TNF-alpha infusion impairs corpora cavernosa reactivity.
BACKGROUND
Erectile dysfunction (ED), as well as cardiovascular diseases (CVDs), is associated with endothelial dysfunction and increased levels of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha).


OBJECTIVE
We hypothesized that increased TNF-alpha levels impair cavernosal function.


METHODS
In vitro organ bath studies were used to measure cavernosal reactivity in mice infused with vehicle or TNF-alpha (220 ng/kg/min) for 14 days. Gene expression of nitric oxide synthase isoforms was evaluated by real-time polymerase chain reaction.


METHODS
Corpora cavernosa from TNF-alpha-infused mice exhibited decreased nitric oxide (NO)-dependent relaxation, which was associated with decreased endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) cavernosal expression.


RESULTS
Cavernosal strips from the TNF-alpha-infused mice displayed decreased nonadrenergic-noncholinergic (NANC)-induced relaxation (59.4 +/- 6.2 vs. control: 76.2 +/- 4.7; 16 Hz) compared with the control animals. These responses were associated with decreased gene expression of eNOS and nNOS (P < 0.05). Sympathetic-mediated, as well as phenylephrine (PE)-induced, contractile responses (PE-induced contraction; 1.32 +/- 0.06 vs. control: 0.9 +/- 0.09, mN) were increased in cavernosal strips from TNF-alpha-infused mice. Additionally, infusion of TNF-alpha increased cavernosal responses to endothelin-1 and endothelin receptor A subtype (ET(A)) receptor expression (P < 0.05) and slightly decreased tumor necrosis factor-alpha receptor 1 (TNFR1) expression (P = 0.063).


CONCLUSIONS
Corpora cavernosa from TNF-alpha-infused mice display increased contractile responses and decreased NANC nerve-mediated relaxation associated with decreased eNOS and nNOS gene expression. These changes may trigger ED and indicate that TNF-alpha plays a detrimental role in erectile function. Blockade of TNF-alpha actions may represent an alternative therapeutic approach for ED, especially in pathologic conditions associated with increased levels of this cytokine.
Carneiro
Fernando S
FS
Institute of Biomedical Sciences, University of Sao Paulo, Pharmacology, Sao Paulo, SP, Brazil. fcarneiro@mcg.edu
Zemse
Saiprazad
S
Giachini
Fernanda R C
FR
Carneiro
Zidonia N
ZN
Lima
Victor V
VV
Webb
R Clinton
RC
Tostes
Rita C
RC
D000818:Animals; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D007172:Erectile Dysfunction / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D015870:Gene Expression; D066298:In Vitro Techniques; D007267:Injections; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000201:enzymology; D009474:Neurons / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D010413:Penis / Q000201:enzymology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014664:Vasodilation / Q000502:physiology
D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase