Blood circulation disturbances contribute to the hearing loss in loud-sound induced trauma, aging, M?ni?re's disease, ototoxic drugs and some forms of sudden deafness. Knowledge of inner ear vascular physiology is fundamental to understanding and treating these hearing conditions, but the field remains poorly explored. The long-term goal of this lab is to determine the common and unique patho-physiological mechanisms of cochlear vessels, the key neurohumoral messengers, receptors and channels responsible for cochlear blood flow regulation, and to discover drugs for prevention and treatment of these hearing losses. Our previous studies have found that the cochlear spiral modiolar artery (SMA) has unique vascular tone control mechanisms in resting membrane potential (RP) regulation and neuromuscular transmission. Based on these findings, this proposal sets the following aims: 1) to determine the mechanism and significance that underlie the bi-modal RP distribution of the SMA cells and the mechanism by which ischemia/reperfusion causes the change of the RP distribution and vasotone response;2) to determine the ion channel(s) and receptor type(s) that mediate the actions of the candidate neurotransmitters (e.g., norepinephrine, acetylcholine, CGRP);3) to identify the role of candidate neurotransmitters in intrinsic neuromuscular transmission in the SMA. These goals will be achieved through experiments using conventional and whole-cell current- and voltage-clamp recording methods on the in vitro vascular smooth muscle cells (VSMC), plus multiple approaches such as computational modeling, vaso-diameter tracking, nitric oxide production- monitoring, immunocytochemistry, RT-PCR and Western blot analyses. With these studies, we expect to find that the Key channel protein, Kir, co-plays with other persistent membrane currents, such as KATP and Na+-K+-pump currents, to generate the bimodal RP and thus to achieve a high autoregulation capacity of cochlear blood flow. We also anticipate that ischemia/reperfusion treatment will cause up-regulation of nitric oxide production, KATP and Kir expression, and thus cause the RP population shift and the vascular responsiveness change. The novel neuromuscular transmission and various drug effects will be characterized. The knowledge obtained will improve our understanding of how cochlear blood flow is regulated and what are the key factors causing cochlear circulation-deficiency, thus contributing to better prevention and treatment of the circulation-implicated hearing loss, and even the heart attack &stroke.
The knowledge obtained should improve our understanding of how cochlear blood flow is uniquely regulated, thus contributing to understanding of circulation-related hearing losses and leading to prevention and treatment of these hearing conditions. The acquired knowledge should also be of significance in broad areas of cardiovascular physiology, and cadiovascular disease pathophysiology.
|Wang, Tian; Yang, Yu-Qin; Karasawa, Takatoshi et al. (2013) Bumetanide hyperpolarizes madin-darby canine kidney cells and enhances cellular gentamicin uptake by elevating cytosolic Ca(2+) thus facilitating intermediate conductance Ca(2+)--activated potassium channels. Cell Biochem Biophys 65:381-98|
|Li, Xin-Zhi; Ma, Ke-Tao; Guan, Bing-Cai et al. (2013) Fenamates block gap junction coupling and potentiate BKCa channels in guinea pig arteriolar cells. Eur J Pharmacol 703:74-82|
|Wu, T; Song, L; Shi, X et al. (2011) Effect of capsaicin on potassium conductance and electromotility of the guinea pig outer hair cell. Hear Res 272:117-24|
|Wu, T; Dai, M; Shi, X R et al. (2011) Functional expression of P2X4 receptor in capillary endothelial cells of the cochlear spiral ligament and its role in regulating the capillary diameter. Am J Physiol Heart Circ Physiol 301:H69-78|
|Ma, Ke-Tao; Guan, Bing-Cai; Yang, Yu-Qin et al. (2011) 2-Aminoethoxydiphenyl borate blocks electrical coupling and inhibits voltage-gated K+ channels in guinea pig arteriole cells. Am J Physiol Heart Circ Physiol 300:H335-46|
|Ma, Ke-Tao; Guan, Bing-Cai; Yang, Yu-Qin et al. (2008) ACh-induced depolarization in inner ear artery is generated by activation of a TRP-like non-selective cation conductance and inactivation of a potassium conductance. Hear Res 239:20-33|
|Guan, B-C; Si, J-Q; Jiang, Z-G (2007) Blockade of gap junction coupling by glycyrrhetinic acids in guinea pig cochlear artery: a whole-cell voltage- and current-clamp study. Br J Pharmacol 151:1049-60|
|Jiang, Zhi-Gen; Shi, Xiao-Rui; Guan, Bing-Cai et al. (2007) Dihydropyridines inhibit acetylcholine-induced hyperpolarization in cochlear artery via blockade of intermediate-conductance calcium-activated potassium channels. J Pharmacol Exp Ther 320:544-51|
|Jiang, Zhi-Gen; Nuttall, Alfred L; Zhao, Hui et al. (2005) Electrical coupling and release of K+ from endothelial cells co-mediate ACh-induced smooth muscle hyperpolarization in guinea-pig inner ear artery. J Physiol 564:475-87|
|Jiang, Zhi-Gen; Shi, Xiaorui; Zhao, Hui et al. (2004) Basal nitric oxide production contributes to membrane potential and vasotone regulation of guinea pig in vitro spiral modiolar artery. Hear Res 189:92-100|