Endothelins: vasoconstrictor effects and localization in canine cerebral arteries.

1. The vascular effects of endothelin and localization of endothelin-like immunoreactivity were characterized in isolated cerebral arteries of dogs. 2. Endothelin-like immunoreactivity was detected in a few populations of endothelial cells of dog basilar artery. 3. Endothelin-1, endothelin-2 and endothelin-3 contracted isolated ring preparations of cerebral arteries in a dose-dependent manner independently of the presence of endothelium. The ED50 values (and 95% confidence intervals) for the contraction were 411 pM (242-697 pM) and 478 pM (295-776 pM) for endothelin-1 and endothelin-2, respectively. Endothelin-3 induced vascular contraction at a higher concentration (ED50 = 26.5 nM, 95% confidence interval = 15.7-45.7 nM). 4. The increases in tone induced by endothelin-1 and endothelin-2 did not return to the resting level after repeated washings, while a rinse with Krebs solution reversed the vasoconstrictor response to endothelin-3. The endothelins did not cause any vasodilator response in arteries precontracted with uridine 5'-triphosphate even in the presence of intact endothelial cells. 5. NiCl2 (1 mM) attenuated the contractions induced by endothelin-3 (10-300 nM) and those to relatively low doses (1 nM) but not higher doses (10-100 nM) of endothelin-1 and endothelin-2. The contractions in response to endothelin-1, endothelin-2 and endothelin-3 were greatly attenuated in Ca(2+)-free solutions although high concentrations of endothelin-1 and endothelin-2 still evoked contractions. 6. These results suggest that the vasoconstriction induced by endothelin-3 and lower doses of endothelin-1 and endothelin-2, largely depends on the influx of Ca2+ ions. The apparent insensitivity to Ni2+ shows that additional distinct mechanisms also operate in the vasconstrictor responses to high concentrations of endothelin-1 and endothelin-2. 7. The presence of endothelin-like immunoreactivity in endothelial cells suggests that endothelin is a potential endogenous spasmogen.

Significance of nerve growth factor content levels after transient forebrain ischemia in gerbils.

Involvement of nerve growth factor (NGF) in the pathogenesis of delayed neuronal death (DND) of CA1 neurons in the hippocampus has been suggested. We measured regional changes in the content of tissue NGF of the hippocampus in the Mongolian gerbil after 5 min forebrain ischemia. The NGF content was found to decrease significantly in the CA3 and dentate regions by 32% two days after ischemia. By contrast in the CA1 region, the level of NGF became significantly elevated by 50% two weeks after ischemia or later. The early reduction of NGF content in the afferent area projecting to the CA1 sector might be primarily linked to the pathogenesis of DND, whereas the delayed increase within the CA1 sector might be a secondary local response mainly of reactive astroglia.

Reduction of delayed neuronal death by inhibition of protein synthesis.

Brief forebrain ischemia in rodents causes delayed neuronal death selectively in the CA1 pyramidal cells of hippocampus. Treatment with a reversible protein synthesis inhibitor, anisomycin, significantly reduced the occurrence of delayed neuronal death in the Mongolian gerbil. This result indicates that de novo synthesis of certain protein(s), collectively termed 'killer protein' is required, possibly due to deprivation of nerve growth factor or other trophic factors.

The effect of bosentan, a new potent endothelin receptor antagonist, on the pathogenesis of cerebral vasospasm.

Using the canine chronic cerebral vasospasm model, we studied the effects of a potent new nonpeptidic endothelin-1 (ET1) receptor antagonist, bosentan (Ro 47-0203, 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyr imidin-4 - yl]-benzenesulfonamide). Endothelin (ET) receptors are composed of the ETA receptors and the ETB receptors; ET1 acts on both of these receptors. Although it has been previously thought that the ETA receptor mediates vasoconstriction, whereas the ETB receptor mediates vasodilation, recent evidence suggests that ETB receptor also contributes to vasoconstriction. Because bosentan is a mixed antagonist that acts on both receptors, its use might indicate whether or not ET is involved in the pathogenesis of cerebral vasospasm. In this study, beagle dogs received a double injection of autologous arterial blood into the cisterna magna at 2-day intervals (i.e., on Days 0 and 2). The diameter of the basilar artery (BA) was angiographically examined up to Day 7. A total of 24 dogs were randomly allocated to either the treatment group or the no-treatment group. Eight dogs were treated with 10 mg/kg bosentan by a one-dose injection into a central venous catheter. Bosentan was given twice a day starting immediately after the first subarachnoid hemorrhage for 6 days until Day 5. Sixteen dogs served as controls, with untreated subarachnoid hemorrhage. After the injection of bosetan, blood pressure decreased by about 25 mm Hg for a few minutes and then returned to normal. In the dogs treated with bosentan, the BA spasm on Day 7 was significantly ameliorated compared with the BA spasm in the untreated dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Norepinephrine in cerebrospinal fluid of patients with cerebral vasospasm.

