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Introduction: Introduction: The association of stress with erectile dysfunction (ED) is well known, however, it is not clear whether psychological stressors affect the vasculature and the erectile tissue in a manner that could contribute to a vasculogenic erectile dysfunction. Besides hormonal changes, cellular damage induced by stress could lead to the activation of the NLRP3, to increase production of cytokines associated with ED. In this study, we aimed to evaluate the reactivity of the corpus cavernosum and pudendal artery of male mice undergoing chronic unpredictable stress (CUS). Objective: Objective: We hypothesize that CUS leads to mitochondrial damage and activates the NLRP3 inflammasome leading to impaired reactivity of the pudendal artery and corpus cavernosum which might cause erectile dysfunction. Methods: Methods: Male C57Bl/6 mice were submitted to 28 days of chronic unpredictable stress (CUS). The pudendal artery and corpus cavernosum were removed and mounted in a myograph to evaluate reactivity. Tissues were kept in physiological salt solution at 37°C, constantly aerated with 95%O2/5%CO2 and concentration-response curves to acetylcholine (ACh; 1 nM – 30 uM) and phenylephrine (PE; 1 nM – 30 uM) were obtained. Using non-linear regression, we obtained the maximal response (Emax) and potency (pEC50) of ACh and PE. Expression of NLRP3, pro-caspase1 and caspase1 were measured in arteries by Western blot. Data are expressed as mean ± S.E.M. P<0.05 was considered statistically different. Results: Results: CUS led to a significant decrease in the maximal relaxation induced by acetylcholine in the pudendal artery (Non-CUS: 96 ± 3% vs CUS: 84 ± 7%, n=6 and 7, respectively) and in the corpus cavernosum (Non-CUS: 88 ± 4% vs CUS: 75 ± 4%, n=7 each group) as well as an impaired contraction to PE in the corpus cavernosum (non-CUS: 1.72 ± 0.17% vs CUS: 1.07 ± 0.15%, n= 7 each group). In arteries, there were no differences in the expression of NLRP3, however, the ratio of caspase1/pro-caspase-1 was increased in CUS, suggesting that CUS increases the NLRP3 inflammasome pathway. Taken together, our data suggest that CUS led to an activation of the NLRP3 inflammasome pathway, and impaired the relaxation of the pudendal artery and corpus cavernosum by a mechanism that might be associated with decreased nitric oxide bioavailability (endothelium-dependent relaxation), whereas impaired contraction might be associated with desensitization of alpha-adrenergic receptors in response to stress. Conclusions: Conclusion: Our findings demonstrate that stress impairs the reactivity of the corpus cavernosum and pudendal artery likely associated with the activation of NLRP3 inflammasome, which might play a role in the development of erectile dysfunction in stressed males. Disclosure: No. [ABSTRACT FROM AUTHOR]

The aim of this work was to evaluate the influence of run training on the responsiveness of corpus cavernosum (CC) from rats made hypertensive by treatment with nitric oxide (NO) synthesis inhibitor. Wistar rats were divided into sedentary control (C-SD), exercise training (C-TR), Nω-nitro-L-arginine methyl ester (L-NAME) sedentary (LN-SD) and L-NAME trained (LN-TR) groups. The run training program consisted in 8 weeks in a treadmill, 5 days/week, each session lasted 60 min. L-NAME treatment (2 and 10 mg/rat/day) started after 4 weeks of prior physical conditioning and lasted 4 weeks. Concentration–response curves were obtained for acetylcholine (ACh), sodium nitroprusside (SNP), sildenafil and BAY 41-2272. The effect of electrical field stimulation (EFS) on the relaxations responses of CC was evaluated. Run training prevented the arterial hypertension induced by L-NAME treatment (LN-SD: 135±2 and 141±2 mm Hg for both doses of L-NAME) compared to LN-SD groups (154±1 and 175±2 mm Hg, for 2 and 10 mg of L-NAME, respectively). Run training produced an increase in the maximal responses (Emax) of CC for ACh (C-SD: 47±3; C-TR: 52±1; and LN-TR: 53±3%) and SNP (C-SD: 89±1; C-TR: 98±1; and LN-TR: 95±1%). Both potency and Emax for ACh were reduced in a dose of 10 mg of L-NAME, and run training restored the reduction of Emax for ACh. No changes were found for BAY 41-2271 and sildenafil. Relaxing responses to EFS was reduced by L-NAME treatment that was restored by prior physical conditioning. In conclusion, our study shows a beneficial effect of prior physical conditioning on the impaired CC relaxing responses in rats made hypertensive by chronic NO blockade.International Journal of Impotence Research (2007) 19, 189–195. doi:10.1038/sj.ijir.3901511; published online 17 August 2006 [ABSTRACT FROM AUTHOR]

