Search

The objective was to design in gerbils a model of reversible decrease in cochlear blood flow (CBF) and analyze its influence on cochlear function. In Mongolian gerbils injected with ferromagnetic microbeads, a magnet placed near the porus acusticus allowed CBF to be manipulated. The cochlear microphonic potential (CM) from the basal cochlea was monitored by a round-window electrode. In 13 of the 20 successfully injected gerbils, stable CBF reduction was obtained for 11.5 min on average. The CM was affected only when CBF fell to less than 60% of its baseline, yet remained >40% of its initial level in about 2/3 of such cases. After CBF restoration, CM recovery was fast and usually complete. Reduced CM came with a 35- to 45-dB threshold elevation of neural responses determined by compound action potentials. This method allowing reversible changes of CBF confirms the robustness of cochlear function to decreased CBF. It can be used to study whether a hypovascularized cochlea is abnormally sensitive to stress., (© 2017 S. Karger AG, Basel.)

Objective: Betahistine is a histamine-like drug that is considered beneficial in Ménière's disease by increasing cochlear blood flow. Acting as an agonist at the histamine H1-receptor and as an inverse agonist at the H3-receptor, these receptors as well as the adrenergic α2-receptor were investigated for betahistine effects on cochlear blood flow., Materials and Methods: A total of 54 Dunkin-Hartley guinea pigs were randomly assigned to one of nine groups treated with a selection of H1-, H3- or α2-selective agonists and antagonists together with betahistine. Cochlear blood flow and mean arterial pressure were recorded for 3 min before and 15 min after infusion., Results: Blockage of the H3- or α2-receptors caused a suppression of betahistine-mediated typical changes in cochlear blood flow or blood pressure. Activation of H3-receptors caused a drop in cochlear blood flow and blood pressure. H1-receptors showed no involvement in betahistine-mediated changes of cochlear blood flow., Conclusion: Betahistine most likely affects cochlear blood flow through histaminergic H3-heteroreceptors., (© 2015 S. Karger AG, Basel.)

Hearing impairment, although uncommon, may occur in patients with a vertebrobasilar artery occlusion disease. The pathogenesis may be an ischemic lesion involving the auditory pathways in the pons and midbrain, the cochlear nucleus, cochlear nerve or the cochlea. The AICA and IAA are the main arteries that supply the peripheral audiovestibular structures of the inner ear and central audiovestibular pathways of the middle cerebellar peduncle and lateral pons., (Copyright © 2012 S. Karger AG, Basel.)

Idiopathic sudden sensorineural hearing loss (SSNHL) represents a frequently encountered otological disease of unknown etiology. In recent years, several inherited risk factors have been found in the pathogenesis of vascular diseases. In the present study, we determined whether specific polymorphism or the combination of polymorphisms in folate-dependent homocysteine metabolism genes can act as predisposing inherited vascular risk factors in the development of SSNHL. We conducted a prospective case-control study using DNA samples extracted from 81 patients diagnosed as suffering from SSNHL and 264 healthy control subjects. Three functional polymorphisms were analyzed by polymerase chain reaction amplification, restriction enzyme digestion, and DNA fragment separation by electrophoresis: methylenetetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, and methionine synthase (MTR) A2756G polymorphisms. The prevalence of the homozygous genotype of MTR 2756GG in the SSNHL patients (9%) was significantly higher than in the control group (4%) (p = 0.011). The allelic frequency of the G allele of the MTR A2756G polymorphism among SSNHL patients (12.5%) was also significantly higher than in the control group (5%) (p = 0.033). The prevalence of patients possessing two polymorphisms (31%) and three polymorphisms (17%) in the SSNHL group was significantly higher than in the control group (23 and 9%, respectively; p = 0.019). The frequency of patients with a very high rank risk (double homozygous) was significantly higher in the SSNHL group, MTHFR 677TT/MTR 2675GG--7%, than the frequency of patients in the control group, MTHFR 677TT/MTR 2675GG--3% (p = 0.030). Certain polymorphisms in genes encoding enzymes in the folate-dependent homocysteine metabolism are associated with SSNHL. In our case-control study, a significant association between MTR 2756GG genotype and SSNHL was found which may represent an inherited vascular risk factor in the pathogenesis of SSNHL., (Copyright 2006 S. Karger AG, Basel.)

