兔膀胱出口部分梗阻模型逼尿肌中内皮素（ET(A)和ET(B)）受体上调及一氧化氮合酶下调

Up-regulation of endothelin (ET(A) and ET(B)) receptors and down-regulation of nitric oxide synthase in the detrusor of a rabbit model of partial bladder outlet obstruction.

作者信息

Khan M A, Dashwood M R, Thompson C S, Mumtaz F H, Mikhailidis D P, Morgan R J

机构信息

Department of Urology, Royal Free Hospital, London, UK.

出版信息

Urol Res. 1999 Dec;27(6):445-53. doi: 10.1007/s002400050134.

DOI:10.1007/s002400050134

PMID:10651133

Abstract

Bladder outlet obstruction (BOO) is associated with altered bladder structure and function. Endothelin-1 (ET-1) has mitogenic and potent contractile properties. There are two ET receptors: ET(A) and ET(B). Nitric oxide synthase (NOS) is the enzyme responsible for the synthesis of nitric oxide (NO) which is involved in smooth muscle relaxation. We investigated whether there are any changes in the density of ET-receptors and NOS in the detrusor and bladder neck in a rabbit model of BOO. Partial BOO was induced in adult male New Zealand White rabbits. Sham operated age-matched rabbits acted as controls. After six weeks the urinary bladders were excised and detrusor and bladder neck sections incubated with radioligands for ET-1, ET(A) and ET(B) receptors and with [3H]-1-NOARG (a ligand for NOS). NADPH histochemistry was also performed. BOO bladder weights were significantly increased (P = 0.002). ET-1 binding and ETA receptor binding sites were significantly increased in the BOO detrusor smooth muscle (P = 0.04, P = 0.03 respectively) and urothelium (P = 0.002, P = 0.02 respectively). ET(B) receptor binding sites were also significantly increased in the BOO detrusor smooth muscle (P = 0.04). However, there was no change in the BOO bladder neck. NOS was significantly decreased in the detrusor smooth muscle (P = 0.003) and urothelium (P = 0.0002). In the bladder neck NOS was also significantly reduced in the urothelium (P = 0.003). NADPH staining was decreased in the detrusor and bladder neck. The up-regulation of ET receptors along with the down-regulation of NOS in the detrusor may contribute to the symptoms associated with BOO. Since ET-1 has a mitogenic role, especially via its ETA receptors, the increase in ETA receptors may also be involved in detrusor hyperplasia and hypertrophy in BOO. ET antagonists may therefore have a role in the treatment of patients with BOO.

摘要

膀胱出口梗阻（BOO）与膀胱结构和功能改变相关。内皮素-1（ET-1）具有促有丝分裂和强大的收缩特性。有两种ET受体：ET(A)和ET(B)。一氧化氮合酶（NOS）是负责合成一氧化氮（NO）的酶，NO参与平滑肌舒张。我们研究了在BOO兔模型中，逼尿肌和膀胱颈中ET受体及NOS的密度是否有变化。对成年雄性新西兰白兔诱导部分BOO。年龄匹配的假手术兔作为对照。六周后切除膀胱，将逼尿肌和膀胱颈切片与ET-1、ET(A)和ET(B)受体的放射性配体以及[3H]-1-NOARG（NOS的一种配体）一起孵育。还进行了NADPH组织化学检测。BOO膀胱重量显著增加（P = 0.002）。BOO逼尿肌平滑肌（分别为P = 0.04，P = 0.03）和尿路上皮（分别为P = 0.002，P = 0.02）中ET-1结合和ETA受体结合位点显著增加。BOO逼尿肌平滑肌中ET(B)受体结合位点也显著增加（P = 0.04）。然而，BOO膀胱颈中没有变化。逼尿肌平滑肌（P = 0.003）和尿路上皮（P = 0.0002）中NOS显著降低。在膀胱颈中，尿路上皮的NOS也显著降低（P = 0.003）。逼尿肌和膀胱颈中的NADPH染色减少。逼尿肌中ET受体的上调以及NOS的下调可能导致与BOO相关的症状。由于ET-1具有促有丝分裂作用，尤其是通过其ETA受体，ETA受体的增加也可能参与BOO中的逼尿肌增生和肥大。因此，ET拮抗剂可能在BOO患者的治疗中发挥作用。