Effect of nicardipine and magnesiumon cerebral infarction - brain surface perfusion technique.

The protective effect of pre- and postischemia treatment of the brain by surface perfusion with nicardipine (Nic) and/or magnesium (Mg) was evaluated in a rat focal cerebral ischemia model. Artificial cerebrospinal fluid was perfused into the subarachnoid space of rats, containing Nic or Nic/Mg prior to vessel occlusion and Nic/Mg after occlusion. Reductions in the total amount of glutamate in the microdialysis perfusate and the volume of infarction tissue stained with 2,3,5-triphenyltetrazolium chloride were significant in all treated groups, even in rats treated after ischemia. An additive effect of Mg was also observed. These results suggest that this method may have clinical applications in patients suffering from ischemic insult.

Effect of the beta-adrenoceptor agonist flerobuterol on serotonin synthesis in the rat brain.

The influence of 2- and 14-day treatments with flerobuterol, a preferential beta(2)-adrenoceptor agonist, on regional serotonin (5-HT) synthesis in the rat brain was studied by autoradiography using alpha-[(14)C]methyl-L-tryptophan. Flerobuterol was delivered at a rate of 0.5 mg/kg/day using osmotic pumps implanted s.c. The 2-day flerobuterol treatment significantly increased plasma Trp, both free and total, and decreased plasma Leu and Ile. This resulted in a significant increase in the facilitated transport of Trp. There was a significant increase in the synthesis of 5-HT in the 2-day treatment group in the dorsal and median raphe as well as in all postsynaptic structures, with the exception of the hypothalamus. In contrast, after a 14-day treatment, the enhanced facilitated transport of Trp was no longer present, and the increase in the rate of 5-HT synthesis persisted only in the parietal and occipital cortex and the superior colliculus. These data suggest that flerobuterol, similar to other beta-adrenergic agonists, acutely increases 5-HT synthesis, in part, through an elevation of brain Trp availability.

Development of a dissecting aneurysm on the vertebral artery immediately after occlusion of the contralateral vertebral artery: a case report.

A 49 year old female presented with subarachnoid hemorrhage due to a ruptured dissecting aneurysm on the left vertebral artery (VA). Following an occlusion test, we performed proximal occlusion of the left VA with detachable balloons. However, a dissecting aneurysm on the right VA developed three weeks later. After an occlusion test had showed no change in cerebral blood flow, auditory brain stem response, or neurological status, proximal occlusion of the right VA was performed. The patient has returned to normal life without neurological deficits. Bilateral dissecting aneurysms of the VA are quite common, but de novo VA dissecting aneurysms or enlargement of such aneurysms after occlusion of contralateral VA are rare. This case suggests that hemodynamics stress may be a causal factor in the development of VA dissecting aneurysms. Careful pre- and post-operative neuroradiological examination of the contralateral VA are required in patients undergoing VA occlusion for dissecting aneurysms.

In vivo-synthesized radioactively labelled alpha-methyl serotonin as a selective tracer for visualization of brain serotonin neurons.

To investigate the use of alpha-[3H]methyl tryptophan (alpha-[3H]MTrp) as a tracer for the in vivo study of brain serotonergic neurons, we examined whether alpha-[3H]MTrp and its metabolite alpha-[3H]methyl serotonin (alpha-[3H]M5-HT) selectively label serotonergic neurons and whether once accumulated in these neurons, the radioactive metabolite behaves like endogenous serotonin. Rats received a systemic injection of 1-5 mCi of alpha-[3H]MTrp and 24 h later their brains were immediately removed or fixed by perfusion before removal. Tissue sections in which serotonergic neurons had been immunostained for 5-HT or its synthesizing enzyme, tryptophan hydroxylase, were processed for radioautography at the light and electron microscopic level. In another group of rats, the release of radioactivity from different brain areas was studied both under basal and depolarizing conditions. In the dorsal raphe nucleus, the light microscopic examination revealed almost complete colocalization between serotonergic neurons and those that accumulated radioactivity, with a heterogeneity in the content of alpha-[3H]M5-HT among the various cells. At the ultrastructural level, immunoidentified serotonergic perikarya and dendritic processes in the dorsal raphe nucleus, as well as nerve terminals in the cerebral cortex were also found to contain alpha-[3H]M5-HT. Under basal conditions, radioactivity was released from the brainstem raphe region and from projection areas such as the striatum and hippocampus. The basal output of alpha-[3H]M5-HT increased approximately twofold after a depolarizing 50 mM KCl solution was added to the perfusion fluid. These findings suggest that newly synthesized alpha-[3H]M5-HT can be released both at somatodendritic and terminal sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of acute fluoxetine treatment on the brain serotonin synthesis as measured by the alpha-methyl-L-tryptophan autoradiographic method.

