Effects of bepridil and lidocaine on the intravenctricular conduction in acutely ischaemic and infarcted canine myocardium

Summary Effects of bepridil, an antiarrhythmic and antianginal drug, on intraventricular conduction in acutely ischaemic and infarcted myocardium were examined in anaesthetized dogs, and compared with those of lidocaine. Bepridil at doses of 2 and 5 mg/kg markedly prolonged the conduction time of a premature excitation induced by a ventricular stimulation in the infarcted zone. The effect of bepridil was dependent on a coupling time of the stimulation. Bepridil showed a marked effect at a coupling time of 150 ms, while it showed no significant effect at a prolonged coupling time of 1 s. In other words, the effect of bepridil was interval-dependent. Lidocaine showed a similar interval-dependent effect, but the effect of lidocaine at a longer coupling time was less than that of bepridil. The premature stimulation produced severely delayed conduction which resulted in reentrant beats. Bepridil blocked these conductions, thereby preventing reentrant beats. In contrast to the depressant effect of bepridil in the infarcted myocardium, bepridil prevented the prolongation of conduction time during acute ischaemia. The alternation of the ST-T complex during acute ischaemia which is also an important arrhythmogenic factor was also attenuated by bepridil. Contrary to bepridil, lidocaine significantly enhanced the conduction delay and the alternation in the ST-T complex. In conclusion, bepridil as well as lidocaine showed an interval-dependent depression of the conduction in the infarcted zone of the heart, whereas during acute ischaemia bepridil in contrast to lidocaine attenuated the conduction delay and ST-T alternans. Send offprint requests to H. Hashimoto at the above address     

Liposome kinetics in infarcted canine myocardium

To study the mechanisms and kinetics of liposome deposition in the region of the experimental myocardial infarction, the myocardial distribution of positive and negative liposomes was determined as a function of regional myocardial blood flow and time after administration. The study was performed in dogs at 1 and 24 h following experimental myocardial infarction. Twenty-four hours after coronary artery occlusion, the initial myocardial distribution of positive and negative liposomes (2 min) is directly proportional to regional myocardial blood flow. With time, there is reduction of the radiotracer associated with negative liposomes from all myocardial regions (p less than 0.01). In contrast, in areas of moderate and severe blood flow reduction, there is progressive accumulation of tracers entrapped or incorporated in positive liposomes. This increment becomes significant in 120 min (p less than 0.005). Similar findings are observed in studies performed 1 h after coronary artery occlusion. Dual-label liposomes [( 3H]cholesterol and [99mTc]diethylenetriamine pentaacetic acid) were used to study the integrity of liposomes in normal and ischemic myocardium. Significant dissociation of the aqueous and lipid labels of positive liposomes is observed 1 h following coronary artery occlusion. In the 24-h myocardial infarction model, dissociation of the aqueous and lipid labels in ischemic myocardium is also observed. This phenomenon is more pronounced with positive than with negative liposomes (p less than 0.02). The leakage of tracers from liposomes may result from destabilization or destruction of liposomes in the ischemic myocardium by the action of phospholipases, catabolites, and local environmental changes. This effect is less marked for negative liposomes. The use of liposomes improved the regional distribution of the tracer in infarcted tissue. However, the absolute amount of tracer delivered to the myocardium is less than that achieved with the free form.     

Electrophysiological effects of lidocaine, l-chlorpheniramine, and bepridil on normal and ouabain-intoxicated canine Purkinje fibers

We compared the electrophysiological effects of lidocaine, l-chlorpheniramine, and bepridil on both normal and ouabain-induced automaticity of canine Purkinje fibers. All three drugs suppressed the automaticity of spontaneously beating Purkinje fibers, but only lidocaine and bepridil reduced the amplitude of delayed afterdepolarizations induced by ouabain. Whereas lidocaine caused equal decreases in delayed afterdepolarization amplitude initiated at cycle lengths of stimulation between 1,000 and 250 ms, bepridil reduced their amplitude more at short than at long cycle lengths. Similarly, bepridil's but not lidocaine's effects on action potential characteristics were also dependent on the cycle length of stimulation; more marked decreases in amplitude and rate of rise of the action potential being observed at short cycle lengths. Lidocaine, alone, also markedly prolonged the period of overdrive suppression.     

Electrophysiologic and inotropic effects of O-benzyl-phosphocreatine in rabbit myocardium

O-benzyl-phosphocreatine-Na (BPC) applied in superfusion increased the action potential amplitude and isometric tension in the isolated sinus node strips, atrial trabeculae and papillary muscles. BPC enhanced the slope of the slow diastolic depolarization evoking the positive chronotropic effect. The drug prolonged the action potential duration in the atrial and ventricular cells. BPC exerted similar effects during hypoxia and cyanide superfusion in the working myocardium. On the other hand, phosphocreatine as well as O-benzyl-phosphoglycocyamine added to the superfusion fluid were ineffective. BPC increased also the ATP content of the superfused contracting atrial trabeculae. These results suggest that BPC crosses the sarcolemma, elevates the ATP content, and thereby it increases the slow inward and can serve as an additional source of the metabolic energy in the cardiac cells.     

Electrophysiological actions of flecainide in normal and infarcted canine Purkinje fibers

The electrophysiological effects of flecainide, 0.1, 0.5 and 1.0 mg/l, on action potential characteristics were examined in normal Purkinje fibers and Purkinje fibers surviving infarction, at stimulation cycle lengths of 1000 and 300 ms. Overshoot, amplitude and dV/dtmax were reduced significantly in a dose-dependent manner by flecainide in both normal Purkinje fibers and Purkinje fibers surviving infarction. Action potential duration was shortened by flecainide to a greater extent: at the cycle length of 1000 ms compared to 300 ms; at 50% repolarization compared to 90%; and in normal preparations compared to infarcted preparations. Activation time was increased by flecainide in a dose-dependent manner in both types of preparations. This effect was enhanced at the shorter cycle length. In both normal and infarcted preparations, flecainide shortened the ERP of those having a longer initial ERP and lengthened those with a shorter ERP. This effect was significant only at the stimulation cycle length of 1000 ms. This study indicates that flecainide has properties unique and different from traditional antiarrhythmic drugs.     

Electrophysiologic and anticholinergic effects of pirmenol enantiomers in guinea-pig myocardium

Summary Since it has been reported that several class I drugs stereoselectively block sodium channels, potassium channels and muscarinic receptors in cardiac tissues, electrophysiologic and anticholinergic effects of enantiomers of pirmenol, a class I antiarrhythmic drug, were examined. Both (+) and (–) pirmenol depressed the maximum upstroke velocity (V_max) of the action potential in a concentration-dependent manner in guinea-pig papillary muscles driven at 1.0 Hz, and there was no significant difference in the potency of the class I effect between the enantiomers. The onset rates of use-dependent block (UDB) of (V_max) at 2.0 Hz for 10 µmol/l (+) and (–) pirmenol were 0.30±0.03 and 0.29±0.01 per action potential, and the recovery time constants from UDB for (+) and (–) pirmenol were 27.0±2.7 and 27.7±1.9 s, respectively, indicating no difference in the binding and unbinding kinetics to the sodium channel between the enantiomers. Both (+) pirmenol and (–) pirmenol prolonged action potential duration (APD) at low concentrations (1–10 µmol/l) and shortened it at high concentrations (30–100 µmol/l) Again, there was little difference with respect to the effects on APD between the enantiomers. However, in the isolated guinea-pig left atria (–) pirmenol more potently antagonized the negative inotropic effect of carbachol than (+) pirmenol, and the pA₂ values for (+) and (–) pirmenol were 6.41 and 6.71, respectively. The functional study was supported by the radioligand binding experiments using [³H]N-methyl scopolamine ([³H]NMS) in guinea-pig left atrial membranes. Specific ([³H]NMS) binding was competitively displaced by the enantiomers, and the apparent dissociation constant for (+) pirmenol (1.95±0.23 µmol/l) was significantly greater than that for (–) pirmenol (0.90±0.18 µmol/l). These results suggest that pirmenol enantiomers stereoselectively interact with cardiac muscarinic receptors but not so with cardiac sodium and potassium channels. Correspondence to M. Kanno at the above address     

Sotalol exhibits reverse use-dependent action on monophasic action potentials in normal but not in infarcted canine ventricular myocardium.

