Coronary sinus retroperfusion combined with intraaortic balloon pumping to perfuse the acutely ischemic myocardium

This study was planned to show the effect of retroperfusion and intraaortic balloon pumping (IABP) on myocardial hemodynamic recovery. Twelve dogs entered this study. Half of them received IABP and coronary sinus retroperfusion (CSPR) combination (Group II) and the remaining received IABP alone (Group I). Left anterior descending artery was occluded for a period of three hours. 15 minutes after occlusion IABP and IABP + CSRP were initiated. The average cardiac output was 1.41 +/- 0.18 L/min in the group I and 1.72 +/- 0.24 L/min in the group II (p < 0.03) after 3 hours of occlusion. Mean arterial pressure was 82.1 +/- 4.8 mmHg in the group I and 89.7 +/- 2.6 mmHg in the group II (p < 0.03). On the basis of this study it was concluded that CSRP + IABP could be an alternative treatment to IABP alone during the acutely developing ischemia.     

The protective reaction of the myocardium to ischemic damage

The morphological and functional consequences of epinephrine-induced myocardial infarction were studied in normo- (Wistar) and hypertensive (ISIAH) rats. After experimental myocardial infarction there was an irreversible transition to the "worn-out" stage or "plastic damage" to the myocardium. Thus, myocardial hibernation in ISIAH rats anticipates and determines the development of myocardial stunning, i.e., irreversible myocardial damage, whereas in the normotensive animals, the protective effect of hibernation is fully shown. The ontogenetic features of myocardial response of ISIAH rats to hypoxia promote transformation of adaptive hibernation and stunning to maladaptive pathological changes causing hypoxic alterations.     

The effect of batroxobin on coronary segmental resistance and coronary blood flow in acute myocardial ischemic dogs

To study the effects of batroxobin on coronary circulation and cardiac performance in acute myocardial ischemia, Batroxobin was given intravenously to dogs with experimental coronary stenosis. A dose-dependent increase of coronary blood flow (CBF) was observed. Forty minutes after batroxobin (2 BU.kg-1 at infusion rate 0.1 BU.kg-1.min-1) administration, CBF increased by 12% (P < 0.05), small coronary resistance(RS) decreased from 4.1 +/- 0.5 to 3.2 +/- 0.5 mmHg.min.ml-1 (P < 0.01), while large coronary resistance(RL) changed insignificantly from 3.9 +/- 0.8 to 3.8 +/- 0.7 mmHg.min.ml-1 (P > 0.05). Two hours following drug administration, the changes in CBF, RS and RL still remained and RT decreased by 13% (P < 0.05). The + LV(dp/dt)max and -LV(dp/dt)max increased by 14% and 16% (P < 0.05) respectively compared with those in control group. It is concluded that batroxobin improves the ischemic canine coronary circulation and cardiac performance by way of lowering the small coronary resistance and thus increasing CBF. The data also suggest the benificial effect of batroxobin in acute myocardial ischemia.     

The protective effect of moderate alcohol consumption on ischemic stroke

Experiments were designed to investigate the influence of estrous cycle and gender of the rat on the effects of a gamma-aminobutyric acid type A (GABA(A)) receptor active neurosteroid, 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone), the benzodiazepine, triazolam, and a GABA(A) receptor antagonistic neurosteroid, delta5-androsten-3beta-ol-17-one sulfate (dehydroepiandrosterone sulfate), on food intake and elevated plus-maze learning behaviors. Allopregnanolone (0.25 mg/kg, s.c.) and triazolam (0.25 mg/kg, i.p.) produced a hyperphagic effect, while dehydroepiandrosterone sulfate (5 mg/kg, s.c.) elicited an anorectic effect. However, allopregnanolone was more potent in diestrous females, whereas triazolam exhibited significantly higher hyperphagic potency in estrus females. The extent of anorexia following dehydroepiandrosterone sulfate was alike in male and female rats. The triazolam- and allopregnanolone-induced hyperphagic effect was blocked by bicuculline (1 mg/kg, i.p.), a selective GABA(A) receptor antagonist. In contrast to triazolam, the hyperphagic effect of allopregnanolone was insensitive to flumazenil (5 mg/kg, i.p.), a benzodiazepine antagonist. Vehicle-treated diestrous rats displayed moderately higher latencies in the elevated plus-maze learning task than estrus or proestrus females. Although allopregnanolone and triazolam elicited equipotent learning deficits in plus-maze learning in male and female rats, the magnitude of impairment-induced by triazolam was significantly higher in diestrous females than proestrus females. Dehydroepiandrosterone sulfate enhanced memory performance only in male rats. Although the use of the elevated plus-maze as a learning paradigm with benzodiazepines and neurosteroids may be sensitive to changes in anxiety, the differential data suggest that neurosteroid-induced effects are at least partly specific to learning behavior. These results confirm the role of estrous cycle and sex of rats in modifying the potency of neurosteroids and benzodiazepines on food consumption and learning and memory processes.     

