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Biomedical subjects

B R Lucchesi

Publications and source records attributed to B R Lucchesi.

At least 19 recordsLinked to original sources
PubMed1992

Myocardial glutathione depletion impairs recovery of isolated blood-perfused hearts after global ischaemia.

This study was performed to determine whether depletion of myocardial glutathione would impair recovery of left ventricular function of blood-perfused, isolated hearts after reversible ischaemic injury. Cats were treated with either vehicle or buthionine sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in the synthesis of glutathione. The feline isolated hearts were perfused with the blood of normal donor cats before and after 40 min of global myocardial ischaemia. The myocardial concentration of glutathione of the BSO group, 178 +/- 38 ng/mg tissue, was significantly less than that of the control group, 292 +/- 38 ng/mg tissue (P < 0.05). The peak left ventricular developed pressure (LVDP) 1 h after reperfusion, expressed as a fraction of the peak LVDP before ischaemia, was 0.87 +/- 0.10 for the control group and 0.64 +/- 0.08 for the BSO group (P = 0.05 vs. control). The peak left ventricular dP/dt after reperfusion, expressed as a fraction of the peak dP/dt before ischaemia, was 1.08 +/- 0.14 for the control group and 0.78 +/- 0.09 for the BSO group (P = 0.05 vs. control). The myocardial creatine kinase activity of the BSO group, 1046 +/- 46 U/g tissue, was not significantly different from that of the control group, 1038 +/- 17 U/g tissue (P = 0.87). Thus, depletion of myocardial glutathione resulted in impaired post-ischaemic contractile function that cannot be attributed to a greater extent of irreversible cell injury.

Animals↗
PubMed1992

Inhibition of platelet-activating factor fails to limit ischemia and reperfusion-induced myocardial damage.

To determine the role of platelet-activating factor (1-O-hexa-decyl-2-acetyl-sn-glyceryl-phosphoryl-choline, PAF) in myocardial ischemic and reperfusion-induced injury, the effects of a PAF receptor antagonist (WEB 2086) were studied in an anesthetized canine model of ischemia (90 min) and reperfusion (6 h). Thirty minutes after onset of ischemia, WEB 2086 was administered as a bolus (20 mg/kg intravenously, i.v.) followed by a continuous 6-h infusion (10 mg/kg/h i.v.). Controls received vehicle alone (0.9% saline). Platelet aggregation was studied at baseline and at 1, 2, 4, and 6 h of drug administration and at the end of the reperfusion period. WEB 2086 treatment did not significantly affect platelet aggregation stimulated by ADP or arachidonic acid (AA). After 1 h of drug infusion, the ex vivo aggregatory response to exogenous (200 nM) PAF was ablated in WEB 2086-treated animals. WEB 2086 administration did not affect heart rate (HR) or mean arterial blood pressure (MAP) during the occlusion or reperfusion phases. During reperfusion of the ischemic tissue, left circumflex coronary artery (LCX) blood flow of WEB 2086-treated animals increased (p < 0.05) above control value. The area of the left ventricle at risk of infarct was not different between control and WEB 2086-treated groups. Infarct size was not significantly reduced in WEB 2086-treated animals. The results of our investigation using a 90-min ischemic period followed by 6-h reperfusion show that pharmacologic antagonism of PAF by WEB 2086 does not protect the heart against ischemia and reperfusion-induced injury.

Animals↗
PubMed1992

Effects of complement activation in the isolated heart. Role of the terminal complement components.

The mechanisms of the complement-mediated myocardial injury associated with ischemia and reperfusion have not been elucidated fully. Complement activation may directly mediate injury through actions of the anaphylatoxins C3a and C5a or generation of the membrane attack complex C5b-9. A model was developed to examine the direct effects of complement activation on heart function, assess myocardial tissue damage, and determine which complement components mediate tissue injury. Isolated rabbit hearts were perfused with Krebs-Henseleit buffer by using a modified Langendorff apparatus. Human plasma was added to the perfusate as a source of complement. Rabbit tissue activates human complement. Treatment with 6% normal plasma resulted in complement activation as assessed by the generation of Bb, C3a, C5a, and SC5b-9. Functional changes in cardiac performance became apparent 7-15 minutes after plasma addition and developed fully over the next 20-30 minutes. The effects were dependent on the complement titer and included 1) an increase in the end-diastolic pressure, 2) a decrease in the developed pressure, 3) an increase in the coronary perfusion pressure, and 4) an increase in lymphatic fluid formation. These effects were not elicited when an inhibitor of complement activation (FUT-175) was present or when heat-inactivated plasma was used. The effects of complement activation on myocardial function could not be reproduced by treatment with recombinant human C5a, zymosan-activated plasma, or plasma selectively depleted of C8. Myocardial tissue accumulated sodium and calcium and lost potassium as a result of complement activation. Activation caused the release of creatine kinase from myocytes and an increase in the radiolabeled albumin space of the hearts. The data demonstrate that complement activation caused decrements in myocardial function and increased the coronary perfusion pressure and lymphatic fluid flow rate. The effects were not mediated by the anaphylatoxins but were dependent on the distal complement component C8, suggesting that C5b-9 was responsible for the physiological changes. Complement activation directly mediated tissue injury in a manner consistent with plasmalemmal disruption as a result of C5b-9 formation. The data suggest that the C5b-9 complex, which is known to form under conditions of ischemia, may contribute directly to myocardial cell injury.

Animals↗
PubMed1991

The anaphylatoxins C3a and C5a are vasodilators in the canine coronary vasculature in vitro and in vivo.

The effect of complement fragments on coronary blood flow in vivo and the contraction of coronary arteries in vitro was determined. In pentobarbital anesthetized dogs, intraarterial bolus injection of C3a and C5a, zymosan-activated serum and methylcholine in the coronary vascular bed caused transient and dose-dependent increases in coronary blood flow. Similar increases were obtained with 25 micrograms of C3a (104 +/- 13%, n = 5) and 0.1 microgram of methylcholine (102 +/- 4%, n = 3). Smaller increases in blood flow were elicited by 25 micrograms of C5a (41 +/- 18%, n = 4) and 0.2 ml of zymosan-activated serum (48 +/- 5%, n = 4). None of these responses were associated with significant changes in left ventricular contractile force measured with a strain gauge, arterial blood pressure, and heart rate. C3a dilated the coronary vascular bed in conscious dogs with an activity equal to or greater than that observed in anesthetized dogs. Isolated canine coronary arteries that were precontracted with serotonin relaxed in response to C3a, whether or not the endothelium was intact. Overall these data suggest that physiologically high doses of anaphylactic complement fragments vasodilate the canine coronary circulation.

Animals↗
PubMed1991

Electrophysiology and antiarrhythmic actions of E-4031 in the experimental animal model of sudden coronary death.

The Class III agent E-4031 was evaluated for its antiarrhythmic and antifibrillatory actions in conscious dogs 3-5 days after anterior myocardial infarction that were responsive to the induction of tachyarrhythmia by programmed electrical stimulation. The administration of E-4031 as an intravenous loading dose (100 micrograms/kg) followed by an infusion for 90 min (10 micrograms/kg/min) suppressed the induction of ventricular tachycardia by programmed electrical stimulation in 6 of 12 dogs and prolonged the cycle length of the induced arrhythmia in 5 of the 6 remaining animals. Continued administration of E-4031 in a dose regimen of 1,000 microgram/kg every 2 h provided significant protection (8 of 10 dogs) against the development of ventricular fibrillation (sudden coronary death) within the first hour after the onset of myocardial ischemia in a region of the ventricle remote from the infarct-related vessel. The incidence of sudden coronary death was 80% in a comparable control group of electrically inducible postinfarcted dogs. Increases in ventricular myocardial refractoriness in the paced QT and QTc intervals suggest that Class III electrophysiologic actions contribute to the antiarrhythmic and antifibrillatory actions of E-4031. The findings suggest that E-4031 may be of clinical utility in the prevention of life-threatening arrhythmias in the setting of myocardial ischemia in the postinfarcted heart.

Animals↗
PubMed1991

Hypothyroidism renders protection against lethal ventricular arrhythmias in a conscious canine model of sudden death.

