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Regulation of Endolymphatic Fluid Volume

ALEC N. SALT Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri 63110, USA

ABSTRACT: Direct measurements of the dispersal of markers in endolymph have failed to support previously established hypotheses of endolymph homeostasis, specifically longitudinal flow, radial flow, and dynamic flow theories. Rather, they suggest that in the normal state endolymph is maintained without a significant involvement of volume flow at all. Ions appear to be transported into and out of the endolymphatic space in a similar manner to that for a single cell, with each ion transport process contributing to the electrolyte pool. In abnormal volume states, however, longitudinal volume flow of endolymph may contribute to homeostasis. Procedures that enlarge the endolymphatic space result in endolymph flow toward the base of the cochlea, contributing to the removal of electrolytes and volume. Similarly, procedures that decrease cochlear endolymph volume induce apically directed flow in the cochlea, contributing to the addition of electrolytes and volume to the endolymphatic space. The endolymphatic sac responds to endolymph volume disturbance, showing opposite responses to volume increases and decreases. Although evidence is still limited, the endolymphatic sac appears to act as a "bidirectional overflow" system. While volume disturbances originating from out-of-balance transport processes anywhere in the labyrinth may be corrected by the sac, dysfunction of the sac itself is likely to have a substantial effect on endolymph status. KEYWORDS: Endolymph; Endolymphatic hydrops; Meniere's disease

ENDOLYMPH TURNOVER The rates of turnover of ions in cochlear endolymph have been established with radiotracer methods. In guinea pigs, endolymph K+, Cl-, and Na+ were shown to be exchanged with perilymph with half-times of 55, 69, and 33 min, respectively.1,2 Comparable rate constants were determined in rats following systemic administration of radiotracer,3 supporting the concept that endolymph ion exchange occurs predominantly with perilymph rather than blood plasma. There are a number of possible mechanisms by which turnover of endolymph electrolytes could be accomplished. One possibility is that it represents a turnover of endolymph volume, with "new" endolymph, including water and all solutes, being secreted in one area and "old" endolymph being removed at another location. Alternatively, the ion turnover may be accomplished by ion transport processes across boundary tissues that may or may not involve significant movements of water, and hence may not have direct or signif-

Address for correspondence: Alec N. Salt, Ph.D., Department of Otolaryngology, Box 8115, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. Voice: (314) 362-7560; fax: (314) 362-7522. [email protected]

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icant impact on volume status. Because the primary difference between these two mechanisms is whether water movements participate in electrolyte movements in the form of volume flow, it is important to differentiate conceptually between ion flows carried by volume flow and ion flows driven by concentration and electrical gradients that may exist in the absence of any volume flow.Volume flow will always result in an associated flow of dissolved solutes, but an ionic flow does not prove that volume flow is occurring unless other mechanisms, such as diffusion, convection, effects of gravity on dense particles, etc., are specifically excluded. Numerous ambiguities exist in the literature when flow of solutes has not been adequately differentiated from volume flow, and in some cases the conclusion of volume flow is not adequately supported. ROLE OF LONGITUDINAL VOLUME FLOWS When a marker is injected into the endolymphatic space, there are many physical processes that can contribute to its spread other than longitudinal volume flow. Since the marker is at its highest concentration near the injection site, it will spread to other regions by diffusion down the prevailing concentration gradient. For particulate markers, such as erythrocytes or solutions of varying density, a density difference relative to the inner ear fluids may allow the substance to move under the action of gravity. Charged substances may be moved by electrical gradients. This may be significant in regions where large voltage gradients exist, such along the lumen of the ductus reuniens between the cochlear and the saccule. Within the cochlea, however, the small longitudinal gradient of endocochlear potential can be calculated to have a negligible influence on longitudinal dispersal. Temperature gradients, if they exist, can induce convection movements. Finally, if the marker is injected in volume, the flow induced by the injection procedure itself must be considered. The most definitive experiments from which longitudinal endolymph flow rate can be derived are those in which marker movements basally and apically away from an injection site were compared simultaneously. Experimental studies in which a marker was iontophoresed into endolymph without volume disturbance found similar spread characteristics in both apical and basal directions, demonstrating that marker movements were dominated by diffusion rather than flow.4,5 The flow rates estimated in these studies were 0.004 and 0.007 mm/min, respectively, rates that were not significantly different from zero. Because it has been calculated that longitudinal flow would have to be as high as 0.2 mm/min to account for the documented turnover of endolymph electrolytes,6 the observation of flow rates substantially lower than this indicates that the majority of ion turnover is accounted for by local mechanisms unrelated to longitudinal flow. Although these studies suggest the standing rate of longitudinal endolymph flow is exceedingly small and does not contribute significantly to homeostasis in the normal state, endolymph flow can be induced under some conditions that can contribute to homeostasis. Injections into the endolymphatic space of volumes greater than 80 nl have been shown to induce flow directed to the base.7 Thus, for the many prior studies in which markers were injected into endolymph in volume,8,9 the observed basally directed flow can be regarded to be an artifact of the injection procedure and does not represent the physiologic state. In contrast, when endolymph volume was