Temporal characteristics of the protective effect of aminoguanidine on cerebral ischemic damage

We investigated the temporal profile of the reduction in focal cerebral ischemic damage exerted by aminoguanidine (AG), an inhibitor of inducible nitric oxide synthase (iNOS). In anesthetized spontaneously hypertensive rats, the middle cerebral artery (MCA) was occluded distal to the origin of the lenticulostriate arteries. Rats were treated with vehicle (saline) or AG (100 mg kg-1, i.p.) immediately after MCA occlusion and, thereafter, two times per day. Rats were sacrificed 1(n = 7), 2(n = 8), 3 (n = 6) or 4 days (n = 5) after MCA occlusion. Injury volume (mm3) was determined in thionin-stained sections using an image analyzer. Volumes were corrected for ischemic swelling. Administration of AG up to 2 days after MCA occlusion did not reduce cerebral ischemic damage (p < 0.05 from vehicle; t-test). Treatment for a longer period decreased injury volume, the reduction averaging 21 +/- 5% at 3 days (p < 0.05) and 30 +/- 9% at 4 days (p < 0.05). Aminoguanidine did not affect ischemic brain swelling (p > 0.05). Administration of AG did not substantially modify arterial pressure, arterial blood gases, pH, hematocrit, plasma glucose and rectal temperature. We conclude that the protective effect of AG is time-dependent and occurs only when the drug is administered for longer than 2 days, starting after induction of ischemia. Because iNOS enzymatic activity develops more than 24 h after MCA occlusion [C. Iadecola, X. Xu, F. Zhang, E.E. El-Fakahany, M.E. Ross, Marked induction of calcium-independent nitric oxide synthase activity after focal cerebral ischemia, J. Cereb. Blood Flow, Metab. 14 (1995) 52-59; C. Iadecola, F. Zhang, X. Xu, R. Casey, M.E. Ross, Inducible nitric oxide synthase gene expression in brain following cerebral ischemia, J. Cereb. Blood Flow Metab. 15 (1995) 378-384.], the data support the hypothesis that the protective effect of AG is medicated by inhibition of iNOS in the post-ischemic brain.     

The effect of hemodilution with stroma-free hemoglobin and dextran on collateral perfusion of ischemic myocardium in the dog

The effect of hemodilution with stroma-free hemoglobin (SFH) solution was assessed on the collateral perfusion of acutely ischemic myocardium in anesthetized dogs. A similar protocol was used in three groups: one hour following occlusion of the LAD coronary artery, a rapid exchange-transfusion was performed and the changes were followed for the subsequent two hours. Group I was hemodiluted with SFH, in Group II whole blood was reinfused, and Group III was hemodiluted with dextran 70. Following the exchange-transfusions, blood flow to the ischemic zone (15 +/- 3 micrometer microspheres) increased in all groups, but only marginally so in Group II (23 +/- 17%). The greatest increments were seen in the SFH-hemodiluted group (Group I) in which endocardial flow increased by 83 +/- 29% (p less than .05) and epicardial flow increased by 45 +/- 21%; these resulted in the greatest improvements in oxygen delivery. Significant increments in blood flow were seen in Group III, as well, but oxygen delivery was less adequate. Group I also exhibited the lowest output of CPK from the heart and was the only one in which indices of left ventricular performance (dP/dt and EDP) were returned to the pre-occlusion level. these findings suggest the possibility that reduction of blood viscosity by dilution with SFH improves collateral perfusion of the ischemic myocardium.     

