Reduction In Cochlear Blood Flow Research Articles

Randomized, placebo-controlled study on efficacy, safety and tolerability of drug-induced defibrinogenation for sudden sensorineural hearing loss: the lessons learned

PurposeDisturbance of cochlear microcirculation is discussed as final common pathway of various inner ear diseases. Hyperfibrinogenemia causing increased plasma viscosity is a possible factor for a critical reduction of cochlear blood flow that might lead to sudden sensorineural hearing loss (SSHL). The aim was to determine the efficacy and safety of drug-induced defibrinogenation by ancrod for SSHL.MethodsDouble-blind, randomized, placebo-controlled, multicenter, parallel group, phase II (proof-of-concept) study (planned enrollment: 99 patients). Patients received an infusion of ancrod or placebo (day 1) followed by subcutaneous administrations (day 2, 4, 6). Primary outcome was the change in pure tone audiogram air conduction average until day 8.ResultsThe study was terminated early due to slow recruiting (31 enrolled patients: 22 ancrod, 9 placebo). A significant improvement of hearing loss was registered in both groups (ancrod: − 14.3 dB ± 20.4 dB, − 39.9% ± 50.4%; placebo: − 22.3 dB ± 13.7 dB, − 59.1% ± 38.0%). A statistically significant group-difference was not detected (p = 0.374). Placebo response of 33.3% complete and 85.7% at least partial recovery was observed. Plasma fibrinogen levels were reduced significantly by ancrod (baseline: 325.2 mg/dL, day 2: 107.2 mg/dL). Ancrod was tolerated well, no adverse drug reaction was of severe intensity, no serious adverse events occurred.ConclusionAncrod reduced fibrinogen levels that support its mechanism of action. The safety profile can be rated positively. Since the planned number of patients could not be enrolled, no efficacy conclusion can be drawn. The high rate of placebo response challenges clinical trials for SSHL and needs to be considered in future investigations.Trial registrationsThis study was registered in the EU Clinical Trials Register, EudraCT-No. 2012-000066-37 at 2012-07-02.

Hearing Impairment in a Mouse Model of Diabetes Is Associated with Mitochondrial Dysfunction, Synaptopathy, and Activation of the Intrinsic Apoptosis Pathway.

Although previous studies continuously report an increased risk of hearing loss in diabetes patients, the impact of the disease on the inner ear remains unexplored. Herein, we examine the pathophysiology of diabetes-associated hearing impairment and cochlear synaptopathy in a mouse model of diabetes. Male B6.BKS(D)-Leprdb/J (db/db, diabetes) and heterozygote (db/+, control) mice were assigned into each experimental group (control vs. diabetes) based on the genotype and tested for hearing sensitivity every week from 6 weeks of age. Each cochlea was collected for histological and biological assays at 14 weeks of age. The diabetic mice exerted impaired hearing and a reduction in cochlear blood flow and C-terminal-binding protein 2 (CtBP2, a presynaptic ribbon marker) expression. Ultrastructural images revealed severely damaged mitochondria from diabetic cochlea accompanied by a reduction in Cytochrome c oxidase subunit 4 (COX4) and CR6-interacting factor 1 (CRIF1). The diabetic mice presented significantly decreased levels of platelet endothelial cell adhesion molecule (PECAM-1), B-cell lymphoma 2 (BCL-2), and procaspase-9, but not procaspase-8. Importantly, significant changes were not found in necroptotic programmed cell death markers (receptor-interacting serine/threonine-protein kinase 1, RIPK1; RIPK3; and mixed lineage kinase domain-like pseudokinase, MLKL) between the groups. Taken together, diabetic hearing loss is accompanied by synaptopathy, microangiopathy, damage to the mitochondrial structure/function, and activation of the intrinsic apoptosis pathway. Our results imply that mitochondrial dysfunction is deeply involved in diabetic hearing loss, and further suggests the potential benefits of therapeutic strategies targeting mitochondria.

The mechanoelectrical transducer channel is not required for regulation of cochlear blood flow during loud sound exposure in mice

The mammalian cochlea possesses unique acoustic sensitivity due to a mechanoelectrical ‘amplifier’, which requires the metabolic support of the cochlear lateral wall. Loud sound exposure sufficient to induce permanent hearing damage causes cochlear blood flow reduction, which may contribute to hearing loss. However, sensory epithelium involvement in the cochlear blood flow regulation pathway is not fully described. We hypothesize that genetic manipulation of the mechanoelectrical transducer complex will abolish sound induced cochlear blood flow regulation. We used salsa mice, a Chd23 mutant with no mechanoelectrical transduction, and deafness before p56. Using optical coherence tomography angiography, we measured the cochlear blood flow of salsa and wild-type mice in response to loud sound (120 dB SPL, 30 minutes low-pass filtered noise). An expected sound induced decrease in cochlear blood flow occurred in CBA/CaJ mice, but surprisingly the same sound protocol induced cochlear blood flow increases in salsa mice. Blood flow did not change in the contralateral ear. Disruption of the sympathetic nervous system partially abolished the observed wild-type blood flow decrease but not the salsa increase. Therefore sympathetic activation contributes to sound induced reduction of cochlear blood flow. Additionally a local, non-sensory pathway, potentially therapeutically targetable, must exist for cochlear blood flow regulation.

Age-Related Hearing Loss Is Accelerated by Repeated Short-Duration Loud Sound Stimulation.

Both age-related hearing loss (ARHL) and noise-induced hearing loss (NIHL) may share pathophysiological mechanisms in that they are associated with excess free radical formation and cochlear blood flow reduction, leading to cochlear damage. Therefore, it is possible that short, but repeated exposures to relatively loud noise during extended time periods, like in leisure (i.e., musical devices and concerts) or occupational noise exposures, may add to cochlear aging mechanisms, having an impact on the onset and/or progression of ARHL. Consequently, the aim of the present study was to determine if repeated short-duration overexposure to a long-term noise could accelerate permanent auditory threshold shifts associated with auditory aging in an animal model of ARHL. Toward this goal, young adult, 3-month-old Wistar rats were divided into two groups: one exposed (E) and the other non-exposed (NE) to noise overstimulation. The stimulation protocol consisted of 1 h continuous white noise at 110 dB sound pressure level (SPL), 5 days a week, allowing 2 days for threshold recovery before initiating another stimulation round, until the animals reached an age of 18 months. Auditory brainstem response (ABR) recordings at 0.5, 1, 2, 4, 8, 16, and 32 kHz were performed at 3, 6, 12, and 18 months of age. The results demonstrate that in the E group there were significant increases in auditory thresholds at all tested frequencies starting already at 6 months of age, which extended at 12 and 18 months. However, in NE animals threshold shifts were not evident until 12 months, extending to 18 months of age. Threshold shifts observed in the E animals at 6 and 12 months were significantly larger than those observed in the NE group at the same ages. Threshold shifts at 6 and 12 months in E animals resembled those at 12 and 18 months in NE animals, respectively. This suggests that repeated noise overstimulation in short-duration episodes accelerates the time-course of hearing loss in this animal model of ARHL.

Resistance of Gerbil Auditory Function to Reversible Decrease in Cochlear Blood Flow

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.

Drug-induced Defibrinogenation as New Treatment Approach of Acute Hearing Loss in an Animal Model for Inner Ear Vascular Impairment.

Disturbance of cochlear microcirculation is considered to be the final common pathway of various inner ear diseases. Hyperfibrinogenemia causing increased plasma viscosity is a known risk factor for sudden sensorineural hearing loss and may lead to a critical reduction of cochlear blood flow. The aim of this study was to evaluate the effect of a substantial reduction of plasma fibrinogen levels by drug-induced defibrinogenation for the treatment of acute hearing loss in vivo. Acute hearing loss was induced by hyperfibrinogenemia (i.v. injection of 330 mg/kg BW fibrinogen), using a guinea pig animal model. Parameters of cochlear microcirculation and hearing thresholds were quantified by intravital microscopy and evoked response audiometry. After obtaining baseline values, the course of hearing loss and disturbances of microcirculation were investigated under influence of intravenous defibrinogenation therapy (ancrod), corticosteroid, or placebo treatment, using 5 animals/group. Acute hyperfibrinogenemia caused hearing loss from 10 ± 7 to 26 ± 10 dB SPL at baseline. Drug-induced reduction of fibrinogen levels showed a significant increase of cochlear microcirculation (1.6-fold) and recovered hearing threshold (11 ± 6 dB SPL). Placebo or corticosteroid treatment had no effect on hearing loss (35 ± 7 dB SPL and 32 ± 18 dB SPL, respectively). Acute hyperfibrinogenemia resulted in hearing loss. Drug-induced reduction of elevated fibrinogen levels caused an increase in cochlear blood flow and a decrease in hearing thresholds. Placebo or corticosteroid treatment had no effect. Reduction of plasma fibrinogen levels could serve as a clinical treatment option for acute hearing loss.

Protective effect of propofol on noise-induced hearing loss

Purpose: Iatrogenic noise produced by mastoid or craniotomy drills may cause hearing damage, which is induced by the generation of reactive oxygen species (ROS) and the reduction of cochlear blood flow (CoBF). This study investigated whether propofol could reduce noise-induced hearing loss (NIHL) in a guinea pig model. Methods: Sixty-four male pigmented guinea pigs were randomly and equally divided into 4 groups: control, noise, propofol and propofol+noise. Propofol was infused intravenously for 20min prior to noise exposure with a loading dose of 5mg·kg−1 for 5min and a maintenance infusion of 20mg·kg−1·h−1 for 135min. For noise exposure, an octave band noise at a 124dB sound pressure level (SPL) was administered to animals for 2h. The mean arterial pressure (MAP) and CoBF were monitored continuously. Auditory function was measured by the level of distortion product otoacoustic emission (DPOAE) before and at 1h, 72h and 240h after noise exposure. Cochlear levels of 8-iso-Prostaglandin F2alpha (8-iso-PGF2α) were measured immediately after the termination of noise exposure. Cochlear silver nitrate staining and outer hair cell (OHC) counting were performed after the final functional test. Results: Noise exposure caused decreases in the CoBF and DPOAE amplitudes, over-generation of 8-iso-PGF2α and the loss of OHCs. Pre-treatment with propofol significantly increased the CoBF and DPOAE amplitudes, decreased 8-iso-PGF2α and the loss of OHCs. Conclusions: Propofol exerted protective effects against NIHL in this animal model by suppressing a lipid peroxidation reaction and improving CoBF.

Protective effect of dexmedetomidine on noise‐induced hearing loss

Noise generated by instruments, such as mastoid or craniotomy drills, may cause hearing damage by reducing the cochlear blood flow (CoBF). This study investigated whether dexmedetomidine can lessen noise-induced hearing loss (NIHL) in a guinea pig model. Animal study using noise stimulation and measurement of hearing and CoBF in guinea pigs. Guinea pigs (n = 8 animals/group) were treated by saline vehicle (control group), dexmedetomidine (1, 3, and 10 μg/kg dex groups), saline and noise (noise group), or 3 μg/kg dexmedetomidine and noise (dex+noise group). For noise exposure, octave band noise at 124 dB sound pressure level was administered to animals for 2 hours. Blood pressure (BP) and CoBF were monitored continuously. Auditory function was measured by the auditory brain-stem response (ABR) before and 1 hour, 3 hours, 8 hours, and 10 days after noise exposure. Plasma norepinephrine (NE) was measured at baseline and 30, 60, 90, and 120 minutes after noise exposure by high-performance liquid chromatography (HPLC). Noise exposure caused temporary and permanent hearing damage. Dexmedetomidine concentrations of 1 μg/kg and 3 μg/kg dose dependently improved CoBF. Administration of 10 μg/kg dexmedetomidine drastically reduced BP and CoBF. Pretreatment with 3 μg/kg dexmedetomidine alleviated the noise-induced reduction in CoBF and improved hearing function by decreasing the permanent and temporary threshold shifts. Dexmedetomidine displayed protective effects against NIHL in this animal model, suppressing activation of the sympathetic nervous system and improving CoBF. These findings could have clinical relevance and deserve further investigation.