The protective effect of hypothyroidism against lethal ventricular tachyarrhythmias (VT) in the subacute phase of experimental myocardial infarction (MI) was investigated in 10 thyroidectomized dogs using a conscious model of sudden coronary death. Four weeks after surgical ablation of the thyroid, and having established biochemical hypothyroidism, anterior MI was produced by 120 min of occlusion-reperfusion of the left anterior descending coronary artery. In the subacute phase of MI, the inducibility of VT was investigated using programmed ventricular stimulation (PVS), and the effects on spontaneous development of ventricular fibrillation (VF) were studied by production of posterolateral ischemia at a site remote from the area of the previous infarction. Ischemia was produced by the passage of anodal direct current through a silver wire electrode implanted in the left circumflex coronary (LCX) artery. The results were compared to those from a cohort of 20 existing euthyroid controls that had undergone an identical experimental protocol. No differences were found in heart rate and other electrocardiographic parameters such as the PR, QRS, and QT (paced at 2.5 Hz) and the QTc interval between the hypo- and euthyroid groups. During PVS in the subacute phase of anterior MI, the measured threshold voltage and ventricular refractory periods were similar in both groups. The incidence of inducibility of VT was 100% in the euthyroid animals compared to 60% in the hypothyroid dogs, suggesting an antiarrhythmic effect of hypothyroidism. The incidence of sustained vs. nonsustained VT was similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Xanthine oxidase inhibition does not limit canine infarct size.

BACKGROUND: Evidence supporting the role of xanthine oxidase in myocardial reperfusion injury is based on studies with pharmacological interventions used to inhibit enzyme function. Controversy exists, however, regarding the true role of xanthine oxidase in reperfusion injury. This study was performed to determine whether xanthine oxidase inhibition limits myocardial injury due to coronary artery occlusion and reperfusion. METHODS AND RESULTS: Anesthetized dogs underwent coronary artery occlusion (90 minutes) and reperfusion (6 hours). Oxypurinol (28 mg/kg) or amflutizole (30 mg/kg), chemically unrelated inhibitors of xanthine oxidase, or vehicle was infused intravenously 15 minutes before and 3 hours after reperfusion. Regional myocardial blood flow was determined with radiolabeled microspheres. Infarct size was determined with the tetrazolium method. Myocardial infarct size (percent of risk region) was less in oxypurinol-treated dogs, 32 +/- 16%, compared with that of the control group, 46 +/- 15%. Infarct size for the amflutizole-treated dogs, 40 +/- 21%, was not significantly different from that of the control group. There were no differences in rate-pressure product or collateral blood flow to account for differences in infarct size. Uric acid concentration in the coronary venous plasma increased after reperfusion in the dogs treated with vehicle but not in the drug-treated dogs. Xanthine oxidase inhibition was demonstrated in each of the drug treatment groups, but only oxypurinol limited the extent of myocardial injury. CONCLUSIONS: Previously reported cardioprotective effects of allopurinol, noted to occur only when the drug was administered chronically, may be related to a property of oxypurinol, a major metabolite of allopurinol. The beneficial effect of oxypurinol is unrelated to inhibition of superoxide formation during xanthine oxidase-catalyzed oxidation of xanthine and hypoxanthine.

Animals↗
PubMed1991

The antifibrillatory actions of UK-68,798, a class III antiarrhythmic agent.