The effect of acute, unilateral transverse venous sinus occlusion on intracranial pressure in normal dogs

Lateral rostrotentorial and caudal suboccipital approaches to the brain were performed on six beagles. Intracranial pressure (ICP) was measured as the two craniectomies were connected by removing the bone of the nuchal crest and occluding the transverse venous sinus. Intracranial pressure remained constant after acute occlusion of the sinus with bone wax and there was no gross evidence of brain edema. All six dogs survived the surgery and five dogs survived for a minimum of 3 months. One dog died acutely during the postoperative period. The exact cause of the cerebellar hemorrhage and infarction found at necropsy in the latter dog was not evident. Anemia occurred in three of the six dogs as a result of intraoperative hemorrhage. All dogs surviving the perioperative period had mild, transient hypermetria and conscious proprioceptive deficits, but were neurologically normal 72 hours after surgery. Results of this study indicate that acute, unilateral transverse sinus occlusion is possible without an increase in ICP. The ability to do this allows access to the rostral aspect of the ipsilateral cerebellum and brain stem.     

Atrial macroreentry involving the myocardium of the coronary sinus: a unique mechanism for atypical flutter

Atrial flutter involving either clockwise or counterclockwise rotation around the tricuspid annulus utilizing the subeustachian isthmus has been well described. However, macroreentrant atrial circuits in atypical atrial flutter in patients who have not undergone previous surgery or without atrial disease are not well defined. We describe a patient without structural heart disease who presented with an atrial macroreentrant rhythm. Entrainment mapping demonstrated a critical isthmus within the coronary sinus. Activation mapping demonstrated double potential throughout the length of the coronary sinus with disparate activation sequences. A circuit involving the myocardium of the coronary sinus, exiting in the lateral left atrium, down the interatrial septum, and reentering into the coronary sinus was identified. Successful ablation of the rhythm was accomplished by a circumferential radiofrequency application within the coronary sinus.     

Experimental application of synchronized coronary sinus retroperfusion (SCSR) and left heart bypass (LHB) for severe cardiogenic shock

In order to evaluate the efficacies of concomitant use of left heart bypass (LHB) and synchronized coronary sinus retroperfusion (SCSR) for ischemic cardiogenic shock refractory to conventional mechanical circulatory assist such as intra-aortic balloon pumping (IABP), experimental comparison studies were made in swine. The acute myocardial infarction model was made by left anterior descending coronary artery (LAD) ligation method. LHB was performed by centrifugal pump (BioMedicus BP-80), supporting flows of half cardiac output. SCSR catheter was inserted into coronary sinus (CS) through external jugular vein. Then arterial blood was pumped from femoral artery to CS with flow of 60 to 70 ml/min which was synchronized to electrocardiogram (ECG). These animals were supported by only SCSR or LHB, and SCSR + LHB, comparing each cardiac performances, infarcted areas and coronary flow. Infarcted areas were evaluated by epicardial mapping ECG. Coronary blood flow and velocity were analyzed by electromagnetic flow meter and ultrasonic pulse doppler velocimeter respectively. In LHB group, coronary blood flow and velocity were increased because of elevation of mean aortic pressure. In addition, LVdp/dt, LVEDP were decreased, indicating left ventricular decompression. However, the infarcted area was slightly reduced. In contrast, it was remarkably reduced by SCSR, and cardiac function recovered gradually from cardiogenic shock. In SCSR + LHB group, the ischemic area was significantly reduced and their hearts completely recovered from cardiogenic shock, demonstrating the good supply and demand balance of myocardial oxygen. The systolic reverse LAD flow and velocity which was increased due to cardiogenic shock, was remarkably reduced. These results suggested this concomitant new application is suitable for recovering from cardiogenic shock due to AMI which is not able to apply antegrade coronary perfusion.     

Early prostaglandin release from the ischemic myocardium in the dog

Cellular consequences of myocardial ischemia were studied in anesthetized dogs. Confirmation of myocardial ischemia was provided by electrocardiographic and biochemical indexes. Prostaglandin F2alpha release into coronary venous blood was significantly elevated during myocardial ischemia, whereas indomethacin treatment prevented this increase in coronary venous prostaglandin F2alpha concentrations. No significant increase in prostaglandin E2 release was observed in response to myocardial ischemia, but indomethacin treatment significantly reduced coronary venous prostaglandin E2 concentrations below those of control values. Within one hour after occlusion of the coronary artery, the S-T segment was significantly altered, and coronary venous prostaglandin F2alpha had increased significantly above the control concentration. These changes persisted during four hours of myocardial ischemia. Plasma creatine phosphokinase activity increased significantly after two hours of myocardial ischemia and remained elevated for the subsequent two hours of ischemia. After four hours of myocardial ischemia, myocardial creatine phosphokinase activity of ischemic myocardium was significantly reduced, and labilization of myocardial treatment prevented increases in prostaglandin release but did not influence other biochemical changes or the electrocardiographic response to ischemia. Thus, prostaglandin release by ischemic myocardial tissue is an early response to the ischemic stimulus.     