The effect of treatment with acute fluoxetine, a serotonin reuptake inhibitor, on the rate of serotonin synthesis in the rat brain was studied through autoradiography following intravenous administration of alpha-methyl-L-[3H]tryptophan. The rate of serotonin synthesis in fluoxetine-treated rats was compared with the rate measured in sham-treated rats (saline injection). Results showed a significant increase in the rate of synthesis in the majority of cerebral structures examined. The greatest increase (given as a percentage of rates in control animals) in the rate of serotonin synthesis was observed in the substantia nigra compacta (344%), hippocampus-CA3 (337%), dorsal hippocampus (283%), and caudate-putamen (232%). Fluoxetine had a less significant effect on the rate of synthesis in the pineal body (44%). Data suggest that acute fluoxetine treatment (30 mg/kg, i.p.) enhances the rate of serotonin synthesis in all the structures of rat brain examined in this work.

Autoradiographic evaluation of the influence of hypothalamic 5,7-dihydroxytryptamine lesion on brain serotonin synthesis.

The influence of a unilateral stereotaxically induced 5,7-dihydroxytryptamine (5,7-DHT) lesion in the dorsolateral hypothalamus on brain serotonin synthesis was evaluated by an autoradiographic method, using labelled alpha-methyl-L-tryptophan (alpha-MTrp). The hypothalamus was selected as the lesion site because it receives well defined and relatively large projections from the raphe nuclei. Data suggest that the unilateral lesion in the dorsolateral hypothalamus had a significant influence (an increase) on the rate of serotonin synthesis in the large majority of ipsilateral brain structures examined. It seems that the effect was the greatest in the hippocampal structures, the thalamus, and the parietal and sensory motor cortices. The average increase in the rate of serotonin synthesis on the lesion side when compared with the contralateral side was between 3% (amygdala) and 52% (dorsal hippocampus; CA3 layer of hippocampus). Since in the sham-injected rats (same volume of saline) there was no obvious injection-contralateral side asymmetry observed (except for two structures, probably affected by the injection needle, which showed a significant difference), we concluded that the effect observed in the present study was most likely related to the 5,7-DHT-induced lesion on the serotonergic terminals in the hypothalamus. Comparison of the rate of synthesis in the dorsal and medial raphe and the pineal body with the rates reported earlier for these structures led us to conclude that either the 5,7-DHT lesion in the hypothalamus did not influence the rates in these structures in their entirety, or the method used was not sensitive enough to reveal this influence. Data reported here also demonstrate how a highly specific tracer (alpha-MTrp), in conjunction with a specific and localized lesion, could aid our understanding of the brain serotonergic system.

Synthesis of serotonin in traumatized rat brain.

Previous studies have demonstrated that focal freezing lesions in rats cause a widespread decrease of cortical glucose use in the lesioned hemisphere and this was interpreted as a reflection of depression of cortical activity. The serotonergic neurotransmitter system was implicated in these alterations when it was shown that (1) cortical serotonin metabolism was increased widely in focally injured brain and (2) inhibition of serotonin synthesis prevented the development of cortical hypometabolism. In the present studies we applied an autoradiographic method that uses the accumulation of the 14C-labeled analogue of serotonin alpha-methylserotonin to assess changes in the rate of serotonin synthesis in injured brain. The results confirmed that 3 days after the lesion was made, at the time of greatest depression of glucose use, serotonin synthesis was significantly increased in cortical areas throughout the injured hemisphere. The increase was also seen in the dorsal hippocampus and area CA3, as well as in the medial geniculate and dorsal raphe, but not in any other subcortical structures including median raphe. Present results suggest that the functional changes in the cortex of the lesioned hemisphere are associated with an increased rate of serotonin synthesis mediated by activation of the dorsal raphe. We also documented by alpha-[14C]aminoisobutyric acid autoradiography that there was increased permeability of the blood-brain barrier, but this was restricted to the rim of the lesion.

Determination of the lumped constant for the alpha-methyltryptophan method of estimating the rate of serotonin synthesis.

The lumped constant (LC) for the alpha-methyl-L-tryptophan method to convert the brain's uptake of labeled alpha-methyl-L-tryptophan into the regional rate of serotonin synthesis was estimated. The method involved independently estimating the unidirectional uptake constant of the tracer (alpha-[14C]methyl-L-tryptophan) to the tissue and the tracee (tryptophan) (with the addition of a radioactive compound) and calculating their ratio. The LC was estimated from logarithmically transformed data. Similar experiments were performed using rats treated with the drug probenecid, which blocks the efflux of 5-hydroxyindoleacetic acid (a metabolite of serotonin) from the brain. The experiments using probenecid, corrected for the difference in the levels of plasma free tryptophan (increased in probenecid-treated rats) relative to control experiments, gave an average LC for the rat brain of 0.46 +/- 0.14 (mean +/- SD). This value was not significantly different from the one obtained in controls (0.43 +/- 0.13). In addition, the LC was also calculated using unidirectional uptake constants in the probenecid-treated rats for alpha-methyl-L-tryptophan and L-tryptophan. This LC value was 0.39 +/- 0.10. There was no significant difference between these three LC values. Thus, an average +/- SD LC of 0.42 +/- 0.07 for 28 brain structures investigated in this study was obtained. Statistically the LC obtained in different structures had a variability that could be accounted for by errors in measurements alone. In other words, dispersion in the LC values could be fully accounted for by chance alone. Data confirmed that the LC value did not change when the rate of serotonin synthesis was increased by probenecid treatment. We also showed that the rate of 5-hydroxyindoleacetic acid accumulation in probenecid-treated rats was 58 pmol g-1 min-1 (rat brain), which is about twice as much as reported by others for a normal rat. This difference could also be accounted for by the increase in the plasma level of free tryptophan in probenecid-treated rats.

Effect of hypothalamic 5,7-dihydroxytryptamine lesion on the anterograde transport of serotonin as measured with labeled alpha-methyl serotonin.

The anterograde axonal transport of serotonin along the medial forebrain bundle (MFB) 5 days after unilateral dorsal hypothalamic 5,7-dihydroxytryptamine (5,7-DHT) lesion was examined in rat brain. Measurements were done using in vivo synthesized radioactively labeled alpha-methyl serotonin (used here as a serotonin tracer), from i.v. injected labeled alpha-methyl-L-tryptophan, a substitute neurotransmitter and analog of serotonin. Data indicated that after destruction of the presynaptic terminals with 5,7-DHT, the rate of axonal transport of serotonin and/or the rate of serotonin synthesis in the spared and/or damaged neurons was increased. The rate of serotonin anterograde transport on the lesioned side was above 25 mm/d compared to 12.31 +/- 0.49 mm/d on the contralateral side and 12.13 +/- 0.44 mm/d in control (sham injected) rats. The difference in rate between the lesioned and control rats was highly significant; P < 0.005 (two-tailed t-test). The amount of neurotransmitter anterogradely transported along the medial forebrain bundle and/or synthesized in the neurons was 18.8 +/- 4.1 times greater on the side of the 5,7-DHT hypothalamic lesion than that on the contralateral sides or that found in the saline-injected rats. There was no difference in the radioactivity found on the left or right side of the medial forebrain bundle in the rats 5 days after lesion in the rostal midbrain with 5,7-DHT. Five days after the lesion there was also no difference in the anterograde protein transport measured by stereotaxic injection of [3H]proline into the dorsal raphe.

Resetting of regional preload due to ventricular shape change alters diastolic and systolic performance.

The diastolic and systolic pressure of one ventricle is increased by an increase in volume and/or pressure of the opposite ventricle; however, a mechanism for the ventricular interaction remains unclear. We hypothesized that the shape change of one ventricle elicited by the opposite ventricle would lead to resetting of the regional length, which may explain the ventricular interaction. We used 15 cross-circulated isovolumically contracting canine hearts in which both ventricular volumes were independently controlled. Diastolic regional segment area was calculated by multiplying circumferential and longitudinal lengths on right ventricular free wall (RVFW; n = 6), interventricular septum (IVS; n = 11), and left ventricular (LV) FW (n = 12). The regional area at relatively small volumes of both ventricles were expressed as 100%. With constant RV volume, increasing LV from 7 to 19 ml increased RV diastolic and systolic pressures by 2.7 and 5.5 mmHg, respectively. Conversely, increasing RV volume increased LV diastolic and systolic pressures by 2.3 and 7.5 mmHg, respectively. Increasing LV volume increased RVFW regional area from 121.0 to 124.6% (P < 0.01) and increased IVS regional area from 103.3 to 108.7% (P < 0.01), whereas the RV volume was held constant. Increasing RV volume also increased LVFW and IVS regional areas from 109.9 to 111.6% (P < 0.01) and from 106.8 to 108.9% (P < 0.05), respectively. Ventricular shape change elicited by ventricular interaction will increase the regional wall area, even though the volume of the chamber is unchanged. The increase in the regional area alters the position of the tissue on its resting and active length-tension relations and, thus, leads to enhancement of the chamber pressure.

Dipyridamole electrocardiography test for the detection of severe coronary artery stenoses.

To investigate the relationship between dipyridamole-induced ST depression and the severity of coronary artery stenosis, the dipyridamole injection test (D) at 0.568 mg/kg/4 min, and the symptom limited treadmill exercise test (T) were performed separately in 16 normal volunteers and 167 patients who underwent coronary arteriography [91 patients without myocardial infarction (non-MI group) and 76 patients with previous myocardial infarction (MI group)]. Standard 12-lead electrocardiogram and body surface mapping of 87 leads were recorded in both tests. None of the normal volunteers had significant ST depression (greater than or equal to 0.10 mV) in D or T. Regarding the non-MI group, D had as high an incidence of ST depression as T (83% vs 93%) in patients with maximal coronary stenosis greater than or equal to 90%, while in those with maximum coronary stenosis less than 90%, D had a lower incidence of ST depression than T (16% vs 48%, p less than 0.01). For the MI group, the incidence of ST depression was compared to the maximal coronary artery stenosis supplying the non-infarcted area. In patients with maximal coronary artery stenosis greater than or equal to 90%, D had as high an incidence of ST depression as T (71% vs 64%). While, D had a lower incidence of ST depression than T (19% vs 35%, p less than 0.05) in those with maximum coronary artery stenosis less than 90%. For the diagnosis of coronary artery stenosis of greater than or equal to 90%, D had as high sensitivity (non-MI group, 82% vs 93%; MI group, 71% vs 64%) and higher specificity (non-MI group, 84% vs 52%, p less than 0.01; MI group, 81% vs 65%, p less than 0.05) compared with T. This study demonstrated that dipyridamole ECG is a sensitive and specific test to detect severe coronary artery stenosis.

The response of left ventricular regional function to afterload stress in patients with old myocardial infarction and ventricular aneurysm.

The functional response of the left ventricle with scar to increased afterload, was examined in 15 patients with old myocardial infarction and left ventricular aneurysm (OMI). Interventional cine left ventriculography during elevating left ventricular pressure with methoxamine. Wall motion was assessed by the radial and the centerline method. Augmented afterload didn't change ejection fraction in patients with OMI, but normalized wall motion (Z) increased in the aneurysmal region and decreased in the remote region in both methods. In the remote region in patients with OMI, afterload stress shortened left ventricular pressure-radial length (P-L) loops along length axis, and reduced percent systolic radial shortening (SS). In the aneurysmal region, P-L loops showed systolic elongation of length at rest and the slope of end-diastolic point to end-systolic point became steeper with increased afterload, resulting in a decrease of aneurysmal expansion. In summary, with increasing afterload, wall motion decreased in non-infarcted regions and increased in aneurysmal regions, in left ventricles with aneurysm. This mechanism may be interpreted as afterload-induced shifts of P-L loops in each region.

Simultaneous assessment of left ventricular wall motion and myocardial perfusion at rest and during exercise by technetium-99m methoxy isobutyl isonitrile.

