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Satoshi Suzuki, Neal F. Kassell and Kevin S. Lee

✓ Hemin is a prominent breakdown product of hemoglobin, and high levels of hemin are found in the cerebrospinal fluid during subarachnoid hemorrhage—induced vasospasm. The possible role of hemin in modifying vascular function was examined in the present study by testing its effects on nitric oxide synthase (NOS) activity in cultured rat aortic smooth-muscle cells. Nitric oxide synthase activity was estimated from the amounts of accumulated nitrite and nitrate, which are oxidative products of nitric oxide (NO). Hemin (1–100 µM) increased the levels of nitrite and nitrate in culture medium in a dose- and time-dependent manner. The hemin-induced elevation of nitrite and nitrate was inhibited significantly by the NOS inhibitor, Nω-nitro-l-arginine (300 µM), and by the protein synthesis inhibitor, cycloheximide (5 µg/ml). These results indicate that hemin is capable of stimulating the expression of an inducible isoform of NOS (iNOS) in vascular smooth muscle. Transcriptional expression of iNOS is known to cause injurious effects on the maintenance of cellular homeostasis by generating extremely high levels of NO. The generation of hemin from methemoglobin during hemolysis of a subarachnoid blood clot could therefore stimulate an excessive production of NO in vascular smooth-muscle cells. It is postulated that this series of events contributes to the development of vascular injury associated with cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

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Satoshi Suzuki, Katsunobu Takenaka, Neal F. Kassell and Kevin S. Lee

✓ The roles of hemoglobin (Hb) in the pathogenesis of cerebral vasospasm remain a matter of discussion. Hemoglobin is known to be released from extravasated red blood cells in a variety of pathological conditions, including subarachnoid hemorrhage. These conditions are often accompanied by infiltration of inflammatory cells and an associated release of multiple cytokines. Certain of these cytokines, including interleukin-1β (IL-1β), are capable of increasing nitric oxide (NO) production via the inducible form of nitric oxide synthase (NOS), and excessive NO production under these conditions may contribute to cellular dysfunction. This study further examines these questions by investigating the effects of Hb on the induction of NOS by IL-1β.

The effects of Hb on IL-1β-induced NO production were examined in cultured smooth-muscle cells of rat aorta (RA-SMC's). Production of NO was estimated from the accumulation of nitrite, an oxidative product of NO, in the culture medium. The synthesis of NO was induced by IL-1β in a concentration-dependent manner. This activation of NO production was inhibited by: 1) a general inhibitor of NOS (Nω-nitro-L-arginine); 2) a protein synthesis inhibitor (cycloheximide); and 3) two selective inhibitors of the inducible form of NOS (hydrocortisone and aminoguanidine). These results suggest that IL-1β promotes the expression of the inducible form of NOS in RA-SMC's. The effects of Hb on NO production were tested by adding purified human Hb to the culture medium of the cells in both the presence and absence of IL-1β. Nitrite accumulation was slightly but significantly increased by Hb in the absence of IL-1β. In contrast, Hb markedly augmented nitrite accumulation induced by IL-1β. This augmentation persisted even after the removal of Hb from the culture medium. The number of cells was not affected by Hb or IL-1β.

The findings demonstrate that Hb can modify cytokine-induced production of NO in RA-SMC's by increasing the inducible form of NOS. These observations suggest that Hb can also modify the action of inflammatory cells by facilitating NO production in target cells.

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Bernhard Sutter, Satoshi Suzuki, Neal F. Kassell and Kevin S. Lee

✓ Increasing evidence suggests that disturbances in the modulatory influence of the vasoactive peptide, calcitonin gene—related peptide (CGRP), contribute to the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). However, only limited success has been achieved in trials attempting to ameliorate vasospasm by modifying CGRP function. To better understand the potential utility of targeting CGRP-mediated relaxation, it is important both to identify the interactions CGRP may have with other elements of the vasospastic response and to characterize the mechanisms through which CGRP elicits vasodilative effects. The present studies examined the effects of CGRP on vascular responsiveness using tension measurements of ring strips of rabbit basilar artery maintained in vitro. Pretreatment of vessels with CGRP (100 nM) inhibited vasoconstrictor responses to the potent protein kinase C (PKC) activator, phorbol 12,13-dibutyrate (PDB). This particular contractile response was selected because PKC-mediated vasoconstriction is a critical component of the vasospastic response after SAH. In a posttreatment paradigm, CGRP was also found to reverse established constriction responses to PDB (2 nM) and histamine (3 µM) in a dose-dependent manner.

When tested against the maximum effective dose of PDB (30 nM) in the posttreatment paradigm, CGRP (100 nM) did not elicit significant relaxation. However, after washing both of these drugs out of the test chamber, a persistent effect of CGRP was revealed: the decay of PDB-induced contraction was accelerated in vessels that had previously been treated with CGRP. These findings indicate that CGRP elicits both immediate and sustained influences on contractile responses mediated by PKC.

Finally, two potential mechanisms for the vascular response to CGRP were examined. Adenosine triphosphate (ATP)—sensitive K+ channels do not appear to participate in CGRP-mediated dilation; inhibitors of these channels, glibenclamide and tolbutamide, did not block CGRP-induced relaxation. In contrast, a possible role for the nucleotide cyclic adenosine monophosphate (cAMP) in the vascular response to CGRP was indicated by the dose-dependent elevation of cAMP levels by CGRP.

