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Objective: The correlation between the isosorbide-induced decompression effect on the endolymphatic space and plasma osmolality (p-OSM) or plasma arginine vasopressin (p-AVP) was investigated on comparing two different dosages of isosorbide (2.8 and 1.4 g/kg) to elucidate why the decompression effect is delayed with a large dose of isosorbide., Materials and Methods: Two experiments were performed using 80 guinea pigs. Experiment 1 was designed to morphologically investigate the sequential influence of the oral intake of 1.4- and 2.8-g/kg doses of isosorbide on the endolymphatic volume. The animals used were 50 guinea pigs (control: 10, experimental: 40). All animals underwent surgical obliteration of the endolymphatic sac of the left ear. One month after the surgery, control animals were sacrificed 3 hours after the intake of distilled water, and experimental animals were sacrificed 3 and 6 hours after the isosorbide intake. All of the left temporal bone served for the quantitative assessment of changes in the endolymphatic space, and the cross-sectional area of the scala media was measured from the mid-modiolar sections of the cochlea.Experiment 2 was designed to investigate changes in p-OSM and p-AVP levels 3 hours after the oral intake of isosorbide. Animals used were 15 guinea pigs (control: 5, experimental: 10). The control group received the oral administration of distilled water (4 ml/kg), and the experimental animals were subdivided into two groups consisting of 10 animals each by the dosage of isosorbide (1.4 or 2.8 g/kg). All animals were sacrificed for the measurement of p-OSM and p-AVP concentrations 3 hours after the intake of water or 70% isosorbide solution., Results: Morphologically, an isosorbide-induced decompression effect was noted in animals with both 1.4- and 2.8-g/kg doses of isosorbide. According to the regression analysis, however, the volumetric decrease of the endolymphatic space was more evident in cases with the small dose (1.4 g/kg) 3 hours after the intake (analysis of covariance [ANCOVA], p < 0.001). Six hours after, the decompression effect was significantly greater in cases with the large dose (2.8 g/kg) (ANCOVA, p < 0.001).Isosorbide intake caused a rise in p-OSM levels dose-dependently. The Cochran-Cox test revealed that the differences in the mean values among control and isosorbide groups were significant (p < 0.01). Regarding the p-AVP level, a significant increase was evident in cases with the large dose (2.8 g/kg) (p < 0.01, Cochran-Cox test), and not in cases with the small dose (1.4 g/kg)., Conclusion: An isosorbide-induced decompression effect of the endolymphatic space was evident in spite of two different dosages of isosorbide (2.8 and 1.4 g/kg). Three hours after the isosorbide intake, however, the decompression effect was more marked in the group with the small dose (1.4 g/kg). Since significant rises in p-OSM and p-AVP were evident in the group with the large dose, this early rise of p-AVP due to dehydration seems to be the major reason for the delayed decompression effect in cases with a large isosorbide intake.

Objective: To experimentally elucidate the pathogenesis of inappropriate co-contraction of facially innervated muscles after severe facial palsy., Methods: Twenty-two guinea pigs with severe facial palsy induced by the interruption of the petrosal artery were used to follow up behavioral facial movement, including the degree of facial palsy and abnormal hyperkinetic facial movement of synkinesis and mass contracture. At the end of the follow-up, the evoked facial compound muscle action potential (evoked FCMP) and antidromically evoked facial nerve response (AFNR) were examined in a few typical cases with complete recovery and with incomplete recovery accompanied by synkinesis. After the follow-up, all animals were sacrificed for morphological studies, which consisted of a light-microscopic study (by Luxol fast blue and hematoxylin and eosin staining or toluidine blue staining) and/or an electron-microscopic study., Results: The initial sign of recovery was mass contracture or spasm. This condition continued for 2 weeks or more. As voluntary facial movement recovered, the mass contracture became unnoticeable. It could not be distinguished when the so-called synkinesis developed. Synkinesis usually developed during the recovery process from severe to moderate palsy, and synkinesis persisted or progressed once it appeared. Histologically, unmyelinated fibers were intermingled with myelinated fibers in an early stage of recovery with mass contracture. In the late stage with the development of synkinesis, however, such an intermingling of unmyelinated and myelinated axons was not observed. In this stage, axons became well myelinated, but they were irregular in shape in cases with synkinesis. Especially, axons irregularly ran at the level of the G1 (at the region of the second genu) segment, and bifurcated axons were sporadically found. The axon count had a tendency to increase toward the periphery. AFNR was not detected, although evoked FCMP could be clearly detected in cases with synkinesis., Conclusion: Misguidance of regenerated axons is an important cause of facial synkinesis in the ischemia-induced facial palsy model. Ephaptic transmission between unmyelinated and myelinated axons is also likely to be responsible for mass contracture manifested in the early stage of the recovery process.

Hypothesis: The endocytosis of cationized ferritin (CF) via a clathrin-mediated pathway is regulated by a signaling network., Background: Marginal cells showed the active endocytosis of CF via a clathrin-mediated pathway. The internalization of receptors through the clathrin-mediated pathway is an important regulatory event in signal transduction. Numerous kinases are involved in endocytosis, and each endocytic route is subjected to high-order regulation by cellular signaling mechanisms., Methods: CF was infused into the cochlear duct with phorbol 12-myristate 13 acetate, okadaic acid, staurosporin, phenylarsine oxide, PD98059, SB20580 and wortmannin. Endocytic activity was measured at 30 minutes post-infusion by transmission electron microscopy., Results: The endocytosis of CF was stimulated by a protein kinase C activator (phorbol 12-myristate 13 acetate) and a protein kinase A activator (8-bromoadenosine-3', 5'-cyclic monophosphate). It was inhibited by protein phosphatase inhibitors (okadaic acid and phenylarsine oxide), mitogen-activated protein kinase/extracellular signal-related kinase inhibitors (PD98059 and SB20580), and a phosphatidylinositol 3-kinase inhibitor (wortmannin)., Conclusion: Our previous study showed the endocytosis of microperoxidase to be strongly dependent on protein kinase C, protein phosphatase, extracellular signal-related kinase, and phosphatidylinositol 3-kinase signaling networks but not on protein kinase A and mitogen-activated protein kinase signaling networks. The present study indicated that the signaling cascade regulating CF's internalization differed from the cascade for microperoxidase's endocytosis.