X-ray microanalysis of mitochondrial deposits in ischemic myocardium

The x-ray microanalysis technique was used to determine the chemical composition of intramitochondrial electron-dense deposits in ischemic myocardial cells. Semi-thin sections were cut from Araldite-embedded tissue and analyzed in a scanning electron microscope equipped with energy- and wavelength-dispersive spectrometers. The energy dispersive spectrum revealed calcium and phosphorus peaks over many mitochondrial deposits. Peak to background ratios of calcium, phosphorus and magnesium obtained with the wavelength dispersive spectrometer were 1.7, 8.8 and 1.2, respectively. There was no consistent relationship in the characteristic peaks of calcium and phosphorus in a given mitochondrial granule. Magnesium appears to be negligible, except in some mitochondrial deposits which lacked calcium, where it was present with a peak to background ratio of two. These results suggest formation of calcium or magnesium phosphate in the mitochondria during ischemia. X-ray microanalysis can provide detailed information on subcellular electrolyte distribution in normal and ischemic myocardial cells and should be attempted with improved methods of tissue preparation.     

The effect of acute hypoxia on the viscoelastic properties of the myocardium

The viscoelastic properties of the isolated rabbit papillary muscle were studied by constructing a semilogarithmic length-tension curve before and after it had undergone 5 minutes of stress relaxation before, during, and after exposure to a solution aerated with 95 per cent nitrogen and 5 per cent carbon dioxide. Stress relaxation was accomplished in each treatment group by a reduction in the tension intercept of the log length-tension curve without significant change in its slope. There was no significant change in either of these parameters between the control, hypoxia, and recovery groups. These findings lead to the conclusions that: (1) the loss of muscle tension during stress relaxation is not due to a change in the elastic properties of the myocardium and (2) hypoxia does not increase the fundamental stiffness characteristics of the cardiac muscle.     

The surgical importance of coronary sinus orifice atresia

Coronary sinus orifice atresia is rare. We describe two cases, one with an atrioventricular septal defect and another with supracardiac totally anomalous pulmonary venous drainage. The association with the latter has not been described previously. The importance of diagnosing the defect is emphasized and surgical treatment is discussed.     

The effect of temperature on potassium chloride contracture in cat myocardium

1. Contracture was induced in cat myocardium by exposure to 140 mM-KC1 In isotonic Tyrode solution. Force of contracture expressed as mg/mm2 (muscle cross-sectional area) falls with increasing cross-sectional area. 2. The effect of temperature on isometric force developed during contracture was evaluated both in normal (untreated) atrial and ventricular muscle and following treatment with sympatholytic drugs. 3. The force of contracture was not significantly affected by sympatholytic drugs at 36 degrees C. 4. In normal atrial and ventricular muscle, force of contracture decreased when the muscle was cooled from 36 to either 29 or 20 degrees C. 5. In atrial muscle, the effect of temperature was not changed by sympatholytic drugs. In contrast, exposure to sympatholytic drugs increased contracture force developed by ventricular muscle at 20 degrees C. Also, contracture force was significantly greater at 20 than at 36 degrees C in ventricular muscle from reserpine-pretreated cats. 6. It is suggested that ventricular muscle becomes more sensitive to the relaxing effects of endogenous catecholamines at temperature is lowered. 7. The differences shown between atrial and ventricular muscle with respect to the effect of temperature and sympatholytic drugs on contracture force may result from the differing amounts of sarcoplasmic reticulum found in these types of cardiac muscle and also from different mechanisms of "excitation-contracture" coupling in atrial and ventricular muscle.     

Effects of lidocaine, phenytoin and quinidine on the ischemic canine myocardium

The effects of therapeutic concentrations of lidocaine, quinidine and phenytoin on the electrograms and excitability of ischemic canine myocardium were investigated. The threshold stimulation current was determined as the minimum current necessary to drive the ventricles at 300 msec intervals. Administration of the drugs did not change the threshold stimulation current of the control myocardium, but lidocaine (P less than 0.002), quinidine (P less than 0.01) and phenytoin (P less than 0.05) all markedly increased the threshold stimulation current of the ischemic tissue. The effects on the electrograms were small but consistent with current electrophysiological knowledge. This selective depression of the electrical activity of the ischemic tissue may form an important mechanism of action of these antiarrhythmic agents. However, this same effect may under certain conditions precipitate serious arrhythmias.     

