Experimental Myocardial Ischemia Research Articles

Interventricular Septal Excursions and Velocities During Experimental Myocardial Ischemia. Effects of Nitroglycerin Infusion

The effects of intravenous nitroglycerin on the excursions and velocities of the interventricular septum were evaluated by use of ultrasound in 20 open-chest dogs during experimental myocardial ischemia. In 10 dogs with acute septal ischemia the systolic and diastolic excursions and velocities of the interventricular septum were reduced (p<0.01), but with the use of nitroglycerin, they increased as follows, although they did not return to the preischemia levels: Systolic septal excursion (p<0.01), systolic septal velocity (p<0.01), diastolic septal excursion (p = 0.01) and diastolic septal velocity (p<0.01). In 10 dogs with acute posterior wall ischemia, the mobility of the interventricular septum increased (p<0.01). This compensatory hyperactivity increased even more with the use of nitroglycerin as follows: Systolic septal excursion (p = 0.05), systolic septal velocity (p = 0.02), diastolic septal excursion (p = 0.05), and diastolic septal velocity (p<0.01). The measurements were obtained using the recently described method of the specific points. Possible mechanisms for these effects include increased regional blood flow, reduced afterload, and mechanical pulling of the ischemic myocardium.

Effects of Nitrous Oxide on Coronary Pressure and Regional Contractile Function in Experimental Myocardial Ischemia

To determine whether nitrous oxide (N2O) worsens myocardial ischemia by diminishing coronary pressure, we performed two sets of experiments using an acutely instrumented swine model of regional coronary ischemia. In constant pressure experiments (n = 11), coronary pressure and heart rate were kept constant as N2O (77%-79%) was substituted for N2 in the inspired gas. Nitrous oxide decreased systolic shortening, measured by sonomicrometry, from 68.0% to 63.6% (P less than 0.05) of preischemic control values in the ischemic zone and from 116.2% to 103.2% (P less than 0.05) of control values in the adjacent normal myocardium. There was no disproportionate effect of N2O on ischemic myocardium, and the N2O-induced depression of contractile function was fully reversible. In a series of constant external stenosis experiments (n = 13), the effects of N2O on heart rate, mean arterial pressure, and the coronary stenosis itself were not controlled. In these experiments, substitution of N2O for N2 induced deterioration in both the ischemic zone (systolic shortening decreased from 68.7% to 58.4% of preischemic control values, P less than 0.05) and in the adjacent normal myocardium (systolic shortening decreased from 113% to 102.9% of preischemic control, P less than 0.05). Nitrous-oxide-induced ischemic zone contractile dysfunction was often not reversible. The pressure gradient across the coronary stenosis did not increase and peripheral coronary pressure did not decrease because of N2O. Diffusion hypoxia was also excluded. This study confirms that N2O has a significant but mild depressant effect on the performance of both normal and ischemic myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Arrhythmias, haemodynamic changes and extent of myocardial damage during coronary ligation in rabbits anaesthetized with halothane, alpha chloralose or pentobarbitone

We investigated the incidence of ventricular arrhythmias, extent of myocardial infarction and alteration in haemodynamic parameters during 30 minutes of coronary arterial occlusion in rabbits anaesthetized with halothane, alpha chloralose and pentobarbitone. Ventricular tachycardia and fibrillation occurred in 10 of 15 given halothane and in 11 of 15 animals given alpha chloralose while of 15 animals given pentobarbitone, 5 developed tachycardia and 8 had fibrillation. Following ligation, blood pressure promptly fell in each group to 71–76% of control values at 1 minute and remained low throughout the occlusion period. This was most marked in the group receiving halothane which had significantly lower pressures at 30 minutes than those anaesthetized with alpha chloralose or pentobarbitone ( P < 0.01 in each case). Those receiving halothane also recovered less on reperfusion. Heart rate remained stable with pentobarbitone anaesthesia during coronary occlusion and reperfusion, but promptly declined in the first minute of occlusion in the groups given halothane and alpha-chloralose and then remained low throughout occlusion, especially in the group given alpha-chloralose ( P < 0.001 vs pentobarbitone and P < 0.01 vs halothane). The extent of myocardial damage was measured from nitroblue tetrazolium-stained sections and expressed as a percentage of the zone at risk, which was obtained in five hearts following 90 minutes coronary ligation. Values were 44.0% with pentobarbitone, 54.0% with alpha chloralose ( P < 0.01 vs pentobarbitone) and 62.1% with halothane ( P < 0.001 vs pentobarbitone). Thus, the choice of anaesthetic employed during experimental myocardial ischaemia may have significant effects on the incidence of ventricular tachycardia, haemodynamic changes and extent of necrosis observed. These findings have important implications for the design of experimental models of myocardial ischaemia.

