Inhibition of phosphodiesterase 3, 4, and 5 induces endolymphatic hydrops in mouse inner ear, as evaluated with repeated 9.4T MRI.
CONCLUSIONS
The data indicate important roles for phosphodiesterase (PDE) 3, 4, 5, and related cAMP and cGMP pools in the regulation of inner ear fluid homeostasis. Thus, dysfunction of these enzymes might contribute to pathologies of the inner ear.


OBJECTIVE
The mechanisms underlying endolymphatic hydrops, a hallmark of inner ear dysfunction, are not known in detail; however, altered balance in cAMP and cGMP signaling systems appears to be involved. Key components of these systems are PDEs, enzymes that modulate the amplitude, duration, termination, and specificity of cAMP and cGMP signaling.


METHODS
To evaluate the role of PDE3, 4, and 5 and associated cAMP and cGMP pools in inner ear function, the effect of cilostamide (PDE3 inhibitor), rolipram (PDE4 inhibitor), and sildenafil (PDE5 inhibitor), administrated via mini-osmotic pumps, on mouse inner ear fluid homeostasis was evaluated using 9.4T in vivo MRI in combination with intraperitoneally administered Gadolinium contrast. Also, using human saccule as a model, the expression of PDEs and related signaling molecules and targets was studied using immunohistochemistry.


RESULTS
PDE3, PDE4, as well as PDE5 inhibitors resulted in the development of endolymphatic hydrops. Furthermore, PDE3B, PDE4D, and some related signaling components were shown to be expressed in the human saccule.
a Department of Experimental Medical Sciences, Section for Diabetes , Metabolism and Endocrinology Lund University Diabetes Centre , Lund , Sweden.
Eva
E
Degerman
b Lund University Bioimaging Center, Lund University , Lund , Sweden.
Rene
R
In 't Zandt
a Department of Experimental Medical Sciences, Section for Diabetes , Metabolism and Endocrinology Lund University Diabetes Centre , Lund , Sweden.
Annki
A
Pålbrink
c Department of Clinical Sciences in Malmö, Islet Cell Exocytosis , Lund University Diabetes Centre, Lund University , Lund , Sweden.|d Clinical Research Centre, Skåne University Hospital , Malmö , Sweden.
Lena
L
Eliasson
e Department of Otorhinolaryngology, Head and Neck Surgery , Copenhagen University Hospital Rigshospitalet , Copenhagen , Denmark.
Per
P
Cayé-Thomasen
f Department of Clinical Sciences, Section for Otorhinolaryngology , Lund University & Skåne University Hospital , Lund , Sweden.
Måns
M
Magnusson
D000818:Animals; D018159:Endolymphatic Hydrops / Q000000981:diagnostic imaging / Q000201:enzymology*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008808:Mice, Inbred CBA; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D015363:Quinolones; D020889:Rolipram; D012444:Saccule and Utricle / Q000201:enzymology*; D000068677:Sildenafil Citrate
D010726:Phosphodiesterase Inhibitors; D015363:Quinolones; C021294:cilostamide; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D020889:Rolipram
Aquaporin2; Ménière’s disease; cilostamide; cochlea; rolipram; sildenafil