Slow Washout Research Articles

Methyl 3β‐(4‐[125I]Iodophenyl)Tropane‐2β‐Carboxylate In Vitro Binding to Dopamine and Serotonin Transporters Under “Physiological” Conditions

Methyl 3 beta-(4-[125I]iodophenyl)tropane-2 beta-carboxylate ([123I]beta-CIT) is a single photon emission computed tomographic radiotracer for in vivo labeling of dopamine (DA) and serotonin (5-HT) transporters. Single photon emission computed tomographic experiments in nonhuman primates showed that [123I]beta-CIT in vivo binding to DA transporters had a much slower washout than binding to 5-HT transporters. This observation was not predicted from previously published in vitro studies. These studies, performed at 22 degrees C in nonphysiological buffer, reported similar affinity of [125I]beta-CIT for DA and 5-HT transporters. We now report [125I]beta-CIT binding parameters to fresh rat membranes at 22 degrees C and 37 degrees C, in a buffer mimicking the composition of cerebrospinal fluid. At both temperatures, binding to DA transporters was best fit by a two-site model, whereas binding to 5-HT transporters was compatible with one population of sites. At 22 degrees C, [125I]beta-CIT showed similar affinity to high-affinity DA (0.39 nM) and 5-HT transporter sites (0.47 nM). Increasing the incubation temperature from 22 degrees C to 37 degrees C reduced binding to DA transporters by 60%, whereas binding to 5-HT transporters was only marginally affected. In vitro kinetic experiments failed to detect significant differences in on or off rates that could explain the observed in vivo kinetics. These experiments thus failed to explain [125I]beta-CIT in vivo uptake kinetics, suggesting the existence of specific factors affecting the in vivo situation.

Comparison of three high affinity SPECT radiotracers for the dopamine D 2 receptor

The regional brain distribution and pharmacological specificity of three high affinity tracers for the dopamine (DA) D 2 receptor: [ 123I]IBF, [ 123I]epidepride, and [ 123I]2′-ISP were assessed by SPECT imaging of non-human primates. The ratios of striatal-to-occipital activities at the time of peak striatal uptake were 2.2, 6.3 and 1.7, respectively. From the peak striatal activities, washout rates were 33, 4 and 16%/h for [ 123I]IBF, [ 123I]epidepride and [ 123I]2′-ISP, respectively. The reversibility of the striatal uptake of all three agents was demonstrated by the rapid displacement induced by the dopamine D 2 selective antipsychotic agent raclopride, which increased washout rates to 96, 58 and 43%/h. The administration of d-amphetamine, which induces release of dopamine, had no noticeable effect on [ 123I]epidepride but increased the washout rate of [ 123I]IBF. These results suggest that, among these three agents, [ 123I]epidepride is the superior tracer for in vivo displacement studies because of its slow washout and high target-to-background ratios. However, for tracer kinetic modeling, [ 123I]IBF may be the superior agent because of its early time of peak uptake and its higher target-to-background ratios than [ 123I]2′-ISP.

The significance of Doppler signals detected by TCD in the diagnosis of embolism in neurosurgery and cerebral angiography

Recently, several authors have reported the character of embolic signals in TCD (transcranial Doppler sonography) as follows: (1) high intensity signals (3-60 dB) greater than the background Doppler spectrum;(2) random occurrence within the cardiac cycle; (3) transient appearance and short duration; (4) bell-shaped signals focused on a small band of frequencies within the Doppler spectrum; (5) harmonic sound quality; (6) monitoring time of over 30 minutes; required and (7) signals must be differentiated from artifacts. We studiedthe detectability of embolic signals using a Doppler recording system. Embolic signals of the middle cerebralartery were monitored by TCD using an experimental animal model and 3 patients with epilepsy or brain tumor who underwent cerebral angiography by the Seldinger method. In the animal model, artificial air emboli were easily detected as short-term and hyper-intense ultrasonic signals, while thrombotic emboli were not identified definitely. Furthermore, our clinical cases suggested that microscopic air emboli at the site of injection of the contrast medium may be prevented by slow washout with saline. We propose new criteria for embolic signals.

The Molecular Basis for Lacidipineʼs Unique Pharmacokinetics

Membrane-active drugs can be characterized by direct measurements of their membrane partition coefficients, washout rates from membranes, and washin rates into membranes. There appears to be a correlation between the duration of action of such membrane-active drugs and the membrane partition coefficient in conjunction with the washout rate. Lacidipine has a high membrane partition coefficient compared to other 1,4-dihydropyridine calcium-channel antagonists and a slow washout rate from membranes. Clinically, it also exhibits an extended duration of action. This control at the membrane molecular level may provide an optimal pharmacokinetic profile for lacidipine in the treatment of hypertension. In addition, these same properties may be important for lacidipine as an antiproliferative agent in the treatment of atherosclerosis.

Predictors of myocardial infarction after distal embolization of coronary vessels with percutaneous transluminal coronary angioplasty. Experience of 21 consecutive patients with distal embolization.

Of 1,855 patients with angina pectoris who underwent percutaneous transluminal coronary angioplasty (PTCA) in our hospital, 21 experienced distal embolization. Five of the patients had slow washout of contrast medium distal to the dilated stenosis accompanied by S-T segment elevation (slow-flow pattern). In the other 16 cases, a dislodged embolus was found distal to the dilated stenosis (occlusive pattern) following balloon inflation. Of the 21 patients, 8 (38%) developed acute myocardial infarction (MI). All patients with acute MI were thought to have intraluminal thrombus on angiography performed before PTCA. Interestingly, patients with recent MI or worsening angina had a significantly higher rate of acute MI (p < 0.05).

Cerebral Awakening Concentration of Sevoflurane and Isoflurane Predicted During Slow and Fast Alveolar Washout

We studied 49 patients of ASA physical status I to determine cerebral anesthetic concentration on awakening calculated with end-tidal anesthetic concentration, when the end-tidal concentration decreased spontaneously. We also attempted to explain the difference in the average of the bracketing alveolar anesthetic concentration that allows and prevents the response to verbal command during recovery from anesthesia (MAC-Awake) between slow and fast alveolar washout by comparing the cerebral anesthetic concentrations with MAC-Awake determined by fast and slow washout. Slow washout was obtained by decreasing anesthetic concentrations in predetermined steps of 15 min, assuming equilibration between brain and alveolar partial pressures. Fast alveolar washout was obtained by discontinuation of the inhaled anesthetic, which had been maintained at 0.5 minimum alveolar anesthetic concentration (MAC) for at least 15 min. MAC-Awake values for sevoflurane and isoflurane obtained by slow washout were 0.34 +/- 0.05 and 0.31 +/- 0.05 (mean +/- SD), respectively, when MAC-Awake was expressed as a ratio to age-adjusted MAC. MAC-Awake values obtained by fast washout (0.22 +/- 0.07 MAC for sevoflurane, 0.22 +/- 0.05 MAC for isoflurane) were significantly smaller than those obtained by slow washout. Anesthetic concentrations in the brain at first eye opening calculated with end-tidal concentrations during fast alveolar washout (0.34 +/- 0.08 MAC for sevoflurane, 0.30 +/- 0.08 MAC for isoflurane) were nearly equal to MAC-Awake obtained by slow alveolar washout. The difference in MAC-Awake between fast and slow alveolar washout could be explained by arterial-to-cerebral and end-tidal-to-arterial anesthetic differences.

Comparison of myocardial perfusion imaging with technetium-99m tetrofosmin versus thallium-201 in coronary artery disease

Technetium-99m (To-99m) tetrofosmin, a new myocardial perfusion imaging agent, was evaluated at exercise and rest in 50 patients with documented coronary artery disease to determine myocardial kinetics, redistribution and ideal imaging time. Planar imaging was performed at 5, 30, 60, 90, 120 and 240 minutes after an injection of Tc-99m tetrofosmin (8 to 10 mCi) at peak graded ergometric exercise. Reinjection (24 to 30 mCi) was performed at rest, 4 hours after the stress injection and also on a separate day, and imaging was repeated. All patients underwent thallium-201 (TI-201) exercise and redistribution (4-hour) imaging. Perfusion defect to normal, and heart to lung ratios were calculated for exercise To-99m tetrofosmin images at each time point. The mean ± SD defect to normal ratios were 0.75 ± 0.10, 0.75 ± 0.10, 0.74 ± 0.09, 0.73 ± 0.10, 0.73 ± 0.10 and 0.72 ± 0.10 at 5, 30, 60, 90, 120 and 240 minutes, respectively (p = NS), suggesting absence of redistribution. There was a significant increase in lung uptake of TI-201 during exercise (p <0.05), but not with To-99m tetrofosmin (p = NS). Washout of To-99m tetrofosmin was calculated in a subset of patients (n = 23). Rapid background clearance enabled postexercise diagnostic imaging as early as 5 minutes after injection. Myocardial retention curves after rest injection suggested that the optimal time for imaging was approximately 30 minutes later. Slow myocardial washout (4%/hour after exercise and 0.6%/hour after rest injection) enabled diagnostic images to be obtained up to 4 hours after each study. Image quality was generally superior to that with TI-201. Tc-99m tetrofosmin has the advantage of early imaging after exercise, with no evidence of redistribution.

Femoral vascular occlusion and ventilation during recovery from heavy exercise

Ventilation and cardiac output subside gradually following cessation of exercise, which is commonly linked to the slow wash-out of materials from the recovering muscles. The effect of hindering the removal of the metabolic products of heavy cycle exercise on the kinetics of ventilation and gas exchange was studied in 5 subjects by occluding the femoral circulation with cuffs during the first 2 min of recovery (15 tests). Fifteen undisturbed recoveries served as controls. Compared to spontaneous recovery, circulatory obstruction induced an immediated (from the first breath) decrease in minute ventilation (V̇ E ), while end-tidal CO 2 ( Pet CO 2 ) as well as lactate and K + in venous blood at forearm did not change significantly. A ventilatory deficit of 27±9 L was observed from the 2 min of occlusion. Following cuff deflation, V̇ E rose 2–3 breaths after Pet CO 2 began to increase in every subject. The mechanisms of the normocapnic reduction of V̇ E during occlusion, as well as the rise of ventilation following cuff release, are still unclear. However, these results argue against any significant role for hyperpnea-inducing intramuscular chemoreception, or point to muscular perfusion as a prerequisite of such a mechanism to operate.

Transfer kinetics of 3,5,3'-triiodothyronine and thyroxine from rat blood to large and small intestines, liver, and kidneys in vivo

Enterohepatic circulation of thyroid hormone in the rat involves transfer of hormone to intestines in bile from the liver and absorption of some intestinal hormone, via portal blood to liver. Transfer of hormone to intestines from mesenteric arterial blood has generally been considered minimal, although this alternate pathway has received little attention. We have measured uptake kinetics of iv trace doses of radioactivity labeled T3 (T3*) and T4* from blood to intestines, longitudinally in 14 segments of total intestines in situ, with bowel contents included and bile duct ligated, and also to liver and kidneys, for comparison. Both T3* and T4* entered the entire length of intestines from blood, and into contents as well as tissue. Tissue uptake of T3* and T4* were fairly uniform longitudinally, but uptake into contents and thus into total intestines (tissue + contents) decreased linearly from pylorus to anus. Unidirectional uptake rate constants (hours-1) or clearance rates (milliliters per h) of T3* were 13 times greater than corresponding T4* fractional uptake rates to intestines. In contrast, T4 mass fluxes (congruent to 38 ng/h.100 g body wt) exceed T3 fluxes (congruent to 6.3 ng/h.100 g body wt) about 6-fold, because plasma contains far more T4 than T3. Comparing these results with published biliary and fecal T3 and T4 flux data, it appears that mesenteric arterial mass influxes to intestines are 3-5 times greater than both biliary secretion and fecal excretion of T3 and T4. Intestinal kinetics, in the absence of biliary influx, are characterized by a moderately rapid uptake followed by a very slow washout phase, which fit into neither the fast nor slow compartment paradigms of a 3-compartment mammillary model, in contrast to liver and kidney kinetics, which fit well into a single fast compartment. Intestinal dynamics are consistent with an organ in which storage and exchange of thyroid hormone dominate over metabolic and excretory processes.

Transfer kinetics of 3,5,3'-triiodothyronine and thyroxine from rat blood to large and small intestines, liver, and kidneys in vivo.

Enterohepatic circulation of thyroid hormone in the rat involves transfer of hormone to intestines in bile from the liver and absorption of some intestinal hormone, via portal blood to liver. Transfer of hormone to intestines from mesenteric arterial blood has generally been considered minimal, although this alternate pathway has received little attention. We have measured uptake kinetics of iv trace doses of radioactivity labeled T3 (T3*) and T4* from blood to intestines, longitudinally in 14 segments of total intestines in situ, with bowel contents included and bile duct ligated, and also to liver and kidneys, for comparison. Both T3* and T4* entered the entire length of intestines from blood, and into contents as well as tissue. Tissue uptake of T3* and T4* were fairly uniform longitudinally, but uptake into contents and thus into total intestines (tissue + contents) decreased linearly from pylorus to anus. Unidirectional uptake rate constants (hours-1) or clearance rates (milliliters per h) of T3* were 13 times greater than corresponding T4* fractional uptake rates to intestines. In contrast, T4 mass fluxes (congruent to 38 ng/h.100 g body wt) exceed T3 fluxes (congruent to 6.3 ng/h.100 g body wt) about 6-fold, because plasma contains far more T4 than T3. Comparing these results with published biliary and fecal T3 and T4 flux data, it appears that mesenteric arterial mass influxes to intestines are 3-5 times greater than both biliary secretion and fecal excretion of T3 and T4. Intestinal kinetics, in the absence of biliary influx, are characterized by a moderately rapid uptake followed by a very slow washout phase, which fit into neither the fast nor slow compartment paradigms of a 3-compartment mammillary model, in contrast to liver and kidney kinetics, which fit well into a single fast compartment. Intestinal dynamics are consistent with an organ in which storage and exchange of thyroid hormone dominate over metabolic and excretory processes.

SPECT imaging of dopamine and serotonin transporters with [123I]β‐CIT: Pharmacological characterization of brain uptake in nonhuman primates

Single photon emission computed tomography (SPECT) studies of regional kinetic uptake and pharmacological specificity of [123I]methyl 3 beta-(4-iodophenyl) tropane-2 beta-carboxylate ([123I]beta-CIT) were performed in nonhuman primates (n = 41). In control experiments, activity was concentrated in striatum and in hypothalamic/midbrain regions. Striatal uptake increased for 140-180 min and displayed stable levels thereafter. Striatal to cerebellar activity ratios were 7.3 +/- 0.9 (mean +/- SEM) at 300 min. About 75% of striatal uptake was displaceable by injection of nonradioactive beta-CIT. Hypothalamic/midbrain activity reached maximal levels at approximately 45 min. A slow washout phase followed this peak activity. Activities in frontal, occipital, and cerebellar regions were characterized by an early peak (20-30 min), followed by rapid washout. Displacement studies demonstrated that striatal uptake was associated with dopamine (DA) transporters, as it was displaced by GBR 12909, a selective DA uptake inhibitor, but not by citalopram, a selective serotonin (5-HT) uptake inhibitor. The inverse was true in the hypothalamic/midbrain area, suggesting that the uptake in this area was associated primarily with 5-HT transporters. Maprotiline, a selective norepinephrine uptake inhibitor, did not affect [123I]beta-CIT uptake. In vivo site occupancy ED50 values of cocaine, 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane (CFT), and beta-CIT were measured in the striatum with a stepwise displacement paradigm. In vivo ED50 values correlated strongly with in vitro IC50 values for binding to DA transporters. Infusion of high dose of L-DOPA (250 mumol/kg) failed to displace striatal [123I]beta-CIT binding, suggesting that the binding would not be affected by L-DOPA administration in Parkinsonian patients. However, studies performed with injection of d-amphetamine indirectly suggested that high synaptic levels of DA may compete with [123I]beta-CIT binding. These studies suggest that [123I]beta-CIT will be a useful SPECT tracer of DA and 5-HT transporters in living human brain.

Characterization of adenomas and metastases in the adrenals: comparison between spin-echo sequences and Gd-DTPA enhanced dynamic studies

Nineteen patients with adrenal masses (9 metastases and 10 adenomas) were studied with magnetic resonance spin-echo sequences and with dynamic perfusion with gradient-echo (GE) sequences after gadolinium diethylenetriamine-pentaacetic acid injection. In studies following Gd-DTPA injection, sequential imaging during suspended respiration was obtained. Signal intensities of adrenal masses and retroperitonel fat were measured in the region of interest. The relative signal intensities of lesion and fat were determined and compared in dynamic contrast-enhanced studies. Results were tabulated and plotted in diagrams as a function of time. Sixteen lesions out of 19 were correctly classified by means of SE sequences, with an 84% diagnostic accuracy, whereas 18 out of 19 lesions were characterized by means of GE sequences, with a 95% accuracy. In the dynamic study, adenomas showed mild enhancement and quicker washout than metastases which, in turn, showed a strong enhancement and a much slower washout. The most significant values were obtained in scans taken after 10 min, where adenomas showed signal to lesion/signal to fat values lower than 1.1, whereas metastases showed much higher values in all cases.

MAC-Awake of Isoflurane, Enflurane and Halothane Evaluated by Slow and Fast Alveolar Washout

End-tidal anaesthetic concentrations at first eye opening in response to a verbal command during recovery from anaesthesia (MAC-awake), were measured for isoflurane (n = 16), enflurane (n = 16) and halothane (n = 14). MAC-awake was measured during either slow or fast alveolar washout. Slow washout was obtained by decreasing anaesthetic concentrations in predetermined steps of 15min, assuming equilibration between brain and alveolar partial pressures. Fast alveolar washout was obtained by discontinuation of the inhalation anaesthetic, which had been maintained at 1 MAC for at least 15 min. Mean MAC-awake obtained with slow alveolar washout was similar for isoflurane (0.25 (SD 0.03) MAC), and enflurane (0.27 (0.04) MAC) and significantly greater than values obtained by fast alveolar washout (isoflurane: 0.19 (0.03) MAC; enflurane: 0.20 (0.03) MAC). The MAC-awake of isoflurane and enflurane was significantly less than that of halothane, which was 0.59 (0.10) MAC as evaluated by the slow and 0.50 (0.05) MAC as evaluated by the fast alveolar washout method. Recovery time from anaesthesia with fast alveolar washout was 8.8 (4.0) min for halothane, which was not different from isoflurane (15 (2.5) min), but significantly shorter than for enflurane (22 (10) min), reflecting differences in the anaesthetic concentration gradient between MAC and MAC-awake values. These data do not support the hypothesis of a uniform ratio between MAC and MAC-awake values.

Dynamic SPECT imaging after injection of the benzodiazepine receptor ligand [ 123I]iomazenil in healthy human subjects

Previous work suggests that iomazenil (formerly known as Ro 16–0154) is a useful ligand for static imaging of the benzodiazepine (BZ) receptor with single photon emission computed tomography (SPECT). The present study evaluated the feasibility of dynamic SPECT imaging of cerebral radioactivity following intravenous [ 123I]iomazenil injection in healthy human subjects, in preparation for future receptor quantitation studies. Maximal brain uptake was reached approximately 25–30 minutes after i.v. administration of the radioligand and represented approximately 12% of the injected dose. The regional distribution of radioactive densities was consistent with the known distribution of BZ receptors in human brain, with highest uptake localized over the occipital area. Washout of cortical radioactivity was regionally variable but relatively slow, with a half-life of approximately 4 hours after the time of peak radioactivity. In summary, [ 123I]iomazenil is a promising SPECT radioligand for the BZ receptor, with high brain uptake, relatively slow washout of radioactivity and appropriate regional distribution.

Protection from reperfusion injury by preconditioning hearts does not involve increased antioxidant defenses.

Preconditioning the heart with 5 min of ischemia renders the heart very resistant to infarction from subsequent ischemia by an unknown mechanism. We investigated whether the protective effect of preconditioning might be related to an increase in rabbit heart antioxidant defenses. The antioxidant activities of catalase, glutathione peroxidase, Mn superoxide dismutase, Cu,Zn superoxide dismutase, glucose-6-phosphate dehydrogenase, glutathione reductase, and total glutathione were measured in ischemic and normal regions from both control and preconditioned rabbit hearts. All hearts experienced 30 min regional ischemia and 5 min reperfusion. None of the antioxidant enzymes changed in activity when comparing nonischemic and postischemic zones in either nonpreconditioned or preconditioned hearts. Total glutathione, however, was reduced in reperfused zones and showed better preservation in preconditioned hearts. To determine whether this preservation resulted from a higher value at the onset of reperfusion or slower washout during reperfusion, we analyzed a second group of nonreperfused hearts after 30 min ischemia. The hearts had normal glutathione content in both ischemic and nonischemic zones of either preconditioned or control hearts. The most likely explanation is that preconditioned hearts experienced less washout of glutathione simply because they were less injured. We therefore conclude that enhancement of antioxidant defenses is not the mechanism of preconditioning.

Response to a smelter closure in Cascade mountain lakes

A statistically significant decrease in sulfate was observed in high elevation Cascade lakes during 1983 through 1988. The total decrease averaged 2.2 μeq L−1 in two slow-flush lakes and 4.2 μeq L−1 in three fast-flush lakes for 1983–1985 vs 1986–1988, respectively. Coincident with these changes in sulfate concentrations were a sharp decrease of SO2 emissions from the ASARCO smelter (100 km SE of the lakes), from 87 to 70 kt yr−1 during 1983–1984 to 12 in 1985, the year of its closure, and a gradual change in SO2 emissions from Mt. St. Helens, from 39 to 27 during 1983–1984 to 5 in 1988. The sharpest decreases occurred in non-marine sulfate in fast-flush lakes from 1984 to 1985 (about 2 μeq L−1) and in slow-flush lakes from 1985 to 1986 (1 μeq L−1, which point to the ASARCO closure as the sole cause. However, some of the more gradual decline in non-marine sulfate observed during 1983 through the 1988 sampling periods may have been due to a slow washout of sulfate enriched ash from the 1980 Mt. St. Helens' eruption. Sulfate concentrations in precipitation also declined significantly by about 2 μeq L−1, but changes in volume-weighted sulfate content were not significant. Lake alkalinity did not show a consistent increase in response to decreased sulfate. This was probably due to either watershed neutralization of acidic deposition or the greater variability in alkalinity measurements caused by small changes in acidic deposition making it difficult to detect changes.

MAC-AWAKE OF ISOFLURANE, ENFLURANE AND HALOTHANE EVALUATED BY SLOW AND FAST ALVEOLAR WASHOUT

End-tidal anaesthetic concentrations at first eye opening in response to a verbal command during recovery from anaesthesia (MAC-awake), were measured for isoflurane (n = 16), enflurane (n = 16) and halothane (n = 14). MAC-awake was measured during either slow or fast alveolar washout. Slow washout was obtained by decreasing anaesthetic concentrations in predetermined steps of 15 min, assuming equilibration between brain and alveolar partial pressures. Fast alveolar washout was obtained by discontinuation of the inhalation anaesthetic, which had been maintained at 1 MAC for at least 15 min. Mean MAC-awake obtained with slow alveolar washout was similar for isoflurane (0.25 (SD 0.03) MAC), and enflurane (0.27 (0.04) MAC) and significantly greater than values obtained by fast alveolar washout (isoflurane: 0.19 (0.03) MAC; enflurane: 0.20 (0.03) MAC). The MAC-awake of isoflurane and enflurane was significantly less than that of halothane, which was 0.59 (0.10) MAC as evaluated by the slow and 0.50 (0.05) MAC as evaluated by the fast alveolar washout method. Recovery time from anaesthesia with fast alveolar washout was 8.8 (4.0) min for halothane, which was not different from isoflurane (15 (2.5) min), but significantly shorter than for enflurane (22 (10) min), reflecting differences in the anaesthetic concentration gradient between MAC and MAC-awake values. These data do not support the hypothesis of a uniform ratio between MAC and MAC-awake values.

Exercise testing and thallium-201 emission computed tomography in patients with intraventricular conduction disturbances

The specificity of exercise thallium-201 emission computed tomography for coronary artery disease was assessed in patients with intraventricular conduction disturbances. Eighty-seven patients were studied: 33 with right bundle branch block (RBBB), 11 with RBBB and left-axis deviation, 11 with left (L)BBB, 12 on right ventricular pacing, and 20 with Wolff-Parkinson-White (WPW) syndrome. A control group of 349 consecutive patients with normal intraventricular conduction was also examined. The specificity of diagnosis of coronary artery disease in patients with LBBB (30%), right ventricular pacing (44%) or RBBB plus leftaxis deviation (50%) was significantly lower than in patients with normal intraventricular conduction (94%; p < 0.01). In contrast, there was no significant difference between specificity in patients with RBBB (86%) or WPW syndrome (90%) and patients with normal intraventricular conduction. Perfusion defects were found in the anterior, septal and inferior segments in patients with LBBB, and in the septal and inferior segments in patients with RBBB plus left-axis deviation despite the absence of coronary stenosis. Furthermore, diffuse slow washout was seen more often in patients with WPW syndrome (35%) than in controls who had normal intraventricular conduction (11%; p < 0.05), despite a good exercise performance in the former group. This study suggests that there is an increased incidence of abnormal perfusion and clearance during exercise thallium-201 emission computed tomography in patients with intraventricular conduction disturbances.

Noninvasive identification of significant narrowing of the left main coronary artery by dipyridamole thallium scintigraphy

To evaluate the usefulness of dipyridamole thallium scintigraphy with tow-level exercise for the identification of left main (LM) coronary artery disease (CAD), 466 consecutive patients with CAD were studied. Thirty-eight patients (8%) had LM stenosis (diameter narrowing ≥50%). The LM scintigraphic pattern was present in 9 of 38 patients with LMCAD and 38 of 428 CAD patients without LMCAD (24 vs 9%; p < 0.005). This pattern was present in 6 of 9 patients with LMCAD without right CAD and in only 3 of 29 patients with LM and right CAD (67 vs 10%; p = 0.0005). Patients with LMCAD had a higher incidence of premature cessation of tow-level exercise (53 vs 21%; p < 0.0001), chest pain (68 vs 48%; p < 0.02), blood pressure decrease of ≥20 mm Hg (44 vs 16%; p < 0.002) and greater ST depression (0.17 ± 0.13 vs 0.06 ± 0.10 mV; p < 0.001) during dipyridamole loading than patients without LMCAD. Stepwise discriminant analysis revealed that the LM scintigraphic pattern and markers of ischemia during dipyridamole loading best identified (p < 0.0001) patients with LMCAD without right CAD (sensitivity 67%, specificity 91%), but this predictability is no better than the LM scintigraphic pattern alone. The combination of clinical markers of ischemia during dipyridamole loading and scintigraphic findings of diffuse slow washout, extensive fixed defects and the LM pattern best identified (p < 0.0001) patients with LM and right CAD (sensitivity 72%, specificity 80%). These results indicate that the LM scintigraphic pattern is specific and sensitive for LMCAD without right CAD. In LM and right CAD, the predictability of this finding is tow, but the addition of clinical markers of ischemia during dipyridamole loading facilitates better identification.

Long-term increases in the evoked population spike in the CA1 region of rat hippocampus induced by beta-adrenergic receptor activation

The effects of the selective beta-adrenergic receptor agonist isoproterenol (ISO) were characterized in the CA1 region of the rat hippocampal slice preparation. As has been previously described, 500 nM ISO increased the amplitude of the evoked population spike response without having any effect upon field EPSP (fEPSP) responses. However, the increase in the population spike response was quite persistent and was not reversed by greater than 30 min of washout in the majority of the slices tested; we have termed this prolonged increase beta-adrenergic potentiation (BAP). As with the acute effect of ISO, BAP is confined to an increase in the population spike response and not the fEPSP. In input-output curves, this was clearly observed as a persistent leftward shift in the EPSP-population spike relationship. Similar long-term increases in the population spike could also be elicited by superfusion of the slices for 10 min with 20-25 microM norepinephrine (NE). Although both the acute and the long-term effects of ISO were blocked by pretreatment with timolol, a beta-adrenergic antagonist, the long-term effects were not reversed by superfusion with timolol following ISO treatment, demonstrating that the prolonged effects were not due to slow washout of ISO from the tissue. BAP was not blocked by pretreatment with 50 microM 2-amino-5-phosphonovaleric acid, an NMDA receptor antagonist that blocks hippocampal long-term potentiation and the long-lasting changes in synaptic responses induced in the dentate gyrus by NE and ISO.(ABSTRACT TRUNCATED AT 250 WORDS)