Minimal ?1- and ?2-adrenoceptor-mediated coronary vasoconstriction in the anaesthetized swine

alpha-Adrenoceptor-mediated coronary vasoconstriction contributes to the initiation and aggravation of experimental and clinical myocardial ischaemia. However, the extent of alpha 1- and alpha 2-adrenoceptor-mediated constriction has not been characterized in the porcine coronary circulation despite the frequent use of this experimental model. Fifteen swine were anaesthetized with either alpha-chloralose, enflurane or isoflurane to determine the amount of alpha-adrenoceptor-mediated coronary constriction elicited by either the selective alpha 1-adrenoceptor agonist methoxamine or the selective alpha 2-adrenoceptor agonist azepexole. The left anterior descending coronary artery was cannulated and perfused by an external pump delivering constant blood flow from the carotid artery. Following bilateral cervical vagotomy and beta-adrenoceptor blockade with propranolol (2 mg kg-1), graded dosages of either one of the alpha-adrenoceptor agonists (9-45 micrograms kg-1 min-1) were infused into the coronary perfusion line while coronary arterial pressure (CAP) was measured through a distal side arm of the cannula to detect changes in coronary vascular resistance. Infusion of the alpha-adrenoceptor agonists was terminated when systemic arterial pressure increased. Sonomicrometers were used to measure anterior left ventricular wall thickening for the assessment of regional contractile function. During methoxamine infusion, no increase in vascular resistance was observed during alpha-chloralose, enflurane or isoflurane anaesthesia, whereas the infusion of azepexole increased CAP from 103 +/- 31 mmHg to 120 +/- 35 mmHg (alpha-chloralose), from 101 +/- 16 mmHg to 122 +/- 11 mmHg (enflurane) and from 84 +/- 20 mmHg to 94 +/- 19 mmHg (isoflurane), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental studies of the physiologic properties of technetium-99m isonitriles

Recently, efforts have been directed at the development of technetium-99m (Tc-99m)-labeled isonitrile compounds for assessment of regional perfusion and viability after experimental myocardial infarction or ischemia. One of the most promising of these agents, Tc-99m sestamibi, has undergone rather extensive laboratory investigation. Like thallium-201 (Tl-201), the uptake of Tc-99m sestamibi in myocardial tissue is proportional to myocardial blood flow after intravenous injection. Similar to other diffusible indicators, Tc-99m sestamibi underestimates blood flow at high flow rates. In low flow regions, the myocardial uptake of this agent is higher relative to nonischemic uptake than is microsphere-determined blood flow. This is attributed to increased extraction at low flows. This first-pass myocardial extraction fraction for Tc-99m sestamibi is less than that for Tl-201. However, Tc-99m sestamibi has a higher parenchymal cell permeability and higher volume of distribution than Tl-201. Tc-99m sestamibi shows minimal “delayed redistribution” after initial intravenous administration. Uptake of Tc-99m sestamibi is not altered by myocardial “stunning” or with ischemic dysfunction produced by sustained low coronary flow. The uptake of the isonitrile is still proportional to blood flow in these situations. In intact animal models, myocardial uptake of Tc-99m sestamibi during coronary occlusion delineates the in vivo area at risk. When Tc-99m sestamibi is administered after reperfusion following variable periods of preceding coronary occlusion, Tc-99m sestamibi uptake delineates the area of viable myocardium that is salvaged and not simply the degree of reflow. This suggests that serial Tc-99m sestamibi imaging might be useful in assessing the efficacy of coronary reperfusion after thrombolytic therapy.

