Farnesoid X receptor activation improves erectile function in animal models of metabolic syndrome and diabetes.
BACKGROUND
The farnesoid X receptor (FXR) is critically involved in the regulation of the hepato-biliary system. Recent data suggest a role for FXR in modulating other metabolic pathways and vascular function.


OBJECTIVE
To investigate whether long-term administration of the selective FXR agonist INT-747 ameliorates erectile function, we tested it in two animal models of metabolic derangements: a rabbit model of high-fat diet (HFD)-induced metabolic syndrome (MetS) and a rat model of streptozotocin (STZ)-induced type 1 diabetes.


METHODS
HFD rabbit or STZ rats with or without chronic INT-747 dosing (10 mg/kg/day for 12 weeks). INT-747 addition to rabbit penile smooth muscle cells (rpSMCs).


METHODS
Effects of INT-747 on metabolic features and erectile function in animal models and clarification of mechanism of action in isolated cells.


RESULTS
INT-747 dosing normalized visceral adiposity and glucose intolerance in HFD rabbits. INT-747 increased penile FXR expression and partially restored endothelial nitric oxide synthase and dimethylarginine dimethylaminohydrolase 1 expression as well as impaired nitric oxide (NO)-dependent relaxation (improved responsiveness to acetylcholine and electrical field stimulation). INT-747 was also effective in regulating NO downstream events, as shown by increased sodium nitroprusside-induced relaxation. Because phosphodiesterase type 5 and protein kinase G (PKG) were unaltered by INT-747, we analyzed the calcium-sensitizing RhoA/ROCK pathway. HFD increased, and INT-747 normalized, RhoA membrane translocation/activation. RhoA/ROCK signaling inhibition by INT-747 was confirmed in rpSMCs by confocal microscopy, MYPT1-phosphorylation, cytoskeleton remodeling, cell migration, and smooth muscle-related genes expression. In STZ rats, FXR penile expression was not altered but was significantly upregulated by INT-747 dosing. In this model, INT-747 improved penile erection induced by electrical stimulation of cavernous nerve and hypersensitivity to intracavernous injection of a ROCK-inhibitor, Y-27632, without improving hyperglycemia.


CONCLUSIONS
In HFD rabbits, INT-747 dosing improved glucose sensitivity and MetS-associated erectile dysfunction, via upregulation of NO transmission and inhibition of RhoA/ROCK pathway. In STZ rats, INT-747 restored in vivo penile erection and sensitivity to ROCK inhibition, independently of effects on glycemia.
Sexual Medicine and Andrology Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy.
Linda
L
Vignozzi
Annamaria
A
Morelli
Sandra
S
Filippi
Paolo
P
Comeglio
Aravinda K
AK
Chavalmane
Matilde
M
Marchetta
Mariateresa
M
Toce
Ravit
R
Yehiely-Cohen
Gabriella B
GB
Vannelli
Luciano
L
Adorini
Mario
M
Maggi
D000818:Animals; D003921:Diabetes Mellitus, Experimental; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D007172:Erectile Dysfunction / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects; D010413:Penis / Q000098:blood supply / Q000166:cytology; D011817:Rabbits; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000627:therapeutic use*; D000099150:Receptor, Farnesoid X-Activated
D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated