The novel antioxidant, AC3056 (2,6-di-t-butyl-4-((dimethyl-4-methoxyphenylsilyl)methyloxy)phenol), reverses erectile dysfunction in diabetic rats and improves NO-mediated responses in penile tissue from diabetic men.
BACKGROUND
Diabetes is associated with a high incidence of erectile dysfunction (ED) and poor response to standard treatments. Oxidative stress could be relevant in the pathophysiology of diabetic ED.


OBJECTIVE
To evaluate the effects of the antioxidant, AC3056 (2,6-di-t-butyl-4-((dimethyl-4-methoxyphenylsilyl)methyloxy)phenol), on diabetic ED.


METHODS
Erectile responses to cavernosal nerve electrical stimulation were determined in streptozotocin-induced diabetic rats. Relaxation of human corpus cavernosal (HCC) tissue and penile resistance arteries (HPRA) from human cavernosal specimens was evaluated in organ chambers and myographs, respectively.


METHODS
The influence of AC3056 on erectile responses, lipid peroxidation, and nitrite plus nitrate serum content, and nuclear factor-kappaB (NF-kappaB) expression in penile tissue, in diabetic rats, and on endothelium-dependent and neurogenic relaxation of HCC and HPRA from diabetic patients was determined.


RESULTS
Eight weeks of diabetes caused ED in rats that was prevented by oral AC3056 (0.3% w/w in rat chow) when given from the induction of diabetes. AC3056 also prevented the diabetes-induced elevation of serum thiobarbituric acid-reactive substances (TBARS), the reduction of serum nitric oxide (NO) derivatives, and the increase of NF-kappaB expression. Acute oral administration of AC3056 (450 mg/kg) partially reversed ED in 8-week diabetic rats. Complete reversion of ED was achieved after 3 days of treatment with 0.3% AC3056. This effect remained after 5 weeks of treatment, but it disappeared after withdrawing for 1 week. Erectile function in diabetic rats was inversely related to serum TBARS. AC3056- (30 microM) reversed endothelial dysfunction in diabetic HCC and enhanced endothelium-dependent relaxation in diabetic HPRA and significantly potentiated neurogenic relaxation of both tissues. The reduced cGMP content in HCC from diabetic patients after exposure to acetylcholine (10 microM) was corrected by AC3056 (30 microM).


CONCLUSIONS
These results suggest that oxidative stress has a relevant role in pathophysiology of diabetic ED and provide a rationale for the use of antioxidant therapy in the treatment of ED in diabetes.
Angulo
Javier
J
Departamento de Investigación, Hospital Ramón y Cajal, Madrid, Spain. jangulo@ibercom.com
Peiró
Concepción
C
Cuevas
Pedro
P
Gabancho
Sonia
S
Fernández
Argentina
A
González-Corrochano
Rocío
R
La Fuente
José M
JM
Baron
Alain D
AD
Chen
Kim S
KS
de Tejada
Iñigo Sáenz
IS
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D015153:Blotting, Western; D003920:Diabetes Mellitus / Q000453:epidemiology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000453:epidemiology*; D006801:Humans; D015227:Lipid Peroxidation; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D017646:Organosilicon Compounds / Q000627:therapeutic use; D010413:Penis / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013858:Thiobarbiturates / Q000097:blood
C542786:AC3056; D000975:Antioxidants; D017646:Organosilicon Compounds; D013858:Thiobarbiturates; D009569:Nitric Oxide; C029684:thiobarbituric acid