Noise exposure induces the formation in the cochlea of 8-isoprostaglandin F(2alpha) (8-iso-PGF(2alpha)), a marker for reactive oxygen species [Ohinata et al., 2000a] and a potent vasoconstrictor, raising the possibility that 8-iso-PGF(2alpha) may be responsible for noise-induced reductions in cochlear blood flow (CBF). To test this hypothesis, CBF was assessed in the guinea pig in response to 'local' (via the anterior inferior cerebellar artery) and systemic (i.v.) delivery of 8-iso-PGF(2alpha) using laser Doppler flowmetry. Local 8-iso-PGF(2alpha) induced a clear reduction in CBF. With systemic infusion, vascular conductance (VC), the ratio of CBF to systemic blood pressure, decreased in a dose-dependent manner up to 30%, consistent with an 8-iso-PGF(2alpha)-induced constriction of the cochlear vasculature. Infusion of SQ29548, a specific antagonist of 8-iso-PGF(2alpha), appropriately blocked an 8-iso-PGF(2alpha)-induced CBF response. Similarly, noise-induced changes in CBF and VC were prevented by infusion of SQ29548 during noise exposure or by antioxidant treatment (glutathione monoethyl ester) prior to exposure. Prevention of isoprostane-mediated vasoconstriction may have clinical utility in the protection from noise-induced hearing loss., (Copyright 2003 S. Karger AG, Basel)

Adenosine triphosphate (ATP) is a major intercellular signalling molecule that is involved in neurotransmission in the central and autonomic nervous systems, regulation of blood flow, and neuroendocrine function. It is also a key signalling molecule involved in normal cochlear homoeostasis, regulating hearing sensitivity, controlling vascular tone and acting as a candidate neurotransmitter at the hair cell afferent synapses. It has also been established that extracellular ATP mediates some pathological processes such as inflammation, apoptosis and cell proliferation. Evidence for a profound influence of extracellular ATP on normal cochlear function offers the tantalizing possibility that extracellular purine nucleotides may play a role in disease processes in the inner ear. This review draws on the current understanding of the pathophysiological role of extracellular ATP in tissues, and the evidence for the functional expression of purinergic signalling elements in the inner ear, to speculate on the potential role of purine nucleotides in cochlear pathology., (Copyright 2002 S. Karger AG, Basel)

A reduction of blood flow in the spiral modiolar artery (SMA), which supplies the cochlea, is implicated in hearing loss and tinnitus. Endothelins are known to be the most potent endogenous vasoconstrictors. The purpose of the present study was to determine whether the SMA responds to endothelin, which receptor type is present and which signal transduction pathway is involved. The SMA was isolated from the gerbil cochlea by microdissection and superfused in a bath chamber on the stage of an inverted microscope. The vascular diameter was measured by video microscopy, and the cytosolic Ca2+ concentration was monitored simultaneously by fluo-4 fluorescence microscopy. ET-1 and ET-3 caused a dose-dependent vasoconstriction with ET-1 being the more potent agonist. The agonist sarafotoxin S6c had no significant effect. The preferential ET(A) receptor antagonist BQ123 had a higher affinity inhibiting the ET-1-induced vasoconstriction than the preferential ET(B) receptor antagonist BQ788. The ET-1-induced vasoconstriction was prevented by inhibition of phospholipase C with U73122. Blockade of the inositol 1,4,5-trisphosphate (IP3) receptor on the sarcoplasmic reticulum Ca2+ stores with 2-aminoethoxydiphenyl borate and depletion of Ca2+ stores by inhibition of the sarcoplasmic Ca2+-ATPase with thapsigargin prevented ET-1-induced cytosolic Ca2+ increase and reduced the ET-1-induced vasoconstriction. These results demonstrate that endothelin causes a vasoconstriction of the SMA, which is mediated via ET(A) receptors. The data suggest that the signal transduction pathway of the ET(A) receptor involves phospholipase C, IP3 receptors and release of Ca2+ from thapsigargin-sensitive Ca2+ stores.

