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Eiichi Tani

Object

Although the agents responsible for production of vasospasm have not yet been clearly identified, the author reviews the molecular mechanisms involved in development of vasospasm mainly based on the experimental data in a canine two-hemorrhage model.

Methods

The blood products after subarachnoid hemorrhage most likely stimulate many cell membrane receptors, such as G protein–coupled receptors and receptor tyrosine kinases, to activate the tyrosine kinase pathway of the vascular smooth muscle cells. The activation of the tyrosine kinase pathway is associated with continuous elevation of intracellular Ca++ levels and activation of μ-calpain; the former may result mainly not from Ca++ release but from Ca++ influx from outside the cells. The increased intracellular Ca++ concentrations stimulate Ca++/calmodulin (CaM)–dependent myosin light chain kinase to phosphorylate myosin light chain continuously during vasospasm. A topical application of genistein, ethylene-glycol-bis(β-aminoethylether) N,N'-tetraacetic acid, or various L-type Ca++ channel blockers likely induces reversal of vasospasm as a result of a decrease in intracellular Ca++ levels. The blood products also activate the rho/rho-associated kinase pathway during vasospasm most likely via G protein–coupled receptors, and the activated rho-associated kinase inhibits myosin phosphatase through phosphorylation at its myosin-binding subunit to induce Ca++-independent development of vasospasm. The enhanced generation of arachidonic acid during vasospasm may also contribute to inhibition of myosin phosphatase, at least in part, through the rho/rho-associated kinase pathway. The activity of myosin phosphatase in vasospam can also be inhibited by activated protein kinase C independently of the rho/rho-associated kinase pathway, but the inhibition may play a minor and transient role in contractile regulation. The protein levels of thin filament–associated proteins, calponin and caldesmon, are progressively decreased in vasospasm, whereas their phosphorylation levels are increased. Both changes probably contribute to the enhancement of smooth muscle contractility. Contractile and cytoskeletal proteins appear to be degraded in vasospasm by proteolysis with activated μ-calpain, suggesting that the intracellular devices responsible for smooth-muscle contraction are severely degraded in vasospasm.

Conclusions

It remains to be determined the extent to which Ca++-dependent and -independent contractile regulations, proteolysis and phosphorylation of thin filament–associated proteins, and degradation of contractile and cytoskeletal proteins are involved in the development of vasospasm.

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Eiichi Tani and Shogo Yamagata

✓ A prolonged vasospasm was produced in the canine basilar artery by injection of fresh autogenous arterial blood into the chiasmatic cistern. Homogenates of lyophilized normal and spastic canine basilar arteries, as well as of lyophilized blood clot around the spastic artery, were made, and their contractile activities were studied in vitro. The homogenates of the lyophilized spastic arteries usually induced a dose-dependent sustained contraction, whereas those of the lyophilized normal arteries often produced a dose-dependent transient contraction, and those of the lyophilized blood clot induced a dose-dependent transient or sustained contraction. The initial maximum contractions produced by the homogenates of the lyophilized normal and spastic arteries were significantly different in their values, suggesting the presence of a vasoactive agent in the spastic artery itself. Preliminary pharmacological analysis of the vasoactive agent was attempted using methysergide and phentolamine.

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Tsuyoshi Matsumoto, Eiichi Tani, Yukio Maeda, and Shigeatsu Natsume

✓ The 47-year-old man reported here showed large encapsulated masses in the left cerebellopontine angle and 6 years later in the enlarged left jugular foramen. Histologically, the tumors demonstrated a large deposit of amyloid composed of immunoglobulin light chain-derived proteins (AL). There was no evidence of chronic inflammatory or infectious processes or immunoglobulin abnormalities.

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Eiichi Tani, Shogo Yamagata, and Yuko Ito

✓ Prolonged vasospasm was produced in the dog basilar arteries by introduction of fresh arterial blood or norepinephrine into the chiasmatic cistern. Myonecrosis was limited to a small number of smooth-muscle cells, and a large number of muscle cells appeared intact. The most characteristic change was the appearance of aggregated granules and vesicles in the widened extracellular space between smooth-muscle cells, particularly near the adventitia and the elastic lamina. The granules were spherical, 50 to 100 nm in diameter, often surrounded by a single membrane, and contained a dense osmiophilic core, about 40 to 90 nm in diameter. In addition, the elastic lamina often became loose and corrugated or broken.