First-pass radionuclide ventriculography followed by myocardial SPECT with technetium-99m methoxy isobutyl isonitrile (Tc-99m MIBI) was performed on 12 patients with suspected coronary artery disease at rest and during exercise. Left ventricular wall motion and myocardial perfusion were assessed simultaneously and compared on a segment-by-segment basis. Segmental agreement between Tc-99m MIBI and Tl-201 with regard to the presence of perfusion defects was 95% (57/60) at rest and 93% (37/40) during exercise. With respect to the assessment of myocardial ischemia and/or infarction, abnormalities in regional wall motion agreed with the presence of myocardial perfusion defects in 18 out of 21 segments (86%). Simultaneous evaluation of regional wall motion and myocardial perfusion by Tc-99m MIBI may provide useful information for the assessment of myocardial ischemia.

Relation between the incidence of arrhythmias and ischemic ST-segment depression during dipyridamole electrocardiography test in patients with coronary artery disease.

To examine the incidence of arrhythmias in dipyridamole infusion and the relation between dipyridamole-induced arrhythmias and ST-segment depression, dipyridamole electrocardiography tests were performed on 100 patients with coronary artery disease. Dipyridamole was infused at a rate of 0.568 mg/kg for 4 min, and 87-lead body surface mapping was performed to determine ischemic ST-segment depression. Positive ischemic response was defined as greater than or equal to 0.10 mV horizontal or downsloping ST-segment depression below the baseline, lasting 80 msec after the J point. Arrhythmias were observed by continuous electrocardiographic monitoring using a CM-5 lead electrocardiography. With respect to ventricular premature contractions (VPC), a group of patients with previous myocardial infarction (MI group) had a significantly higher incidence than a group of patients without previous myocardial infarction (non-MI group) before (16.7% vs. 1.7%, p less than 0.01) and after (38.1% vs. 3.4%, p less than 0.005) the dipyridamole infusion. The incidence of supraventricular premature contractions (SVPC), however, was not significantly different between the MI and non-MI groups. A group of patients with positive ischemic response had a significantly higher incidence of SVPC after the dipyridamole infusion than a group of patients with negative ischemic response (p less than 0.005). However, there was no significant difference in the incidence of VPC between the negative and positive ischemic response groups. These results suggest that dipyridamole-induced VPC is not always associated with ischemic ST-segment depression, but dipyridamole-induced SVPC is associated with dipyridamole-induced ischemic ST-segment depression in patients with coronary artery disease.

Functional recovery of hibernating myocardium after coronary bypass surgery: does it coincide with improvement in perfusion?

To determine the relationship between functional recovery and improvement in perfusion after coronary artery bypass graft surgery (CABG), 49 patients were studied. Radionuclide angiography was performed before, 1 month after, and 6 to 12 months after CABG to evaluate regional wall motion. Exercise thallium-201 myocardial perfusion imaging was done before and 1 month after CABG to assess regional perfusion. Preoperative asynergy was observed in 108 segments, and 74 of them showed an improvement in wall motion 1 month after CABG (segment A). Sixty-six of these segments (89%) were associated with an improvement in perfusion. Eight segments that had not improved 1 month after CABG demonstrated a delayed recovery of wall motion 6 to 12 months after CABG (segment B). However, seven of eight segments (88%) already showed an improvement in perfusion 1 month after CABG. A total of 82 segments exhibited functional recovery after CABG and were considered hibernating segments. In the preoperative study segment B more frequently had areas of akinesis or dyskinesis than segment A (75% vs 34%, p less than 0.05). The mean percent thallium-201 uptake in segment B was lower than that in segment A (74% +/- 9% vs 83% +/- 8%, p less than 0.05). Functional recovery of hibernating myocardium usually coincided with an improvement in perfusion. However, delayed functional recovery after reperfusion was observed in some instances. Severe asynergy and severe thallium-201 defects were more frequently observed in these segments with delayed recovery. Hibernating myocardium might remain stunned during those recovery periods.

Signal-averaged body surface mapping for the assessment of low-amplitude potentials. Detailed maps during early ventricular activation in normal subjects.