The content of norepinephrine (NE) in the ventricular, basal cisternal, and lumbar cerebrospinal fluid (CSF) was determined in 19 patients with ruptured cerebral aneurysms at different intervals according to the presence or absence of vasospasm. Twelve were operated on within 3 days after subarachnoid hemorrhage (SAH), prior to the occurrence of vasospasm. Postoperatively, CSF was continuously drained from a basal cistern or lateral ventricle. Norepinephrine was assayed by the highly sensitive automated fluorometric method. The concentration of NE increased in all sites of CSF sampling along with the appearance of vasospasm. Above all, the cisternal CSF of patients with vasospasm contained significantly higher NE (0.246 +/- 0.049 ng/ml, mean +/- SEM) compared to those without vasospasm (0.075 +/- 0.001 ng/ml) (p less than 0.001). However, since this increase cannot be considered to be high enough locally to constrict cerebral arteries, this might be only a secondary phenomenon due to release of NE into CSF from various sources in the brain.

Clinical signs and evoked response alterations associated with chronic experimental cord compression.

Cortical and spinal evoked potentials were used to monitor the effect of experimental chronic cord compression in cats. An implantable compression screw made it possible to maintain the animals unrestrained. The mean compression period was 10 weeks (maximum 16.5 weeks). Compression was increased by stepwise tightening of the screw at intervals of 4 to 7 days under ketamine anesthesia. Evoked potentials were monitored before and after each compression step with repeated recordings, and were analyzed in terms of alterations in amplitude, latency, and waveform. Amplitude response curves were plotted where the amount of compression at each recording was expressed as a percentage of total compression. Changes in spinal evoked potentials occurred rather early (mean 36% of total compression), while obvious cortical evoked potential changes appeared rather late (mean 91% of total compression). Neurological alterations appeared later than alterations in spinal evoked response but prior to alterations in cortical evoked response. Thus, alterations in cortical somatosensory evoked potentials in the presence of chronic spinal compression indicate a severe degree of compression and do not seem to be of diagnostic value in the early detection of chronic spinal cord compression. It is suggested that the monitoring of spinal rather than cortical evoked responses would be more useful in locating and detecting chronic compression spinal cord damage.

Experimental investigation on the spinal cord evoked injury potential.

Averaged somatosensory evoked potentials from the epidural space in response to sciatic nerve stimulation were recorded in bipolar and common reference mode in cats following various types of injury. An investigation was conducted on the development and properties of the spinal evoked response recorded from the center of the injury site, designated here as the "spinal cord evoked injury potential." Typically it is a two-peak monophasic positive potential, approximately 40 msec in duration, with a slight negative afterwave. With increasing distance from the site of injury, its amplitude rapidly decreases, whereas latency remains constant. The common reference recording technique resulted in an earlier and better demonstration of the evoked injury potential, especially when it was transitory or incomplete. When impairment of conduction developed gradually, the evoked injury potential developed gradually too. In serial recordings along the spinal cord axis, the transition from a normal triphasic to a monophasic evoked injury potential allowed a precise localization of the lesion. These data suggest that the diagnostic value of intraoperative spinal cord monitoring may be increased by adopting a technique that incorporates several epidural recordings with a common reference recording technique. The spinal cord evoked injury potential seems to be a more sensitive indicator of spinal cord injury than the cortical evoked potential. The findings are discussed in the light of the presently developing spinal cord monitoring techniques.

Recirculation model following MCA occlusion in rats. Cerebral blood flow, cerebrovascular permeability, and brain edema.

