Effects of noise and quinine on the vessels of the stria vascularis: An image analysis study

Am J Otolaryngol 6:280-289, 1985

Effects of Noise and Quinine on the Vessels of the Stria Vascularis: An Image Analysis Study D. IAN SMITH,PH.D., MERLE LAWRENCE,PH.D., AND JOSEPHE. HAWKINS, JR., D.Sc. Surface preparations of the stria vascularis from guinea pigs exposed to wide-band noise or intoxicated with quinine monohydrochloride dihydrate were studied by light microscopy and computerized image analysis in order to evaluate quantitatively the effects of these agents on two characteristics of the strial vasculature: vascular density and erythrocyte distribution. An image analyzer was used to measure the area of strial vessel lumen and erythrocyte distribution as a fraction of the total area of strial tissue under observation. The results demonstrate that changes in the strial vessels do occur in guinea pigs exposed to noise or given large doses of quinine. Localized vessel narrowings caused by swollen endothelial cells and possibly by contraction of pericytes were found in both experimental groups, but there was no apparent tonotopical relationship between these effects and the reduction in cochlear potentials. A significant reduction in the number of erythrocytes was found in all turns of the cochlea in both experimental groups. Although a significant difference in vascular density was found among turns of the cochlea in both experimental and control animals, there was no widespread change in vascular density as a result of either noise exposure or quinine treatment.

It has long been assumed that some hearing disorders are caused by vascular changes in the inner ear or by vascular pathology affecting the blood supply to the labyrinth. Included in the list of types of hearing loss that have been attributed to vascular changes are presbycusis, sudden hearing loss, Meniere's disease, noiseinduced hearing loss, and the ototoxicity of quinine and salicylates. The suspicion of a vascular c o m p o n e n t in various t y p e s of hearing loss, however, is based primarily on clinical signs and speculation rather than on direct histologic evidence. Experimentation has provided seemingly conflicting evidence with regard to the possible efReceived December 7, 1984, from the Siegel Institute, Michael Reese Medical Center, and the Department of Surgery (Otolaryngology), University of Chicago, Chicago, Illinois (Dr. Smith), and the Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, Michigan (Drs. Lawrence and Hawkins). Accepted for publication March 12, 1985. Supported by NIH grants NS-07106 and NS-11731. Address correspondence and reprint requests to Dr. Smith: Siegel Institute, Michael Reese Medical Center, 3033 S. Cottage Grove Ave., Chicago, IL 60616.

fects of various traumatic agents on the cochlear vasculature in laboratory animals. Previous investigations have provided qualitative descriptions of increase, decrease, or absence of change in vessel caliber, and in red blood cell (RBC) distribution in cochlear vessels following noise exposure and quinine intoxication. One reason for this discrepancy is the difficulty in quantifying various measurements of the inner ear vasculature. The interpretation of results from many of these studies is made difficult by the variety of methodologies used and by the descriptive nature of their findings. Previous investigations have u s e d various agents to induce hearing impairment experimentally. Two methods of producing hearing loss in animals in the laboratory are exposure to noise and quinine intoxication, both of w h i c h have been thought to cause vascular changes. Studies of the effects of noise on cochlear microcirculation, 1-5 inner ear fluids, 6-11 and the capillary network of the cochlea 12-21 have provided evidence both for and against vascular changes following noise e x p o s u r e (see A x e l s s o n and Vertes 19 and Lawrence 22 for reviews of the lit-

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erature on this topic). Similarly, investigations of the ototoxicity of quinine have failed to provide a consensus regarding the possibility of vascular c h a n g e s . 12,23-32 With regard to both of these known ototraumatic agents, one important question remains unresolved: Are there changes in the strial vasculature concomitant with a decrement in cochlear and whole-nerve electrophysiology resulting from moderate-level noise exposure or quinine intoxication? The object of this study was to measure quantitatively vascular density and RBC distribution in the stria vascularis and to establish the presence or absence of changes in these d i m e n s i o n s associated with a previously defined reduction in cochlear and wholenerve action potentials induced by noise exposure or quinine intoxication. METHODS

Three groups of guinea pigs (a total of approximately 50 animals) were used in the experiment. They were placed in control, noise-exposed, and quinine-intoxicated categories. Cochlear microphonics (CM) and compound action potentials (CAP) were recorded using a roundwindow electrode in all animals. These biopotentials were used to m o n i t o r the changes in cochlear function induced in the experimental animals.

