Aspirin Administration can not Improve Erectile Dysfunction, whether with Higher Dosage or Longer Duration

Aspirin Administration can not Improve Erectile Dysfunction, whether with Higher Dosage or Longer Duration | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Aspirin Administration can not Improve Erectile Dysfunction, whether with Higher Dosage or Longer Duration Tao Li, Yiting Jiang, Gang Shan, Chao Luo, Guangshi Du, Xinzhu Qi, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2963216/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Aspirin is the most widely used medicine since its synthesis, we aim to investigate the controversial relationship between aspirin and erectile function. Methods Thirty-six healthy young rats were grouped and administrated with small (10 mg/kg/d) and big (150 mg/kg/d) dose aspirin for 1 and 3 months, respectively; eighteen rats with bilateral cavernous nerve crush (BCNC) process were gavaged with small dose aspirin for 1 month. The 6-keto PGF 1a , PGE 2 , and TXB 2 in corpus cavernosum were detected to verify the bioactivity of aspirin. The mICP, mICP/MAP ratio, and concentrations of total NO, cAMP, as well as cGMP were selected to determine the erectile function. Results For the healthy young rats, aspirin significantly decreased the 6-keto PGF 1a and PGE 2 levels than control group, however, mICP, mICP/ MAP, total NO, cAMP, and cGMP levels was similar, whether with bigger dosage or longer duration. In BCNC groups, aspirin also significantly inhibited prostaglandin productions, however, it did not improve the impaired erectile function as well. Conclusion Long-term aspirin (even with higher dosage or longer duration) administration did not strength nor deteriorate erectile function for healthy young rats, while it did not improve the BCNC-induced erectile dysfunction as well. Aspirin Erectile function Prostaglandin Chronic inflammation Figures Figure 1 Figure 2 Figure 3 Figure 4 Background As a classical nonprescription drug, aspirin was one of the most common medicine since its first synthesis 100 years ago (W. K. Huang, Tu, & See, 2015 ). With the anti-inflammatory and anti-platelet mechanisms, it revealed a ‘magical’ effect to prevent cancer development (Thun, Jacobs, & Patrono, 2012 ; Ulrich, Bigler, & Potter, 2006 ), including colorectal (Burn et al., 2020 ), ovarian (Webb, 2018 ), and breast cancer (Woloshin & Schwartz, 2004 ). Numerous studies also found that aspirin significantly reduced prostate cancer (PCa) incidence (Prause et al., 2020 ), decreased lethal risk, and inversely associated with the mortality and fatality (Hurwitz et al., 2019 ; Sauer et al., 2018 ; Skriver et al., 2019 ); although some authors reported a negative relation (Zhou et al., 2017 ). Erectile dysfunction (ED) means inability to attain or maintain sufficient erection for a satisfactory sexual performance (Bohm et al., 2007 ; Fazio & Brock, 2004 ), it is common in PCa patients whether receive surgery (J. Yuan et al., 2010 ) or radiotherapy (Fazio & Brock, 2004 ; J. Yuan et al., 2010 ) and impairs their life quality (Shiri et al., 2006 ). Some studies also explored the impact of aspirin on erectile function, however, these results were controversial (Chen & Yin, 2017 ; Senbel, 2011 ). It was known that ED was characterized with atherosclerosis (Blumentals, Gomez-Caminero, Joo, & Vannappagari, 2004 ; Fazio & Brock, 2004 ), endothelial dysfunction (Blumentals et al., 2004 ; Bohm et al., 2007 ; Gleason et al., 2011 ; Hafez et al., 2014 ; Patel et al., 2016 ; Shiri et al., 2006 ), and high circulating pro-inflammatory marker levels (Patel et al., 2016 ). Authors speculated that aspirin was beneficial for ED, considering it prevented atherosclerosis, preserved endothelial function (Blumentals et al., 2004 ; Chen & Yin, 2017 ; Gleason et al., 2011 ; Sadeghipour, Ghasemi, Nobakht, Ebrahimi, & Dehpour, 2007 ), and its anti-inflammatory property (Patel et al., 2016 ; Sadeghipour et al., 2007 ). On the contrary, others thought that aspirin deteriorated erectile function as it inhibited cyclooxygenase (COX) pathway to decrease vasodilative agents of prostaglandin I 2 (PGI 2 ) and prostaglandin E 2 (PGE 2 ) (Mollace, Muscoli, Masini, Cuzzocrea, & Salvemini, 2005 ), which have been used for penile rehabilitation (Fazio & Brock, 2004 ; Javier Angulo, 2002 ; Lin et al., 2013 ; Senbel, 2011 ). In addition, a clinical study recruiting 4 726 males also concluded that NSAIDs had no impact on erectile function, after a strict controlling of NSAIDs indications (Patel et al., 2016 ). As ED was common for PCa patients, and aspirin revealed prevention effect on PCa, it would be interesting to clarify the association between aspirin and erectile function. In this study, we firstly investigated whether aspirin has a dose- or duration-dependent impact on rats’ erectile function, then assessed whether it preserved erectile function on bilateral cavernous nerve crush (BCNC) rats (accepted as radical prostatectomy induced ED model) (J. Yuan et al., 2010 ). Materials and methods Animals Fifty-four male Sprague-Dawley rats weighting 240-260g was obtained from Experimental Animal Center of Guizhou Medical University. We confirmed that all experiments were performed in accordance with relevant guidelines and regulations; all rats were housed and cared for under strict guidelines. This study was approved by the Animal Ethics Committee of Guizhou Medical University (2304361). Experiment I with healthy young rats : Thirty-six rats were randomly divided into six groups: (A) 1-Con, control with normal saline [NS], (B) 1-Small, some dose aspirin, (C) 1-Big, big dose aspirin, the total intervention period was 1 month; (D) 3-Con, (E) 3-Small, (F) 3-Big, this intervention duration was 3 months. Small and big aspirin dose were 10 mg/kg/d and 150 mg/kg/d, respectively, according to previous studies (Bhatt, Shukla, Raval, & Goswami, 2016 ; Liu, Jiang, Zhang, & Ou, 2010 ). Experiment II with BCNC rats : Eighteen rats were randomly divided into three groups: (G) Con, (H) BCNC, rats were performed with BCNC procedure to mimic ED after radical prostatectomy (J. Yuan et al., 2010 ), (I) BCNC-Asp, rats after BCNC were gavaged with a small dose aspirin (10 mg/kg/d). The intervention duration was 1 month. Erectile function measurement At the end of experiments, erectile function was assessed for all rats as previous described (T. Li et al., 2019 ; J. Yuan et al., 2010 ). Briefly, 2% isoflurane mixed with air was used for inhalation anesthesia. After the exposure and intubation of penile foot and carotid artery, concentration of isoflurane was descended to 1%. The cavernous nerve was