The electrophysiologic and antifibrillatory properties of UK-68,798 were studied in vivo in a conscious canine model of sudden coronary death. Electrophysiologic testing was performed on conscious male mongrel dogs (14.5-21.5 kg) 3 to 5 days after surgical induction of an anterior myocardial infarction by occlusion (2 h)-reperfusion of the left anterior descending coronary artery. Compared to saline-treated control animals, UK-68,798 at a dose of 0.9 mg/kg i.v. did not (P = .083) suppress the induction of ventricular tachycardia by programmed electrical stimulation. Six of 12 UK-68,798-treated dogs remained inducible, whereas 10 of 12 vehicle-treated dogs responded to electrical induction of arrhythmia. When compared to predrug inducibility, UK-68,798 significantly (P = .007) reduced the incidence of programmed electrical stimulation-induced ventricular tachycardia. In five of the six dogs inducible after UK-68,798 administration, the cycle length of the induced ventricular tachycardia was prolonged (P = .007) compared to the predrug cycle length. Heart rate, PR interval and QRS duration were not affected by UK-68,798 administration. The rate-corrected QT interval was prolonged (P less than .05) by UK-68,798. The ventricular effective refractory period was increased by UK-68,798 (158 +/- 7 msec, predrug vs. 185 +/- 7 msec, postdrug). Subsequent to programmed electrical stimulation, a 150 microA anodal current was applied to the luminal surface of the left circumflex coronary artery to induce transient episodes of posterolateral ischemia in response to electrolytic injury of the vessel wall.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1990

Cardioprotective effects of amlodipine on ischemia and reperfusion in two experimental models.

The cardioprotective effect of amlodipine, a long-acting dihydropyridine derivative, was studied in 2 experimental models of ischemia and reperfusion. Isolated and blood-perfused feline hearts were made globally ischemic for 60 minutes and then reperfused for 60 minutes. Alterations of left ventricular developed pressure and compliance were monitored in both amlodipine-treated hearts and saline-treated control animals. Changes in perfusion pressure indicated that amlodipine significantly reduced myocardial oxygen consumption and coronary vascular resistance. Furthermore, a progressive increase in resting left ventricular diastolic pressure indicated that amlodipine, administered before the onset of global ischemia, attenuated the development of ischemic contracture. Return of contractile function 60 minutes after reperfusion and maintenance of tissue concentrations of electrolytes were significantly better in the amlodipine-treated group than in the control animals. In intact canine hearts, regional myocardial ischemia was induced for 90 minutes, followed by 6 hours of reperfusion. Although the hemodynamic variables and the size of the region of risk did not differ significantly between treated animals and control animals, the infarct size was significantly smaller in the amlodipine-treated group than in the control animals, and a gradual reduction in coronary blood flow was observed in the control group that was prevented in the amlodipine group. A comparison of these findings with those observed with oxygen radical scavengers also is discussed. A detailed report of these studies was published in The American Journal of Cardiology (1989;64:101I-116I). This review is included here to maintain continuity of the symposium for the convenience of the reader.

Amlodipine↗
PubMed1990

Myocardial ischemia, reperfusion and free radical injury.

Reperfusion of coronary arteries to limit myocardial ischemic injury and extent of myocardial necrosis is possible by either the use of fibrinolytic therapy, coronary angioplasty or coronary artery bypass surgery. The concept that early reperfusion may salvage jeopardized myocardium is derived from basic experimental studies which purported to demonstrate that the ultimate extent of irreversible myocardial injury could be reduced by reperfusion of the ischemic myocardium within 3 hours from the onset of regional myocardial ischemia. It is firmly established that salvage of ischemic myocardium is dependent on early restoration of blood flow to the myocardium at risk. Despite dependency on reoxygenation for ultimate survival, myocardial tissue that is reperfused and reoxygenated may be subjected to additional injurious insult due to reactive metabolites of oxygen. The cytotoxic species of oxygen are referred to as "oxygen free radicals." Coincident with the influx of inflammatory cells into the reperfused region is an additional loss of otherwise viable myocardial cells. There is strong support for the concept that the polymorphonuclear leukocyte is a contributor to the phenomenon of "reperfusion" or "reoxygenation" injury in the blood perfused heart. This discussion focuses on the role of the neutrophil as a potential contributor to the extension of tissue injury and reviews those interventions, which although in the experimental stage, offer promise of becoming therapeutically important in the future and may help elucidate the mechanisms underlying the potentially deleterious role of the neutrophil in situations involving whole blood reperfusion of the ischemic myocardium.

Animals↗
PubMed1990

Free radicals and ischemic tissue injury.