Protective Role of Hydrogen Sulfide against Noise-Induced Cochlear Damage: A Chronic Intracochlear Infusion Model

BackgroundA reduction in cochlear blood flow plays an essential role in noise-induced hearing loss (NIHL). The timely regulation of cochlear perfusion determines the progression and prognosis of NIHL. Hydrogen sulfide (H2S) has attracted increasing interest as a vasodilator in cardiovascular systems. This study identified the role of H2S in cochlear blood flow regulation and noise protection.Methodology/Principal FindingsThe gene and protein expression of the H2S synthetase cystathionine-γ-lyase (CSE) in the rat cochlea was examined using immunofluorescence and real-time PCR. Cochlear CSE mRNA levels varied according to the duration of noise exposure. A chronic intracochlear infusion model was built and artificial perilymph (AP), NaHS or DL-propargylglycine (PPG) were locally administered. Local sodium hydrosulfide (NaHS) significantly increased cochlear perfusion post-noise exposure. Cochlear morphological damage and hearing loss were alleviated in the NaHS group as measured by conventional auditory brainstem response (ABR), cochlear scanning electron microscope (SEM) and outer hair cell (OHC) count. The highest percentage of OHC loss occurred in the PPG group.Conclusions/SignificanceOur results suggest that H2S plays an important role in the regulation of cochlear blood flow and the protection against noise. Further studies may identify a new preventive and therapeutic perspective on NIHL and other blood supply-related inner ear diseases.

Commentary on “Occupational Noise, Smoking and a High Body Mass Index are Risk Factors for Age-Related Hearing Impairment and Moderate Alcohol Consumption is Protective: a European Population-Based Multicentre Study” by Fransen et al., J. Assoc. Res. Otolaryngol. DOI 10.1007/s10162-008-0123-1

Commentary on “Occupational Noise, Smoking and a High Body Mass Index are Risk Factors for Age-Related Hearing Impairment and Moderate Alcohol Consumption is Protective: a European Population-Based Multicentre Study” by Fransen et al., J. Assoc. Res. Otolaryngol. DOI 10.1007/s10162-008-0123-1

Hyperbaric oxygen in the treatment of sudden deafness

Currently, the treatment of sudden deafness (SD) is based mainly on complete bed rest and the administration of corticosteroids. Hyperbaric oxygen therapy (HBOT) has previously been suggested as adjunctive treatment. We describe two cases of successful HBOT for SD. The first patient presented with moderate mid-frequency hearing loss without accompanying symptoms, whereas the second patient had moderate low-frequency hearing loss with persistent tinnitus and a single episode of vertigo. HBOT in addition to conventional treatment soon after diagnosis resulted in full recovery of hearing in both patients. The pathogenesis of SD may involve a reduction in cochlear blood flow and perilymph oxygenation, making early HBOT a reasonable treatment modality for this condition.