Role of aminoacyl-tRNA-synthetases in changes in rate of protein biosynthesis in rabbit liver during myocardial ischemia

Composition of high-molecular-weight aminoacyl-tRNA synthetases complexes from rabbit liver both in norm and after 12 h experimental myocardial ischemia (EMI) has been investigated. Partial redistribution of aminoacyl-tRNA synthetases activity from 1820 kD complex into 840 kD complex was observed in case of EMI which resulted in changes of protein biosynthesis rate in cell-free system.

Gd-DOTA enhanced MRI of experimental myocardial ischemia: Determination of the area at risk and infarct size

Gd-DOTA enhanced MRI of experimental myocardial ischemia: Determination of the area at risk and infarct size

The effect of biomass of the cultured polyscias filicifolia bailey cells on the levels of ATP, ADP and AMP in liver of rabbits with experimental myocardial ischemia

The effect of biomass of the cultured polyscias filicifolia bailey cells on the levels of ATP, ADP and AMP in liver of rabbits with experimental myocardial ischemia

Alpha-adrenergic mechanisms in myocardial ischemia.

alpha-Adrenoceptor-mediated effects of sympathetic activation on the heart and coronary circulation are reviewed with emphasis on the pathophysiology of myocardial ischemia. A classification of alpha-adrenoceptor subtypes is presented, and the effects of alpha-adrenoceptor activation on presynaptic sympathetic nerve terminals, cardiomyocytes, endothelium, platelets, and coronary smooth muscle cells are discussed. alpha-Adrenergic coronary vasoconstriction at rest and during situations of sympathetic activation such as exercise and excitement is analyzed for the segmental, transmural, and regional distribution of coronary blood flow. Evidence for a significant contribution of alpha-adrenergic coronary vasoconstriction to experimental and clinical myocardial ischemia is provided. Cardiomyocyte alpha-adrenoceptor activation may be involved in ischemic and reperfusion arrhythmias. The participation of presynaptic and postsynaptic alpha-adrenoceptors, as well as of alpha 1- and alpha 2-adrenoceptors, in experimental and clinical myocardial ischemia will require further investigation.

Defibrotide reduces infarct size in a rabbit model of experimental myocardial ischaemia and reperfusion.

1. Defibrotide, a single-stranded polydeoxyribonucleotide obtained from bovine lungs, has significant anti-thrombotic, pro-fibrinolytic and prostacyclin-stimulating properties. 2. The present study was designed to evaluate the effects of defibrotide on infarct size and regional myocardial blood flow in a rabbit model of myocardial ischaemia and reperfusion. 3. Defibrotide (32 mg kg-1 bolus + 32 mg kg-1 h-1, i.v.) either with or without co-administration of indomethacin (5 mg kg-1 x 2, i.v.) was administered 5 min after occlusion of the left anterior-lateral coronary artery and continued during the 60 min occlusion and subsequent 3 h reperfusion periods. 4. Defibrotide significantly attenuated the ischaemia-induced ST-segment elevation and abolished the reperfusion-related changes (R-wave reduction and Q-wave development) in the electrocardiogram. In addition, defibrotide significantly improved myocardial blood flow in normal and in ischaemic, but not in infarcted sections of the heart. The improvement in blood flow in normal perfused myocardium, but not in the ischaemic area was prevented by indomethacin. 5. Although the area at risk was similar in all animal groups studied, defibrotide treatment resulted in a 51% reduction of infarct size. Indomethacin treatment abolished the reduction of infarct size seen with defibrotide alone. 6. The data demonstrate a considerable cardioprotective effect of defibrotide in the reperfused ischaemic rabbit myocardium. This effect may be related, at least in part, to a stimulation of endogenous prostaglandin formation. Other possible mechanisms are discussed.

Clycerinated fibers of rat cardiomyocytes as a model for preclinical trials of antianginal agents

The damaging action of ischemia in the myocardium leads to profound dystrophic changes at the myocyte organelle level [5, ii]. these changes also involve the myocardial contractile protein system, leading not only to irreversible loss of contractility of the myofilaments [I], but also to deformation and partial disappearance of actin and myosin filaments [4]. The writers showed previously [2] that treatment of animals with experimental myocardial ischemia (EMI) with various antianginal agents has a positive action on contractility of the contractile apparatus of the ischemic myocardium. The complexity of the search for and evaluation of antianginal agents has to be taken into account [7].

Influence of iloprost on eicosanoid generation and lipid levels in experimental myocardial ischemia in dogs

Anaesthetized mongrel dogs were subjected to occlusion of a coronary artery. The resulting myocardial infarction was observed for three hours. One hour after occlusion, infusion of the stable prostacyclin analogue iloprost or saline was started. In the control group myocardial infarction was associated with an increase of the ratio TXB 2 6 - keto-PGF 1a which was abolished by iloprost treatment. After occlusion in the control group, the atherosclerosis index (TC-HDLC): HDLC was increased, but in the iloprost-treated group it was significantly decreased. The results of this study suggest that the administration of iloprost is able to prevent changes in eicosanoid metabolism and lipoprotein pattern after coronary artery occlusion in dogs.

The effects of PAF antagonists on arrhythmias and platelets during acute myocardial ischaemia and reperfusion

The aim of the study was to examine a possible role for platelet activating factor (PAF) in experimental myocardial ischaemia and reperfusion. Anaesthetized open-chest greyhounds were subjected to 40 min of coronary artery (LAD) occlusion followed by reperfusion. Blood samples for platelet counting were obtained from a local coronary vein draining the ischaemic region. Pretreatment with PAF antagonists BN52021 (5 mg kg-1 i.v.) or SRI63441 (10 mg kg-1 i.v.), 15 min prior to occlusion reduced the ventricular ectopic count during the ischaemic period from 614 +/- 82 (controls) to 296 +/- 145 (BN52021) and 474 +/- 200 (SRI63441). Both drugs also reduced the incidence of ventricular fibrillation (VF) (during ischaemia and reperfusion) from 90% (controls), to 50% (BN52021) and 43% (SRI63441). Ischaemia was accompanied by a 32 +/- 7% reduction in coronary venous platelets; this was attenuated by both BN52021 (-2 +/- 6%) and SRI63441) (-1 +/- 5%). These results suggest that PAF may contribute to ischaemia and reperfusion-induced arrhythmias by activating platelets.

Cardiovascular effects of acute hypercholesterolemia in rabbits. Reversal with lovastatin treatment.

Hypercholesterolemia was induced in New Zealand white rabbits by feeding them a 0.5% cholesterol-enriched rabbit chow for 2 wk. Half of the cholesterol-fed rabbits were given lovastatin, a potent inhibitor of hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase), the rate limiting enzyme in cholesterol biosynthesis, and the other half were given its vehicle (i.e., DMSO). At the end of 2 wk, the rabbits underwent experimental myocardial ischemia or a sham ischemia procedure. Ischemic animals fed the cholesterol-enriched diet for 2 wk experienced much greater cardiac damage than ischemic rabbits fed the control diet, despite the absence of any atherosclerosis. Lovastatin was shown to protect the ischemic rabbit myocardium by three different indices of ischemic damage: (a) maintenance of creatine kinase (CK) activity in the ischemic myocardium; (b) reduced loss of free amino-nitrogen containing compounds from the ischemic myocardium; and (c) blunting the rise of plasma CK activity. These effects were not due to differences in myocardial oxygen demand between the groups. Arteries isolated from animals fed the cholesterol-enriched diet developed defects in endothelium-dependent relaxation in both large vessels as well as coronary resistance vessels. Acute hypercholesterolemia increases the severity of myocardial ischemia while at the same time impairing endothelium-dependent relaxation. These deleterious changes can be significantly attenuated by treatment with lovastatin.

