein endothelial cells were compared with cells that were briefly stimulated with 1 U/mL thrombin for 15 minutes and then incubated without thrombin for periods up to 72 hours. A comparison was also made between unstimulated cells and cells continuously exposed to thrombin for up to 48 hours. Thrombin stimulation, brief or continuous, had no significant effect on subsequent biosynthesis of vWf protein or vWf-specific mRNA. Since thrombin releases vWf only from the storage pool, we examined the possibility of diversion of newly synthesized vWf from the constitutive pathway to the regulated pathway. Cells were pulse-labeled, incubated for 15 minutes with and without thrombin, chased for various periods in unlabeled media, and briefly restimulated with thrombin. No significant redistribution of vWf between the two pathways was observed as a result of thrombin stimulation for the time periods tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Blotting, Northern↗

PubMed1989

Antiplatelet monoclonal F(ab')2 antibody directed against the platelet GPIIb/IIIa receptor complex prevents coronary artery thrombosis in the canine heart.

Interactions between platelets with injured vascular endothelium contribute to thrombotic occlusion. A murine monoclonal antibody [7E3 F(ab')2] to the platelet GPIIb/IIIa 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 microA 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 less than 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 less than 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 less than 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 less than 0.05). The labeling of platelets with 111indium showed accumulation of radioactivity 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 less than 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 GPIIb/IIIa 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 current induced intimal injury of the LCCA.

Animals↗

PubMed1989

Streptokinase improves reperfusion blood flow after coronary artery occlusion.

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.

Animals↗

PubMed1989

F(ab')2 fragments of anti-Mo1 (904) monoclonal antibodies do not prevent myocardial stunning.

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.

Animals↗

PubMed1988

Recombinant single-chain urokinase-type plasminogen activator (rscu-PA) induces thrombolysis and systemic fibrinolysis in a canine model of coronary artery thrombosis.

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 microA) 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 micrograms/kg bolus rscu-PA + 20-40 micrograms/kg/min infusion rscu-PA for 30 min, n = 5) thrombolysis occurred in one case (20%) and this artery reoccluded. In group B (250 micrograms/kg bolus rscu-PA + 25 micrograms/kg/min infusion rscu-PA for 30 min, n = 6) all reperfused and only one reoccluded (16.6%). In group C (200 micrograms/kg bolus rscu-PA + 100 micrograms/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 less than 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.

Animals↗

PubMed1988

Increase in experimental infarct size with digoxin in a canine model of myocardial ischemia-reperfusion injury.

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.

Animals↗

PubMed1988

Myocardial dysfunction and coronary vasoconstriction induced by platelet-activating factor in the post-infarcted rabbit isolated heart.

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 AGEPC 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.

Animals↗

PubMed1988

Carboxyl-terminal amino acid sequences of two variant forms of the gamma chain of human plasma fibrinogen.

The gamma chain of human fibrinogen has been shown to be heterogeneous; three forms of various sizes are normally present in plasma. To further characterize the two less prevalent elongated variants, we have purified the three forms of the gamma chain, isolated unique tryptic fragments, and sequenced the variant portions of each chain. The intermediate-sized form (gamma 55) has a sequence identical to the longest variant (gamma 57.5) from residue Val-408 to Pro-423, which is the C terminus of the gamma 55 chain. The gamma 57.5 chain extends an additional four amino acids. The C-terminal amino acid sequence and corresponding nucleotide sequence of the gamma 55 chain show marked similarity with an elongated gamma-chain variant of rat fibrinogen. In addition, a remarkable similarity in both amino acid and nucleotide sequence was noted between the human gamma 55 chain and the C-terminal extension in human and bovine A alpha chain of fibrinogen, which are encoded by the cDNA but are posttranslationally cleaved and are not found in plasma. The findings suggest an evolutionary conservation in the C-terminal amino acid sequence found in both the fibrinogen A alpha and gamma chains in several species.

Amino Acid Sequence↗

PubMed1988

Sustained limitation by superoxide dismutase of canine myocardial injury due to regional ischemia followed by reperfusion.

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.

Animals↗