Body surface isopotential maps around early ventricular activation were investigated in 30 normal subjects by the use of the authors' signal-averaged body surface mapping system. The number of beats averaged was 96-154 (mean, 127). Two distinct patterns were recognized in the appearance of a maximum at the onset of ventricular activation: the maximum in the first type (n = 16) was located on the right anterior chest; the maximum in the second type (n = 14) was on the central or left anterior chest. The site of the earliest ventricular activation was considered to be different in each of these types. During early ventricular activation, 25 subjects (83%) had two minima: one was on the left lateral chest and the other was on the left back. The two minima probably reflect two different receding activation fronts in the ventricles. The data in the present study are important to the understanding of the early ventricular activation process, as well as the diagnosis of heart diseases in which this process is disturbed.

Significant stenosis of coronary arteries in patients with single and multiple vessel diseases without previous myocardial infarction.

To determine what degree of stenosis should be counted as a significant lesion in each of 3 major coronary arteries in classification of the number of vessels involved, coronary arteriographic percent diameter narrowing (by quantitative angiography) was compared with thallium-201 scinitgraphic redistribution on treadmill exercise in 47 patients with evidence of exercise myocardial ischemia and greater than or equal to 50% diameter narrowing (visual assessment) in at least 1 major coronary artery. Severity of exercise-induced myocardial ischemia for the entire left ventricle (assessed by averaged redistribution index) was separated most sufficiently with definition of 63-64% or greater between patient groups with no- and single-, single- and double-, and double- and triple-vessel diseases. Collaterals and intraventricular contractile interaction are possibly the factors making definition more severe in extensive coronary artery disease. Since the visual method gives an overestimation of stenosis, it was concluded that vessel diameter narrowing of 70% or more should be regarded as significant in patients with single and multiple vessel diseases if the visual method is used.

The relationship between chest pain during thallium-201 scintigraphy with dipyridamole and myocardial ischemia.

Dipyridamole thallium-201 scintigraphy (DP-Tl) and coronary angiography were studied on 74 patients with suspected coronary artery disease. We compared the clinical features, hemodynamic responses, angiographic results and scintigraphic findings of patients who had chest pain during DP-Tl testing ('chest pain' group) with those of patients who did not have chest pain ('no pain' group). Thirty eight (51%) of the 74 patients developed chest pain. Heart rate and rate pressure product during DP infusion of 'chest pain' group were greater than those of the 'no pain' group (p less than 0.05). Ischemic ST depression was more frequently observed among 'chest pain' patients (p less than 0.01). There were no differences in angiographic severity of coronary artery disease between 'chest pain' and 'no pain' group. Also, we could find no differences in extent and severity scores of perfusion defects and washout abnormalities between the two groups. However, when patients with myocardial infarction were excluded, the 'chest pain' group had significantly greater extent and severity scores of washout abnormalities than the 'no pain' group (extent score: 38 +/- 8 vs 18 +/- 5, p less than 0.05, severity score: 55 +/- 15 vs 18 +/- 7, p less than 0.01). Our study indicated that in patients without myocardial infarction, patients with 'chest pain' had more severe ischemia than 'no pain' patients. But in patients with myocardial infarction, myocardial ischemia not accompanied by chest pain might be as severe as that with chest pain. The presence or absence of myocardial infarction might have great influence on results regarding the relation of chest pain to myocardial ischemia.

[Simultaneous assessment of wall motion and myocardial perfusion by technetium-99m methoxy isobutyl isonitrile].

The aim of this study was to assess whether or not myocardial uptake of Technetium-99m methoxy isobutyl isonitrile (Tc-MIBI) indicated myocardial viability. We performed simultaneous Tc-MIBI angiography and myocardial SPECT at rest on 12 patients with suspected coronary artery disease. Left ventricle was divided into 3 segments, and regional wall motion was graded as normal, hypokinesis and akinesis/dyskinesis. Myocardial uptake of Tc-MIBI was assessed as normal, reduced and absent in each segment. In segments with normal and reduced Tc-MIBI uptake, 7% (2 of 28) and 33% (2 of 6) showed wall motion abnormalities of akinesis/dyskinesis, respectively. However, all segments with absent Tc-MIBI uptake had asynergy of akinesis/dyskinesis (2 of 2, 100%). Myocardial Tc-MIBI uptake at rest indicated wall motion abnormalities and was considered to be useful for the evaluation of myocardial viability. First-pass radionuclide angiography followed by myocardial SPECT with Tc-MIBI demonstrated to be useful for the simultaneous assessment of the left ventricular wall motion and myocardial perfusion.