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ENOS PATHWAY, INHIBITING OXIDATIVE STRESS AND APOPTOSIS IN THE CORPUS CAVERNOSUM
THE JOURNAL OF UROLOGYâ
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Predictive nomograms have established these as the important predictors of BCR. PDE5i groups were: low use (never/sometimes) vs. high use (regularly/routinely/more than once a day). Risk groups were low risk (G 6/7 and organ confined disease) or intermediate/high risk (all others). Correlation coefficients and Chi-square was used for univariate analysis and logistic regression was used for multivariable analysis. RESULTS: Mean age of the 655 men was 617 years. 117 men (18%) had BCR. The mean time to BCR was 1.41.4 years. PDE5i groups: 55% low use, 45% high use. On univariate analysis, age, PSA, G, SMS, SVI, EPE, and LNI were all associated with BCR (p¼0.02 to p<0.001). PDE5i group assignment was not significant. There were 16% in the low use PDE5i group with BCR vs 20% in the high use PDE5i group with BCR (RR¼1.3: 95% CI: 0.84-1.86, p¼0.28). On multivariable analysis, G, SMS, SVI, ECE, and LNI were all associated with BCR (p¼0.05 to p¼0.001). Age (OR: 1.02, 95% CI: 0.99-1.06, p¼0.22), PSA (OR: 1.02, 95% CI: 0.98-1.06, p¼0.31), and PDE5i group assignment (OR: 1.52, 95% CI: 0.95-2.43, p¼0.08) were not significant predictors in the model. Risk groups were low risk (178 men) and intermediate/high risk (476 men) disease. We could not replicate the analysis with the low risk group since only 5 men had BCR. In the high risk group, there were 112 (23%) who had BCR. The pattern of results for disease characteristics were similar as above. The PDE5i variable, on univariate analysis the group assignment was not significant. There were 22% in the low use PDE5i group with BCR vs 26% in the high use PDE5i group with BCR (RR¼1.3: 95% CI: 0.81-1.90, p¼0.33). In multivariable analysis, PDE5i group assignment was again not a significant predictor of BCR (OR: 1.37, 95% CI: 0.84-2.22, p¼0.20). CONCLUSIONS: This is assessment of risk is based on a drug exposure algorithm, which has not been reported before. There does not seem to be a significant association between PDE5i use and BCR. Source of Funding: none
MP86-12 HUMAN TISSUE KALLIKREIN 1 RESTORES ERECTILE FUNCTION OF STREPTOZOTOCIN- INDUCED DIABETIC RATS BY ACTIVATING PI3K/ENOS PATHWAY, INHIBITING OXIDATIVE STRESS AND APOPTOSIS IN THE CORPUS CAVERNOSUM Yang Luan*, Yajun Ruan, Tao Wang, Yan Zhang, Kai Cui, Rui Li, Jun Yang, Ruibao Chen, Shaogang Wang, Jihong Liu, Zhangqun Ye, Wuhan, China, People’s Republic of INTRODUCTION AND OBJECTIVES: Our previous study has proved the protective role of human tissue kallikrein 1 (hKLK1) in erectile function of aged rats with the transgenic Sprague-Dawley (SD) rats harboring hKLK1 gene (TGR), but its effect on diabetic erectile dysfunction (ED) is still unknown. METHODS: Eight-week-old male wild type SD rats (WTR) and age matched TGR were randomly divided into five groups: citrate buffer treated (1) WTR and (2) TGR; streptozotocin-induced (3) diabetic wild type rats (WTDM) and (4) diabetic transgenic rats (TGDM); (5) TGDM with daily administration of bradykinin receptor 2 inhibitor HOE 140 (TGDMH). Erectile response was measured by cavernous nerve electrostimulation after 12-week treatment. Then the corpus cavernosum (CC) tissues were harvested for hKLK1 gene identification and mechanism exploration. The regulation of hKLK1 on PI 3 kinase (PI3K)/ endothelial nitric oxide synthase (eNOS) pathway was detected within CC in vivo and TGR derived cavernous smooth muscle cell (CSMC) in vitro. In addition, the effect of hKLK1 on oxidative stress and apoptosis in CC of diabetic rats and high glucose treated CSMC was also evaluated. RESULTS: hKLK1 attenuated the decreased erectile function of WTDM, while the protective effect was abolished in TGDMH. The decrease of PI3K(p55), AKT, eNOS, phospho-eNOS(Ser1177), cyclic guanosine monophosphate (cGMP) and increase of phosphoeNOS(Thr495), phosphodiesterase type 5, L-type calcium channel in CC of WTDM were improved in that of TGDM, but deteriorated again by HOE 140. Meanwhile, hKLK1 could elevate the level of cGMP and
Vol. 195, No. 4S, Supplement, Tuesday, May 10, 2016
reduce the concentration of Ca2+ in CSMC in vitro, but these changes were diminished by B2R, PI3K or eNOS inhibitors. In addition, the CC of WTDM had higher proteins expression of nicotinamide adenine dinucleotide phosphate oxidase, malondialdehyde level, lower activity of superoxide dismutase and elevated apoptosis percentage when compared to WTR. However, hKLK1 improved these parameters in TGDM and inhibition with HOE 140 would abolish these advantages. Besides, the level of reactive oxygen species (ROS) and apoptosis rate elevated in high glucose treated CSMC in a concentration-dependent manner and hKLK1 could considerably inhibit the generation of ROS and cell apoptosis in vitro. CONCLUSIONS: These results indicate that hKLK1 could restore diabetic ED through activation of PI3K/eNOS signaling and inhibition of oxidative stress and apoptosis in CC. Source of Funding: This work was supported by grants from the National Natural Science Foundation of China (NSFC #81270690)
MP86-13 IMPACT OF TESTOSTERONE DEFICIENCY ON ERECTILE FUNCTION RECOVERY POST-RADICAL PROSTATECTOMY Lawrence C. Jenkins*, James A. Eastham, Vincent P. Laudone, Christian J. Nelson, John P. Mulhall, New York, NY INTRODUCTION AND OBJECTIVES: Testosterone (T) is necessary for the proper maintenance of cavernosal erectile tissue. Animal models have demonstrated that castrate levels of T are associated with venous leak development. Furthermore, in the setting of cavernous nerve injury, low T results in poorer cavernous nerve recovery and grater degrees of erectile function impairment. We examined the impact of low T levels on erectile function recovery (EFR) post-radical prostatectomy (RP). METHODS: We retrospectively reviewed records of patients who has undergone RP. Patients completed an IIEF, in particular the EF domain (EFD) at each visit including prior to and following RP. We included subjects (i) with valid EFD scores pre-surgery (ii) with valid EFD ( 6) at least 18m post-surgery (iii) who had been operated on by surgeons with greater than 20 years experience each (iv) who had bilateral nerve sparing (v) with an early morning total T level 3 months of RP. Correlation coefficients were calculated for univariate analysis, and multiple regression was used for multivariable analysis. In multivariable analysis, age, baseline EFD, and baseline T were used to predict post-surgery EFD. RESULTS: 157 men met the eligibility criteria. The mean age was 588 years. The vascular co-morbidities were: 5% diabetes, 41% hypertension, 47% high cholesterol. The mean time of last post-surgery EFD score was 31.2 years (range¼1.5-6.7 years). The mean pre and post-surgery EFD scores were: 26.65.2 and 20.78.7. On univariate analysis, age (r¼-0.18, p¼0.03) and baseline EFD (r¼0.32, p<0.001) were related to post-surgery EFD. Baseline T did not show a relationship with post-surgery EFD (r¼0.04, p¼0.66). On multivariable analysis using these three variables to predict post-surgery EFD, baseline EFD remained a significant predictor (beta¼0.30, p<0.001) while age (beta¼-0.13, p¼0.09) approached significance. Baseline T (beta¼0.03, p¼0.68) was not a significant predictor of post-surgery EFD. CONCLUSIONS: T level at baseline does not appear to have a significant effect on EFR at 24 months. Possibly erectile tissue is preserved by patients using penile rehabilitation protocols during their recovery period even in men with low T. Source of Funding: none
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Predictive nomograms have established these as the important predictors of BCR. PDE5i groups were: low use (never/sometimes) vs. high use (regularly/routinely/more than once a day). Risk groups were low risk (G 6/7 and organ confined disease) or intermediate/high risk (all others). Correlation coefficients and Chi-square was used for univariate analysis and logistic regression was used for multivariable analysis. RESULTS: Mean age of the 655 men was 617 years. 117 men (18%) had BCR. The mean time to BCR was 1.41.4 years. PDE5i groups: 55% low use, 45% high use. On univariate analysis, age, PSA, G, SMS, SVI, EPE, and LNI were all associated with BCR (p¼0.02 to p<0.001). PDE5i group assignment was not significant. There were 16% in the low use PDE5i group with BCR vs 20% in the high use PDE5i group with BCR (RR¼1.3: 95% CI: 0.84-1.86, p¼0.28). On multivariable analysis, G, SMS, SVI, ECE, and LNI were all associated with BCR (p¼0.05 to p¼0.001). Age (OR: 1.02, 95% CI: 0.99-1.06, p¼0.22), PSA (OR: 1.02, 95% CI: 0.98-1.06, p¼0.31), and PDE5i group assignment (OR: 1.52, 95% CI: 0.95-2.43, p¼0.08) were not significant predictors in the model. Risk groups were low risk (178 men) and intermediate/high risk (476 men) disease. We could not replicate the analysis with the low risk group since only 5 men had BCR. In the high risk group, there were 112 (23%) who had BCR. The pattern of results for disease characteristics were similar as above. The PDE5i variable, on univariate analysis the group assignment was not significant. There were 22% in the low use PDE5i group with BCR vs 26% in the high use PDE5i group with BCR (RR¼1.3: 95% CI: 0.81-1.90, p¼0.33). In multivariable analysis, PDE5i group assignment was again not a significant predictor of BCR (OR: 1.37, 95% CI: 0.84-2.22, p¼0.20). CONCLUSIONS: This is assessment of risk is based on a drug exposure algorithm, which has not been reported before. There does not seem to be a significant association between PDE5i use and BCR. Source of Funding: none
MP86-12 HUMAN TISSUE KALLIKREIN 1 RESTORES ERECTILE FUNCTION OF STREPTOZOTOCIN- INDUCED DIABETIC RATS BY ACTIVATING PI3K/ENOS PATHWAY, INHIBITING OXIDATIVE STRESS AND APOPTOSIS IN THE CORPUS CAVERNOSUM Yang Luan*, Yajun Ruan, Tao Wang, Yan Zhang, Kai Cui, Rui Li, Jun Yang, Ruibao Chen, Shaogang Wang, Jihong Liu, Zhangqun Ye, Wuhan, China, People’s Republic of INTRODUCTION AND OBJECTIVES: Our previous study has proved the protective role of human tissue kallikrein 1 (hKLK1) in erectile function of aged rats with the transgenic Sprague-Dawley (SD) rats harboring hKLK1 gene (TGR), but its effect on diabetic erectile dysfunction (ED) is still unknown. METHODS: Eight-week-old male wild type SD rats (WTR) and age matched TGR were randomly divided into five groups: citrate buffer treated (1) WTR and (2) TGR; streptozotocin-induced (3) diabetic wild type rats (WTDM) and (4) diabetic transgenic rats (TGDM); (5) TGDM with daily administration of bradykinin receptor 2 inhibitor HOE 140 (TGDMH). Erectile response was measured by cavernous nerve electrostimulation after 12-week treatment. Then the corpus cavernosum (CC) tissues were harvested for hKLK1 gene identification and mechanism exploration. The regulation of hKLK1 on PI 3 kinase (PI3K)/ endothelial nitric oxide synthase (eNOS) pathway was detected within CC in vivo and TGR derived cavernous smooth muscle cell (CSMC) in vitro. In addition, the effect of hKLK1 on oxidative stress and apoptosis in CC of diabetic rats and high glucose treated CSMC was also evaluated. RESULTS: hKLK1 attenuated the decreased erectile function of WTDM, while the protective effect was abolished in TGDMH. The decrease of PI3K(p55), AKT, eNOS, phospho-eNOS(Ser1177), cyclic guanosine monophosphate (cGMP) and increase of phosphoeNOS(Thr495), phosphodiesterase type 5, L-type calcium channel in CC of WTDM were improved in that of TGDM, but deteriorated again by HOE 140. Meanwhile, hKLK1 could elevate the level of cGMP and