In 12 anesthetized mongrel dogs (30 mg/kg pentobarbital), a thoracotomy was performed, and the left anterior descending coronary artery was ligated proximally. Eight to 12 days later, monophasic action potentials were recorded endocardially from the apex of the noninfarcted right ventricle and infarcted areas of the left ventricle, and the effects of 1.5 mg/kg intravenous sotalol were evaluated. Monophasic action potentials from the infarcted zone of the left ventricle were obtained from areas where fractionated bipolar electrograms could be recorded; this was histologically confirmed. After sotalol, in sinus rhythm, the monophasic action potential duration at 90% repolarization of the infarcted zone increased from 186 +/- 31 to 226 +/- 45 ms (+ 22%, p less than 0.05), and monophasic action potential duration of the noninfarcted zone increased from 184 +/- 31 to 225 +/- 47 ms (+ 22%, p less than 0.05). Programmed ventricular stimulation was performed with single extrastimuli at a basic drive cycle length of 300 ms. With long coupling intervals (290 ms), monophasic action potential duration of the infarcted zone increased from 165 +/- 23 to 183 +/- 25 ms (+ 11%, p less than 0.05) after sotalol; and monophasic action potential duration of the noninfarcted zone increased from 159 +/- 20 to 180 +/- 25 ms (+ 13%, p less than 0.05). With short coupling intervals (200 ms), the monophasic action potential duration of the noninfarcted zone increased from 157 +/- 19 to 173 +/- 18 ms (+ 10%, p less than 0.05), and monophasic action potential duration of the noninfarcted zone increased from 150 +/- 18 to 157 +/- 18 ms (+ 5%, NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of quinidine on transmembrane action potentials of normal and infarcted canine Purkinje fibers.

Fourteen days after proximal ligation of the left anterior descending coronary artery (LAD) of mongrel dogs, the effects of quinidine on action potentials of normal and infarcted Purkinje fibers were evaluated. The concentration-dependent (10(-7)-3 x 10(-5) M) and frequency-dependent (1 and 3 Hz) actions of quinidine were evaluated by the following parameters: maximum upstroke velocity (Vmax), action potential duration at 50 and 95% repolarization (APD50, APD95), effective refractory period (ERP), resting membrane potential (RMP), and action potential amplitude (APA). Quinidine reduced Vmax in normal and abnormal Purkinje fibers in a concentration- and frequency-dependent manner; these effects were more pronounced in infarcted tissue. The APD50 was shortened significantly at 1 Hz in noninfarcted Purkinje fibers, whereas in infarcted Purkinje fibers quinidine had no effect on APD50. The APD95 was not significantly altered by quinidine in normal Purkinje fibers; in infarcted areas APD95 was significantly prolonged at 1 and 3 Hz. The effective refractory period (ERP) was prolonged in normal and infarcted Purkinje fibers, these effects were more marked in ischemically damaged fibers. No effects were observed on resting membrane potential (RMP). APA was reduced significantly after quinidine at 1 and 3 Hz; there was no difference between normal and infarcted tissue. These data indicate a differential effect of quinidine in normal and infarcted Purkinje fibers which may be an important mechanism of action of quinidine in infarcted tissue.     