ElectrophysiologicRecordings Albino guinea pigs weighing between 275 and 350 g were lightly anesthetized with pentobarbital sodium (7.5 mg/kg intraperitoneally) and with a combination of droperidol and fentanyl citrate (Innovar-Vet) (0.2 ml/kg, intramuscularly) administered 15 minutes later. Atropine sulfate (0.125 ml/kg) was also administered intramuscularly to suppress hypersalivation and bradycardia. When necessary, supplemental doses of pentobarbital (3.7 mg/kg intraperitoneally) and Innovar-Vet (0.1 ml/kg intramuscularly) were administered. The animals were kept warm by a heating blanket, and rectal t e m p e r a t u r e was monitored with a thermistor. A light source directed at the head was used to maintain the temperature of the surgical field at rectal temperature (38.5~ The animals did not require artificial ventilation, and a head h o l d e r was not used. The bulla was exposed by a conventional postauricular dissection, and the pinna was re-

moved, leaving a ring of cartilage at the meatus to facilitate the connection of a sound speculum. Using a dental drill, a 1.5-mm-diameter hole was made in the ventral surface of the bulla, approximately 2 m m above the styloid process. A wire loop electrode (silver with a bare diameter of 0.076 mm) was guided through the hole in the bulla and placed on the round window membrane. A wire inserted into the neck muscles served as a r e f e r e n c e electrode. Continuous tones were used to produce CM. The pure tones were generated by a dynamic transducer and conveyed to the left ear by a sound tube. The sound tube was coupled to the auditory canal through a clear acrylic plastic speculum, which f o r m e d a tight seal with the cartilage of the meatus. Transient stimuli for eliciting CAP were produced by a 1.3-cm condenser microphone, which was coupled to the auditory canal with an acrylic speculum. Sound stimuli were either clicks (one cycle of a 10 kHz sine wave) presented every 100 msec, or tonal bursts of I msec rise-fall time w i t h a p p r o x i m a t e l y sinusoidal rising and falling envelopes. The tonal bursts were 10 msec in duration and were repeated every 100 msec. Sound levels for both pure tones and transient stimuli were measured in dB with reference to a 1-V input to the attenuator network. The recordings were c o n d u c t e d in a sound-attenuated, electrically shielded booth. The potentials were preamplified differentially 1,000-fold with band-pass settings at 30 Hz and 30 kHz. Cochlear microphonic voltage (RMS) was measured with a wave analyzer, and CAP thresholds and amplitudes were measured visually from an oscilloscope. The CM intensity functions were plotted from all animals (control and experimental) at 1.5 and 8.8 kHz to monitor general cochlear electrophysiology. Intensity functions were recorded at other frequencies (0.2, 0.7, and 3.0 kHz) in most animals. The CM response to increasingly loud pure tones was measured in 5-dB steps to the point of significant d e p a r t u r e from linearity (about 1 mV at 1.5 kHz). Stimuli were not presented at intensitites beyond this point to avoid overloading the ear. All stimuli were presented only long enough to permit accurate recordings of the CM. The CAP intensity functions were plotted for two control animals and 18 experimental ani~ mals to monitor general electrophysiologic per~ formance of the cochlear nerve. The CAP amplitude was recorded in 5-dB steps in response to increasingly loud click stimuli until a maximum

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CM output was elicited (by a 1.5-kHz tone) in the pre-exposure intensity function. Random noise levels ranged from 97 to 107 dB(C). After cessation of the noise exposure followed by a 30minute period of recovery, CM and CAP were again measured, and the animal was immediately killed. Quinine. Following the initial electrophysiologic monitoring, quinine monohydrochloride dihydrate dissolved in water (33 mg/ml) was injected in small doses intramuscularly. Total amounts given ranged from 67 mg/kg to 250 rag/ kg. Thirty minutes after each injection, the CAP in response to a click stimulus was monitored. Subsequent injections of the drug and monitoring of CAP were continued until a significant shift (15 dB or greater) in CAP to a click stimulus threshold was produced. A post-exposure measure of electrophysiologic function was then recorded, and the animal was immediately killed.

IMAGEANALYSIS SYSTEM

Figure 1. Block diagram of the image analyzing system. A camera scans the optical image of a surface preparation and produces a video signal, which is transmitted to the image analyzing system and converted to a digital signal composed of approximately 500,000 discrete picture points (Fig. 2, top). A light pen is used to trace directly on the monitor those features of the video image one wants to measure, i.e., blood vessels or RBCs (Fig. 2, bottom). The area measurements are relayed to a minicomputer (PDP-11/04), which computes the ratio of the number of picture points detected by the standard computer to the total number of picture points within the field image.

output was reached. The CAP amplitude was measured directly from the oscilloscope and was recorded as the peak-to-peak voltage of the first negative wave of the CAP relative to the baseline. The CAP thresholds to tonal bursts were measured in two control animals and 20 experimental animals. Response to tonal bursts of various frequencies (2, 4, 8, 16, 32, and 40 kHz) were measured in an attempt to monitor the electrophysiologic performance of different portions of the cochlea.

Light Microscopic Evaluation Surface preparations (whole mounts) from the lateral wall of the cochlear duct from animals in each group were obtained by a method based on that described by Engstrom et a l . 34 and by Hawkins and Johnsson. 35 The tissue was fixed and stained using 3.0 per cent glutaraldehyde in 0.1 M sodium cacodylate buffer (pH 7.2), followed by 1.0 per cent osmium tetroxide in 0.1 M sodium cacodylate, then dehydrated in steps from 35 to 70 per cent ethyl alcohol, and stored in 70 per cent alcohol at 4~ until they were dissected. Sections of the lateral wall and the organ of Corti were removed from each turn ( a p e x , T 3, T 2, base, and hook) and mounted in glycerol on glass slides under coverslips. The entire strial vasculature, throughout the length of the cochlea, was viewed in surface preparations from 12 cochleas: four control, four noise-exposed, and four quinine-intoxicated. The surface preparations were examined in a blind study using phase-contrast microscopy.

Induced Hearing Impairment Morphometric Evaluation

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of Otolaryngolagy 282

Experimental animals were exposed to noise or given quinine following the initial monitoring of electrophysiologic function. Noise. Each animal was exposed to random noise until the amplitude of the CM response to a 1.5-kHz tone was reduced by 20 dB in the linear portion of the intensity function. The intensity of the noise exposure was determined for each guinea pig based on its pre-exposure intensity function; noise was presented to the ear at 15 dB above the intensity at which the maximum

Surface preparations of the lateral wall of the cochlear duct were examined with an image analysis system (Fig. 1). Optical images of surface preparations were produced by a phase-contrast light microscope and then projected onto the image monitor. A light-pen was used to "edit" the image in order to distinguish the capillary lumen and RBCs from the surrounding tissue (Fig. 2). In each cochlea, measurements were obtained from six portions ("fields") of the stria,

SMITH ET AL. each of approximately 16,000 ~m 2, selected at random from the midportion of each of the four lower turns of the cochlea, and including nearly the entire apical turn. Measurements were made without prior knowledge of whether the tissue was from control or experimental animals. The image analysis system measured the area of the vessel lumen (A'L), the area of the portions of strial capillary lumen occupied with RBCs (and occasionally other blood cell types) (A'~Bc), and the area of the total field (A'F). Vascular density (A'L/A'F) and RBC distribution (A'RBc/A'F) were then computed.

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alterations in cochlear function were induced by the noise exposure and by the drug treatment. Figure 3 (top) summarizes the changes in electrophysiologic function for a representative animal following noise exposure (102 dB[C] for 45 minutes) and a 30-minute period of recovery. (The duration of the noise exposure required to produce a 20 dB reduction in the amplitude of the CM response to the 1.5-kHz tone ranged from 27 to 197 minutes.) In all subjects, CM response showed a tendency for greater loss at lower frequencies. The CAP t h r e s h o l d shifts for tone bursts below 16 kHz always showed a greater loss than the CM loss (at 1.5 kHz), while the response to higher frequencies was variable, with peak losses in the range of 8 kHz to 16 kHz. Figure 3 (bottom) summarizes the effects of quinine intoxication on CM response and clickand tone-burst-evoked CAP thresholds in one animal given quinine (200 mg/kg). Quinine had a selective effect on CAP threshold, although CM was suppressed in most animals. The results show a particular effect on CAP in response to high- and l o w - f r e q u e n c y tone bursts, with a lesser effect on intermediate frequencies.

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Figure 4. Phase-contrast micrographs of the stria vascularis from the endolymphatic surface. A, T 3 of control animal. Notice the high degree of hemoconcentration and the relative uniformity of the diameter of each individual vessel throughout its length. B, T 3 of a noiseexposed animal. Capillaries void of RBCs are seen. C, apex of a noise-exposed animal. A vessel narrowing is seen (arrow). D, 7 2 of a quinine-intoxicated animal. Capillaries void of RBCs are seen. E, apex of a quinine-intoxicated animal. A capillary narrowing is seen (arrow).

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Surface Preparations Figures 4A through 4E are phase-contrast phot o m i c r o g r a p h s of surface preparations of the stria vascularis (viewed from the endolymphatic surface). Figure 4A is from a control guinea pig. This micrograph illustrates two important characteristics of the normal stria vasculature: 1) There is a high degree of hemoconcentration. All strial vessels were invariably found to be completely filled with RBCs (other blood cell types were occasionally seen). In most vessels it was difficult to distinguish individual RBCs because of the extent to w h i c h they were p a c k e d together. 2) Strial capillaries are generally large in diameter. The caliber of individual vessels can vary greatly from one to another, within any portion of the stria. However, the diameter of each i n d i v i d u a l vessel remains relatively uniform throughout its length. Figures 4B through 4E are micrographs from noise-exposed and quinine-intoxicated animals which illustrate two important findings in the tissue from both experimental groups: 1) a reduction in the number of RBCs found in some of the strial vessels; and 2) an occasional narrowing of the vessel lumen, which appeared to be caused by swelling of endothelial cells, with possible involvement of surrounding pericytes.

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Measurements of vascular density were compiled from each of the three groups (control, noise-exposed, and quinine-intoxicated) by averaging the six field measurements (A'L/A'F) recorded from each turn, in each animal, by group (Fig. 5A). These data were evaluated with a factorial analysis of variance (ANOVA). The mean data show that there is a slight decrease in vascular density in the basal turn for both experimental groups. However, the ANOVA indicates that there is no statistically significant difference in vascular density among the three groups, in any of the five turns. The ANOVA s h o w s a highly significant difference (P < 0.01) in vascular density among turns of the cochlea, for each of the three groups, w i t h the basal turn showing the highest density.

RBC Distribution The results of the RBC distribution data for each group, by turn, are summarized in Figure 5B. These data were compiled for both experimental groups by averaging the six field mea-

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of change between the experimental groups and the control groups is approximately equal at each of the cochlea. Similar to the results seen in the vascular density data, there is a highly significant difference (P < 0.01) in the RBC distribution between turns, for each of the three groups.