A new model for establishing a successful and consistent arterial recirculation has been devised following middle cerebral artery (MCA) occlusion in the rat. A snare ligature was introduced at the stem of the MCA just distal to the lenticulostriate branches, and occlusion and recirculation were performed by pulling and releasing the thread. This method had an advantage over the use of a small clip which caused damage to the artery without good recirculation. Study of local cerebral blood flow using carbon-14 (14C)-iodoantipyrine, of cerebrovascular permeability using 14C-aminoisobutyric acid, and of brain-water content using the microgravimetric technique was performed upon recirculation following various periods of occlusion and compared with the results in permanent ischemia. A reactive hyperemia was noted within the previously ischemic area immediately upon recirculation following either a 30-minute or a 2-hour ischemic period. One or 2 hours later, delayed hypoperfusion developed in this region, but the circulation over the periphery of the ischemic area recovered well. Cerebrovascular permeability was not, however, altered during the time courses studied. Topographic changes in tissue specific gravity were compared between permanent and transient ischemia in the corresponding time-courses. Although there was a greater decrease in tissue specific gravity following recirculation when the ischemic period was maintained longer, edema formation was resolved by recirculation. Further study is required to determine thresholds of ischemic brain damage and edema formation at recirculation following focal cerebral ischemia.

The determination of brain water content: microgravimetry versus drying-weighing method.

The microgravimetric technique and the drying-weighing method for the determination of brain water content are analyzed and compared. A new method has been devised for the automatic production of the gradient column. For gravimetry, tissue samples weighing more than 30 mg have proven adequate for measurement. Specific gravity (SG) should be determined as early as 1 minute after tissue is inserted into the gradient column. Calculations of cerebral blood volume (CBV) from changes in SG of both brain tissue and intravascular perfusate have shown that the SG of brain tissue is considerably influenced by changes in CBV. This is because the SG of blood is higher than that of brain tissue, and may lead to a decrease of SG of about 0.002 in anemic cortex and of 0.001 in anemic white matter, which will simulate a false increase in tissue volume as water of 4% and 2%, respectively. This methodological error may be relevant when the early stages of ischemic brain edema development are studied. Water content of brain tissue can also be determined with acceptable accuracy by vacuum freeze-drying samples of brain tissue weighing about 100 mg. In contrast to cortex, white matter shows a wide range of individual and regional differences in water content. Thus, conclusions on the presence of brain edema drawn from tissue water determinations should always be subjected to cautious analysis and criticism.

Vasospasm assessed by angiography and computerized tomography.

In 44 consecutive cases of ruptured cerebral aneurysm, vasospasm was demonstrated pre- or postoperatively. These cases were examined by bilateral carotid angiography and computerized tomography (CT), and the relationship between the angiographically visualized distribution of vasospasm, the neurological symptoms, and infarction seen on CT was evaluated. Vasospasm occurred in only some intracranial portions of the cerbral arteries that were immersed in blood-stained cerebrospinal fluid. Angiographically, diffuse vasospasm extensively involving bilateral carotid systems indicated the gravest prognosis for patients. Vasospasm affecting one carotid system and the anterior cerebral arteries on the opposite side often produced permanent neurological deficits. On the contrary, when vasospasm was restricted to one carotid system or to bilateral anterior cerebral arteries, it was usually associated with temporary neurological symptoms; however, it always produced residual neurological symptoms if it extended to the ascending branches (M3) of the middle cerebral arteries. Computerized tomography definitely demonstrated a low-density area or infarction in the territory of the spastic arteries in 25 (71%) of 35 cases with vasospasm. A low-density area was always detected when vasospasm occurred in M3 segments.

Prevention of cerebral vasospasm by actinomycin D.

The role of endothelin, a newly found vasoconstrictor peptide, is examined in the pathogenesis of cerebral vasospasm after experimental subarachnoid hemorrhage (SAH) in the dog. Endothelin immunoreactivity was overexpressed in the endothelium of the vasospastic basilar artery. Because endothelin synthesis is regulated at the messenger ribonucleic acid transcription level, the effect of actinomycin D, a ribonucleic acid synthesis inhibitor, was studied as a means of preventing vasospasm. It was found that treatment with intravenous actinomycin D for 5 days beginning on the day of SAH completely inhibited the development of vasospasm. This novel experimental therapy may lead not only to the elucidation of the pathogenesis of cerebral vasospasm but also to the availability of a prophylactic adjuvant therapy for patients with SAH.

Biodegradation of dibenzothiophene and 4,6-dimethyldibenzothiophene by Sphingomonas paucimobilis strain TZS-7.