electrically stimulated by a stimulator at 5 V with 20 HZ and 5 µs for 50 s, while intracavernous pressure (ICP) and mean arterial pressure (MAP) were simultaneously recorded with a BL420 bio-function experimental system. The maximum (mICP)/MAP ratio was then calculated and analyzed. The penis was harvested and washed with PBS, then cut into pieces and stored with liquid nitrogen. Prostaglandins (PGs) 6-keto PGF 1a (stable metabolites of PGI 2 ), PGE 2 , and thromboxane B 2 (TXB 2 ) (stable metabolites of TXA 2 ) was measured by commercial enzyme linked immunosorbent assay (ELISA) kit (Caymen Chemical, Ann Arbor, MI, USA). As was described (Cong, Xiao, Biancani, & Behar, 2007 ), the distal penis were snipped and homogenized in homogenization buffer (1 mM ethylenediaminetetraacetic acid, 0.1 M phosphate buffer (pH 7.4), and 20 ug/ml indomethacin) at 4°C to inhibit arachidonic acid transferred to PGs. The homogenate was centrifuged (12,000 g, 20 min, 4°C) and the supernatant was obtained for analysis following manufacturer's instructions. After normalizing to total protein, the final PGs concentrations were expressed as pg/mg protein. cAMP, cGMP and total NO The proximal penis was cut and homogenized in phosphate buffer solution, then centrifuged (12,000 g for 20 min, at 4°C) for supernatant (T. Li et al., 2019 ). cAMP and cGMP were analyzed by ELISA kit ((Nanjing Jiancheng Bioengineering Institute, Nanjing, Jiangsu Province, China) under the manufacturer's recommendations. For total NO concentration, the commercial Nitrate/Nitrite Fluorometric Assay kit (Caymen Chemical, Ann Arbor, MI, USA) was purchased to measure the nitrate + nitrite level (metabolites of NO) (Jung et al., 2010 ; J. Li et al., 2014 ). Statistical analysis All data were showed as mean ± SEM and analyzed by GraphPad Prism 5 software (GraphPad Sofware, Inc., La Jolla, CA, USA). After proving Gaussian distribution using Kolmogorov-Smirnov-test, the differences between multiple groups were compared using one-way of variance analysis, while for case of differences the Student’s t-test was applied. A value of p < 0.05 was considered significant. Result Experiment I with healthy young rats : Erectile function The administration of small- and big-dose aspirin for 1 month had no impact on mICP (p = 0.9420) and mICP/MAP ratio (p = 0.6194); after a longer duration of 3 months, no significant difference was found on mICP (p = 0.7009) and mICP/MAP ratio (p = 0.7759) as well. In addition, there was no significant difference between small and big aspirin groups (Fig. 1 ). These results indicating that aspirin had no duration- or dose-dependent influence on erectile function. PGs and cAMP Aspirin significantly decreased 6-keto PGF 1a (p = 0.0021, 0.0048) and PGE 2 (p = 0.0023, 0.0155) concentrations, both for 1 month and 3 month groups; however, no difference was found between small and big aspirin groups. In addition, aspirin did not influence TXB 2 (p = 0.0941, 0.1146) and cAMP (p = 0.8099, 0.5565) levels, both for 1 month and 3 month groups, while there was no difference between small and big aspirin rats as well (Fig. 2 ). Total NO and cGMP Aspirin had no impact on the concentration of total NO (p = 0.8158, 0.7846) and cGMP (p = 0.0533, 0.1199), both for 1 month and 3 month (Fig. 2 ). Experiment I with BCNC rats : Erectile function The mICP (p = 0.0004) and mICP/MAP ratio (p < 0.0001) in BCNC and BCNC-Asp groups were significantly lower than control group, however, no difference was found between BCNC and BCNC-Asp groups (Fig. 3 ); meaning that aspirin did not preserve the impaired erectile function. PGs and cAMP BCNC-Asp group revealed significantly lower 6-keto PGF 1a (p = 0.0147) and PGE 2 (p = 0.0097) concentration than control and BNCN group, while the TXB 2 (p = 0.7018) level was similar. Moreover, BCNC and BCNC-Asp groups showed significantly declined cAMP (p = 0.0126) concentration than control group, however, no difference was observed between them (Fig. 4 ). Total NO and cGMP BCNC and BCNC-Asp groups exhibited significantly lower total NO (p = 0.0225) and cGMP (p = 0.0009) levels than control groups, while no difference was found between them (Fig. 4 ). Discussion Penile erection is a complex neutrally and endocrine haemodynamic event (Hafez et al., 2014 ; Minhas, Cartledge, Eardley, Joyce, & Morrison, 2001 ). The relaxant trabecular smooth muscle can lead increased blood flow to distend the sinusoids of corpora cavernosa, which causes mechanical compression of emissary veins to prevent blood draining, this finally results penile erection (Fazio & Brock, 2004 ). PGs have exhibited protective roles in many physiopathological conditions including normal penile erection (Mollace et al., 2005 ). As the primary arachidonic acid metabolite, PGI 2 possesses the highest potency to relax penile arteries (Javier Angulo, 2002 ), inhibits platelet aggregation (Jiuhong Yuan, 2009 ), and acts an essential role of vascular protector (Jiuhong Yuan, 2009 ). Briefly, PGI 2 stimulates adenylyl cyclase to produce cAMP by combing PGI receptor (IP), then the increased cAMP causes smooth muscle relaxation and promotes penile blood flow by leading a cascade of phosphorylation and inhibiting myosin lightchain kinase; while PGE 2 exerts a similar relaxation effect by binding PGE receptor (EP) (Lin et al., 2013 ). According to these theory, PGI 2 and PGE 1 were selected for penile rehabilitation (Fazio & Brock, 2004 ; Javier Angulo, 2002 ; Lin et al., 2013 ; Senbel, 2011 ); and authors claimed that aspirin could disturb the physiological process of penile erection and increased ED risk, as it inhibited COX pathway to reduce the relaxant agents of PGI 2 and PGE 2 (Gleason et al., 2011 ; Senbel, 2011 ; Shiri et al., 2006 ). Actually, our results verified that aspirin significantly decreased PGs production (Fig. 2 ). However, it neither changed the relaxant agent of cAMP (Fig. 2 ), nor impaired the normal erectile function which proved by mICP and mICP/ MAP ratio (Fig. 1 ); this was in accordance with previous basic (Kim, Kim, Davies, Hagen, & Carson, 1995 ) or clinical (Bohm et al., 2007 ; Kupelian, Hall, & McKinlay, 2013 ; Patel et al., 2016 ) studies. These authors stated that TXA 2 could hydrolyze phosphoinositides to second messengers of inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) (J. Huang, 2004 ), while accumulated IP3 increased calcium (Ca 2+ ) to mediate the contraction of human trabecular smooth muscle and penile arteries (Bornman, Franz, Jacobs, & Du Plessis, 1987 ; J. Huang, 2004 ; Javier Angulo, 2002 ). Penile hypercoagulability induced by TXA 2 also played a key initiating role in penile vascular changes to impair erectile function (Bornman et al., 1987 ; Senbel, 2011 ). However, the contractive agent of TXA 2 was inhibited when the relaxant PGI 2 and PGE 2 were suppressed (Bornman et al., 1987 ; Javier Angulo, 2002 ; Lin et al., 2013 ). Moreover, the TP signaling revealed a broad range of cellular responses. TPα could stimulate cAMP production and TPβ reduce it (Hirata, Ushikubi, Kakizuka, Okuma, & Narumiya, 1996 ; J. Huang, 2004 ); while EP2/4 increased cAMP but EP3 decreased it (Iwasaki et al., 2013 ). Considering the PGs receptor pathways in a cell- and tissue-specific preference (J. Huang, 2004 ), it may contribute to an unchanged cAMP level (Levine, Nandi, & King, 1990 ). All these might explain why aspirin did not deteriorate erectile function. In fact, NO is the principal neurotransmitter in maintaining erection (Hafez et al., 2014 ; Minhas et al., 2001 ; Sadeghipour et al., 2007 ). It can activate guanylate cyclase to produce cGMP, this alteration changes ion channel permeability of potassium (K + ) and calcium (Ca 2+ ) to decrease cytosolic calcium level, finally causing relaxation of smooth muscle in corpus cavernosum (Fazio & Brock, 2004 ; Minhas et al., 2001 ; Ruan, Mohite, So, & Ruan, 2013 ). However, the relationship between PGs and NO was controversial which remained better investigation (Lin et al., 2013 ; Mollace et al., 2005 ; Pluchart, Khouri, Blaise, Roustit, & Cracowski, 2017 ). Firstly, some authors found that PGIs promoted eNOS level (Lin et al., 2013 ), and PGE 1 simulated NOS enzyme activity (Escrig, Marin, & Mas, 1999 ; Senbel, 2011 ); all these could enhance NO production and strengthened erectile ability (Escrig et al., 1999 ; Senbel, 2011 ). So they thought that aspirin might deteriorate normal erectile function (Hafez et al., 2014 ) by attenuating NOS activity and declining NO production (Hafez et al., 2014 ; Mollace et al., 2005 ). On the contrary, some studies revealed that aspirin increased NO bioavailability (Hafez et al., 2014 ) by preserving the impaired eNOS (Gao et al., 2017 ; Hafez et al., 2014 ) and iNOS (Nishio & Watanabe, 1998 ), thus it could potentiate endothelial-dependent relaxation of corpus cavernosum (Azadzoi et al., 1992 ; Hafez et al., 2014 ; Minhas et al., 2001 ) and improve erectile function (Hafez et al., 2014 ; Sadeghipour et al., 2007 ; Saroukhani et al., 2013 ). Considering this discrepancy, we analyzed the relationship between aspirin and NOS activity by recording total NO levels (Mollace et al., 2005 ). We found that aspirin did not change NO concentration, whether with higher dosage (150 mg/kg/d) nor longer duration (3 months); while the constant cGMP levels also indirectly reflected that aspirin had no impact on NOS activity. In combination with the mICP and mICP/MAP ratio, we speculated that long-term aspirin did not impair or enhance normal erectile in the healthy young rat model, this was similar with published clinical studies (Bener, Al-Hamaq, Kamran, & Al-Ansari, 2008 ; Bohm et al., 2007 ; Kupelian et al., 2013 ; Patel et al., 2016 ). It has been reported that BCNC-induced ED was characterized with impaired eNOS (J. Yuan et al., 2010 ). Considering the promising role of aspirin in PCa (Downer et al., 2017 ; Rothwell et al., 2011 ; Smith et al., 2017 ), we investigated whether aspirin restored the impaired eNOS to improve ED. We found that aspirin (10 mg/kg/d for one month) in BCNC rats significantly decreased PGs, however, it neither increased cAMP and cGMP/NO pathway, nor improved the damaged erectile function. The present study has several limitations. Firstly, although both PGs and NO was essential for erectile function, we did not clarify the complex interactions between them. Secondly, we choose BCNC rat model to investigate whether aspirin could preserve the impaired erectile function for PCa patients, however it may not totally present all process of erectile function, while aging, diabetes, hypertension, dyslipidemia or other model with metabolic syndrome might be better. Conclusion For healthy young rats with aspirin taking, we observed decreased PGs levels, however aspirin did not strength or deteriorate normal erectile function, whether with bigger dosage or longer duration. In addition, aspirin also did not preserve impaired erectile function, as shown on BCNC-induced ED model. Declarations Author contribution Tao Li, Yiting Jiang, and Gang Shan conceived and designed the experiments. Chao Luo, Guangshi Du, Xinzhu Qi, and Ye Tian performed the experiments. Yiting Jiang and Fu Luo analyzed data. Tao Li and Yiting Jiang wrote the manuscript. Yuan Tian and Jiang Gu revised it. All authors read and approved the final manuscript. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Acknowledgments This manuscript was funded by The Science and Technology Department of Guizhou Province (QianKeHe LH Zi【2016】7148) and the National Natural Science Foundation of China (Grant No. 82060276). Ethics approval: This study was approved by the Animal Ethics Committee of Guizhou Medical University (2304361). Consent to participate: This is an animal study. Consent for publication: All authors agree to publish. Competing interests: The authors declare no competing interests References Azadzoi, K. M., Kim, N., Brown, M. L., Goldstein, I., Cohen, R. A., & Saenz de Tejada, I. (1992). Endothelium-derived nitric oxide and cyclooxygenase products modulate corpus cavernosum smooth muscle tone. J Urol, 147 (1), 220–225. doi: 10.1016/s0022-5347(17)37201-4 Bener, A., Al-Hamaq, A. O., Kamran, S., & Al-Ansari, A. (2008). 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BJU Int, 99 (1), 177–182. doi: 10.1111/j.1464-410X.2006.06530.x Saroukhani, S., Emami-Parsa, M., Modabbernia, A., Ashrafi, M., Farokhnia, M., Hajiaghaee, R., & Akhondzadeh, S. (2013). Aspirin for treatment of lithium-associated sexual dysfunction in men: randomized double-blind placebo-controlled study. Bipolar Disord, 15 (6), 650–656. doi: 10.1111/bdi.12108 Sauer, C. M., Myran, D. T., Costentin, C. E., Zwisler, G., Safder, T., Papatheodorou, S., & Mucci, L. A. (2018). Effect of long term aspirin use on the incidence of prostate cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol, 132 , 66–75. doi: 10.1016/j.critrevonc.2018.09.013 Senbel, A. M. (2011). Functional inhibition of erectile process in rats by indomethacin. World J Urol, 29 (4), 523–527. doi: 10.1007/s00345-010-0600-0 Shiri, R., Koskimaki, J., Hakkinen, J., Tammela, T. L., Auvinen, A., & Hakama, M. (2006). Effect of nonsteroidal anti-inflammatory drug use on the incidence of erectile dysfunction. J Urol, 175 (5), 1812–1815; discussion 1815–1816. doi: 10.1016/s0022-5347(05)01000-1 Skriver, C., Dehlendorff, C., Borre, M., Brasso, K., Larsen, S. B., Dalton, S. O.,.. . Friis, S. (2019). Use of Low-Dose Aspirin and Mortality After Prostate Cancer Diagnosis: A Nationwide Cohort Study. Ann Intern Med, 170 (7), 443–452. doi: 10.7326/m17-3085 Smith, C. J., Dorsey, T. H., Tang, W., Jordan, S. V., Loffredo, C. A., & Ambs, S. (2017). Aspirin Use Reduces the Risk of Aggressive Prostate Cancer and Disease Recurrence in African-American Men. Cancer Epidemiol Biomarkers Prev. doi: 10.1158/1055-9965.epi-16-1027 Thun, M. J., Jacobs, E. J., & Patrono, C. (2012). The role of aspirin in cancer prevention. Nat Rev Clin Oncol, 9 (5), 259–267. doi: 10.1038/nrclinonc.2011.199 Ulrich, C. M., Bigler, J., & Potter, J. D. (2006). Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nat Rev Cancer, 6 (2), 130–140. doi: 10.1038/nrc1801 Webb, P. M. (2018). Does aspirin have a role in management of ovarian cancer? Lancet Oncol, 19 (8), 1011–1012. doi: 10.1016/s1470-2045(18)30420-0 Woloshin, S., & Schwartz, L. M. (2004). Association of aspirin use and hormone receptor status with breast cancer risk. Jama, 292 (12), 1426–1427; author reply 1427. doi: 10.1001/jama.292.12.1426-b Yuan, J. (2009). A new strategy, SuperEnzyme gene therapy in penile rehabilitation. J Sex Med. doi: 10.1111/j.1743-6109.2008.01191.x Yuan, J., Lin, H., Li, P., Zhang, R., Luo, A., Berardinelli, F.,.. . Wang, R. (2010). Molecular mechanisms of vacuum therapy in penile rehabilitation: a novel animal study. Eur Urol, 58 (5), 773–780. doi: 10.1016/j.eururo.2010.07.005 Zhou, C. K., Daugherty, S. E., Liao, L. M., Freedman, N. D., Abnet, C. C., Pfeiffer, R., & Cook, M. B. (2017). Do Aspirin and Other NSAIDs Confer a Survival Benefit in Men Diagnosed with Prostate Cancer? A Pooled Analysis of NIH-AARP and PLCO Cohorts. Cancer Prev Res (Phila), 10 (7), 410–420. doi: 10.1158/1940-6207.capr-17-0033 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2963216","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":204738100,"identity":"f5e593ed-23a2-482c-8558-69af508ea23e","order_by":0,"name":"Tao Li","email":"","orcid":"","institution":"Affiliated Hospital of Guizhou Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tao","middleName":"","lastName":"Li","suffix":""},{"id":204738101,"identity":"c9250650-0ef1-4712-b8e8-7997f4b1f861","order_by":1,"name":"Yiting Jiang","email":"","orcid":"","institution":"The Ninth People’s Hospital of Chongqing","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yiting","middleName":"","lastName":"Jiang","suffix":""},{"id":204738102,"identity":"0976ed8a-8645-4291-a27e-c4c6ae5dbc59","order_by":2,"name":"Gang Shan","email":"","orcid":"","institution":"Guizhou Provincial People's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gang","middleName":"","lastName":"Shan","suffix":""},{"id":204738105,"identity":"8473f479-0efd-4764-97cc-f767222afddc","order_by":3,"name":"Chao Luo","email":"","orcid":"","institution":"Affiliated Hospital of Guizhou Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chao","middleName":"","lastName":"Luo","suffix":""},{"id":204738106,"identity":"88f68851-2f0d-4715-8575-b2437c35b0f4","order_by":4,"name":"Guangshi Du","email":"","orcid":"","institution":"Translational Medicine Research Center of Guizhou Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Guangshi","middleName":"","lastName":"Du","suffix":""},{"id":204738108,"identity":"fdc3a5cd-5e20-4cc9-a8af-d436e0ba90ac","order_by":5,"name":"Xinzhu Qi","email":"","orcid":"","institution":"Guizhou Institute for Food and Drug Control","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xinzhu","middleName":"","lastName":"Qi","suffix":""},{"id":204738110,"identity":"947e6f9f-61fb-4d99-b241-dd6760b0c547","order_by":6,"name":"Ye Tian","email":"","orcid":"","institution":"Guizhou Provincial People's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ye","middleName":"","lastName":"Tian","suffix":""},{"id":204738114,"identity":"8b80fac7-374d-487b-b8e6-b265537a5f18","order_by":7,"name":"Fu Luo","email":"","orcid":"","institution":"Guizhou Provincial People's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Fu","middleName":"","lastName":"Luo","suffix":""},{"id":204738116,"identity":"7b362554-bfc7-49b1-bbf6-0b1f797f259e","order_by":8,"name":"Yuan Tian","email":"","orcid":"","institution":"Affiliated Hospital of Guizhou Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuan","middleName":"","lastName":"Tian","suffix":""},{"id":204738118,"identity":"8c8d026d-2c12-4361-bd0a-6c3c9be592ec","order_by":9,"name":"Jiang Gu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyUlEQVRIiWNgGAWjYBAC+/kPGw4k/rOptz/eQKQWA4bkgwcesKUlMJw5QLSWtOSDD9gOJzDcSCBSiznDGYMDCTyH8xhnPt54g6HGJpqgFsvGHqAWifRiZum0YguGY2m5DQT1HOYBajGwZmyTzjGTYGw4TISWYyAtCcyMPZJniNRicIYt4UDCAefEGRI8RGqRnMF84EBiQ5qxAQ/QLwnE+IVfgrH5488GGzkD9sMbb3yosSHCL8iOlEggRTlEC6k6RsEoGAWjYGQAAHjDQ/lnmCj5AAAAAElFTkSuQmCC","orcid":"","institution":"Affiliated Hospital of Guizhou Medical University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jiang","middleName":"","lastName":"Gu","suffix":""}],"badges":[],"createdAt":"2023-05-21 15:59:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2963216/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2963216/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":37685803,"identity":"870e8584-9197-4248-a15b-f03c606a1e31","added_by":"auto","created_at":"2023-05-30 17:13:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":114052,"visible":true,"origin":"","legend":"\u003cp\u003eA: Representative maximum intracavernous pressure (mICP) tracing under cavernous nerve stimulation for experiment I with healthy young rats. B and C: Statistical analysis for mICP and mICP/mean arterial pressure (MAP) ratio, respectively.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2963216/v1/43dd94fa2e315fbe35500289.png"},{"id":37685805,"identity":"a6499ead-a888-49a6-a568-e35aa970663e","added_by":"auto","created_at":"2023-05-30 17:13:15","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":158643,"visible":true,"origin":"","legend":"\u003cp\u003eStatistical analysis of 6-keto PGF\u003csub\u003e1a\u003c/sub\u003e, PGE\u003csub\u003e2\u003c/sub\u003e, TXB\u003csub\u003e2\u003c/sub\u003e, cAMP, total NO, and cGMP levels for experiment I with healthy young rats.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-2963216/v1/b6bd121d537b42cad502ae82.png"},{"id":37685804,"identity":"cb191615-09c9-4eff-ab9d-8a498587b489","added_by":"auto","created_at":"2023-05-30 17:13:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":84595,"visible":true,"origin":"","legend":"\u003cp\u003eA: Representative mICP tracing under cavernous nerve stimulation for experiment II with BCNC rats. B and C: Statistical analysis for mICP and mICP/MAP ratio, respectively.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-2963216/v1/509d289a8ffb0583636fe35e.png"},{"id":37685806,"identity":"4a694a65-2a63-474e-bdb0-43c8e50801f7","added_by":"auto","created_at":"2023-05-30 17:13:15","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":140138,"visible":true,"origin":"","legend":"\u003cp\u003eStatistical analysis of 6-keto PGF\u003csub\u003e1a\u003c/sub\u003e, PGE\u003csub\u003e2\u003c/sub\u003e, TXB\u003csub\u003e2\u003c/sub\u003e, cAMP, total NO, and cGMP levels for experiment II with BCNC rats.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-2963216/v1/4f356e542eb9293ef4e40a15.png"},{"id":39552348,"identity":"6a336dc6-c8c0-43e8-aa19-0541d17aa4c8","added_by":"auto","created_at":"2023-07-05 06:44:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1686849,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2963216/v1/de4fa809-e429-410c-bf7f-0ea168a003cd.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Aspirin Administration can not Improve Erectile Dysfunction, whether with Higher Dosage or Longer Duration","fulltext":[{"header":"Background","content":"\u003cp\u003eAs a classical nonprescription drug, aspirin was one of the most common medicine since its first synthesis 100 years ago (W. K. Huang, Tu, \u0026amp; See, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). With the anti-inflammatory and anti-platelet mechanisms, it revealed a \u0026lsquo;magical\u0026rsquo; effect to prevent cancer development (Thun, Jacobs, \u0026amp; Patrono, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Ulrich, Bigler, \u0026amp; Potter, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2006\u003c/span\u003e), including colorectal (Burn et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2020\u003c/span\u003e), ovarian (Webb, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2018\u003c/span\u003e), and breast cancer (Woloshin \u0026amp; Schwartz, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). Numerous studies also found that aspirin significantly reduced prostate cancer (PCa) incidence (Prause et al., \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2020\u003c/span\u003e), decreased lethal risk, and inversely associated with the mortality and fatality (Hurwitz et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Sauer et al., \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Skriver et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2019\u003c/span\u003e); although some authors reported a negative relation (Zhou et al., \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2017\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eErectile dysfunction (ED) means inability to attain or maintain sufficient erection for a satisfactory sexual performance (Bohm et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Fazio \u0026amp; Brock, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2004\u003c/span\u003e), it is common in PCa patients whether receive surgery (J. Yuan et al., \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2010\u003c/span\u003e) or radiotherapy (Fazio \u0026amp; Brock, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; J. Yuan et al., \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2010\u003c/span\u003e) and impairs their life quality (Shiri et al., \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). Some studies also explored the impact of aspirin on erectile function, however, these results were controversial (Chen \u0026amp; Yin, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Senbel, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2011\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIt was known that ED was characterized with atherosclerosis (Blumentals, Gomez-Caminero, Joo, \u0026amp; Vannappagari, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Fazio \u0026amp; Brock, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2004\u003c/span\u003e), endothelial dysfunction (Blumentals et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Bohm et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Gleason et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Hafez et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Patel et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Shiri et al., \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2006\u003c/span\u003e), and high circulating pro-inflammatory marker levels (Patel et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Authors speculated that aspirin was beneficial for ED, considering it prevented atherosclerosis, preserved endothelial function (Blumentals et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Chen \u0026amp; Yin, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Gleason et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Sadeghipour, Ghasemi, Nobakht, Ebrahimi, \u0026amp; Dehpour, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2007\u003c/span\u003e), and its anti-inflammatory property (Patel et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Sadeghipour et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2007\u003c/span\u003e). On the contrary, others thought that aspirin deteriorated erectile function as it inhibited cyclooxygenase (COX) pathway to decrease vasodilative agents of prostaglandin I\u003csub\u003e2\u003c/sub\u003e (PGI\u003csub\u003e2\u003c/sub\u003e) and prostaglandin E\u003csub\u003e2\u003c/sub\u003e (PGE\u003csub\u003e2\u003c/sub\u003e) (Mollace, Muscoli, Masini, Cuzzocrea, \u0026amp; Salvemini, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2005\u003c/span\u003e), which have been used for penile rehabilitation (Fazio \u0026amp; Brock, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Javier Angulo, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2002\u003c/span\u003e; Lin et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Senbel, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). In addition, a clinical study recruiting 4 726 males also concluded that NSAIDs had no impact on erectile function, after a strict controlling of NSAIDs indications (Patel et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2016\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAs ED was common for PCa patients, and aspirin revealed prevention effect on PCa, it would be interesting to clarify the association between aspirin and erectile function. In this study, we firstly investigated whether aspirin has a dose- or duration-dependent impact on rats\u0026rsquo; erectile function, then assessed whether it preserved erectile function on bilateral cavernous nerve crush (BCNC) rats (accepted as radical prostatectomy induced ED model) (J. Yuan et al., \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2010\u003c/span\u003e).\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e \u003cb\u003eAnimals\u003c/b\u003e \u003c/p\u003e \u003cp\u003eFifty-four male Sprague-Dawley rats weighting 240-260g was obtained from Experimental Animal Center of Guizhou Medical University. We confirmed that all experiments were performed in accordance with relevant guidelines and regulations; all rats were housed and cared for under strict guidelines. This study was approved by the Animal Ethics Committee of Guizhou Medical University (2304361).\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003eExperiment I with healthy young rats\u003c/span\u003e:\u003c/p\u003e \u003cp\u003eThirty-six rats were randomly divided into six groups: (A) 1-Con, control with normal saline [NS], (B) 1-Small, some dose aspirin, (C) 1-Big, big dose aspirin, the total intervention period was 1 month; (D) 3-Con, (E) 3-Small, (F) 3-Big, this intervention duration was 3 months. Small and big aspirin dose were 10 mg/kg/d and 150 mg/kg/d, respectively, according to previous studies (Bhatt, Shukla, Raval, \u0026amp; Goswami, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Liu, Jiang, Zhang, \u0026amp; Ou, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2010\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003eExperiment II with BCNC rats\u003c/span\u003e:\u003c/p\u003e \u003cp\u003eEighteen rats were randomly divided into three groups: (G) Con, (H) BCNC, rats were performed with BCNC procedure to mimic ED after radical prostatectomy (J. Yuan et al., \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2010\u003c/span\u003e), (I) BCNC-Asp, rats after BCNC were gavaged with a small dose aspirin (10 mg/kg/d). The intervention duration was 1 month.\u003c/p\u003e\n\u003ch3\u003eErectile function measurement\u003c/h3\u003e\n\u003cp\u003eAt the end of experiments, erectile function was assessed for all rats as previous described (T. Li et al., \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; J. Yuan et al., \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). Briefly, 2% isoflurane mixed with air was used for inhalation anesthesia. After the exposure and intubation of penile foot and carotid artery, concentration of isoflurane was descended to 1%. The cavernous nerve was electrically stimulated by a stimulator at 5 V with 20 HZ and 5 \u0026micro;s for 50 s, while intracavernous pressure (ICP) and mean arterial pressure (MAP) were simultaneously recorded with a BL420 bio-function experimental system. The maximum (mICP)/MAP ratio was then calculated and analyzed. The penis was harvested and washed with PBS, then cut into pieces and stored with liquid nitrogen.\u003c/p\u003e\n\u003ch3\u003eProstaglandins (PGs)\u003c/h3\u003e\n\u003cp\u003e6-keto PGF\u003csub\u003e1a\u003c/sub\u003e (stable metabolites of PGI\u003csub\u003e2\u003c/sub\u003e), PGE\u003csub\u003e2\u003c/sub\u003e, and thromboxane B\u003csub\u003e2\u003c/sub\u003e (TXB\u003csub\u003e2\u003c/sub\u003e) (stable metabolites of TXA\u003csub\u003e2\u003c/sub\u003e) was measured by commercial enzyme linked immunosorbent assay (ELISA) kit (Caymen Chemical, Ann Arbor, MI, USA). As was described (Cong, Xiao, Biancani, \u0026amp; Behar, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2007\u003c/span\u003e), the distal penis were snipped and homogenized in homogenization buffer (1 mM ethylenediaminetetraacetic acid, 0.1 M phosphate buffer (pH 7.4), and 20 ug/ml indomethacin) at 4\u0026deg;C to inhibit arachidonic acid transferred to PGs. The homogenate was centrifuged (12,000 g, 20 min, 4\u0026deg;C) and the supernatant was obtained for analysis following manufacturer's instructions. After normalizing to total protein, the final PGs concentrations were expressed as pg/mg protein.\u003c/p\u003e\n\u003ch3\u003ecAMP, cGMP and total NO\u003c/h3\u003e\n\u003cp\u003eThe proximal penis was cut and homogenized in phosphate buffer solution, then centrifuged (12,000 g for 20 min, at 4\u0026deg;C) for supernatant (T. Li et al., \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). cAMP and cGMP were analyzed by ELISA kit ((Nanjing Jiancheng Bioengineering Institute, Nanjing, Jiangsu Province, China) under the manufacturer's recommendations. For total NO concentration, the commercial Nitrate/Nitrite Fluorometric Assay kit (Caymen Chemical, Ann Arbor, MI, USA) was purchased to measure the nitrate\u0026thinsp;+\u0026thinsp;nitrite level (metabolites of NO) (Jung et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2010\u003c/span\u003e; J. Li et al., \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2014\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll data were showed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM and analyzed by GraphPad Prism 5 software (GraphPad Sofware, Inc., La Jolla, CA, USA). After proving Gaussian distribution using Kolmogorov-Smirnov-test, the differences between multiple groups were compared using one-way of variance analysis, while for case of differences the Student\u0026rsquo;s t-test was applied. A value of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Result","content":"\u003cp\u003e \u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003eExperiment I with healthy young rats\u003c/span\u003e:\u003c/p\u003e\n\u003ch3\u003eErectile function\u003c/h3\u003e\n\u003cp\u003eThe administration of small- and big-dose aspirin for 1 month had no impact on mICP (p\u0026thinsp;=\u0026thinsp;0.9420) and mICP/MAP ratio (p\u0026thinsp;=\u0026thinsp;0.6194); after a longer duration of 3 months, no significant difference was found on mICP (p\u0026thinsp;=\u0026thinsp;0.7009) and mICP/MAP ratio (p\u0026thinsp;=\u0026thinsp;0.7759) as well. In addition, there was no significant difference between small and big aspirin groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). These results indicating that aspirin had no duration- or dose-dependent influence on erectile function.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003ePGs and cAMP\u003c/h3\u003e\n\u003cp\u003eAspirin significantly decreased 6-keto PGF\u003csub\u003e1a\u003c/sub\u003e (p\u0026thinsp;=\u0026thinsp;0.0021, 0.0048) and PGE\u003csub\u003e2\u003c/sub\u003e (p\u0026thinsp;=\u0026thinsp;0.0023, 0.0155) concentrations, both for 1 month and 3 month groups; however, no difference was found between small and big aspirin groups.\u003c/p\u003e \u003cp\u003eIn addition, aspirin did not influence TXB\u003csub\u003e2\u003c/sub\u003e (p\u0026thinsp;=\u0026thinsp;0.0941, 0.1146) and cAMP (p\u0026thinsp;=\u0026thinsp;0.8099, 0.5565) levels, both for 1 month and 3 month groups, while there was no difference between small and big aspirin rats as well (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eTotal NO and cGMP \u003c/h3\u003e\n\u003cp\u003eAspirin had no impact on the concentration of total NO (p\u0026thinsp;=\u0026thinsp;0.8158, 0.7846) and cGMP (p\u0026thinsp;=\u0026thinsp;0.0533, 0.1199), both for 1 month and 3 month (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003eExperiment I with BCNC rats\u003c/span\u003e:\u003c/p\u003e\n\u003ch3\u003eErectile function\u003c/h3\u003e\n\u003cp\u003eThe mICP (p\u0026thinsp;=\u0026thinsp;0.0004) and mICP/MAP ratio (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) in BCNC and BCNC-Asp groups were significantly lower than control group, however, no difference was found between BCNC and BCNC-Asp groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e); meaning that aspirin did not preserve the impaired erectile function.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003ePGs and cAMP\u003c/h3\u003e\n\u003cp\u003eBCNC-Asp group revealed significantly lower 6-keto PGF\u003csub\u003e1a\u003c/sub\u003e (p\u0026thinsp;=\u0026thinsp;0.0147) and PGE\u003csub\u003e2\u003c/sub\u003e (p\u0026thinsp;=\u0026thinsp;0.0097) concentration than control and BNCN group, while the TXB\u003csub\u003e2\u003c/sub\u003e (p\u0026thinsp;=\u0026thinsp;0.7018) level was similar. Moreover, BCNC and BCNC-Asp groups showed significantly declined cAMP (p\u0026thinsp;=\u0026thinsp;0.0126) concentration than control group, however, no difference was observed between them (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eTotal NO and cGMP\u003c/h3\u003e\n\u003cp\u003eBCNC and BCNC-Asp groups exhibited significantly lower total NO (p\u0026thinsp;=\u0026thinsp;0.0225) and cGMP (p\u0026thinsp;=\u0026thinsp;0.0009) levels than control groups, while no difference was found between them (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePenile erection is a complex neutrally and endocrine haemodynamic event (Hafez et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Minhas, Cartledge, Eardley, Joyce, \u0026amp; Morrison, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2001\u003c/span\u003e). The relaxant trabecular smooth muscle can lead increased blood flow to distend the sinusoids of corpora cavernosa, which causes mechanical compression of emissary veins to prevent blood draining, this finally results penile erection (Fazio \u0026amp; Brock, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2004\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePGs have exhibited protective roles in many physiopathological conditions including normal penile erection (Mollace et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). As the primary arachidonic acid metabolite, PGI\u003csub\u003e2\u003c/sub\u003e possesses the highest potency to relax penile arteries (Javier Angulo, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2002\u003c/span\u003e), inhibits platelet aggregation (Jiuhong Yuan, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2009\u003c/span\u003e), and acts an essential role of vascular protector (Jiuhong Yuan, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). Briefly, PGI\u003csub\u003e2\u003c/sub\u003e stimulates adenylyl cyclase to produce cAMP by combing PGI receptor (IP), then the increased cAMP causes smooth muscle relaxation and promotes penile blood flow by leading a cascade of phosphorylation and inhibiting myosin lightchain kinase; while PGE\u003csub\u003e2\u003c/sub\u003e exerts a similar relaxation effect by binding PGE receptor (EP) (Lin et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). According to these theory, PGI\u003csub\u003e2\u003c/sub\u003e and PGE\u003csub\u003e1\u003c/sub\u003e were selected for penile rehabilitation (Fazio \u0026amp; Brock, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Javier Angulo, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2002\u003c/span\u003e; Lin et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Senbel, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2011\u003c/span\u003e); and authors claimed that aspirin could disturb the physiological process of penile erection and increased ED risk, as it inhibited COX pathway to reduce the relaxant agents of PGI\u003csub\u003e2\u003c/sub\u003e and PGE\u003csub\u003e2\u003c/sub\u003e (Gleason et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Senbel, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Shiri et al., \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2006\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eActually, our results verified that aspirin significantly decreased PGs production (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). However, it neither changed the relaxant agent of cAMP (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), nor impaired the normal erectile function which proved by mICP and mICP/ MAP ratio (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e); this was in accordance with previous basic (Kim, Kim, Davies, Hagen, \u0026amp; Carson, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e1995\u003c/span\u003e) or clinical (Bohm et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Kupelian, Hall, \u0026amp; McKinlay, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Patel et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2016\u003c/span\u003e) studies. These authors stated that TXA\u003csub\u003e2\u003c/sub\u003e could hydrolyze phosphoinositides to second messengers of inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) (J. Huang, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2004\u003c/span\u003e), while accumulated IP3 increased calcium (Ca\u003csup\u003e2+\u003c/sup\u003e) to mediate the contraction of human trabecular smooth muscle and penile arteries (Bornman, Franz, Jacobs, \u0026amp; Du Plessis, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e1987\u003c/span\u003e; J. Huang, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Javier Angulo, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2002\u003c/span\u003e). Penile hypercoagulability induced by TXA\u003csub\u003e2\u003c/sub\u003e also played a key initiating role in penile vascular changes to impair erectile function (Bornman et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e1987\u003c/span\u003e; Senbel, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). However, the contractive agent of TXA\u003csub\u003e2\u003c/sub\u003e was inhibited when the relaxant PGI\u003csub\u003e2\u003c/sub\u003e