The regulation of cochlear blood flow is crucial for auditory function due to the sensitivity of this sensory organ to hypoxia. Part of the regulation of cochlear blood flow occurs in the spiral modiolar artery, which provides the main blood supply to the cochlea. Blood flow in general is most effectively regulated through the control of the vascular diameter. The vascular diameter is determined by the degree of constriction of the smooth muscle cells in the vascular wall. A constriction of the smooth muscle cells reduces the diameter of the vascular lumen and thereby decreases blood flow, whereas a relaxation of the smooth muscle cells increases blood flow. The degree of constriction of the smooth muscle cells in the spiral modiolar artery is carefully controlled and must be adjusted properly to the demands of the cochlear tissues. To achieve proper control, smooth muscle cells integrate information from various sources. Vasoconstrictors and dilators may originate from the innervation surrounding the vessel, from endothelial cells lining the vascular lumen or from the smooth muscle cells themselves. Recent advances revealed that smooth muscle cells from different arterioles differ widely in their endowment with mechanisms that regulate the degree of smooth muscle cell tone. Signal transduction mechanisms, which mediate these neurogenic, local and paracrine regulations of smooth muscle contractility are now beginning to be understood. This report reviews recently obtained evidence for adrenergic regulation of cochlear blood flow and then focuses on a novel vasodilation mechanism that involves ryanodine receptors, Ca2+ sparks and the activation of Ca2+-activated K+ channels.

An experimental model of cochlear ischemia using the photosensitization reaction of rose bengal (RB) is reported. Ischemia was induced by the systemic administration of RB solution and localized irradiation of the cochlea with a green light of specific wavelength for RB activation. After the RB solution was administered, the cochlear blood flow was temporarily increased and then decreased, and the latency of wave I of the auditory brainstem response increased and the amplitude of wave I decreased after RB injection and finally wave I disappeared completely. A histological study revealed thrombus formation in the vessels of the irradiated cochlea not only in the stria vascularis and the spiral ligament, but also in the modiolus. L-Histidine, a scavenger of singlet oxygen (1O2) and hydroxyl radical (.OH), significantly prolonged cochlear dysfunction, but D-mannitol, a specific scavenger of.OH did not, suggesting that 1O2 has an important role in this reaction.

An in vivo method for assessment of changes in hydroxyl radical levels in cochlear perilymphatic spaces is described and applied to cochlear ischemia-reperfusion in the mouse. Cochlear blood flow was reversibly reduced by compression of the anterior inferior cerebellar arterial network. Changes in the production of hydroxyl radicals, used as an index of tissue production of reactive oxygen species (ROS), were determined by measuring the conversion of salicylate to 2,3-dihydroxybenzoic acid. Low levels of salicylate (0.1 mM) in artificial perilymph were applied by perfusion of the cochlea using a round window entry and apical exit. Perfusate was collected and analyzed by high-performance liquid chromatography. Forty minutes of partial ischemia led to a > 10-fold average increase over baseline in the concentration of hydroxyl radical, which increase persisted for at least 40-80 min following reperfusion. Our observations support previous results obtained using less direct methods, indicating that cochlear ischemia-reperfusion and related damage is associated with elevated ROS levels. Development of an in vivo method for assessing changes in cochlear ROS in mice will facilitate the study of the relation between deafness genes, vulnerability to insults and dynamics of cellular processes that produce and regulate ROS.

