Endolymphatic hydrops induced by different mechanisms responds differentially to spironolactone: a rationale for understanding the diversity of treatment responses in hydropic inner ear disease

Abstract

Background: The exact pathophysiological mechanism(s) underlying endolymphatic hydrops (EH) remain elusive. We have previously shown that chronic administration of vasopressin and inhibitors of the cAMP/cGMP degrading enzymes (PDE3, PDE4, PDE5) results in the development of EH to mice.

Aims/objectives: Evaluate the ability of spironolactone, an aldosterone antagonist, to prevent EH, when induced by different pathways.

Material and methods: Mice were treated for 4 weeks with vasopressin, the PDE3 inhibitor cilostamide and the PDE4 inhibitor rolipram in the presence or absence of spironolactone. EH was assessed using high resolution 9.4T MRI. The expression of proteins in human saccule sensory epithelium was studied with immunohistochemistry.

Results: Spironolactone prevents EH induced by vasopressin and rolipram, but not hydrops induced by cilostamide. The aldosterone target ENaC and the mineralocorticoid receptor were expressed in the human saccule sensory epithelium.

Conclusions: The effect of spironolactone on EH appears to be pathway-dependent and may provide explanations why certain drugs may be effective in some patients with hydropic ear disease while not in others.

Significance: Extrapolating this finding to the clinic supports that a personalized medicine approach is probably necessary in the treatment of diseases involving EH, as different pathways may be needed to be targeted for treatment.

Chinese abstract

背景：内淋巴积水（EH）的确切病理生理机制尚不清楚。我们之前已经证明, 长期服用加压素和cAMP/cGMP降解酶抑制剂（PDE3、PDE4、PDE5）会导致小鼠的内淋巴积水。

目的：评价醛固酮拮抗剂螺内酯在不同途径诱导下预防EH的能力。

材料和方法：小鼠在有或无螺内酯的情况下, 用加压素、PDE3抑制剂西洛他明和PDE4抑制剂罗利帕姆治疗4周。采用高分辨率9.4T MRI评估EH。用免疫组织化学方法研究蛋白质在人球囊感觉上皮中的表达。

结果：螺内酯对加压素和罗力普仑诱导的EH有抑制作用, 而对西洛他明诱导的水肿无抑制作用。醛固酮靶向ENAC和盐皮质激素受体在人球囊感觉上皮中被表达。

结论：螺内酯对EH的影响似乎是途径依赖性的, 这可能解释某些药物对某些水样耳病患者有效而对其他患者无效的原因。

意义：将这一发现外推到临床, 我们认为个人化医治法可能是治疗EH有关疾病所必需的, 因为治疗可能需要不同的途径。

Keywords:

• Magnetic resonance imaging
• cochlea
• endolymphatic hydrops
• vasopressin
• cilostamide
• rolipram
• PDE3
• PDE4
• spironolactone
• Menière’s disease

Acknowledgements

Lund University Bioimaging Center (LBIC) is gratefully acknowledged for providing experimental resources. ED and AP are affiliated with Lund University Diabetes Center (LUDC).

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The work was supported by grants from the Swedish Diabetes Foundation, the Swedish Foundation for Strategic Research Dnr IRC 15-0067, the Albert Påhlsson Foundation, Sweden, the Crafoord Foundation, Sweden, Diabetes Wellness Sweden, Skane County Council’s Research and Development Foundation, Sweden and the Medical Faculty, Lund University, Sweden.