Effect of sodium benzoate on cerebral and hepatic energy metabolites in spf mice with congenital hyperammonemia

The outer hair cell (OHC) is known to have the ability to change its length in response to voltage changes across its membrane. The apparent function of this OHC motility is to enhance the tuning of the basilar membrane. The model presented in this paper represents the displacement-to-voltage and voltage-to-displacement transducers of the OHC explicitly, each as low-pass filter functions. The model results show that this OHC representation is sufficient to provide a model of cochlear mechanics with mechanical tuning at the inner hair cell which is comparable to the threshold tuning curves observed in single auditory nerve fibers. The enhancement of tuning provided by OHC motility can be interpreted as the combined action of a cochlear amplifier and a second filter. This model demonstrates that realistic cochlear tuning does not require intrinsic resonance in any cochlear structure other than the basilar membrane.     

Relationship between iodine-123-beta-methyl-p-iodophenyl-pentadecanoic acid washout ratio and oxygen consumption in normal and ischemic myocardium

The relationship between oxygen consumption and iodine-123-beta-methyl-p-iodophenyl-pentadecanoic acid (123I-BMIPP) washout at rest and after exercise was investigated in normal and ischemic myocardium. Sixteen healthy volunteers and 14 patients with ischemic heart disease were examined. After injection of 111MBq of 123I-BMIPP, serial single photon emission computed tomography imaging was performed to evaluate washout ratio after 30 min and 1 hour of rest and after exercise. In the volunteers, the mean washout ratio was 3.3 +/- 3.5% after 1 hour of rest and increased during exercise. The exercise washout ratio showed a better correlation with net pressure rate product (net PRP: cumulative values of PRP during exercise) than with the peak PRP. The exercise washout ratio showed a strong correlation with the net PRP in the range from 180 to 300 x 10(3) mmHg. beat/min and a plateau of 10-15%. In the nine ischemic patients with net PRP > or = 300 x 10(3) mmHg.beat/min, the exercise washout ratio values were significantly elevated in normal segments relative to ischemic segments (10.1 +/- 1.9% vs 4.7 +/- 2.9%, p < 0.001). In the five ischemic patients with net PRP < 300 x 10(3) mmHg.beat/min, washout ratio at rest and after exercise did not differ significantly between normal and ischemic segments. 123I-BMIPP washout ratio increased with increased oxygen consumption during exercise in normal myocardium but not in ischemic myocardium. The patient must exercise before fatty acid metabolism can be compared between normal and ischemic myocardium.     

The relationship between regional blood flow and contractile function in normal, ischemic, and reperfused myocardium

We administered streptozotocin (STZ) and alloxan (AL) to the musk shrew (Suncus murinus, Insectivora) to determine the effective diabetogenic dose of the two toxins for this species. A single intraperitoneal (i.p.) injection of 75 mg/kgBW or the consecutive 5-day s injection of 25 mg/kgBW of STZ to non-fasted shrews, effectively (100%) induced hyperglycemia (> or = 300 mg/dl) with hypoinsulinaemia (< 30% of control level) in male shrews at 10 days after administration. Morphological studies showed cytological changes of B cells in the pancreatic islets of diabetic shrews. Hyperglycemic shrews induced by STZ were thus in IDDM (insulin dependent diabetes mellitus), and showed high susceptibility to the diabetogenic effect of STZ as compared with rodents. Shrews showed a sex difference in the diabetogenic susceptibility to STZ as do mice (male > female). They also showed a species specific resistance to the diabetogenic effect of AL. Of the eight shrews (with 8-hr fasting) that has been treated with a single injection of 200 mg/kgBW of AL, seven (88%) survived at least 10 days, showing no signs of hyperglycemia. All shrews died within 3 day s after injection of 250 or 300 mg/kgBW. These results indicated that the STZ-induced diabetic shrew is a unique animal model and may be useful for IDDM research. On the other hand, the musk shrew was highly resistant to the diabetogenic effects of AL.     

Ventilatory response to severe acute hypoxia in guinea-pigs and rats with high hemoglobin-oxygen affinity induced by cyanate