The results of a series of scanning electron microscopical studies were used to construct a model for the vascular pathways in the inner ear. Corrosion cast preparations of the vessels of the inner ear of the adult rat were used in this study. The inner ear is, like a hand, an end organ containing four sense organs (cochlea, saccule, utricle and the cristae ampullaris). All these specific inner ear structures have their own vascular supply. We have developed a blood flow diagram of the inner ear. This model was used for a classification of different types of ischemia in the inner ear and forms a concept for some forms of sensorineural hearing loss and vertigo. Four types of inner ear ischemia are proposed. In type I (a or b) of inner ear ischemia only the vessels of the cochlea are involved resulting in two types of hearing loss without vertigo. Type II is characterized by ischemia of a part of the cochlea and a part of the vestibular system. In type III (a or b) only the vestibular system is involved, while in type IV no blood circulation will be present in the inner ear resulting in total deafness and severe vertigo. Inner ear partition at ultramicroscopical level of these structures may be possible in the future and new imaging techniques will probably support the vascular schematic model presented in this study.

Laser Doppler flowmetry was used to assess cochlear blood flow (CoBF) in guinea pigs with experimental endolymphatic hydrops following intravenous infusion of 5 types of drugs: 50% glycerol, 70% isosorbide, 20% mannitol, 7% sodium bicarbonate, and 1% diphenidol. The magnitude of the CoBF changes following infusion tended to be smaller in the hydropic ears than in the normal control ears. A significant reduction in CoBF changes was observed in hydropic ears infused with isosorbide and sodium bicarbonate. These results suggest that the cochlear microvascular sensitivity to various stimuli such as drug infusion is reduced in hydropic ears. This may result from atrophy of the stria vascularis which is often observed in the hydropic ears of guinea pigs. Thus it seems likely that the same reaction occurs in the inner ear of patients with Ménière's disease in whom atrophy of the stria vascularis is also presumed to exist in conjunction with extensive endolymphatic hydrops. Therefore, it seems probable that the function of the microvasculature of the stria vascularis is impaired in the inner ear of patients with Ménière's disease, resulting in the slow progressive deterioration of the inner ear with time.

Anesthetized and artificially ventilated guinea pigs were exposed to broad-band noise of 95, 101, 106 or 115 dB SPL for 30 min and studied for 180 min after cessation of noise. The partial pressure of oxygen (pO2) in the perilymph, the cochlear blood flow (CoBF) and auditory-evoked potentials were continuously recorded. Arterial blood pressure, electrocardiogram, inspiratory and expiratory gas levels, arterial blood gas levels and acid-base status were kept stable to exclude influences of these parameters on cochlear parameters. Exposure to 95 dB SPL did not affect perilymphatic pO2 or CoBF. Cochlear microphonics (CMs) were reduced, but compound action potentials of the auditory nerve (CAPs) and auditory brainstem potentials (ABRs) increased after exposure to this low-level noise. Perilymphatic pO2 decreased during exposure to 101 dB SPL and then further decreased during the subsequent 60 min after cessation of the noise. CoBF did not change significantly during and 30 min after noise but then paralleled the decline of perilymphatic pO2. However, both parameters showed a clear indication of recovery in the second and third hours after noise. At 101 dB SPL, CMs were again reduced immediately, CAPs were unaltered and ABRs again increased. Exposure to 106 and to 115 dB SPL resulted in a decrease in both perilymphatic pO2 and CoBF; this decrease began during the exposure but became progressively worse after the noise. Hearing loss was observed immediately with exposure and showed no signs of further deterioration after cessation. The observed time courses of changes are important. They reveal that hearing loss and cochlear hypoxia precede reduction in CoBF due to noise exposure. The potential mechanisms underlying these effects are discussed.

Cochlear blood flow (CoBF) and cerebral blood flow (CBF) were measured using laser Doppler flowmetry and the microsphere method during CO2 and O2 gas mixture inhalation in rabbits. Both methods revealed that CBF was increased by CO2 inhalation. CoBF measured by laser Doppler measurement decreased during CO2 inhalation while that measured by the microsphere method showed a slight increase, but lateral wall blood flow in the cochlea measured by the microsphere method showed no significant change. Our results obtained with laser Doppler flowmetry were not inconsistent with those reported in humans. It is considered that the rabbit, in which thick bone surrounds the cochlea, is a good model for the experimental evaluation of the laser Doppler technique used in the clinical measurement of CoBF.

