Endolymphatic Sac Drainage Surgery and Plasma Stress Hormone Vasopressin Levels in Meniere's Disease

Meniere's disease is a common inner ear disorder accompanied by vertigo attacks and fluctuating hearing loss that some believe is due to a stressful lifestyle. To elucidate the scientific relationship in neuro-endocrinology between Meniere's disease and stress, we examined the surgical results of endolymphatic sac drainage surgery and changes in stress-induced plasma arginine-vasopressin levels. We enrolled 100 intractable Meniere's patients and examined surgical results and plasma vasopressin levels. Fifty-four chronic otitis media patients who underwent tympano-mastoidectomy formed a control group. We assessed surgical results during a 2-year follow-up period, including vertigo and hearing loss. We examined plasma vasopressin levels just before surgery and 1 week, 1 year, and 2 years after surgery. In patients with intractable Meniere's disease, plasma vasopressin levels were significantly reduced 1 week after surgery compared to the decrease observed in chronic otitis media patients after tympano-mastoidectomy. In intractable Meniere's disease, long-lasting low plasma vasopressin levels after surgery were associated with significantly good surgical results. In recurrent Meniere's disease, a gradual plasma vasopressin level elevation was observed after surgery, followed by recurrent vertigo attacks and sensorineural hearing loss. It is suggested that long-lasting high levels of plasma vasopressin could have adverse effects on inner ear water metabolism and the subsequent Meniere's disease symptoms. Effective treatments for Meniere's disease might be best based on the maintenance of low plasma vasopressin levels.

Lixivaptan, a New Generation Diuretic, Counteracts Vasopressin-Induced Aquaporin-2 Trafficking and Function in Renal Collecting Duct Cells

Vasopressin V2 receptor (V2R) antagonists (vaptans) are a new generation of diuretics. Compared with classical diuretics, vaptans promote the excretion of retained body water in disorders in which plasma vasopressin concentrations are inappropriately high for any given plasma osmolality. Under these conditions, an aquaretic drug would be preferable over a conventional diuretic. The clinical efficacy of vaptans is in principle due to impaired vasopressin-regulated water reabsorption via the water channel aquaporin-2 (AQP2). Here, the effect of lixivaptan—a novel selective V2R antagonist—on the vasopressin-cAMP/PKA signaling cascade was investigated in mouse renal collecting duct cells expressing AQP2 (MCD4) and the human V2R. Compared to tolvaptan—a selective V2R antagonist indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia—lixivaptan has been predicted to be less likely to cause liver injury. In MCD4 cells, clinically relevant concentrations of lixivaptan (100 nM for 1 h) prevented dDAVP-induced increase of cytosolic cAMP levels and AQP2 phosphorylation at ser-256. Consistent with this finding, real-time fluorescence kinetic measurements demonstrated that lixivaptan prevented dDAVP-induced increase in osmotic water permeability. These data represent the first detailed demonstration of the central role of AQP2 blockade in the aquaretic effect of lixivaptan and suggest that lixivaptan has the potential to become a safe and effective therapy for the treatment of disorders characterized by high plasma vasopressin concentrations and water retention.

Social isolation rearing-induced anxiety and response to agomelatine in male and female rats: Role of corticosterone, oxytocin, and vasopressin

Background: The chronobiotic antidepressant, agomelatine, acts via re-entrainment of circadian rhythms. Earlier work has demonstrated late-life anxiety and reduced corticosterone in post-weaning social isolation reared (SIR) rats. Agomelatine was anxiolytic in this model but did not reverse hypocortisolemia. Reduced corticosterone or cortisol (in humans) is well-described in anxiety states, although the anxiolytic-like actions of agomelatine may involve targeting another mechanism. Central oxytocin and vasopressin exert anxiolytic and anxiogenic effects, respectively, and are subject to circadian fluctuation, while also showing sex-dependent differences in response to various challenges. Aims and methods: If corticosterone is less involved in the anxiolytic-like actions of agomelatine in SIR rats, we wondered whether effects on vasopressin and oxytocin may mediate these actions, and whether sex-dependent effects are evident. Anxiety as assessed in the elevated plus maze, as well as plasma vasopressin, oxytocin, and corticosterone were analyzed in social vs SIR animals receiving sub-chronic treatment with vehicle or agomelatine (40 mg/kg/day intraperitoneally at 16:00) for 16 days. Results: Social isolation rearing induced significant anxiety together with increased plasma vasopressin levels, but decreased corticosterone and oxytocin. While corticosterone displayed sex-dependent changes, vasopressin, and oxytocin changes were independent of sex. Agomelatine suppressed anxiety as well as reversed elevated vasopressin in both male and female rats and partially reversed reduced oxytocin in female but not male rats. Conclusion: SIR-associated anxiety later in life involves reduced corticosterone and oxytocin, and elevated vasopressin. The anxiolytic-like effects of agomelatine in SIR rats predominantly involve targeting of elevated vasopressin.