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.
Vignozzi
Linda
L
Sexual Medicine and Andrology Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy.
Morelli
Annamaria
A
Filippi
Sandra
S
Comeglio
Paolo
P
Chavalmane
Aravinda K
AK
Marchetta
Matilde
M
Toce
Mariateresa
M
Yehiely-Cohen
Ravit
R
Vannelli
Gabriella B
GB
Adorini
Luciano
L
Maggi
Mario
M
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