Laparoscopic pelvic lymph node dissection has been applied as a minimally invasive staging technique for men with prostate cancer. This procedure has been shown to shorten markedly postoperative hospitalization, decrease analgesic requirements and shorten convalescence period compared to open pelvic node dissection. However, the laparoscopic procedure takes longer to perform and many disposable instruments are used, thus increasing the cost. We determine the overall cost of laparoscopic versus open pelvic lymph node dissection. Between January 1989 and April 1992, 61 men underwent only staging pelvic lymph node dissection for cancer of the prostate at a single university teaching hospital. Of these patients 11 and 50 underwent open and laparoscopic pelvic lymph node dissection, respectively. Information from the hospital business office was reorganized into preoperative, intraoperative and postoperative expenses. All individual charges were transformed up or down to the dollar amounts of the 1990 to 1991 fiscal year so as to correct for inflationary changes. Preoperative costs were not significantly different between the 2 operative approaches. Intraoperative expenses were 52% greater if laparoscopic pelvic lymph node dissection was performed and can be explained by the longer operative times and use of disposable instrumentation. However, the postoperative period lasted an average of 1.61 days following laparoscopic pelvic lymph node dissection. Postoperative nursing and analgesic requirements were significantly more for patients undergoing open pelvic lymph node dissection. The overall postoperative costs following open pelvic lymph node dissection were 280% more expensive than for the laparoscopic procedure. The overall total costs were approximately $1,250 more for laparoscopic pelvic lymph node dissection. Wages lost or earned during this period and rapid return to normal activity following laparoscopic pelvic lymph node dissection would, in our opinion, justify this additional cost.     

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.     

Hyperammonemic encephalopathy after chemotherapy. Survival after treatment with sodium benzoate and sodium phenylacetate

A 16-year-old boy had hyperammonemia and encephalopathy develop after high-dose chemotherapy for acute lymphoblastic leukemia. He was treated successfully with the ammonia-trapping agents sodium benzoate and sodium phenylacetate.     

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.     

Role of cellular energetics in ischemia-reperfusion and ischemic preconditioning of myocardium

A short period of ischemia followed by reperfusion produces a state of affairs in which the cells' potential for surviving longer ischemia is enhanced. This is called ischemic preconditioning. The effects of preconditioning are also related to the reperfusion damage which ensues upon tissue oxygenation. The role of the cellular energy state in reperfusion damage remains an enigma, although ischemic preconditioning is known to trigger mechanisms which contribute to the prevention of unnecessary ATP waste. In some species up to 80% of ATP hydrolysis in ischemia can be attributed to mitochondrial F1-F0-ATPase (ATP synthase), and a role for its inhibitor protein (IF1) in ATP preservation has been proposed. Although originally regarded as limited to large animals with a slow heart beat, inhibition by IF1 is probably a universal phenomenon. Coincidentally with ATPase inhibition, the decline in cellular ATP slows down, but even so the difference in ATP concentration between preconditioned and non-conditioned hearts is still small at the final stages of a long ischemia, when the beneficial effect of preconditioning is observable, although the energy state during reperfusion remains low in hearts which do not recover.     

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.     

Perfusion of ischemic myocardium during anesthesia with sevoflurane

BACKGROUND: Sevoflurane produces direct vasodilation of coronary arteries in vitro and decreases coronary vascular resistance in vivo, pharmacologic properties that may contribute to the development of "coronary steal." This investigation examined the effects of sevoflurane on the distribution of regional myocardial perfusion in chronically instrumented dogs with steal-prone coronary artery anatomy. METHODS: Dogs were chronically instrumented for measurement of aortic and left ventricular pressure, diastolic coronary blood flow velocity and subendocardial segment length. After recovery from surgery, dogs underwent repetitive, brief, left anterior descending coronary artery (LAD) occlusions via an implanted hydraulic vascular occluder to enhance collateral development. A progressive left circumflex coronary artery (LCCA) stenosis was also obtained using an ameroid constrictor. After development of LCCA stenosis, the LAD was totally occluded to produce a model of multivessel coronary artery disease. Systemic hemodynamics, regional contractile function and myocardial perfusion measured with radioactive microspheres were assessed in the conscious state and during sevoflurane anesthesia at 1.0 and 1.5 MAC with and without restoration of arterial blood pressure and heart rate to conscious levels. RESULTS: Total LAD occlusion with simultaneous LCCA stenosis increased heart rate, mean arterial pressure, left ventricular systolic and end-diastolic pressures, end-diastolic segment length, and rate-pressure product in conscious dogs. Subsequent administration of sevoflurane caused dose-related decreases in arterial pressure, left ventricular systolic pressure, double product, and peak rate of increase of left ventricular pressure at 50 mmHg. Perfusion of normal myocardium was unchanged during sevoflurane anesthesia. In contrast, sevoflurane caused dose-dependent decreases in blood flow to myocardium supplied by the stenotic LCCA, which returned to control levels after restoration of heart rate and arterial pressure. No reduction in collaterally derived blood flow to the occluded region was produced by 1.0 or 1.5 MAC sevoflurane. No redistribution of blood flow away from the occluded LAD region to normal or stenotic myocardium occurred during sevoflurane anesthesia. In fact, increases in the ratio of blood flow between occluded and normal zones or occluded and stenotic zones were observed in the subepicardium during 1.5 MAC sevoflurane with maintenance of the heart rate and arterial pressure at conscious levels. CONCLUSIONS: The results demonstrate that sevoflurane does not reduce or abnormally redistribute myocardial blood flow derived from coronary collateral vessels in a chronically instrumented canine model of multivessel coronary artery obstruction.     