Free radical scavengers vitamins A, C, and E plus magnesium reduce noise trauma

Free radical formation in the cochlea plays a key role in the development of noise-induced hearing loss (NIHL). The amount, distribution, and time course of free radical formation have been defined, including a clinically significant formation of both reactive oxygen species and reactive nitrogen species 7–10 days after noise exposure. Reduction in cochlear blood flow as a result of free radical formation has also been described. Here we report that the antioxidant agents vitamins A, C, and E act in synergy with magnesium to effectively prevent noise-induced trauma. Neither the antioxidant agents nor the magnesium reliably reduced NIHL or sensory cell death with the doses we used when these agents were delivered alone. In combination, however, they were highly effective in reducing both hearing loss and cell death even with treatment initiated just 1 h before noise exposure. This study supports roles for both free radical formation and noise-induced vasoconstriction in the onset and progression of NIHL. Identification of this safe and effective antioxidant intervention that attenuates NIHL provides a compelling rationale for human trials in which free radical scavengers are used to eliminate this single major cause of acquired hearing loss.

Mechanisms of noise-induced hearing loss indicate multiple methods of prevention

Recent research has shown the essential role of reduced blood flow and free radical formation in the cochlea in noise-induced hearing loss (NIHL). The amount, distribution, and time course of free radical formation have been defined, including a clinically significant late formation 7–10 days following noise exposure, and one mechanism underlying noise-induced reduction in cochlear blood flow has finally been identified. These new insights have led to the formulation of new hypotheses regarding the molecular mechanisms of NIHL; and, from these, we have identified interventions that prevent NIHL, even with treatment onset delayed up to 3 days post-noise. It is essential to now assess the additive effects of agents intervening at different points in the cell death pathway to optimize treatment efficacy. Finding safe and effective interventions that attenuate NIHL will provide a compelling scientific rationale to justify human trials to eliminate this single major cause of acquired hearing loss.

Preventing internal auditory artery vasospasm using topical papaverine: an animal study.

Internal auditory artery (IAA) spasm is thought to be one of the causes of postoperative sensory hearing loss after attempted hearing preservation removal of an acoustic neuroma. The use of topical papaverine, a nonspecific vasodilator, to prevent vascular insufficiency to the inner ear and to improve hearing outcomes has been suggested but not proven. Vasospasm was mechanically induced by compressing the IAA in the control ears of six rabbits after application of topical saline. The subsequent reduction of cochlear blood flow (CBF) was measured using a laser-Doppler (LD) flow-monitoring technique. Functional loss of cochlear activity was verified with distortion product otoacoustic emissions (DPOAE). The contralateral experimental ears were treated with the topical application of papaverine directly to the IAA and cochleovestibular nerve complex. CBF and DPOAE were compared between the control and papaverine treated ears for 3-minute and 5-minute IAA compressions. Every control ear demonstrated some degree of postcompression IAA vasospasm (i.e., reduced CBF) and reduction of DPOAE. Nearly complete recovery of CBF and DPOAE to baseline was observed in all of the papaverine treated ears. An animal model of IAA vasospasm was described. Mechanically induced vasospasm of the IAA was prevented by the topical application of papaverine. These findings have clinical implications for surgical procedures involving the internal auditory canal/cerebellopontine angle such as acoustic neuroma removal.

Effects of round window membrane rupture on cochlear blood flow and endocochlear potential

The degree of hearing loss and audiogram shape vary in patients with perilymphatic fistula. The cause of variability is not well known. To determine the effect of perilymphatic fistula on cochlear function, we studied the effect of round window membrane rupture on cochlear blood flow (CBF) by placing a laser-Doppler probe to the basal turn in 20 guinea pigs. In 10, endocochlear potential (EP) was measured by inserting a glass microelectrode through the stria vascularis of the basal turn. During 60 minutes following round window membrane rupture, CBF decrease of more than 15% was observed in 9 of 20 animals, and EP decrease of more than 15% was observed in 5 of 10. A significant correlation was observed between the degree of CBF reduction and EP reduction. In 3 animals in which CBF decreased after round window membrane rupture, temporal bones were studied histologically. One cochlea showed endolymphatic hydrops and another cochlea showed significant hemorrhage in the scala tympani after rupture. These results suggested that CBF impairment is associated with cochlear dysfunction in perilymphatic fistula.