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reduced by perfusion of the perilymphatic spaces with hypertonic medium, an apically directed endolymph flow was induced of sufficient magnitude to contribute to the addition of electrolytes to the endolymphatic space.5 It therefore appears that longitudinal endolymph flow can be basally or apically directed under conditions of volume disturbance, but is almost absent when volume is not disturbed. Recent studies indicate that at least part of the flow to or from the base under conditions of volume disturbance is directed to or from the endolymphatic sac. Rask-Andersen et al.10 showed that endolymph volume disturbances altered both the density and distribution of the stainable homogenous substance in the lumen of the endolymphatic sac and the morphology of the epithelial walls bounding the sac. An acute enlargement of the endolymphatic space by injection of artificial endolymph into the cochlea resulted in a loss of homogenous substance. In contrast, the reduction of endolymph volume by withdrawal of endolymph or by perfusion of the perilymphatic spaces with hypertonic solution resulted in an increase in density of the luminal substance in the sac. These observations confirm that the endolymphatic sac is highly sensitive to endolymph volume disturbances. ROLE OF RADIAL FLOW The suggestion that endolymph flows radially in volume, driven by bulk secretion at one tissue and resorption by another, has been speculated but never demonstrated experimentally. Naftalin and Harrison11 proposed that in order to account for K+ secretion and Na+ resorption, radial flow was directed from Reissner's membrane towards stria vascularis, this latter structure acting as a selective absorption site. Variants of the radial flow theory were supported by Lawrence et al.12 and were incorporated into a "dynamic flow theory,"13 a concept that attempted to reconcile data in support of local ion exchange and longitudinal flow by suggesting that both occurred. As stated above, however, the presence or contribution of radial volume flow has never been demonstrated experimentally. Furthermore, in view of the known turnover rate of endolymph, the contribution of radial volume flow to ionic movements can be calculated to be negligible. If one considers that half of the endolymph solutes are replaced in an hour, this would set the maximum radial flow rate to have moved fluid approximately halfway across the endolymphatic space (seen in cross section) in an hour. In contrast, it can be calculated that by diffusion, small solutes will distribute radially across the endolymphatic space within approximately 15 s. Thus, movements of solute by radial volume flow, if it even exists, would have a minimal influence on solute distribution because it is orders of magnitude slower than diffusion. Furthermore, if there were a radial flow, with local secretion and removal of endolymph, there should be a corresponding baseline rate of clearance for all substances. Our studies with exogenous markers have shown that cationic markers are cleared with varying half-times, but one anionic marker, AsF6-, showed dispersal characteristics that were accounted for almost totally by longitudinal diffusion, with extremely low clearance corresponding to a half-time of over 500 min.14 Such a low clearance should not be possible if endolymph turned over in volume. Thus, the evidence for a significant contribution of radial endolymph flow is very weak. The known turnover of ions can be totally accounted for by circulating radial currents, a major proportion of which are associated with the transduction process. Finally, the

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concepts of longitudinal flow and radial flow do not take into account the unique electrochemistry of the endolymph and energetic aspects of endolymph homeostasis. By virtue of the high endolymph potassium concentration, and in the cochlea the EP, potassium in endolymph is at high electrochemical potential with respect to cells bounding the space as well as to perilymph. The raised potential for K+ provides the energy to drive the transduction current through the hair cells. The elevation of K+ to this potential requires the expenditure of considerable metabolic energy, as indicated by the high metabolic rate of stria vascularis.15 To have expended such energy raising the electrochemical potential of K+, only to release endolymph volume by some local mechanism for the purposes of turnover, would be an energetically inefficient process. Instead, the local turnover of K+ represents the circulating current of K+, and thus a flow of K+, but no volume movements have yet been demonstrated to be associated with this ion flow. The concept that endolymph is secreted and resorbed locally in volume is therefore becoming increasingly unlikely.