Electrophysiologic effects of cocaine on the canine ventricle

To evaluate the electrophysiologic effects of cocaine on the ventricle, 12 conscious dogs were studied before and after a bolus and infusion of cocaine titrated to maximum tolerance or to an increase in the mean blood pressure by at least 15%. Plasma cocaine levels, blood pressure, and surface and intracardiac electrograms were recorded. Programmed electrical stimulation was performed from the right ventricle at drive cycle lengths of 400 and 350 ms with introduction of up to three extrastimuli. The right ventricular effective refractory period decreased by 10% (p less than or equal to 0.01) and the mean blood pressure increased by 19% (p less than or equal to 0.01). No sustained spontaneous or induced ventricular arrhythmias were recorded after cocaine administration. There were no significant changes in pacing threshold, intraventricular conduction, heart rate, QRS or QTc intervals. The cocaine dose infused was 2.1 +/- 1.0 mg/kg; cocaine plasma levels were 1969 +/- 959 ng/ml immediately after the bolus and 508 +/- 234 ng/ml at the end of the study. It is concluded that in a presumably normal canine heart and at the doses given that cocaine decreases right ventricular effective refractory period, does not change intraventricular conduction, and does not result in sustained spontaneous or induced ventricular arrhythmias.     

Electrophysiologic effects of saterinone and milrinone in the isolated guinea pig myocardium

The positive inotropic agent milrinone and the newly synthesized compound saterinone [+/-)-1,2-dihydro-5-[4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl] propoxy]phenyl]-6-methyl-2-oxo-3-pyridine-carbonitrile, BDF 8634) dose-dependently increased the contractile force of guinea pig left atria. During a 90-min exposure, 10(-4) mol/l saterinone caused a continuous increase of the functional refractory period (FRP), while the initial positive inotropic effect faded gradually. No change of the FRP was observed with milrinone. Saterinone (10(-4) mol/l) also increased the action potential duration and the FRP of guinea pig papillary muscles, while milrinone had no influence on either parameter. Both milrinone and saterinone increased the amplitude, depolarization velocity and duration of slow response action potentials in K+-depolarized muscles. These effects appeared in the presence of tetrodotoxin or propranolol and could be reversed by carbachol. It is concluded that saterinone increases the force of contraction and the slow inward current by inhibiting cardiac phosphodiesterase. The increase of the FRP may be attributed to a decrease of the membrane K+ conductance.     

The effects of dipyridamole on blood flow and oxygen handling in the acutely ischaemic and normal canine myocardium

1. The effects of the intravenous administration of dipyridamole (0.25 mg/kg) were examined in a canine preparation that enabled simultaneous measurements to be made of blood flow in ischaemic and in essentially normal areas of the myocardium and also of oxygen handling (availability, consumption and extraction) in both these regions.2. When administered to dogs anaesthetized with trichlorethylene 2-3 h after acute ligation of the descending branch of the left coronary artery, dipyridamole markedly increased blood flow in essentially normal regions (left circumflex flow) but failed to increase flow in the area supplied by the ligated vessel (measured by (133)xenon clearance and by retrograde flow). In five of the six animals definite decreases in flow (; stealing ') were observed in the ischaemic region. These flow changes were related to the decreased trans-ventricular perfusion pressure (diastolic peripheral coronary pressure minus left ventricular end-diastolic pressure) and were accompanied by electrocardiographic evidence of increasingly severe myocardial ischaemia. The results support the suggestion that only increasing the perfusion gradient will usefully improve blood flow (and hence oxygen availability) to the acutely ischaemic myocardium.3. Despite these effects on ischaemic muscle blood flow, the oxygen tension of the blood draining the infarcting muscle was markedly elevated. The conclusion is drawn that dipyridamole decreases the efficiency of the myocardial circulation by opening up vessels that do not take part in tissue exchange.     

Effect of adenosine on transmural flow gradients in normal canine myocardium

Previous reports suggest that in comparison to epicardial flow the response of endocardial blood flow to systemic adenosine is limited. However, intravenous adenosine results in reflex tachycardia and hypotension, which we avoided in six anesthetized dogs by infusing adenosine into the left circumflex (LCx) artery to evaluate the endocardial/epicardial ratio during partial and full vasodilation. The mean (+/- SD) LCx endocardial/epicardial ratio was 1.37 +/- 0.18 with partial vasodilation and 0.81 +/- 0.06 with full vasodilation, which represents an initial increase followed by a decrease when compared with the normal left anterior descending values (p less than 0.05). This biphasic response in the endocardial/epicardial ratio with increasing vasodilation was a direct effect of adenosine, as no hemodynamic alterations occurred during the protocol. These data suggest that in an experimental model with a relative tachycardia the endocardial layer is more sensitive to adenosine but there is a greater capacity to increase flow in the epicardial layer.     

Electrophysiologic and hemodynamic effects of sodium bicarbonate in a canine model of severe cocaine intoxication

OBJECTIVE: Cocaine toxicity causes myocardial depression, malignant dysrhythmias, and sudden death, partially due to cocaine-related myocardial sodium channel blockade. Because of cocaine's ability to block cardiac sodium channels, sodium bicarbonate (NaHCO3) has been proposed as an antidote. The hypothesis of this study was that NaHCO3 would correct cocaine-induced conduction abnormalities and resultant hemodynamic compromise in an animal model simulating severe cocaine intoxication. METHODS: Design: Prospective, controlled, experimental study in which 15 anesthetized dogs were given three successive boluses of cocaine (7 mg/kg) and then randomized to receive NaHCO3, 2 mEq/kg (n = 8) or placebo (n =7). Measurements: Arterial, left ventricular, and pulmonary artery pressures; cardiac output (CO); electrocardiogram (ECG); blood gases; and serum concentrations of cocaine were measured at baseline, at fixed time intervals after each bolus of cocaine, and then after administration of NaHCO3 or placebo. Statistical significance was determined by analysis of variance (ANOVA) for repeated measures. RESULTS: Seven dogs experienced significant arrhythmias, including VT, pulseless electrical activity, and third-degree atrioventricular block; 2 of these dogs expired prior to receiving NaHCO3 and were excluded. Immediately after administering NaHCO3, QRS duration decreased by 30% (p < 0.001), returning to baseline more quickly than in the control group. This effect was associated with a brief 30% decrease in MAP (p = NS). After NaHCO3, CO increased 78% and remained increased for 5 min (p < 0.007). One dog converted from complete heart block to sinus rhythm shortly after NaHCO3 administration. CONCLUSIONS: NaHCO3 improved ECG changes secondary to cocaine toxicity and improved myocardial function.     

Electrophysiologic effects of encainide (MJ 9067) on canine purkinje fibres

Microelectrodes were used to characterize the actions of a new antiarrhythmic compound, encainide, 4-methoxy-2′-[2-(1-methyl-2-piperidyl)-ethyl] benzanilide, on transmembrane potentials generated by isolated canine Purkinje fibres in tissue bath. Encainide, 1×10^?7 M, had no effect on resting potential (RP) and action potential (AP) of stimulated fibres or automaticity of spontaneously fibres. Encainide (1×10^?6 M) shortened phase 2 and action potential duration (APD) at 50, 75 and 100% of repolarization; AP rate of rise (V?max) decreased only ～15% at 3 h exposure, while RP was unchanged. Higher concentrations also shortened phase 2 and APD, markedly decreased V?mac, depressed the membrane responsiveness curve and increased conduction time. Encainide, 1×10^?6 M, increased ERP/APD₁₀₀. These effects were rapidly reversed by washing with drug-free solution. Encainide (1×10^?5 M) decreased the automatic rate of spontaneously beating untreated fibres and stretch-depolarized fibres, but had little effect on catecholamine-enhanced automaticity. Encainide, 1×10^?5 M, delayed the onset of ouabain toxicity. These findings suggesting that the antiarrhythmic effect of encainide may arise from its depression of V?max and memrane responsiveness, increase in ERP/APD₁₀₀ and inhibition of automaticity, are discussed in light of the similarity of the actions of this new drug to the known properties of lidocaine and quinidone.     