Clinical implications for therapy: possible cardioprotective effects of ACE inhibition.

1. The circulating and tissue renin-angiotensin systems (RAS) contribute importantly to cardiovascular homeostasis. Systemic and/or local activation of the RAS is seen in many pathological conditions of the cardiovascular system (e.g. hypertension and congestive heart failure). Increased angiotensin production participates in the pathophysiology of these and other disease states. Accordingly, inhibitors of the renin angiotensin system have a broad spectrum of therapeutic efficacy. 2. Angiotensin-converting enzyme (ACE) inhibitors are effective antihypertensive agents that do not adversely affect serum lipid levels. In addition, they reduce left ventricular hypertrophy. 3. ACE inhibitors cause coronary vasodilation and reduce ventricular work and wall stress. They have been shown to reduce experimental infarct size and to increase anginal threshold in humans. 4. After experimental or human myocardial infarction that results in significant left ventricular dysfunction, ACE inhibitors prevent ventricular dilatation and development of congestive heart failure, and may improve survival. 5. ACE inhibitors can prevent ventricular fibrillation and contractile impairment (stunned myocardium) associated with reperfusion injury after experimental myocardial ischaemia. 6. ACE inhibitors reduce preload and afterload, improve exercise capacity, reduce ventricular arrhythmias, and improve patient survival in clinical cardiac failure. 7. Taken together, inhibition of the RAS may potentially result in primary as well as secondary protective effects on the cardiovascular system.

Cardioprotective actions of thromboxane receptor antagonism in ischemic atherosclerotic rabbits.

Atherosclerosis was induced in New Zealand White rabbits by feeding them a 0.5% cholesterol-enriched rabbit chow for 10-12 wk. Half of the cholesterol-fed rabbits were given BM 13505, a specific thromboxane A2/endoperoxide (TxA2/PGH2) receptor antagonist, and the other half were given its vehicle (i.e., 2% Na2CO3). At the end of 10-12 wk, the rabbits underwent experimental myocardial ischemia or an identical sham operation, except that the coronary artery was not occluded. BM 13505 was shown to protect the ischemic rabbit myocardium by three different methods: 1) maintenance of myocardial tissue creatine kinase (CK) activity in the ischemic myocardium; 2) reduced loss of free amino nitrogen-containing compounds from the myocardium; and 3) blunting the rise of plasma CK activity. Part of the mechanism for these effects may be due to inhibition of platelet aggregation and blockade of the vasoconstrictor effect of TxA2. However, these protective effects were not due to differences in myocardial oxygen demand among the groups. Finally, BM 13505 exhibited an antiatherogenic effect by reducing the deposition of cholesterol in the aortic wall and by retarding plaque formation in coronary arteries. However, it does not achieve this antiatherogenic effect by lowering plasma cholesterol concentrations or by scavenging superoxide free radicals. Thus blockade of TxA2 receptors exerts a variety of beneficial effects that reduce the severity of ischemic damage resulting from myocardial ischemia.

