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Functional plasticity of autonomic pelvic ganglia in rat models of overactive bladder

Other Titles
 과민성방광 쥐 모델에서 자율골반신경절의 기능적 가소성 
Issue Date
Dept. of Medicine/박사
Peripheral autonomic major pelvic ganglion (MPG) neurons are essential for the generation of storage and voiding reflexes. Under certain pathophysiological conditions such as spinal cord injury and chronic cystitis, plastic alterations in MPG neurons may cause abnormal functions of the bladder. Benign prostatic hyperplasia (BPH), a common problem affecting middle-aged and elderly men, is characterized by the overgrowth of prostatic tissue surrounding the urethra which causes lower urinary tract symptoms (LUTS) such as urgency, frequency, nocturia, incomplete bladder emptying, and weak urine flow. Overactive bladder (OAB) is a syndrome characterized by urinary urgency with frequency and nocturia. To date, neurogenic mechanisms underlying OAB remain poorly understood. The hypothesis of the present study is that OAB is associated with changes in functions of MPG and dorsal roots ganglion (DRG) neurons in bladder outlet obstruction (BOO) rat models. To prove the hypothesis it was examined whether partial BOO alters expression and activity of nicotinic acetylcholine receptors (nAChRs) involved in synaptic transmission within MPG, and excitability of MPG and DRG neurons innervating the urinary bladder. Toward this end, rat models of partial urethral obstruction (PUO) and BPH were produced by partial urethra ligation and sc injection of testosterone/17--estradiol, respectively. The bladder muscles were hypertrophied in PUO and BPH rats. Cystometry revealed that PUO and BPH increased bladder capacity, threshold pressure for voiding, micturition volume, residual volume after voiding, and intermicturition oscillatory frequency, indicating development of OAB. Real-time PCR analysis showed that the nAChRs 3 and β4 subunits were up-regulated in MPG neurons of BOO rats. Then, nAChR currents were measured in DiI-labeled sympathetic and parasympathetic MPG neurons innervating the bladder detrusor muscles. As results, nAChR current densities were significantly increased in parasympathetic MPG neurons, but not in sympathetic PG neurons. Taken together, these data suggest that BOO-induced OAB is associated with phenotype-specific up-regulation of nAchRs in the MPG neurons innervating the bladder. Under the current-clamp mode of the patch-clamp technique, action potentials were recorded in DRG and MPG neurons of control and BOO rats. BOO produced hyperexcitability of the bladder DRG and MPG neurons via reducing rheobase and AHP duration. One of the ionic mechanisms underlying the hyperexcitability is up-regulation of T-type Ca2+ channels expressed in DRG and sympathetic MPG neurons. The decreased AHP duration also suggest that expression of Ca2+-activated Cl- and/or K+ (i.e., SK channels) might be altered in the bladder DRG and MPG neurons of BOO rats. In conclusion, BOO-induced OAB might be associated with enhanced ganglionic transmission and/or hyperexcitability of peripheral autonomic motor and sensory neurons innervating the bladder. Clinically, use of T-type Ca2+ channel blockers might be a potential option of pharmacologic management of OAB
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