Electrophysiologic effects of bretylium tosylate on the canine heart during coronary artery occlusion and reperfusion

The electrophysiologic and antiarrhythmic actions of bretylium tosylate were studied after acute coronary artery occlusion and reperfusion in pentobarbital-anesthetized dogs. Three groups of animals were studied: Group I (n = 8) served as saline controls, Group II (n = 7) received bretylium tosylate (10 mg/kg i.v.) 60 min prior to coronary artery occlusion, and Group III (n = 5) received bretylium tosylate (30 mg/kg i.v.) in three divided doses over the 24 h prior to coronary artery occlusion. In Groups II and III the effective refractory period of the nonischemic myocardium was not altered by bretylium before or during the occlusion period, nor was it influenced by bretylium during the subsequent reperfusion period. In Group I the effective refractory period of the ischemic myocardium decreased 24 +/- 3.0% after coronary occlusion and increased 12 +/- 3% above the preocclusion level on reperfusion. In Group II the effective refractory period of the ischemic myocardium decreased 28 +/- 3.2% after coronary occlusion but did not overshoot preischemic levels on reperfusion. In Group III the effective refractory period decreased 15 +/- 3.8% following coronary occlusion and did not overshoot preocclusion levels during reperfusion. The ventricular activation times of the normal and ischemic myocardium were not affected by bretylium tosylate during occlusion or reperfusion in Group II or III. Significant reperfusion arrhythmias were observed only in Groups I and II. These data suggest that bretylium tosylate exerts its antiarrhythmic actions in ischemic myocardium by reducing the dispersion of cardiac refractoriness produced by coronary artery occlusion and, consequently, abolishing the abrupt change in cardiac refractoriness that follows coronary artery reperfusion. These antiarrhythmic actions of bretylium are pronounced in the chronically treated group, suggesting an electrophysiologic basis of the delayed antiarrhythmic actions of bretylium.     

The role of beta-adrenoceptors in coronary blood flow distribution in normal and ischemic canine myocardium.

beta-Adrenoceptor agonists increase myocardial ischemic injury, mainly by elevating myocardial oxygen consumption. Moreover, it has been shown that isoprenaline may "steal" regional myocardial blood flow (RMBF) from ischemic to non ischemic areas and from epicardium to endocardium. The mechanisms of these two isoprenaline-induced redistributions of RMBF have been investigated by the use of radioactive microspheres in an experimental model of canine myocardial ischemia with simultaneous measurement of ST-segment elevation. Isoprenaline increased RMBF in both epi- and endocardial non ischemic areas and in epicardial ischemic areas, leading to a significant decrease in the endo/epi ratio. After atenolol, isoprenaline still increased RMBF but to a lesser extent and the endo/epi ratio was still decreased. Salbutamol, in doses inducing no significant changes in cardiac parameters or myocardial oxygen consumption, produced effects similar to those of isoprenaline. These results indicate a non-homogeneous beta2-stimulation-induced vasodilation in endo- and epicardium, which might be due either to the higher epicardial coronary vasocilatory reserve or to a heterogeneous distribution of transmural beta2-adrenoceptors. Isoprenaline also decreased the ischemic/non ischemic total blood flow ratio (I/NI) and caused further increases in ST-segment elevation. These effects were abolished by atenolol pretreatment, indicating the deleterious effects of isoprenaline-induced tachycardia in this I/NI decrease and in the ischemic injury.     