Together these studies indicate that CGRP can modulate the contractile response to PKC activation. These effects are associated with increases in the levels of cAMP, but occur independently of fluxes through ATP-sensitive K+ channels.

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Experimental cerebral vasospasm

Part 1: Factors contributing to early spasm

Hajime Nagai, Yoshiaki Suzuki, Mitsuo Sugiura, Satoshi Noda and Hideo Mabe

✓The authors describe a model for making an experimental subarachnoid hemorrhage that closely simulates human aneurysmal rupture. A needle previously inserted into the posterior communicating artery is subsequently withdrawn by traction on a thread. Using this model they demonstrate biphasic spasm by measurement of cerebral blood flow and angiography after rupture of the artery; the early spasm lasted 60 minutes and the late spasm began 3 or 4 hours after subarachnoid hemorrhage and continued for several days. The authors discuss the pathogenesis of early and late spasm.

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Satoru Shimizu, Satoshi Utsuki, Sachio Suzuki, Hidehiro Oka and Kiyotaka Fujii

✓Although the Codman-Hakim programmable valve is popular, several problems arising from its design have been described. The authors report an additional cause of shunt obstruction in the system. A 6-year-old girl who had received a ventriculoperitoneal shunt with the Codman-Hakim programmable valve system presented with worsening consciousness. The valve proved hard to flush, and emergency revision of the valve was performed. Examination of the extracted valve revealed that the pressure control cam had migrated into the outlet of the valve, thus causing the obstruction. A crack in the plastic housing surrounding the cam suggesting a past impact to the system was also revealed. These factors should thus be kept in mind as potential sources of obstruction of the valve system, especially in patients susceptible to episodes of head impact.

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Satoshi Utsuki, Hidehiro Oka, Sumito Sato, Sachio Suzuki, Satoru Shimizu, Satoshi Tanaka and Kiyotaka Fujii

✓The response of nonfluorescing infiltrating tumors that had been exposed to 5–aminolevulinic acid and irradiated using a laser at a wavelength of 405 nm was analyzed intraoperatively using spectroscopy. Histological analyses demonstrated that neoplastic cells were present in the tissue region that displayed a peak at 636 nm, whereas no neoplastic cells were present in the region that exhibited only the excitation light peak. The authors conclude that the intraoperative use of laser spectroscopy can allow the diagnosis of infiltrating tumor and the detection of boundaries of the infiltrate when standard fluorescence techniques fail.

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Koji Yoshimoto, Shunji Nishio, Satoshi Suzuki, Masashi Fukui and Kanehiro Hasuo

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Kiyonobu Ikezaki, Toshio Matsushima, Yasuo Kuwabara, Satoshi O. Suzuki, Tomojiro Nomura and Masashi Fukui

✓ Thirteen children with moyamoya disease who had no apparent cerebral infarction or hemorrhage were examined pre- and postoperatively by means of positron emission tomography (PET) to investigate the underlying cerebral circulation and metabolism and the effect of bypass surgery. The preoperative regional cerebral blood flow (rCBF) and mean transit time were significantly decreased and increased, respectively, in the cerebral cortex of these patients compared to control values. The regional cerebral blood volume (rCBV) and the regional oxygen extraction fraction (rOEF) had significantly increased to compensate for the reduced rCBF and perfusion pressure and also to maintain the regional cerebral metabolic rate of oxygen (rCMRO2). In the basal ganglia, rCBV elevation was more prominent than that in the cerebral cortex, although changes in rCBF, rOEF, and rCMRO2 were relatively minor.

Postoperative improvements were observed predominantly near the cortex where bypass surgery had been performed and in the basal ganglia. Direct and combined indirect bypass procedures improved cerebral circulation more effectively than single indirect bypass surgery. Although the angiographic findings were not always compatible with the clinical results, the postoperative improvements on PET scans correlated with the disappearance of transient ischemic attacks. In addition to the clinical courses and angiographic findings, PET analysis was indispensable in evaluating the cerebral circulation and metabolism in childhood moyamoya disease.

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Toshiki Aoki, Katsunobu Takenaka, Satoshi Suzuki, Neal F. Kassell, Oren Sagher and Kevin S. Lee

✓ The importance of factors within hemolysate in modulating oxyhemoglobin (oxyHb)-induced contraction was examined in an in vitro model of rabbit basilar arteries. When the basilar arteries were exposed to purified oxyHb alone, the contractile response observed was significantly weaker than that seen in arteries exposed to hemolysate containing an equal concentration of oxyHb. In order to delineate the nature of the factors within hemolysate that facilitate contraction, hemolysate was fractionated, and various components were tested individually for their ability to elicit this effect. A low-molecular-weight fraction of hemolysate, ranging from 0.5 to 2.0 kD, elicited only a mild contraction. However, when this fraction was combined with purified oxyHb, the contractile response was comparable in magnitude to that of unfractionated hemolysate. These studies confirm that purified oxyHb is capable of inducing contraction in vitro. The data also demonstrate that oxyHb elicits a significantly weaker contraction than does hemolysate. In addition, the results suggest that low-molecular-weight components in hemolysate (in the 0.5- to 2.0-kD range), while incapable of inducing a potent contraction alone, may act in concert with oxyHb to elicit the vasoconstriction seen following subarachnoid hemorrhage.