Vessel Narrowings Figure 5C summarizes the results of the light microscopic evaluations of surface preparations for the incidence of vessel narrowings. The data were compiled in a blind study by averaging the number of vessel narrowings per millimeter of strial length found in each turn, from each animal, by group, for 12 animals. The results were transformed (by taking the square root of each averaged value) in order to fit better the requirements of the factorial analysis of variance test. The ANOVA indicates that there is a significant difference (P < 0.01) in the number of vessel narrowings between the control group and both experimental groups. The ANOVA also shows that for both the noise-exposed and the quinineintoxicated tissue, the increase in the incidence of vessel narrowings is approximately equal in each turn of the cochlea. DISCUSSION

The data collected in this study permitted a statistical analysis of quantitative measurements of the strial vessels in control and in experimental animals. The results of the measurements resolve some of the important questions raised by previous investigations concerning cochlear microcirculation by demonstrating that changes in the strial vessels do occur in guinea pigs exposed to noise or given large doses of quinine.

Vessel Narrowings

American JournQI of

Otolaryngology 286

Localized narrowings of the lumen in strial vessels were found in all turns of the cochlea in both noise-exposed and quinine-intoxicated animals. These vessel narrowings appear to be produced by swollen endothelial cells and possibly pericyte contraction. Similar changes in strial capillaries have been reported in previous studies following exposure to various agents: noise e x p o s u r e , 14,17,36,37 quinine intoxication, 27,31 salicylates, 27 antibiotics, 36 histamine, 38 bumetanide, 39 and in congenital deafness. 4~This phenomenon appears to represent a part of a general response of the strial vasculature to a

wide range of ototraumatic agents and other factors. It should be noted that similar narrowings were occasionally seen in some control animals, although at a significantly lower rate of incidence than in either experimental group. Important questions concerning the possible role of endothelial ceils and pericytes in controlling microcirculation remain u n r e s o l v e d . 41-47 Kimura and Ota 54 noted that strial pericytes contain filaments similar to those found in smooth muscle, yet conclusive evidence of active pericyte contraction is lacking. 47 Recent studies have reported contractile properties in capillaries in frog skeletal muscle 48 and rabbit and frog mesentery49'5~ in which electrical stimulation caused a bulging of endothelial nuclei into the lumen accompanied by a reduction or cessation of blood flow. Majno et el. 51 reported endothelial contraction induced by histamine-type mediators in the rat cremaster muscle, with no evidence of pericyte contraction. It has been suggested that the mechanism of this phenomenon involves the activity of specialized endothelial cells that contain contractile proteins. 51-53 Direct comparisons between the response of strial capillaries and the response of vessels from other organs may not be valid; strial capillaries are unique in being intraepithelial and are not innervated by autonomic fibers. 54 The changes in strial microcirculation found in this investigation involve a mechanism that differs from that responsible for the reduction in blood flow in the finger with auditory noise exposure. 55 The latter involves peripheral vasoconstriction mediated by the sympathetic nervous system, and possibly blood-borne vasoconstrictors (angiotensin II).56 Similarly, the effect of quinine seen on the strial vessels in this,study is in contrast to the reported effect of this drug on the retinal vessels, a phenomenon which has undoubtedly influenced theories on the ototoxicity of quinine. In quinine intoxication, the optic disk becomes pale as a result of extreme narrowing of the vessels along their entire length, 57-59 whereas in this study vessel narrowings were spotty. There are several mechanisms by which the agents used in this investigation may have induced the changes found in the strial vessels: changes in vessel permeability resulting from mechanical stimulation; and the local release of humoral mediators, such as histamine or prostaglandins, or other blood-borne hormones and metabolites. The expansion of the endothelial cells restricting the vessel lumen found with exposure to noise or quinine may result from osmotic changes induced by alterations in the en-