Histamine modification of spontaneous rate and rhythm in infarcted canine ventricle

Histamine (10(-3) M) increased the spontaneous rate similarly in isolated preparations of normal left ventricular tissue from control, i.e. normal and sham-operated, dogs (control preparations) and in preparations consisting of normal and contiguous infarcted left ventricular tissue from dogs with subacute, i.e. 24 hours after left coronary artery ligation, myocardial infarction (infarcted preparations). Histamine (10(-3) M) markedly enhanced the irregular rhythm of infarcted preparations. The H1-receptor antagonist, chlorpheniramine (10(-4) M), and the H2-receptor antagonist, cimetidine (10(-3) M), antagonized the effects of histamine (10(-3) M) on the spontaneous rate of both control and infarcted preparations. The H1-receptor agonist, 2-pyridyl ethylamine (PEA, 10(-4) M), increased the spontaneous rate of control and infarcted preparations; these effects were antagonized by chlorpheniramine (10(-4) M). The H2-receptor agonist, dimaprit, had no effect. Similar to histamine (10(-3) M), PEA (10(-4) M) enhanced the irregular rhythm of infarcted preparations; dimaprit had no effect. High local concentrations of histamine may occur in poorly perfused ischemic tissue. The enhancement of irregular rhythm produced by histamine, and the specific H1-receptor agonist, PEA, leads us to suggest its involvement in arrhythmias associated with subacute myocardial infarction.     

Neutrophil depletion suppresses 111In-labeled platelet accumulation in infarcted myocardium

Platelets and neutrophils accumulate rapidly in infarcted myocardium. Although antineutrophil agents reduce the size of the infarcted area, this is not observed with antiplatelet drugs. The possibility that myocardial ischemia-induced platelet deposition was secondary to a neutrophil-mediated event was assessed by injecting prostacyclin-washed autologous 111In-labeled platelets and measuring the amount of radioactivity in different regions of the heart following 90-min occlusion of the left anterior descending coronary artery followed by reperfusion for periods up to 5 h. Platelet deposition during the reperfusion phase was linear with time and similar to the time course of neutrophil accumulation. There was a transmural distribution of radioactivity across the myocardium where the "zone" between infarcted and risk regions, called the "interface," greater than infarct greater than risk greater than normal. Neutropenia (21 +/- 2% control levels), induced with specific sheep anti-dog neutrophil antiserum, had minimal effects on platelet aggregation ex vivo, but significantly reduced platelet accumulation in the ischemic myocardium following 5-h reperfusion and abolished the transmural platelet distribution. These results suggest that myocardial platelet deposition is secondary to a neutrophil-mediated event in this occlusion-reperfusion model of myocardial injury. Interactions between platelets and neutrophils at the site of tissue damage may influence the process of myocardial ischemic injury.     

Effects of zoledronate in the repair of chronically infarcted rat myocardium

Zoledronate (Zol), one of the class of bisphophonate drugs, is commonly used to treat postmenopausal osteoporosis. Treatment of liposomal bisphosphonates has been shown to worsen myocardial infarct repair in an experimental model. The purpose of this study was to investigate the effect of Zol in the repair of chronically infarcted myocardium without liposomal encapsulation to mimic the clinical setting. Zol (20 μg/kg, a dose known to treat experimental osteoporosis in rats, n = 15) was administered subcutaneously to female Sprague-Dawley rats 1 day before coronary artery ligation. Rats receiving phosphate-buffered saline (n = 12) were used as controls. Left ventricular function, infarct size, and remodeling were studied at 4 weeks postinfarction. Zol pretreatment did not affect left ventricular ejection fraction in hearts with myocardial infarction (49.5 ± 1.4% in Zol; 50.6 ± 2.1% in phosphate-buffered saline). Infarct size was similar in Zol versus untreated hearts (34.2% ± 2.9% in Zol; 33.4% ± 2.9% in phosphate-buffered saline). Left ventricular cavity volume and circumference, infarct thickness, and expansion index were comparable between the groups. To investigate a potential effect of Zol on tissue macrophage infiltration after myocardial infarction, heart specimens were harvested 48 hours postinfarction and sections were immunostained with CD68 antibody, a macrophage-specific marker. Results of macrophage immunostaining revealed that the level of tissue macrophage infiltration was similar between groups. In conclusion, administration of Zol before myocardial infarction had no adverse effects on cardiac contractile function, infarct size, or remodeling. These results suggest that treatment of Zol given before the onset of myocardial infarction does not cause worsening of infarct repair.