Strain TZS-7, tentatively identified as Sphingomonas paucimobilis, was isolated from crude oil for its ability to degrade dibenzothiophene (DBT) and 4,6-dimethyldibenzothiophene (4,6-dmDBT). This strain did not utilize DBT or 4,6-dmDBT as the sole source of sulfur. However, the degradative activity was induced by various aromatic compounds, including DBT, fluorene, anthracene, naphthalene and toluene. Three products formed from 4,6-dmDBT degradation were detected and two of these were proposed to be 7-methyl-3-hydroxy-2-formylbenzothiophene and 7-methylbenzothiophene-2,3-dione by gas chromatography-mass spectrometry analysis. These findings proved that 4,6-dmDBT is degraded through a ring-destructive pathway by resting cells of strain TZS-7.

Orbitozygomatic approach by transposition of temporalis muscle and one-piece osteotomy.

BACKGROUND: A more simplified and easier technique for the orbitozygomatic approach is sought. We have developed a new modification to fully expose the temporal base before using one-piece craniotomy. METHODS: By transposing the temporalis muscle underneath the zygomatic arch before osteotomy, the temporal base and the inferior orbital fissure can be fully exposed. Craniotomy is made in one piece with the frontotemporal and orbitozygomatic bone together by using a high-speed drill. RESULTS AND CONCLUSIONS: Osteotomy was easy and the cosmetic result was satisfactory. This technique also allows better access to the subtemporal region without removing the zygomatic arch.

Jugular bulb diverticulum associated with lower cranial nerve palsy and multiple aneurysms.

BACKGROUND: Jugular bulb diverticulum is a rare condition that has never been reported in association with lower cranial nerve palsy. CASE DESCRIPTION: A 54-year-old woman developed acute swallowing disturbance and hoarseness. Neuroradiological examinations demonstrated a jugular bulb diverticulum as well as unruptured internal carotid and basilar tip aneurysms on the same side. Laboratory data for both serum and cerebrospinal fluid were normal. Steroids were given, and the cranial nerve palsy disappeared within 1 month. The aneurysms were successfully clipped. During the follow-up period of more than 1 year, the patient has done well and has no neurological deficit. CONCLUSION: This is the first reported case of jugular bulb diverticulum associated with a lower cranial nerve palsy and multiple aneurysms. We recommend close observation of patients with this condition regardless of its clinical presentation.

Pure cortical ischemia versus striatal ischemia. Circulatory, metabolic, and neuropathologic consequences.

Selective ischemic damage was produced either involving only the cortex or together with the striatum by occlusion of the middle cerebral artery proximal or distal to the lenticulostriate artery in the rat. The consequences in local cerebral blood flow, local cerebral glucose utilization, and neuropathology were investigated in the acute stage of ischemia. Caudate damage produced by proximal occlusion resulted in such secondary alterations as enhanced blood flow and metabolism in areas remote from the main lesion, such as in the globus pallidus and substantia nigra ipsilateral to occlusion. After distal occlusion, however, there were two patterns distinctly different from each other in the appearance of the autoradiograms. One was ipsilateral and the other was contralateral enhancement of blood flow and metabolism involving the striato-pallido-nigral axis without any striatal damage. We therefore suggest that these secondary alterations in circulation and metabolism contribute to a varied neurological dysfunction after focal cerebral ischemia. Furthermore, our currently introduced model of selective ischemic lesioning is important in studying the roles of cortical and striatal influences in ischemic pathophysiology.

Primary empty sella syndrome caused by an abnormal dilatation of the optic recess.

A new variety of primary empty sella syndrome is reported. A partial herniation of the optic chiasm into an enlarged empty sella compressed by a dilated optic recess mimicking a cystic tumor was confirmed at operation. The pathogenesis and the treatment of this type of empty sella syndrome are discussed.

Transcranial approach for transsphenoidal encephalocele: report of two cases.