Introduction: Childhood obesity is a worrisome health concern for children and teenagers, as it can contribute to several health issues in adulthood, including diabetes, high blood pressure, and high cholesterol. These conditions have been associated with sexual dysfunction. However, the precise impact of early childhood obesity on erectile function in adult males remains uncertain. Objective: We hypothesized that overfeeding during early childhood can have lasting effects on body fat distribution, blood pressure, and erectile function in young adult males. Methods: On postnatal day (PND 1), Wistar rats were separated into two groups: normal litter (NL) with 10 pups per dam, or small litter (SL) with 3 pups per dam. Male rats (n = 8-10 per group) were then assessed at two different time points: during the prepubertal stage (PND 40) and in adulthood (PND 120). Erectile function was assessed only after sexual maturation (i.e., on PND 120). Body weight, retroperitoneal and perigonadal adipose tissue (fat pad weight/100g of the body) were evaluated. The mean blood pressure (MBP) was recorded in conscious rats using the indirect tail-cuff method. Following euthanasia at PND 120, the corpus cavernosum was removed to perform functional studies using a strip myograph. Contractile and relaxation responses were evaluated by electrical field stimulation (EFS) and concentration-response curves (CRC) to phenylephrine [Phe, 1nM-30μM, millinewton (mN)] or acetylcholine (Ach 1nM-30μM, % relaxation) were performed. Results: At the prepubertal stage, SL rats had higher body weight (NL 149±3 vs. SL 186±5, g, p<0.05), and increased retroperitoneal (NL 0.17±0.01 vs. SL 0.32±0.03, g, p<0.05) and perigonadal (NL 0.38± 0.02 vs. SL 0.45±0.03, g, p<0.05) adipose tissue. At PND 120, SL group presented increased body weight (NL 534±13vs. SL 631.6±10, g/100g, p<0.05), retroperitoneal (NL 1.31±0.11vs. SL 1.82±0.14, g/100g, p<0.05) and perigonadal (NL1.74±0.10vs. SL 2.18±0.15, g/100g, p<0.05) adipose tissue when compared with NL group. Moreover, SL rats presented increased MBP (NL 114.9±0.58 vs SL 120.5±1.2, mmHg). The corpus cavernosum of SL rats at PND 120 had increased contraction induced by EFS for all frequencies (1 Hz: NL 0.5 ± 0.2 mN vs SL 0.9 ± 0.2 mN; 4 Hz: NL 1.2 ± 0.3 mN vs SL 1.8 ± 0.2 mN; 16 Hz: NL 1.9 ± 0.4 mN vs SL 3 ± 0.4 mN), whereas the relaxation was decreased (1 Hz: NL 0.77 ± 0.18% vs SL 0.27 ± 0.09%; 4 Hz: NL 2.48 ± 0.26% vs SL 1.36 ± 0.41%; 16 Hz: NL 3.06 ± 0.28% vs SL 2.39 ± 0.53%). CRC showed increased contractile response to Phe (Emax NL 2.3±0.3 vs. SL 3.8± 0.6, mN, p=0.05) and reduced potency of ACh (pEC50 NL 6.4±0.6 vs SL 4.9±0.7, mN, p=0.1) in the corpus cavernosum of SL. Incubation with indomethacin (10uM) abolished the differences in the contractile response induced by EFS or Phe between SL and NL, suggesting a heightened inflammatory response. Conclusions: These data suggest that early childhood obesity has long-lasting negative implications on sexual function in adulthood. Disclosure: No. [ABSTRACT FROM AUTHOR]

Introduction: Erectile dysfunction (ED) may be an early marker for cardiovascular diseases, and it is often associated with an hypercontractility of the corpus cavernosum (CC) as a consequence of increased reactive oxygen species (ROS), which favors the flaccid state of the penis. Leucine Rich Repeat Containing 8 (LRRC8A) Volume Regulated Anion Channels (VRACs) regulates Nox1 and modulates the extracellular production of superoxide anion (O2•-). Downregulation of LRRC8A is associated with decreased production of O2•- and we have demonstrated improved relaxation and reduced contraction of the pudendal artery in LRRC8A knockout mice. Objective: We hypothesized that the role of LRRC8A in contractile responses to phenylephrine (PE) and electrical field stimulation (EFS) in the CC of diabetic mice would be exaggerated compared to that in normal mice. Methods: To test this hypothesis, the CC of diabetic (dbdb-/-) mice was mounted in a myograph, and contraction elicited by PE or EFS was performed in the presence of apocynin (non-selective NOX inhibitor), GKT137831 (NOX1/4 inhibitor) and montelukast (LRRC8A inhibitor). In LRRC8A KO dbdb-/- mice, contractions to PE and EFS were obtained in the absence or in the presence of GKT137831. Results: In the CC, the maximal contraction to PE was increased in diabetic animals, and in the presence of 3 mM of apocynin, the contractile response was markedly diminished in both control and diabetic mice. The LRRC8A inhibitor, montelukast, significantly reduced PE-induced contraction of the CC reaching maximal contraction of 69 + 7% and 65 + 10% in the control and diabetic group, respectively, compared to the contraction in the absence of the inhibitor. In the presence of the Nox1/Nox4 inhibitor, GKT137831, the contraction elicited by PE was reduced only in the diabetic group (68 + 9% of the maximal contraction), whereas in the control group this reduction was not significant (82 + 14% of the PE-maximal contraction). In the LRRC8A KO dbdb-/- mice, the contraction to EFS was similar to dbdb-/-, however, GKT137831 reduced the contraction to EFS with lesser magnitude of inhibition in the LRRC8A KO dbdb-/- mice (35% of inhibition) compared to dbdb-/- mice (50% of inhibition), suggesting that the participation of O2•- in the contractile response was reduced by the lack of functional LRRC8A. Conclusions: LRRC8A modulates the contractile response of the CC induced by α-adrenergic stimulation and in diabetes, this may be associated with O2•- production, which plays a role in the development of ED. Inhibition of LRRC8A may be a therapeutic target to prevent hypercontractility of arteries and CC in vasculogenic ED. Disclosure: No. [ABSTRACT FROM AUTHOR]