Altered distribution of lysosomal cathepsin D in ischemic myocardium

To determine the influence of cardiac ischemia on the activity and subcellular localization of lysosomal cathepsin D, anesthetized rabbits were subjected to ligation of the circumflex coronary artery. Total enzyme activity remained unchanged throughout the 2-h ischemic period, but the subcellular distribution of cathepsin D, as analyzed by biochemical and immunohistochemical techniques, was altered dramatically. A marked increase in nonsedimentable (i.e., 40,000-g supernate) activity developed by 30-45 min and increased further by 2 h. Simultaneously, the immunofluorescent localization of cathepsin D was also changed significantly. Within 30-60 min after occlusion, the fine, particulate staining observed in control myocytes was replaced by bright fluorescent patches composed of large granules. Many of these structures displayed prominent halos of diffuse fluorescent staining in the neighboring myocytic cytoplasm, apparently outside lysosomes per se. After 2 h, when nonsedimentable activity was maximally elevated, most of the fluorescent particles had disappeared completely. During this same interim there was no detectable change in the distribution of lysosomal cathepsin D within interstitial cells. These results are consistent with the hypothesis that an early feature of cardiac ischemia is the release of cathepsin D from myocytic lysosomes into the cytosol of damaged cells.     

Relationship between epicardial ST-segment elevation and myocardial ischemic damage after experimental coronary artery occlusion in dogs

The relationship between early and late epicardial electrocardiographic changes as well as those in regional myocardial blood flow (MBF) and the severity of myocardial damage was determined in 12 anesthetized dogs with left anterior descending coronary artery ligation. Radioactive microspheres (15 mum) were used to measure regional MBF at 15 min (early) and 24 h (late) after coronary occlusion. Severity of myocardial damage was assessed by the extent of myocardial creatine phosphokinase depletion 24 h after coronary ligation. There was a close linear correlation between myocardial creatine phosphokinase activity and regional MBF both early (r=0.93, 2P less than 0.001) and late (r=0.88, 2P less than 0.001). An inverse but less precise relationship existed between acute epicardial ST-segment elevation and early (r=-0.41, 2P less than 0.001), or late (r=0.35, 2P less than 0.05) regional MBF. Similarly, a weak correlation was found between myocardial creatine phosphokinase (IU/mg protein) at 24 h and early epicardial ST (millivolt) elevation (r=-0.36, 2P less than 0.02). In the center zones of the infarct with MBF 1/10 of normal, about 35% of the areas with normal QRS width had no epicardial ST-segment elevation 15 min after coronary occlusion. About 44% of the areas which developed pathological Q-waves in the electrocardiogram at 24 h had no ST elevation 15 min after coronary ligation. Late evolution of abnormal Q-waves occurred almost invariably in areas in which the early MBF was reduced to less than 50% of normal and in areas which subsequently had myocardial creatine phosphokinase levels reduced to less than 60% of normal. After coronary occlusion, the severity of the ultimate myocardial damage, which was directly proportional to the degree of reduction in MBF, was therefore not reliably predicted by the early epicardial ST-segment elevation. The data obtained in these studies suggest the need for caution in the use of acute ST-segment elevation as a predictive index of the extent or severity of myocardial ischemic damage.     

The effect of indomethacin on renal function in pentobarbital-anesthetized dogs

The effects of indomethacin, an inhibitor of prostaglandin synthesis, on renal blood flow, glomerular filtration rate, urine flow and excretion of sodium and potassium were studied in the anesthetized dog. Indomethacin, 2.5 mg/kg i.v., decreased renal blood flow but increased aortic pressure and calculated renal vascular resistance. Glomerular filtration rate was not influenced by the synthetase inhibitor. Sodium excretion was decreased and para-aminohippurate extraction was increased after administration of indomethacin. Transient decreases in urine flow and potassium excretion were observed; however, both parameters returned to control value 75 minutes after administration of indomethacin. The early decrease in urine flow rate correlated closely with the decrease in sodium excretion. These data suggest that in the anesthetized dog, endogenous prostaglandins may serve to maintain renal blood flow but not glomerular filtration rate. Under the conditions of the present experiments, sodium excretion and to a lesser extent potassium excretion have been suggested as being dependent on prostaglandin synthesis.