SMITHET AL. dothelial cell membrane. For example, recent studies have demonstrated that quinine blocks Ca + +-dependent K + permeability of mammalian hepatocytes and RBCs. 6~ A similar effect on the endothelial cell membrane may lead to an osmotic swelling of the cell or initiate an active expansion of the endothelium. RBC Distribution

The number of RBCs in the strial vessels decreased significantly in both experimental groups. This finding provides quantitative confirmation of results reported by Lawrence62 and by Duvall et al. 17 with regard to a reduction in RBCs following noise exposure and is in agreement with results from descriptive studies of cochlear vessels following q u i n i n e . 27'29 Lawrence 62 reported strial (and spiral) capillaries void of RBCs only in the portion of the cochlea believed to be maximally stimulated by the pure-tone (4 kHz) exposure. This result suggests that there may be a tonotopical relation between the frequency of the exposure and the portions of the cochlea in which changes in RBC content are found. If such a tonotopical relation does in fact exist, it is not surprising that in the current investigation changes in RBC distribution were found in all turns of the cochlea, as a wide-band noise exposure was used. The RBC distribution measurements provide an indirect measure of local hematocrit, which was reduced in the strial vessels in both experimental groups. It is assumed that plasma fills those portions of the vessel lumen void of RBCs. J o h n s o n 63 and Johnson et al. 64 investigated the microcirculation in the cat mesentery and found a direct relationship between RBC velocity and hematocrit in individual capillaries. They concluded that the hematocrit in a single capillary is not a direct function of absolute flow velocity, but rather is determined by the relative flow rate between the capillary and its feeding vessel, and the hematocrit in the feeding vessel. This effect was seen at the bifurcation of capillaries and at the branching of capillaries from larger vessels. They suggested that this effect was caused by the phenomenon of plasma skimming, which causes the unequal distribution of RBCs at the bifurcation of a vessel. Krogh41 had described this effect and observed that the contraction of a branch of an artery resulted in a decreased hematocrit in the downstream vessel. This relation between hematocrit and capillary blood flow velocity has been demonstrated in human skin vessels by Fagrell and Intaglietta. 65

The current study did not measure blood flow. However, it is possible to hypothesize that the reduction in local hematocrit found in both experimental groups was the result of a reduction in flow velocity in the strial vessels relative to the flow rate in the branches of the radiating arterioles supplying the strial network or in vessels farther upstream. To speculate further, it may be that the vessel narrowings or possible changes in vessel caliber in supplying arterioles are responsible for the inferred changes in flow velocity, an effect demonstrated with electrical stimulation of muscle and mesentery endothelium.48-50 SUMMARY

Localized vessel narrowings caused by swollen endothelial cells, with the possible involvement of pericytes, were found in the stria vascularis in guinea pigs with a defined loss of electrophysiologic performance resulting from either noise exposure or quinine intoxication. A significant reduction in RBC distribution was found in all turns of the cochlea in both noiseexposed and quinine-intoxicated animals as compared with control animals. Although a significant difference in vascular density was found among turns of the cochlea in both experimental and control animals, there was no widespread change in vascular density as a result of noise exposure or drug treatment. In humans, quinine intoxication and noise exposure cause similar patterns of hearing impairment: reduction of hearing acuity and tinnitus. The results of this study have demonstrated changes in the strial vessels induced by quinine and noise. Because of the similarity of their effects on hearing and the similarity in the vascular changes found in this investigation in noise-exposed and quinine-intoxicated animals, it is conceivable that a direct relationship exists between the changes seen in the strial vessels and the impairment of hearing associated with these agents. (Similar vascular changes have been described in animals following acute administration of sodium salicylate, 27 which also causes reduction of hearing acuity and tinnitus in humans.) Because there was no apparent tonotopical relation between the electrophysiologic changes recorded and the observed vascular changes, the existence of a causal relation between the latter and temporary hearing loss remains to be established. The methods developed in this study for obtaining quantitative measurements of vascular density and RBC distribution

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in cochlear vessels, together with techniques for measuring regional blood flow in the cochlea, provide a basis for further investigations of the relation between vascular disorders in the cochlea and hearing impairment.

