Akinobu Kakigi

Endolymphatic hydrops induced by chronic administration of vasopressin

Recently, many lines of evidence have supported the possibilities that vasopressin (VP) is closely linked to the formation of endolymphatic hydrops in Menieres disease. In the present study, it was examined whether or not the chronic administration of VP might induce endolymphatic hydrops. For this purpose, histological studies and VP radioimmunoassay were independently performed in 20 and 40 guinea pigs, respectively. The degree of hydrops was quantitatively assessed by the increase ratio (IR) of the scala media area in the mid-modiolar sections of the cochlea. The IR was defined by the following equation: 100x(A-B)/B (A: the cross-sectional area of the bulging scala media; B: the no-bulging scala media, enclosed by an idealized straight Reissners membrane). VP was administered at the rates of 200 microU/kg/min, 400 microU/kg/min and 1000 microU/kg/min for 1 week via the osmotic mini-pump. The IR of the total of the apical, second, third and basal turns (means+/-S.D.s) were 4.4+/-0.7, 10.4+/-1.8, 17.4+/-7.9 (n=10 ears, each) in respective doses of VP. Comparing with that of the control animals (5.2+/-1.7, n=10 ears), the area increased significantly in the VP dosage of 400 and 1000 microU/kg/min (Bonferronis method, P<0.05). Plasma VP concentrations produced by the VP administration in these dosages were 2.2+/-0.4, 3.5+/-0.8 and 14.0+/-3.9 (n=10, each) pg/ml. Although 3.5 pg/ml is the upper limit of plasma VP concentration in normal human subjects, 14.0 pg/ml was almost the same concentration as those observed in the acute phase of Menieres disease (Takeda et al., 1995). Therefore, the formation of endolymphatic hydrops in cases of Menieres disease might be caused by high concentrations of plasma VP.

Antidiuretic Hormone (ADH) and Endolymphatic Hydrops

Plasma antidiuretic hormone (p-ADH) concentrations were determined with a radioimmunoassay, using a reversed-phase C18 silica column, in 300 patients with vertigo, dizziness and/or deafness; 119 of them had a diagnosis of Menières disease. The p-ADH level was significantly elevated in patients with Menieres disease and others with endolymphatic hydrops, e.g. cochlear Menières disease or delayed hydrops. By contrast, the p-ADH level was not so high in cases without the endolymphatic hydrops. The increase in the p-ADH level was closely linked to vertigo attacks, the glycerol test results and an enhanced negative summating potential (-SP) in electrocochleogram (ECochG). These results lead to the assumption that disorders of ADH-dependent hormonal control in the inner ear may constitute the possible mechanism underlying vertiginous attacks and deafness in patients with endolymphatic hydrops.

The effects of V2 antagonist (OPC-31260) on endolymphatic hydrops.

In the present study, two experiments were performed to investigate the influence of OPC-31260 on experimentally induced endolymphatic hydrops in guinea pigs and the regulation of aquaporin-2 (AQP2) mRNA expression in the rat inner ear. In morphological studies, the increases in the ratios of the length of Reissners membrane (IR-L) and the cross-sectional area of the scala media (IR-S) were quantitatively assessed among normal guinea pigs (normal ears) and three groups with hydropic ears: hydropic ears with no infusion (non-infusion hydropic ears), hydropic ears with an infusion of physiological saline into the scala tympani (saline-infused hydropic ears) and hydropic ears with infusion of 0.3% OPC-31260 into the scala tympani (OPC-infused hydropic ears). IR-Ls in the experimental groups were markedly larger than in the normal ear group, but there was no significant difference among the groups of non-infusion hydropic ears, saline-infused hydropic ears and OPC-infused hydropic ears. The IR-Ss of non-infusion hydropic ears and saline-infused hydropic ears (48.8-49.3%) were statistically different from that of normal ears (6.5%) (Dunnet multiple comparison test, P<0.01). However, IR-S of the OPC-infused hydropic ears (-14.8%) was significantly smaller than those of non-infusion hydropic ears and saline-infused hydropic ears (one-way ANOVA, P<0.01). In the quantitative polymerase chain reaction study, a comparison of the ratio of AQP2 and beta-actin mRNA (MAQP2/Mbeta-actin) was made between water-injected and OPC-31260-injected rats. An intravenous injection of OPC-31260 resulted in a significant decrease in MAQP2/Mbeta-actin both in the cochlea and in the endolymphatic sac (t-test, P<0.001). These results indicate that water homeostasis in the inner ear is regulated via the vasopressin-AQP2 system, and that the vasopressin type-2 antagonist OPC-31260 is a promising drug in the treatment of Menieres disease.

Aquaporin-2 regulation by vasopressin in the rat inner ear

Our previous studies have suggested a close relationship between vasopressin and endolymphatic hydrops, or the increased volume of endolymph in the inner ear. Endolymphatic hydrops is also thought to occur in Ménières disease patients. In the kidney collecting duct, vasopressin induces the expression of aquaporin-2 (AQP2), resulting in increased water reabsorption. We explored the possibility, using a quantitative PCR method, that vasopressin regulates the expression of AQP2 mRNA in the rat inner ear, as it does in the kidney. The levels of AQP2 mRNA in the cochlea and endolymphatic sac were significantly higher in rats treated with vasopressin than the levels in control animals. We speculate that over-expression of AQP2 may be involved in the formation of endolymphatic hydrops.