To understand the importance of oxygen transport to the inner ear tissue, we studied, in guinea pigs, the relationship between cochlear blood flow and endocochlear direct-current potential (EP) under different respiratory conditions. EP, a functional parameter of the stria vascularis, was recorded by a microelectrode inserted into the lateral wall of the chochlea. To measure the cochlear blood flow (CoBF), we employed laser Doppler flowmetry and recorded the flow with a probe placed on the same spot on the lateral wall. During 3 min of asphyxia, CoBF and systemic blood pressure showed irregular biphasic increases, while the EP decreased to reach a negative value. In the hypoxemia experiment, which was induced by stepwise reduction of the respiratory rate to 60%, increases in CoBF and blood pressure were evident during hypoventilation with an intermediate position of EP in the positive range. The mechanisms of these increases in two parameters are discussed from the viewpoints of sympathicotonic activity in the autonomic nervous system and the vasodilating action of CO2 during hypercapnia. In the hyperoxemia experiment, which was induced by stepwise increase in the respiratory rate to 140%, CoBF and blood pressure were found to decrease during hyperventilation with no significant change of EP. The decrease in blood pressure was considered to be due to the increase in intrathoracic pressure caused by the increased rate of artificial respiration. As for the concomitant decrease in CoBF, chemical regulation of PCO2 in the vascular bed of the lateral wall of the cochlea was thought to be a contributory factor.

In order to determine the effects on the cochlea of circulatory disturbance in the basilar artery system, the cochlear action potential (AP) and the cochlear blood flow were measured in cats with the artery occluded. The occlusion was performed in the basilar, the anterior cerebellar and in the internal auditory arteries. During occlusion the decrease in the cochlear blood flow was greatest in the internal auditory artery and the least in the basilar artery. While the cochlear blood flow showed various levels of decrease depending on the occlusion site and the individual animal, the degree of AP alteration correlated with the decreased rate in the cochlear blood flow.

Blood flow measurements were carried out on 18 coloured guinea pigs (8 animals served as control group) before and during definite sound exposure (12 kHz, 110 dB SPL). The exposure time amounted to 60 min. The anaesthesia was carried out according to the following schedule: a mixture consisting of 70 mg alpha-chloralose/kg b.w. and 400 mg urethane/kg b.w. was injected intraperitoneally. The relaxation was performed by means of i.p. application of 3 mg Tricuran/kg b.w./h. The hydrogen clearance measurements (HCM) were carried out under artificial respiration with control of arterial pH, endexpiratory CO2 content, as well as blood pressure and body temperature. After a duration of noise exposure of 30-45 min the cochlear blood flow reached an average level of 80% of the initial point. This level remained mainly unchanged until the end of noise exposure (60 min). Our HMC's confirm Laser Doppler flowmetry findings.

The right superior cervical ganglia of 11 cats were removed. After intravenous injection of horseradish peroxidase, both sides of the cochleas were infused with 2% glutaraldehyde and the lateral wall of the cochlea was then microdissected. As control group, both sides of the cochleas of 4 cats were extracted while the superior cervical ganglia remained intact. The samples were incubated after a modified Graham-Karnovsky method and observed by light microscopy. The diameters of the capillaries of the stria vascularis and spiral ligaments were measured. In 8 cats (73%), the diameters of the capillaries of the stria vascularis on the side on which sympathectomy was performed were significantly greater than those on the opposite side. There was no statistical difference between the diameters of the capillaries of the spiral ligament on either the sympathectomized side or the intact side, except in 2 cats. In the control group (in which the superior cervical ganglia were left intact), no statistical difference was found as regards the diameters of the stria vascularis capillaries on either the left or right side. In summary, sympathectomy affected only the capillaries of the stria vascularis and not those of the spiral ligament.

Cochlear blood flow in the rabbit was determined before and after injection of hyperosmotic solutions of galactose and isosorbide. After doses similar to those which can produce hearing improvements in patients with Ménière's disease, cochlear blood flow was increased by 30-60%.