Proarrhythmic effects of DL- and D-sotalol on the "border zone" between normal and ischemic regions of isolated ventricular myocardium and antiarrhythmic effects on reperfusion

Considering the Survival With ORal D-sotalol (SWORD) study results, in which mortality was higher in patients treated by the pure class III agent D-sotalol, we tested DL- and D-sotalol (5 and 10 microM) in an in vitro model of "border zone" arrhythmias. Isolated guinea-pig ventricular strips were partly exposed to normoxia ("Normal Zone," NZ) and partly to modified Tyrode's solution ("Ischemic Zone," IZ) for 15 or 30 min ("ischemia"), followed by return to normoxia for 30 min ("reperfusion"). Resting membrane potential, action potential (AP) amplitude, and maximal upstroke velocity of AP were not significantly modified. DL- And D-sotalol, 5 and 10 microM, lengthened AP duration 90% (APD90) in NZ (p < 0.05), whereas these drugs were unable to prevent ischemia-induced APD shortening. By using the accelerated failure time Weibull's model, and a large number of reference experiments to control random variability of analyzed covariates, DL- and D-sotalol increased significantly the incidence of spontaneous arrhythmias during ischemia (chi2 = 24.79; p = 0.0367): 83 (5 microM D- and DL-sotalol), 86, and 62% (10 microM D- and DL-sotalol, respectively) versus 32% of controls. During reperfusion, 10 microM DL-sotalol prevented the occurrence of spontaneous arrhythmias (chi2 = 46.74; p = 0.0001) similar to what seen with the beta-blocking agent propranolol (10 microM). These data, providing evidence for proarrhythmic effects of DL- and D-sotalol on border-zone arrhythmias, concomitant with differential class III actions on NZ versus IZ, might be considered for understanding the SWORD study results.     

Studies on local contractile characteristics in normal and ischemic myocardium and the role of collateral circulation in restoration of contraction abnormalities during ischemia (author''s transl)

The presence of supernormal excitation was confirmed repeatedly in all 10 cases following cardiac surgery. By the stimulation of minimum subthreshold impulses capable of originating ventricular responses, the supernormal excitation was limited only at the descending limb of T wave. The duration lasted only 0.02 sec at the minimum subthreshold stimuli. But the higher subthreshold stimuli produced the longer duration of supernormal excitation phase. The duration of the excitation phase prolonged towards the following R wave, hardly extending towards the preceding R wave, with the increase of subthreshold stimuli.     

Tension-frequency relationships in normal and cardiomyopathic dog and hamster myocardium

The objective of this study was to evaluate the tension-frequency relationship in normal and cardiomyopathic myocardium from one species with a negative or biphasic relationship, the hamster, and one with a positive relationship, the dog. Left ventricular papillary muscles from 100-day-old normal Syrian and cardiomyopathic (CHF-147) hamsters and right ventricular papillary muscles or trabeculae from normal mongrel dogs and dog with pacing-induced heart failure were used for the study. Stimulation frequency was varied from 1 to 90/min and isometric contractions recorded at each frequency prior to and after the addition of phenylephrine 10 microM. A tension-frequency relationship at varying extracellular calcium concentrations (1.25, 2.5 and 5.0 mM) was also constructed in normal hamster myocardium. Ryanodine 1.2 microM was added to a bath with normal hamster muscles and a force-frequency relationship constructed prior to and after adding phenylephrine 10 microM. A calcium dose-response curve in normal and cardiomyopathic dog myocardium was also constructed. Normal and cardiomyopathic hamster myocardium had a biphasic tension-frequency relationship with the increase in tension during the second phase being greater in normal v cardiomyopathic hamster myocardium (0.66 +/- 0.19 v 0.12 +/- 0.03 g/mm2, P < 0.05). The initial decrease in tension in response to increasing stimulation frequency was markedly attenuated in normal hamster myocardium by increasing extracellular calcium concentration. Developed tension was eliminated at lower stimulation rates by ryanodine such that when developed tension did occur, it increased with increasing stimulation rates. The addition of phenylephrine to hamster myocardium modified the tension-frequency relationship of both normal and cardiomyopathic dog myocardium and their response to phenylephrine were similar. In each case, tension increased progressively with increasing stimulation rate. Although the absolute increase in tension caused by increasing extracellular calcium was less in cardiomyopathic dog myocardium, the percent increase in tension and shortening was greater. We conclude that the tension-frequency relationship of normal and cardiomyopathic hamster myocardium are biphasic, with the initial negative phase being the result of limitations of sarcoplasmic reticulum calcium handling. Phenylephrine modifies this relationship to a uniphasic positive one, likely by its effects on both the sarcolemma and the sarcoplasmic reticulum. Also, the tension-frequency relationship of normal and cardiomyopathic dog myocardium are similar and unmodified by phenylephrine.     