Expressions of Aquaporin-2, Vasopressin Type 2 Receptor, Transient Receptor Potential Channel Vanilloid (TRPV)1, and TRPV4 in the Human Endolymphatic Sac†

Objective: To localize aquaporin (AQP)2, vasopressin type 2 receptor (V2‐R), and transient receptor potential channel vanilloid subfamily 1, 4 (TRPV1, TRPV4) in the human endolymphatic sac (ES).

Three-dimensional and ultrastructural relationships between intermediate cells and capillaries in the gerbil stria vascularis

Structural relationships between intermediate cells and capillaries in the stria vascularis of gerbils were examined by confocal laser microscopy and electron microscopy. Immunostaining for an inward rectifier K(+) channel (Kir4.1), which was localized to intermediate cells, was used to determine the three-dimensional distribution of intermediate cells. These cells constituted a honeycomb-like network, and their dendritic processes surrounded not only capillaries but also the basolateral surface of epithelial marginal cells. On the basis of the above finding and the large K(+) conductance in intermediate cells, we propose that the network composed of intermediate cells has a spatial K(+) buffering function. Transmission electron microscopy revealed the absence of the basal lamina in some regions and the presence of a gap junction-like membrane association between intermediate cells and pericytes and/or endothelial cells. This result supported our previous finding that intermediate cells were dye-coupled with pericytes and endothelial cells. The presence of gap junctions between intermediate cells and pericytes and/or endothelial cells suggests that endothelial cells and pericytes may play roles other than forming a structural route for blood circulation.

Aquaporin-1 (AQP1) is expressed in the stria vascularis of rat cochlea.

Cochlea endolymph, produced by the stria vascularis, is essential for normal inner ear function. Abnormal endolymphatic volumes correlate closely with pathological conditions such as Ménières disease. The critical roles played by aquaporins, which facilitate osmotic movement of water molecules, are known in a variety of tissues. We investigated the expression of aquaporin-1 (AQP1) in the rat inner ear using reverse transcription polymerase chain reaction and immunohistochemical methods. We obtained novel data showing that not just AQP1 mRNA but also AQP1 protein is expressed in the stria vascularis, in addition to other data confirming previous reports. AQP1 immunoreactivity localized to the intermediate cells in the stria vascularis. The above finding suggests that AQP1 may play a role in the water distribution associated with vigorous ion transport in the stria vascularis since the intermediate part of the stria vascularis contains both intermediate cells and the basolateral parts of marginal cells, both of which express ion transporters abundantly.

Expression of IL‐33 and its receptor ST2 in chronic rhinosinusitis with nasal polyps

Interleukin (IL)−33 is a novel member of the IL‐1 cytokine family and a ligand for the orphan IL‐1 family receptor ST2. IL‐33 induces T helper 2‐type inflammatory responses and is considered to play a crucial role in allergic inflammatory reactions such as asthma and atopic dermatitis. However, the role of IL‐33 and its receptor ST2 in chronic rhinosinusitis remains unclear.

Hormonal Aspects of Ménière’s Disease on the Basis of Clinical and Experimental Studies

Conclusions: Endolymph homeostasis is thought to be mediated by the vasopressin-aquaporin-2 (VP-AQP2) system in the inner ear. Endolymphatic hydrops, the morphological characteristics of Ménière’s disease (MD), seems to reflect the malregulation of the VP-AQP2 system in inner ear fluid. The elevation of plasma vasopressin (p-VP) level, which is often observed in MD and its related diseases, might be one of the causative factors underlying these diseases. Purpose of Review: Review of the role of the VP-AQP2 system in the inner ear fluid homeostasis and in the formation and development of endolymphatic hydrops. Recent Clinical and Experimental Findings: A clinical survey has revealed that the p-VP level is often elevated in MD and its related diseases and that the increase in the p-VP level was closely linked to vertigo attacks in MD. Experimental studies have revealed that proteins and mRNAs of aquaporin-2 and vasopressin type 2 receptor were expressed in the stria vascularis of the cochlea and the epithelium of the endolymphatic sac, and that the volume of the endolymphatic compartment was mediated by the activity of the VP-AQP2 system in the inner ear.

Effects of gadolinium injected into the middle ear on the stria vascularis.

Conclusion.The concentration of gadolinium (Gd) used clinically showed no remarkable effects on the stria vascularis; however, a higher concentration had adverse effects. The concentration of Gd must be borne in mind when injecting Gd into the tympanic cavity. Objective. Endolymphatic hydrops has been visualized using high resolution MRI with the intratympanic administration of Gd in patients with Menieres disease. We attempted to investigate the effects of Gd on the stria vascularis. Materials and methods. Gd hydrate diluted eightfold with saline or non-diluted Gd or saline was injected into the tympanic cavity of guinea pigs. To investigate the effects of Gd on the stria vascularis, we measured endocochlear DC potential (EP) and observed the stria vascularis using transmission electron microscopy. Results. Intratympanic injections of Gd hydrate diluted eightfold with saline (1/8 Gd) and saline did not cause apparent changes in the EP. Moreover, the amplitude of the EP decreased significantly 60 min after non-diluted Gd was injected. Transmission electron micrographs of the stria vascularis revealed no significant morphological difference between the ears injected with 1/8 Gd and those injected with saline. There was significant morphological change in the ear injected with non-diluted Gd. The intercellular spaces were markedly enlarged.