The cochlear and cerebral blood flow were simultaneously measured with the microsphere method in albino rabbits before and after administration of prazosin (0.5 mg/kg body weight) and before and during an increase in intracranial pressure (ICP) and intracochlear pressure. Increments in ICP were induced by intracranial infusion of Ringer solution prewarmed to body temperature. The increments were accompanied by an intravenous administration of prazosin to abolish the Cushing effect. The cochlear blood flow was unaffected by the intravenously administered prazosin. A decrease was found when the perfusion pressure of the cochlear, i.e. mean arterial blood pressure minus ICP fell below 5 kPa.

This paper reports the results of a scanning electron microscopy study of corrosion cast preparation of the vessels in the cochlea of the rat. This method confirms the general findings about the cochlear vascularization, but also gives the opportunity to study the detailed pattern of the vascular supply of the stria vascularis in the round window area. The basal end of the stria vascularis has a remarkably different vascular anatomy compared with the other areas of the cochlea. The possible role of the vessels in the round area is discussed.

The cochlear blood flow was measured with the microsphere method before, during and after CO2 inhalation in anesthetized rabbits. Different gas mixtures and exposure times were used. The greatest increase of cochlear blood flow was measured after 5 min inhalation of 7% CO2 in air (115%) and the least increase (44%) in animals breathing 7% CO2 in oxygen. The difference is explained as due to a vasoconstriction caused by a high oxygen tension counteracting the vasodilating effect of CO2. The treatment with CO2 of supposed vascular diseases in the cochlea is discussed and the negative effects due to respiratory acidosis are emphasized.

The microsphere method was adapted in 1974 for studies of cochlear blood flow. Since then it has been used in Uppsala, Sweden, at the Department of Otolaryngology, University Hospital, for investigations of the blood flow circulation in the inner ear. The experience with the technique, the subjects, the actual projects and the results are presented and discussed.

The cochlear blood flow was studied with the microsphere method in guinea pigs, rats and cats. Results from experiments using different sizes of microspheres were compared and the effect of middle ear infection or perforation of the otic capsule on the cochlear microcirculation was investigated. Neither the opening of the cochlear bony wall nor the middle ear infection influenced the blood flow in the cochlea. 9- and 15-micrometer spheres were given simultaneously and the results were equivalent, indicating no more shunting of the smaller ones than of the bigger ones. Thus, the smaller spheres are to be preferred, since the smaller ones can be used in a larger number without negative effects on the general circulation. In cats, the cochlear blood circulation was determined before and during cervical sympathetic stimulation. Sympathetic stimulation caused a reduction of 25% of the cochlear blood flow.

The effect of noise and unilateral transection of the cervical sympathetic trunk on cochlear blood flow was studied in anesthetized cats. The sound pressure level was 100 dB and the exposure time 6 min. Neither noise nor sympathectomy were found to affect the blood flow.

The problem of the perilymph origin--influx of cerebrospinal fluid (CSF) versus ultrafiltration within the cochlea--cannot be solved by mere qualitative proofs of tracer passage through the cochlear aqueduct. In order to gain quantitative data on the possible perilymph sources, an experimental study was designed to follow the time course of dye concentrations in the cisternal CSF and in the perilymph after tracer injection into the CSF at the vertex. By comparing the resulting concentration peaks in both fluids, the mean peak of the perilymph tracer concentrations was found to reach 36% of the maximum CSF concentration only. It is concluded that the local perilymph production within the cochlea exceeds the influx of CSF by a ratio of about 2:1. A working hypothesis of the double perilymph origin is discussed.

Cochlear and cerebral blood flows were measured in albino rabbits by the microsphere method before and 15 min after intravenous administration of glycerol. Both cochlear and cerebral blood flow were significantly increased. The increase in cochlear blood circulation is interpreted as a contributory factor in producing the improvements in hearing threshold seen in the positive glycerol test in Ménière's disease.