Vol. 195, No. 4S, Supplement, Tuesday, May 10, 2016
reduce the concentration of Ca2+ in CSMC in vitro, but these changes were diminished by B2R, PI3K or eNOS inhibitors. In addition, the CC of WTDM had higher proteins expression of nicotinamide adenine dinucleotide phosphate oxidase, malondialdehyde level, lower activity of superoxide dismutase and elevated apoptosis percentage when compared to WTR. However, hKLK1 improved these parameters in TGDM and inhibition with HOE 140 would abolish these advantages. Besides, the level of reactive oxygen species (ROS) and apoptosis rate elevated in high glucose treated CSMC in a concentration-dependent manner and hKLK1 could considerably inhibit the generation of ROS and cell apoptosis in vitro. CONCLUSIONS: These results indicate that hKLK1 could restore diabetic ED through activation of PI3K/eNOS signaling and inhibition of oxidative stress and apoptosis in CC. Source of Funding: This work was supported by grants from the National Natural Science Foundation of China (NSFC #81270690)
MP86-13 IMPACT OF TESTOSTERONE DEFICIENCY ON ERECTILE FUNCTION RECOVERY POST-RADICAL PROSTATECTOMY Lawrence C. Jenkins*, James A. Eastham, Vincent P. Laudone, Christian J. Nelson, John P. Mulhall, New York, NY INTRODUCTION AND OBJECTIVES: Testosterone (T) is necessary for the proper maintenance of cavernosal erectile tissue. Animal models have demonstrated that castrate levels of T are associated with venous leak development. Furthermore, in the setting of cavernous nerve injury, low T results in poorer cavernous nerve recovery and grater degrees of erectile function impairment. We examined the impact of low T levels on erectile function recovery (EFR) post-radical prostatectomy (RP). METHODS: We retrospectively reviewed records of patients who has undergone RP. Patients completed an IIEF, in particular the EF domain (EFD) at each visit including prior to and following RP. We included subjects (i) with valid EFD scores pre-surgery (ii) with valid EFD ( 6) at least 18m post-surgery (iii) who had been operated on by surgeons with greater than 20 years experience each (iv) who had bilateral nerve sparing (v) with an early morning total T level 3 months of RP. Correlation coefficients were calculated for univariate analysis, and multiple regression was used for multivariable analysis. In multivariable analysis, age, baseline EFD, and baseline T were used to predict post-surgery EFD. RESULTS: 157 men met the eligibility criteria. The mean age was 588 years. The vascular co-morbidities were: 5% diabetes, 41% hypertension, 47% high cholesterol. The mean time of last post-surgery EFD score was 31.2 years (range¼1.5-6.7 years). The mean pre and post-surgery EFD scores were: 26.65.2 and 20.78.7. On univariate analysis, age (r¼-0.18, p¼0.03) and baseline EFD (r¼0.32, p<0.001) were related to post-surgery EFD. Baseline T did not show a relationship with post-surgery EFD (r¼0.04, p¼0.66). On multivariable analysis using these three variables to predict post-surgery EFD, baseline EFD remained a significant predictor (beta¼0.30, p<0.001) while age (beta¼-0.13, p¼0.09) approached significance. Baseline T (beta¼0.03, p¼0.68) was not a significant predictor of post-surgery EFD. CONCLUSIONS: T level at baseline does not appear to have a significant effect on EFR at 24 months. Possibly erectile tissue is preserved by patients using penile rehabilitation protocols during their recovery period even in men with low T. Source of Funding: none