There is growing evidence that reperfusion of ischemic organs is associated with the formation of free radicals that exacerbate the ischemic injury. Free radicals may damage viable tissue via the peroxidation of lipids and oxidation of protein sulfhydryl groups, leading to perturbations of membrane permeability and enzyme function. Steven Werns and Benedict Lucchesi discuss evidence that activated neutrophils are an important source of free radicals after cardiac and intestinal ischemia, and assess the strategies that have been investigated as ways of alleviating damage caused by free radicals during ischemia-reperfusion.

Animals↗
PubMed1990

Profibrillatory actions of pinacidil in a conscious canine model of sudden coronary death.

Pinacidil is one of a number of new antihypertensive agents possessing an action that involves an enhanced potassium efflux in cardiac and vascular smooth muscle. An associated feature of pinacidil is a shortening of the cardiac action potential duration, which may constitute a potentially proarrhythmic effect. The present study evaluated pinacidil (0.3 mg/kg/h i.v. for 6 h) on the postinfarcted canine heart in a subset of dogs unresponsive to programmed electrical stimulation during the subacute phase of anterior myocardial infarction, and known to be at low risk of ventricular fibrillation in response to acute posterolateral ischemia. Results were compared with a comparable control group of vehicle-treated, noninducible animals. Nonsustained ventricular tachyarrhythmia developed in 2 of 15 pinacidil-treated animals as compared to the initiation of ventricular tachycardia in 1 of 16 postinfarcted hearts (p = 0.96) in the control group. Thus, pinacidil did not alter the responsiveness of the postinfarcted heart with respect to the electrical induction of tachyarrhythmias. The subsequent development of an acute ischemic event at a site remote from the previous myocardial infarction was associated with a greater incidence of ventricular fibrillation within 1 h from the onset of ischemia in the pinacidil-treated animals (9/15; 60%) as compared to the control group (1/15; 6.7%; p = 0.007). The 24-h cumulative mortality, likewise, was greater in the pinacidil-treated group [13/15 (87%)] as compared to the vehicle-treated control group 3/15; 20%; p = 0.001. Significant cardiovascular and electrophysiologic effects of pinacidil included an increase in heart rate (124 +/- 6-143 +/- 10 beats/min, p less than 0.05) and reductions in the refractory periods of normal (178 +/- 2-166 +/- 4 ms, p less than 0.05) and peri-infarcted (170 +/- 5-185 +/- 5 ms, p less than 0.01) myocardial regions. It is concluded that pinacidil does not alter the responsiveness of the postinfarcted heart to programmed electrical stimulation. However, in the presence of a superimposed acute ischemic event, pinacidil increases the potential for the development of ventricular fibrillation in a subset of postinfarcted animals that otherwise show a low risk with respect to the development of lethal arrhythmias. It is hypothesized that the increased tendency to develop ventricular fibrillation is associated with the pinacidil-induced reduction in the ventricular refractory period. This conclusion is consistent with the known ability of pinacidil to enhance potassium efflux during myocardial repolarization and to decrease the duration of the action potential.

Action Potentials↗
PubMed1990

Effects of combined thromboxane synthetase inhibition/thromboxane receptor antagonism in two models of sudden cardiac death in the canine: limited role for thromboxane.

The effects of combined thromboxane synthetase inhibition and thromboxane receptor antagonism (TSI/TRA) were studied in conscious and in anesthetized canine models of sudden cardiac death. Administration of the TSI/TRA, R68070 10 mg/kg intravenously (i.v.), decreased thrombin-stimulated thromboxane synthesis and significantly antagonized platelet aggregation in response to the thromboxane-mimetic U46,619. In the conscious canine model, R68070 did not change ventricular refractoriness, did not prevent induction of ventricular arrhythmias by programmed electrical stimulation, and failed to prevent development of spontaneous ventricular fibrillation (VF) in response to ischemia produced at a site remote from the area of previous myocardial infarction (R68070 mortality = 70%, vehicle = 100%, p = NS). In the anesthetized canine model, R68070 prevented development of ischemia in 7 of 11 animals and reduced mortality significantly (R68070 27% and vehicle 73%; p = 0.038). R68070 inhibited thrombus formation in both models (R68070 conscious 7.0 +/- 2.6 mg and vehicle conscious 15 +/- 7.6 mg, p = NS; R68070 anesthetized 5.9 +/- 1.9 mg and vehicle anesthetized 17.7 +/- 4.3 mg; p less than 0.05). The results suggest that inhibition of thromboxane-dependent activity during acute recovery from infarction was able to protect the myocardium from developing ischemia in response to current-mediated intimal damage in a noninfarct-related artery. In the subacute phase of recovery from infarction, when the underlying myocardial substrate is susceptible to electrical derangement induced by transient ischemia, thromboxane inhibition in itself was unable to prevent ischemia-induced sudden cardiac death. Although R68070 may delay onset of ischemia due to thrombotic occlusion of the coronary artery, there does not appear to be an antiarrhythmic/antifibrillatory action to be derived from interfering with the synthesis or receptor-mediated action of thromboxane. Furthermore, R68070 does not alter the electrophysiologic properties of the heart which would result in an antiarrhythmic or antifibrillatory action.