虚血による心室細動時の心筋細胞膜カルシウム・チャンネルの変化

To explore possible roles of the calcium channel of myocardial cell membrane in the pathogenesis of ventricular fibrillation (Vf), we examined changes in the myocardial cell membrane 3H-nitrendipine (3H-N)-binding site in dogs with Vf in experimental myocardial ischemia. In animals which developed Vf 15±2 min after coronary ligation, the ischemic myocardium had a significantly larger number of 3H-N-binding sites (296±4 fmol/mg protein) compared to the nonischemic area (240±10). In animals in which Vf was elec trically induced 20min after coronary artery ligation, there was no increase of Bmax in ischemic (221±6) and nonischemic (227±5) area.Therefore, these results indicate that increase in Bmax in the ischemic area in Vf is not asecondary phenomenon caused by Vf. In animals without Vf, the number of binding sites (Bmax) did not increase significantly in the 15- and 30-min ischemic (216±3, 245±11) and nonischemic (227±, 213±7) area. No significant change was observed in the Kd for is chemia, nonischemia, or the ischemic period between the those groups. It is known that the myocardial cell membrane binding site of 3H-N is closely linked with voltage-de pendent Ca channel (VDCC). We concluded that the increase in the number of 3H-Nbinding sites that is VDCC, is one of the major factors responsible for development of Vf at about 15-min ischemia.

Hydrogen peroxide myocardial perfusion contrast echocardiography: I. Experimental study.

Myocardial perfusion contrast two-dimentional echocardiography (2-DE) is a new method for determining the extent of experimental myocardial ischemia and infarction. 172 aortic root injections of a fresh mixture of 1 ml of 0.75 % hydrogen peroxide (H2O2) and blood, and 75 pulmonary wedge injections of 1 ml of 3 % H2O2 were given to 24 open-chest dogs before and after ligation of the left anterior descending coronary artery (LAD) and four short-axis and long-axis views of the left ventricle were examined. 164 (95%) aortic root injections and 30 (40 %P< 0.05) pulmonary wedge injections showed homogeneous echocardiographic contrast intensification of normal myocardium before ligation of LAD and distinctly delineated echocardiographic contrast defect after ligation of LAD. When compared with aortic root injection, H2O2 pulmonary wedge injection has the adventage of less invasiveness and remains to be further studied.

Effects of dimethyl sulfoxide on systemic and cerebral hemodynamic variables in the ischemic canine myocardium.

The effects of dimethyl sulfoxide (DMSO) infusion on cerebral blood flow (CBF) and systemic hemodynamics were studied in a canine model of myocardial ischemia. Immediately after ligation, cardiac output dropped from 2.09 +/- 0.11 (SEM) in the control group and 1.79 +/- 0.13 in the DMSO group to 1.07 +/- 0.21 and 1.0 +/- 0.08 L/min, respectively; there were no significant differences for 2 h. By the third hour and thereafter, the DMSO group had a significantly (p less than .05) higher cardiac output (1.65 +/- 0.08 L/min) than the control group (1.15 +/- 0.10 L/min). The cardiac output increase at 3 h was accompanied by significantly (p less than .05) lower systemic vascular resistance (SVR) in the DMSO group (5315 +/- 248 dyne X sec/cm5) as compared to the control group (7892 +/- 442 dyne X sec/cm5). There were no significant differences in heart rate, mean arterial pressure, pulmonary artery wedge pressure, or cerebral or pulmonary resistances in the control as compared to the DMSO group. Higher CBF values were noted at one hour and thereafter in the DMSO as compared to the control group (p less than .05). Low-dose DMSO given as an iv bolus improved cardiac output and CBF and lowered SVR in this canine model of experimental myocardial ischemia.

Development and Validation of Ambulatory Monitoring to Characterize Ischemic Heart Disease Out of Hospital

The ST segment has long been used as a measure of experimental and clinical myocardial ischemia and injury. Ambulatory monitoring of the electrocardiogram makes recognition and quantification of both symptomatic and asymptomatic myocardial ischemia in patients with coronary artery disease possible. A body of evidence, including the known characteristics of ST-segment shifts in patients with and without coronary artery disease and validation studies with positron tomography, is presented to support the use of the electrocardiogram during dynamic activity as a valid marker of reversible myocardial ischemia. Recommendations for monitoring based on this information are provided.