Regional vasodilating properties of isoflurane in normal swine myocardium

BACKGROUND: Studies of the coronary vasodilating properties of isoflurane have produced inconsistent results. Isoflurane has been reported to cause minimal or no coronary vasodilation, mild dose-related vasodilation, or even near-maximal coronary vasodilation. The current study was performed to clarify the direct coronary vasodilating potency of isoflurane. METHODS: We determined the vasodilating properties of isoflurane in regionally perfused swine myocardium. Six domestic swine were anesthetized with pentobarbital and fentanyl. The left anterior descending artery (LAD) was cannulated and perfused with blood drawn from the carotid artery and passed thorough a membrane oxygenator. LAD arterial flow was controlled by a calibrated roller pump with continuous digital readout, and LAD arterial pressure was measured directly. The anterior interventricular vein was cannulated and dimension crystals placed in the LAD-perfused myocardium. The vasodilation response to 0, 1, 2, and 3% isoflurane administered via the membrane oxygenator was determined and compared to maximal vasodilation produced by regional intracoronary administration of adenosine. RESULTS: Systemic blood pressure and heart rate remained constant throughout the experiment. With 3% isoflurane, systolic shortening and regional myocardial oxygen consumption decreased by 60 and 20%, respectively. The same concentration increased coronary blood flow by 51 +/- 34% and reduced coronary vascular resistance by 32.9 +/- 11.0%. Neither coronary blood flow nor coronary vascular resistance was affected with 1% isoflurane. Regional coronary administration of adenosine produced much greater changes in both coronary blood flow (+591%) and coronary vascular resistance (-92.5%). Isoflurane increased the venous oxygen content of the anterior interventricular vein in a dose-dependent fashion from 4.85 vol% at control to 6.17, 7.01, and 8.63 vol% at 1, 2, and 3% isoflurane, respectively. CONCLUSIONS: We conclude that isoflurane is a mild dose-dependent coronary vasodilator. At a 1% concentration, the coronary vasodilating properties of isoflurane are minimal.     

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.     

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.     

Length dependence of calcium- and force-transients in normal and failing human myocardium

Two questions were analysed: (1) Is the Frank-Starling mechanism operative in failing human myocardium? (2) Are length-dependent changes in force accompanied by length-dependent changes in intracellular calcium transients in human myocardium? METHODS: (I) in electrically stimulated left-ventricular trabeculae [normal donor heart (NDH), n = 8; end stage dilated cardiomyopathy (DCM), n = 11], isometric force development was analysed as a function of muscle length (37 degrees C, oxygenated Krebs-Henseleit solution, supramaximal electrical stimulation, frequency: 1 Hz). (II) Myocardium from the same patients were loaded with the fluorescent dye FURA-2/AM for simultaneous measurements of intracellular calcium transient (ICT) and force development at different muscle lengths. Muscle length, resting force, developed force and intracellular Calcium ("ratio method") were monitored continuously. RESULTS: (I) developed force increased up to an optimum as a function of muscle length in NDH- and DCM-myocardium. The slope of this increase was flatter in DCM-myocardium (P < 0.01). (II) In NDH- and DCM-myocardium, diastolic and systolic calcium increased significantly with muscle length. With decreasing muscle lengths the ICT became broader, the diastolic decay was retarded and the peak of the ICT was flatter. At Lmax the calcium amplitude was 23% smaller in DCM than in NDH (P < 0.04). CONCLUSION: there is a clear length dependence of active force in DCM-myocardium. The length dependence of force development is associated with length-dependent modulations of the ICT. The flatter slope of the length-force curve in DCM may be partly explained by altered intracellular calcium handling in failing myocardium.     

Potassium metabolism in the normal and ischemic heart cell

Potassium is an important electrolyte in heart cells and has the greatest membrane permeability in the unexcited state. Hence it is responsible for th generation of the resting membrane potential. Clinical disorders of conduction and impulse formation occur within physiological values of serum potassium. Potassium is indirectly involved in excitation-contraction coupling, and its relation to intracellular calcium metabolism is reviewed. While potassium movements within the cell are metabolic-dependent, it is also true that the activity of metabolic pathways is affected by changes in potassium concentration. During anoxia and ischemia, sodium and calcium are gained by the myocyte, and potassium and magnesium are lost by the cell. At the same time, the action potential duration is abbreviated, the slope of the action potential downstroke (phase 2) is increased, and the resting membrane potential may be reduced. A relationship between disturbances in intracellular potassium and ischemic arrhythmias appears likely.