References

21. 22. 23. 24.

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1. Perlman HB, Kimura RS: Cochlear blood flow and acoustic trauma. Acta Otolaryngol 54:99-110, 1962 2. Suga F: Cochlear functions and cochlear-blood flow in acoustic trauma. Jibi To Rinsho Otologia (Fukuoka) 8 (suppl 3):187-202, 1962 3. Hultcrantz E: The effect of noise on cochlear blood flow in the conscious rabbit. Acta Physiol Scand 106:2937, 1979 4. Hultcrantz E, Angelborg C, and Beausang-Linder M: Noise and cochlear blood flow. Arch Otorhinolaryngol 224:103-106, 1979 5. Prazma J, Vance SG, Bolster DE, et al: The effect of one hour of noise exposure on cochler blood flow. Read before the Association for Research in Otolaryngology, St. Petersburg, Fla, February 1984 6. Misrahy GA, Hildreth KM, Shinabarger EW, et al: Endolymphatic oxygen tension in the cochlea of the guinea pig. J Acoust Soc Am 30:247-250, 1958 7. Misrahy GA, Shinabarger EW, Arnold JE: Changes in cochlear endolymphatic oxygen availability, action potential, and microphonics during asphyxia, hypoxia, and exposure to loud sounds. J Acoust Soc Am 30:701-704, 1958 8. Misrahy GA, Arnold JE, Mundie JR, et al: Genesis of endolymphatic hypoxia following acoustic trauma. J Acoust Soc Am 30:1082-1088, 1958 9. Maass B, Baumgartl H, Lubbers DW: Messungen mit Nadelelektroden zum Studium der sauerstoff Nersorgung und Mikrozirkulation des Innenohres. Arch Otorhinolaryngol 214:109-124, 1976 10. Maass B, Baumgartl H, Lubbers DW: Lokale PO2- und pH2-Messungen mit Mikrokoaxialnadelektroden an der Basalwindung der Katzencochlea nach akuter oberer zernikaler Sympathekomie. Arch Otorhinolaryngol 221:269-284, 1978 11. Nuttall AL, Hultcrantz E, Lawrence M: Does loud sound influence the intracochlear oxygen tension? Hearing Res 5:285-293, 1981 12. Ruedi L: Some animal experimental findings on the functions of the inner ear. Trans Am Otol Soc 39:1848, 1951 13. Lawrence M, Gonzales F, Hawkins JE jr: Some physiological factors in noise-induced hearing loss. Am Ind Hyg Assoc J 28:425-430, 1967 14. Hawkins JE jr: The role of vasoconstriction in noise-induced hearing loss. Ann Otol Rhinol Laryngol 80:903-913, 1971 15. Kellerhals B: Pathogenesis of inner ear lesions in acute acoustic trauma. Acta Otolaryngol 73:249-253, 1972 16. Kellerhals B: Acoustic trauma and cochlear microcirculation. Adv Otol Rhino Laryngol 18:91-168, 1972 17. Duvall AJ, Ward WD, Lauhala KE: Stria ultrastructure and vessel transport in acoustic trauma. Ann Otol Rhinol Laryngol 83:498-514, 1974 18. Axelsson A, Vertes D: Methodological aspects for the study of cochlear blood vessels, in Portmann M, Aran JM (eds): Inner Ear Biology. Paris, Colloques INSERM, 1977, pp 265-270 19. Axelsson A, Vertes D: Histological findings in cochler vessels after noise, in Hamernik RP, Henderson D, Salvi DJ (eds): New Perspectives on Noise-Induced Hearing Loss. New York, Raven Press, 1982, pp 49-68 20. Axelsson A, Vertes D, Miller J: Immediate noise effects

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43.

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