"POOL" CONCEPT OF ENDOLYMPH HOMEOSTASIS In contrast to conventional, flow-based models of endolymph homeostasis, a working hypothesis has been adopted in which the endolymphatic system can be viewed as a series of "pools," as illustrated in FIGURE 1. There are many active and passive processes and many tissues that may in the steady state or periodically impact the status of the pool, of which some examples are shown below each pool. Flow between the compartments occurs as needed to balance the levels of the individual pools. In this simplified representation, flow would be driven by differences in height of the pools, but in the ear, flow would be driven by the elastic properties of the membranes bounding endolymph. Under this scheme, there may be volume disturbances of endolymph associated with each ion transport process, but they will only be relevant if the combined impact of all the processes acting on one compartment results in net volume loss or gain. Under these circumstances it may be possible that local volume regulation processes within the compartment may act to correct the disturbance. In the cochlea, there is evidence that small volume changes occurring at less than 5 nl/min are corrected locally, without inducing longitudinal flow.7 Increases or decreases of cochlear endolymph volume beyond the capacity of local mechanisms result in substantial longitudinal volume flows. For volume increases, flow is directed out of the cochlea through the ductus reuniens, and for volume decreases, flow is directed into the cochlea, flowing toward the apex. Local volume regulation processes in the saccule or in other vestibular structures (not shown) are similarly possible but have not yet been demonstrated. The endolymphatic sac is assumed to perform volume regulation with a greater capacity than other parts of the endolymphatic system. There are, however, no available quantitative measurements of the capacity of the sac to secrete or absorb endolymph, and the mechanisms involved in detection and correction of volume status remain to be demonstrated. It remains possible that in the undisturbed state an exceedingly small baseline longitudinal flow exists, which may not contribute significantly to ionic homeostasis, but which may play some essential role in volume regulation.

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FIGURE 1. "Pool" analogy for the role of endolymph volume flows in homeostasis. Endolymphatic compartments are represented as a number of pools connected by small ducts. Many transport processes may impact the volume status of each compartment as shown below each, but in the normal state the summed influence on volume is small. Local volume regulation processes may exist in each compartment. In the case of volume disturbances, flow to or from the endolymphatic sac may contribute to the restoration of normal volume. Vestibular structures (not shown) represent additional connected pools that may also influence volume of the system.

RELEVANCE TO ENDOLYMPHATIC HYDROPS AND MENIERE'S DISEASE A key principle of the above scheme is that longitudinal endolymph flow is not required to maintain the normal ionic composition of endolymph. This explains why, after surgical ablation of the endolymphatic sac, normal chemical composition of endolymph is maintained for weeks after hydrops develops.16,17 Ion concentrations eventually appear to decline as part of a complex cascade of secondary pathological changes. Equally important is an explanation for the development of hydrops following ablation of the sac. The important feature here is that chemical homeostasis of endolymph and volume homeostasis of endolymph appear to occur by distinct and possibly unrelated processes. It is conceivable that an extremely low rate of standing flow, less than 1 nl/min, may be present in the normal state which would have insignificant influence on marker dispersal and chemical homeostasis of endolymph, but could play an essential role in volume regulation. The origin of endolymphatic hydrops in humans is commonly believed to be the result of an overaccumulation of endolymph produced in the labyrinth or in a failure of the endolymphatic sac to absorb the excess volume. Acute manipulations of endolymph volume in animals have shown that the sac normally responds to excess endolymph volume by a loss of the luminal homogenous substance and responds to

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endolymph insufficiency by an increase in density of the luminal substance.10 Based on these observations, we would interpret the observation of an endolymphatic sac filled with dense luminal substance as an indication that the sac was producing endolymph volume. Examination of the endolymphatic sacs from patients with Meniere's disease has found a significantly higher incidence of eosinophilic intraluminal precipitate relative to non-Meniere controls.18 These findings suggest that even with endolymphatic hydrops present, endolymphatic sac morphology is consistent with the sacs secreting endolymph volume, raising the intriguing possibility that the hydrops may be caused by an inappropriate volume secretion by the sac.