Adenosine Diphosphate↗
PubMed1990

Antiarrhythmic and electrophysiologic actions of CK-3579 and sematilide in a conscious canine model of sudden coronary death.

The antiarrhythmic and antifibrillatory actions of the CK-3579 and sematilide, two new class III antiarrhythmic drugs, administered in a multiple-dose regimen were evaluated in conscious dogs 3-5 days after anterior myocardial infarction. The study population consisted of three groups of 10 dogs each, in which all animals entered into the final protocol developed nonsustained or sustained ventricular tachycardia in response to programmed electrical stimulation using one, two or three premature stimuli. Each drug was administered intravenously in a dose of 3.0 mg/kg every 3 h for a total of six doses. Sematilide significantly suppressed the induction of ventricular tachyarrhythmia by programmed electrical stimulation in six of 10 postinfarcted dogs, whereas CK-3579 suppressed the induction of tachyarrhythmia in only two of 10 animals. Despite its ineffectiveness in preventing electrical induction of tachycardia, CK-3579 produced a significant increase in the cycle length of the induced ventricular rhythm. The administration of each drug was associated with an increase in the ventricular refractoriness and in the paced QT interval, suggesting that class III electrophysiologic properties contribute to the antiarrhythmic action of each drug. In addition, CK-3579 was shown to have beta 1-adrenoceptor blocking properties. The subsequent induction of an acute ischemic event in a region remote from the infarct-related artery was associated with a high incidence (80%, eight of 10 postinfarcted dogs) of ventricular fibrillation within the first hour after the onset of myocardial ischemia in the vehicle-treated control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1990

Effect of diltiazem on experimental coronary artery thrombosis in dogs.

The effect of the calcium channel blocker diltiazem on arterial thrombosis was determined in anesthetized dogs subjected to continuous anodal stimulation of the intimal surface of the left circumflex coronary artery (LCCA). Infusion of saline (n = 6) or diltiazem (80 micrograms/kg plus 20 micrograms/kg/min i.v.; n = 6) was begun 15 min before electrical stimulation. Diltiazem prolonged the P-R interval by 28% and reduced mean arterial blood pressure (ABP) by 9%. All animals developed occlusive thrombosis. Saline- and diltiazem-treated dogs did not differ in the time to occlusion (204 +/- 30 and 153 +/- 27 min, respectively) and LCCA thrombus mass (25 +/- 4 and 24 +/- 3 mg, respectively). LCCA flows measured intermittently during thrombogenesis also did not differ between treatment groups, although the frequency of spontaneous flow increases which interrupted the flow declines was reduced 53% by diltiazem. In separate diltiazem-treated dogs (80 micrograms/kg plus 20 micrograms/kg/min i.v. for 2 h; n = 7) the ex vivo platelet aggregation response to platelet-activating factor (PAF) was inhibited (-45%), but not the response to collagen. When 5 and 25 mumols/l diltiazem was tested in vitro, again the aggregation response to PAF was reduced (-25 and -81%, respectively) while that to collagen was unaffected. These results demonstrate that diltiazem does not impede thrombus formation in vivo when given at a dose that exerts threshold hemodynamic activity and significantly impairs platelet function.

Anesthesia↗
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↗