Acute vardenafil administration improves bladder oxygenation in spontaneously hypertensive rats.
BACKGROUND
In human bladder, phosphodiesterase type 5 (PDE5) is present not only in the muscular wall but also in the vascular beds, suggesting a role for PDE5 inhibitors in favoring bladder blood flow and tissue oxygenation.


OBJECTIVE
To investigate whether acute administration of vardenafil could affect bladder oxygenation in spontaneously hypertensive rats (SHR), an animal model of naturally occurring overactive bladder.


METHODS
The effect of vardenafil on hypoxia-induced alterations was studied in vivo in SHR by acute dosing (10 mg/kg, 90 minutes before sacrifice) and in vitro in human bladder smooth muscle cells (hBCs).


METHODS
Bladder oxygenation was detected using the hypoxyprobe immunostaining. The expression of some hypoxia markers (vascular endothelial growth factor [VEGF] and endothelin-1 type B [ETB] receptor) was also evaluated by immunohistochemistry and Western blot. Gene expression in hBC was quantified by real-time reverse transcription-polymerase chain reaction.


RESULTS
Rat bladder PDE5 immunopositivity was detected in the muscular wall and in the endothelial and smooth muscle cells of blood vessels. In SHR bladder, a significant increase of hypoxic cells, VEGF, and ETB expression was observed when compared with their normotensive counterpart Wistar Kyoto rats (WKY). Vardenafil treatment dramatically decreased hypoxyprobe staining, as well as VEGF and ETB expression in SHR bladder up to WKY level. Accordingly, in SHR bladder, vardenafil administration significantly blunted relaxation induced by the selective ETB agonist IRL-1620. In hBCs, experimental hypoxia significantly induced gene expression of hypoxia markers (carbonic anhydrase IX and VEGF), which was not changed by simultaneous treatment with vardenafil. Conversely, the hypoxia-related induction of smooth muscle-specific genes (alphaSMA, SM22alpha, and desmin) was significantly reduced by vardenafil.


CONCLUSIONS
SHR showed bladder hypoxia which was significantly reduced by acute vardenafil treatment. Thus, besides relaxing muscular wall, PDE5 inhibition may positively affect urinary vesicle blood perfusion.
Morelli
Annamaria
A
Department of Clinical Physiopathology, University of Florence, Florence, Italy.
Filippi
Sandra
S
Comeglio
Paolo
P
Sarchielli
Erica
E
Chavalmane
Aravinda K
AK
Vignozzi
Linda
L
Fibbi
Benedetta
B
Silvestrini
Enrico
E
Sandner
Peter
P
Gacci
Mauro
M
Carini
Marco
M
Vannelli
Gabriella B
GB
Maggi
Mario
M
D000818:Animals; D002478:Cells, Cultured; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics / Q000378:metabolism; D004334:Drug Administration Schedule; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D008297:Male; D009130:Muscle, Smooth / Q000098:blood supply* / Q000473:pathology; D010101:Oxygen Consumption / Q000187:drug effects* / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology*; D011470:Prostatic Hyperplasia / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044023:Receptor, Endothelin B / Q000187:drug effects / Q000235:genetics; D013450:Sulfones / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D001743:Urinary Bladder / Q000098:blood supply* / Q000473:pathology; D053201:Urinary Bladder, Overactive / Q000473:pathology / Q000503:physiopathology*; D000069058:Vardenafil Dihydrochloride; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*
D007093:Imidazoles; D010879:Piperazines; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; D013450:Sulfones; D014227:Triazines; D042461:Vascular Endothelial Growth Factor A; D014665:Vasodilator Agents; D000069058:Vardenafil Dihydrochloride; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5