Effects of Neuropeptide Y on Cochlear Blood Flow in Guinea Pigs

The aim of this study was to clarify the effects of neuropeptide Y (NPY) on cochlear blood flow (CBF) in pigmented guinea pigs. NPY was administered with or without noradrenaline (NA) by systemic perfusion or perilymphatic local perfusion, and CBF was measured using a laser Doppler flowmeter. The systemic and perilymphatic administrations of NPY with NA induced greater prolongation of the increase in and recovery of CBF than the administration of NA or NPY alone. Continuous reduction in CBF induced by NPY may play an important role in the pathogenesis of stress-induced sensorineural hearing losses, such as sudden deafness.

Effects of Neuropeptide Y on Cochlear Blood Flow in Guinea Pigs

The aim of this study was to clarify the effects of neuropeptide Y (NPY) on cochlear blood flow (CBF) in pigmented guinea pigs. NPY was administered with or without noradrenaline (NA) by systemic perfusion or perilymphatic local perfusion, and CBF was measured using a laser Doppler flowmeter. The systemic and perilymphatic administrations of NPY with NA induced greater prolongation of the increase in and recovery of CBF than the administration of NA or NPY alone. Continuous reduction in CBF induced by NPY may play an important role in the pathogenesis of stress-induced sensorineural hearing losses, such as sudden deafness.

Laser Doppler measurements of inner ear blood flow during experimental thrombosis of cochlear blood vessels in the guinea pig.

This study investigated the vascular effect of ferromagnetic obstruction of cochlear blood vessels in the guinea pig using dual-channel laser Doppler flowmetry. To improve this technique, we tested new types of magnets and iron spheres. In so doing, the cochlear temperature was lowered selectively and general hypothermia was avoided. The success of vascular impairment in the inner ear was found to depend on the experimental conditions used. Given normothermic conditions (38 degrees C body temperature), a clear reduction in cochlear blood flow (CBF) was found in only about 30% of the animals tested when an aluminium-nickel-cobalt alloy magnet and carbonyl iron spheres were used, while this ratio increased to about 80% under general hypothermia (33 degrees C). Using a stronger neodymium-iron-boron magnet and smaller-sized iron spheres, we found the success of vascular obstruction to be approximately 70% under normothermia and 100% with local hypothermia (to 33 degrees C) of the cochlea. Although the extent of vascular impairment revealed a considerable interindividual variation, the present findings demonstrate that ferromagnetic intervention in CBF with dual-channel laser Doppler flowmetry can be used to investigate the effect of quantified cochlear ischemia on inner ear physiology in the guinea pig model and test various therapeutic strategies.

Blood Flow-independent Accumulation of Cisplatin in the Guinea Pig Cochlea

Considerable interindividual variability in the ototoxic effect of cisplatin has become the unpredictable dose-limiting factor in its use as curative as well as palliative therapy. The drug accumulates in highly vascular areas in the cochlea, causing dose-related hair cell loss. The purpose of this study was to assess blood flow-dependent aspects of cisplatin absorption in the cochlea in order to better understand factors that may influence cisplatin-induced ototoxicity. The effect of reduced cochlear blood flow on the ototoxic action of cisplatin was studied in guinea pigs. Before cisplatin administration the cochlear vasculature in each animal was unilaterally pre-constricted, by the application of 2% epinephrine to the round window. A 20-30% reduction in cochlear blood flow, assessed by laser Doppler flowmetry, was maintained before and after intravenous infusion of 0.1% cisplatin. Cisplatin infusion affected cochlear blood flow but not vessel conductivity. The cochlear blood flow decrease, maintained by local epinephrine application to the round window during cisplatin infusion, did not alter the cisplatin-induced hearing loss. In addition, the concentration of free cisplatin in scala tympani perilymph did not differ between epinephrine-treated and non-treated ears. Our results indicate that cisplatin transport into the cochlea is not an energy-dependent process in the lateral wall vasculature.

Noise-induced cochlear hypoxia is intensity dependent, correlates with hearing loss and precedes reduction of cochlear blood flow.

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.