ACKNOWLEDGMENT This work was supported in part by research grant DC01368 from the National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, Maryland.

REFERENCES 1. KONISHI, T., P.E. HAMRICK & P.J. WALSH. 1978. Ion transport in the guinea pig cochlea. I. Potassium and sodium transport. Acta Otolaryngol. 86: 22­34. 2. KONISHI, T. & P.E. HAMRICK. 1978. Ion transport in the cochlea of guinea pig. II. Chloride transport. Acta Otolaryngol. 86: 176­184. 3. STERKERS, O., G. SAUMON, P. TRAN BA HUY & C. AMIEL. 1982. K, Cl and H2O entry in endolymph, perilymph and cerebrospinal fluid in the rat. Am. J. Physiol. 243: F173­ 180. 4. SALT, A.N. & R. THALMANN. 1989. Rate of longitudinal flow of cochlear endolymph. In Meniere's Disease. J.B. Nadol, Ed.: 69­73. Kugler Press. Amsterdam. 5. SALT, A.N. & J.E. DEMOTT. 1995. Endolymph volume changes during osmotic dehydration measured by two marker techniques. Hear. Res. 90: 12­23. 6. SALT, A.N. & R. THALMANN. 1988. Interpretation of endolymph flow results. Hear. Res. 33: 279­284. 7. SALT, A.N. & J.E. DEMOTT. 1997. Longitudinal endolymph flow associated with acute volume increase in the cochlea. Hear. Res. 107: 29­40. 8. GUILD, S.R. 1927. The circulation of the endolymph. Am. J. Anat. 39: 57­81. 9. LUNDQUIST, P.G., R. K IMURA & J. WERSALL. 1964. Experiments in endolymph circulation. Acta Otolaryngol. Suppl. 188: 194­201. 10. RASK-ANDERSEN, H., J.E. D EMOTT, D. BAGGER-SJOBACK & A.N. S ALT. 1999. Morphological changes of the endolymphatic sac induced by microinjection of artificial endolymph into the cochlea. Hear. Res. 138: 81­90. 11. NAFTALIN, L. & M.S. HARRISON. 1958. Circulation of labyrinthine fluids. J. Laryngol. 72: 118­136. 12. LAWRENCE, M., D. WOLKS & W.B. LITTON. 1961. Circulation of the inner ear fluids. Ann. Otol. 70: 753­776. 13. LUNDQUIST, P.G. 1976. Aspects on endolymphatic sac morphology and function. Arch. Oto-Rhino-Laryngol. 212: 231­240. 14. SALT, A.N. & J.E. DEMOTT. 1994. Time course of endolymph volume increase in experimental hydrops measured in vivo with an ionic marker. Hear. Res. 74: 165­ 172. 15. THALMANN, R., J. KUSAKARI & T. MIYOSHI. 1973. Dysfunctions of energy releasing and consuming processes in the cochlea. Laryngoscope 83: 1690­1712. 16. KONISHI, T., A.N. SALT & R.S. KIMURA. 1981. Electrophysiological studies of experimentally induced endolymphatic hydrops in guinea pigs. In Meniere's Disease--

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Pathogenesis, Diagnosis and Treatment. K.H. Vosteen, H. Schuknecht, C.R. Pfaltz, et al., Eds.: 47­58. George Thieme Verlag. New York. 17. SZIKLAI, I., E. FERRARY, K.C. HORNER, O. STERKERS & C. AMIEL. 1992. Time-related alteration of endolymph composition in an experimental model of endolymphatic hydrops. Laryngoscope 102: 431­438. 18. IKEDA, M. & I. SANDO. 1984. Endolymphatic duct and sac in patients with Meniere's disease. Ann. Otol. Rhinol. Laryngol. 93: 540­546.

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