BACKGROUND: Whereas the transcranial approach has been regarded as the therapy of choice for transethmoidal encephalocele, its feasibility for transsphenoidal encephalocele has remained controversial, particularly in neonates and infants. CASE REPORT: Two cases of transsphenoidal encephalocele operated transcranially are presented. In the first case, this 6-year-old boy underwent a transpalatal operation with repair of a cleft palate in another hospital before admission. Reoperation via the transcranial route was carried out because of postoperative recurrent meningitis. With partial resection of the anterior wall, the encephalocele could be separated from the underlying tissue, and the interspace was filled with the pericranial flap. He made an uneventful recovery and has been well for the past 3 years. The second was a 3-month-old baby with a large encephalocele filling the nasopharyngeal space. As the cleft palate was absent, the transcranial approach was employed. In this case, the herniated tissue was excised at the lowest level possible. Postoperatively, panhypopituitarism became manifest. Re-evaluation of the preoperative magnetic resonance imaging (MRI) disclosed a small mass far below the dorsum sellae, which turned out to be an anomalous pituitary gland on histologic examination. CONCLUSIONS: The transcranial approach is considered a valid alternative for the therapy of transsphenoidal encephalocele, particularly when the transpalatal approach is unfeasible. While the anterior wall of the herniated sac may be safely resected, the posterior wall should under no circumstances be sacrificed. The preoperative MRI is essential, as it may provide valuable information as to the location of vital structures within the herniated tissue.

Lipocortin-1 fails to ameliorate ischemic brain edema in the cat.

It has been reported that corticosteroids exert their anti-inflammatory action through de novo synthesis of phospholipase-inhibitory proteins called lipocortins (annexins). We postulated that the following may lessen the effectiveness of corticosteroids on acute ischemic brain edema: 1) lipocortins are induced several hours after administration of steroids; 2) de novo synthesis of lipocortins is suppressed in the ischemic brain; and 3) lipocortins induced systemically do not pass through the blood-brain barrier (BBB) to reach the sites of ischemic edema. To test this hypothesis, we examined whether dexamethasone, given long before ischemia or direct administration of recombinant lipocortin-1, combined with or without BBB opening, ameliorate ischemic brain edema. Three hours before occlusion of the middle cerebral artery (MCA) in the cat, 4 mg/kg of dexamethasone was injected intravenously. The animals were subjected to 4 hours of ischemia. Alternatively, 2 ug/ml (total volume 10 ml) of recombinant human lipocortin-1 (annexin-I) was perfused intermittently into the ischemic focus by catheterization into the MCA. Artificial opening of the BBB was performed by intra-arterial mannitol infusion. None of these strategies demonstrated amelioration of ischemic edema. We conclude that: Dexamethasone and recombinant lipocortin-1 seem unlikely to have robust effects on amelioration of acute ischemic edema.

Lipocortin-1 fails to ameliorate cold-injury brain edema in the rat.

Based on evidence that corticosteroids exert their anti-inflammatory action via de novo synthesis of phospholipase A2 inhibitory proteins called lipocortins, we examined effects of high dose dexamethasone and recombinant human lipocortin-1 (annexin-I) on cold-injury brain edema in the rat. Since it takes several hours for lipocortins to be induced, dexamethasone (10 mg/kg) was injected intraperitoneally 3 hours before cold injury. Recombinant lipocortin-1 was administered intraventricularly at three different doses (0.01 mg/kg, 0.05 mg/kg, or 0.1 mg/kg: total volume 20 microliters), or via the internal carotid artery at a dose of 10(-7) M (2 ml). To induce cold injury, a liquid-nitrogen-cooled probe was placed on the exposed dura of male Wistar rats (330-370 kg) for 1 minute. Specific gravimetry and/or a wet-dry weighing method were used for measurement of brain edema at 24 or 48 hours after lesion production. In the present study, dexamethasone and recombinant lipocortin-1 failed to attenuate edema formation. The anti-inflammatory effects of dexamethasone or exogenous lipocortin-1 seemed unlikely to affect cold-injury brain edema.

Surgery or gamma -knife for the treatment of arteriovenous malformations?

Decision making for either surgery or gamma-knife for the treatment of arteriovenous malformations (AVMs) cannot be uniform. The skill of the neurosurgeon in operating on AVMs is now being compared with that of the gamma-knife. The decision varies from case to case and is to be taken by the neurosurgeon. This report presents three cases in which such decision making was not easy. Case 1 was a non-ruptured cingulate AVM of 2.5 cm diameter in the cingulate cortex. The operative field was anticipated to be very narrow between the parietal bridging veins. Case 2 was a tiny ruptured AVM in the speech-motor area which was buried underneath the cortex. Case 3 was a large ruptured thalamo-stiriate-capsular AVM with feeders from the anterior and posterior choroidal arteries. All cases were operated without serious morbidity. A combination of pre-operative intravascular surgery (cases 1 and 3) or postoperative gamma-knife (case 3) was adopted. In conclusion, there is no unitary rule to decide on surgery or gamma-knife for the treatment of AVMs. It depends on what good or harm the responsible surgeon or the gamma-knife does.