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Keizo Kaba, Eiichi Tani, Tatsuo Morimura, and Tsuyoshi Matsumoto

✓ The effects of calcium channel blockers and calmodulin inhibitors on vincristine cytotoxicity were studied in vitro with five glioma cell lines: three human glioblastomas, one rat glioma, and one mouse ependymoblastoma. One human glioblastoma and the rat glioma were resistant to vincristine in contrast to other glioma cells. The resistance to vincristine was considerably decreased by nontoxic or marginally toxic concentrations of calcium channel blockers or calmodulin inhibitors, although the former was more effective than the latter. In the presence of verapamil, the vincristine cytotoxicity, as measured by cell doubling times, increased 90- and 84-fold in the vincristine-resistant human glioblastoma and rat glioma, respectively. The decrease in the resistance to vincristine was related to a marked increase in the intracellular level of that drug, probably mediated by inhibiting its outward transport. The in vivo studies showed that verapamil or nicardipine administered daily with vincristine for 10 days significantly enhanced the chemotherapeutic effect of vincristine in an intracranially transplanted rat glioma model. An approximately 32% to 118% increase in life span occurred with 15 mg/kg/day of verapamil, depending on the doses of vincristine.

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Eiichi Tani, Shogo Yamagata, Yukio Maeda, and Yuko Ito

✓ The cytochemical localization of adenylate cyclase and guanylate cyclase was studied in the arteries of the circle of Willis in dogs. The reaction products of both adenylate and guanylate cyclases were similarly distributed and selectively localized predominantly adjacent to sarcoplasmic reticulum and sparsely to mitochondria and outer nuclear membranes of vascular smooth muscles. The observations could suggest a close association of the intracellular localizations of both cyclases and the intracellular calcium storage sites, and ultimately contribute to our complete understanding of regulation of cerebral blood flow and vasospasm.

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Yukio Maeda, Eiichi Tani, and Tsumoru Miyamoto

✓ Experimental cerebral vasospasm was produced in the canine basilar artery by an intracisternal injection of fresh autogenous arterial blood, and prostaglandins generated in spastic and nonspastic arteries were assessed by thin-layer chromatography. Prostaglandins synthesized in normal arteries were 6-keto-prostaglandin (PG)F, PGF, PGE2, and PGD2; 6-keto-PGF was the most abundant prostaglandin. The study of platelet aggregation suggested that prostacyclin (PGI2)-like activity was manufactured by the normal basilar artery. At 5 minutes after the intracisternal blood injection, no significant changes were evident in syntheses of prostaglandins generated by spastic artery. However, PGE2 synthesis was significantly increased in spastic artery 2 days after the intracisternal blood injection, and 6-keto-PGF and PGF synthesis and PGE2 synthesis were significantly decreased and increased, respectively, in spastic artery 6 days after the intracisternal blood injection. No significant changes were found in syntheses of 6-keto-PGF, PGF, and PGE2 manufactured by nonspastic arteries at any stage. Formation of thromboxane B2 was not detected in normal, spastic, or nonspastic arteries.

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Toyokazu Fukumori, Eiichi Tani, Yukio Maeda, and Atsuhiko Sukenaga

✓ Isolated canine basilar artery contracted by prostaglandin E2, hemoglobin, or serum was relaxed in a dose-dependent manner by the addition of 10−8M to 10−6M prostacyclin (PGI2), and was scarcely relaxed by 10−9M PGI2. In other studies, intravenous administration of PGI2 (25 or 75 ng/kg/min), indomethacin (4 mg/kg), or indomethacin (4 mg/kg) plus PGI2 (25 ng/kg/min) failed to reverse angiographic delayed vasospasm produced in vivo in the canine basilar artery by an intracisternal injection of blood. In addition, no significant increase occurred in mean values of regional cerebral blood flow (rCBF) with any treatments, and mean rCBF difference in dogs treated by PGI2 infusion at 25 ng/kg/min was 2.5 ± 1.2 ml/100 gm/min and only significantly increased (p < 0.01). Mean arterial blood pressure was significantly reduced by PGI2 infusion at 25 (p < 0.05) or 75 ng/kg/min (p < 0.005).

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Nobuo Kochi, Eiichi Tani, Masayuki Yokota, and Yasuhiro Nakaya

✓ A 56-year-old man with lung cancer developed a massive intracerebral hematoma resulting from rupture of a small neoplastic aneurysm in a cortical branch of the left posterior temporal artery. Histologically, undifferentiated squamous cells formed an embolus in the aneurysm and destroyed the aneurysm wall. No tumor mass was evident around the aneurysm.

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Yukio Maeda, Eiichi Tani, Masaru Nakano, and Tsuyoshi Matsumoto

✓ The case is presented of a 36-year-old woman with a plasma-cell granuloma arising in the fourth ventricle. The mass appeared on computerized tomography as a well circumscribed area of slightly high density that was markedly enhanced with contrast medium. Microscopic examination showed a mixed-cell population with a predominance of plasma cells, and the tumor was characterized immunohistochemically by polyclonal plasma-cell proliferation.