and PGE\u003csub\u003e2\u003c/sub\u003e were suppressed (Bornman et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e1987\u003c/span\u003e; Javier Angulo, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2002\u003c/span\u003e; Lin et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). Moreover, the TP signaling revealed a broad range of cellular responses. TPα could stimulate cAMP production and TPβ reduce it (Hirata, Ushikubi, Kakizuka, Okuma, \u0026amp; Narumiya, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e1996\u003c/span\u003e; J. Huang, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2004\u003c/span\u003e); while EP2/4 increased cAMP but EP3 decreased it (Iwasaki et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). Considering the PGs receptor pathways in a cell- and tissue-specific preference (J. Huang, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2004\u003c/span\u003e), it may contribute to an unchanged cAMP level (Levine, Nandi, \u0026amp; King, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e1990\u003c/span\u003e). All these might explain why aspirin did not deteriorate erectile function.\u003c/p\u003e \u003cp\u003eIn fact, NO is the principal neurotransmitter in maintaining erection (Hafez et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Minhas et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2001\u003c/span\u003e; Sadeghipour et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2007\u003c/span\u003e). It can activate guanylate cyclase to produce cGMP, this alteration changes ion channel permeability of potassium (K\u003csup\u003e+\u003c/sup\u003e) and calcium (Ca\u003csup\u003e2+\u003c/sup\u003e) to decrease cytosolic calcium level, finally causing relaxation of smooth muscle in corpus cavernosum (Fazio \u0026amp; Brock, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Minhas et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2001\u003c/span\u003e; Ruan, Mohite, So, \u0026amp; Ruan, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). However, the relationship between PGs and NO was controversial which remained better investigation (Lin et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Mollace et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2005\u003c/span\u003e; Pluchart, Khouri, Blaise, Roustit, \u0026amp; Cracowski, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Firstly, some authors found that PGIs promoted eNOS level (Lin et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2013\u003c/span\u003e), and PGE\u003csub\u003e1\u003c/sub\u003e simulated NOS enzyme activity (Escrig, Marin, \u0026amp; Mas, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Senbel, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2011\u003c/span\u003e); all these could enhance NO production and strengthened erectile ability (Escrig et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Senbel, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). So they thought that aspirin might deteriorate normal erectile function (Hafez et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2014\u003c/span\u003e) by attenuating NOS activity and declining NO production (Hafez et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Mollace et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). On the contrary, some studies revealed that aspirin increased NO bioavailability (Hafez et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2014\u003c/span\u003e) by preserving the impaired eNOS (Gao et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Hafez et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2014\u003c/span\u003e) and iNOS (Nishio \u0026amp; Watanabe, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e1998\u003c/span\u003e), thus it could potentiate endothelial-dependent relaxation of corpus cavernosum (Azadzoi et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1992\u003c/span\u003e; Hafez et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Minhas et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2001\u003c/span\u003e) and improve erectile function (Hafez et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Sadeghipour et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Saroukhani et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2013\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eConsidering this discrepancy, we analyzed the relationship between aspirin and NOS activity by recording total NO levels (Mollace et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). We found that aspirin did not change NO concentration, whether with higher dosage (150 mg/kg/d) nor longer duration (3 months); while the constant cGMP levels also indirectly reflected that aspirin had no impact on NOS activity. In combination with the mICP and mICP/MAP ratio, we speculated that long-term aspirin did not impair or enhance normal erectile in the healthy young rat model, this was similar with published clinical studies (Bener, Al-Hamaq, Kamran, \u0026amp; Al-Ansari, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Bohm et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2007\u003c/span\u003e; Kupelian et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Patel et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2016\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIt has been reported that BCNC-induced ED was characterized with impaired eNOS (J. Yuan et al., \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). Considering the promising role of aspirin in PCa (Downer et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Rothwell et al., \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Smith et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2017\u003c/span\u003e), we investigated whether aspirin restored the impaired eNOS to improve ED. We found that aspirin (10 mg/kg/d for one month) in BCNC rats significantly decreased PGs, however, it neither increased cAMP and cGMP/NO pathway, nor improved the damaged erectile function.\u003c/p\u003e \u003cp\u003eThe present study has several limitations. Firstly, although both PGs and NO was essential for erectile function, we did not clarify the complex interactions between them. Secondly, we choose BCNC rat model to investigate whether aspirin could preserve the impaired erectile function for PCa patients, however it may not totally present all process of erectile function, while aging, diabetes, hypertension, dyslipidemia or other model with metabolic syndrome might be better.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eFor healthy young rats with aspirin taking, we observed decreased PGs levels, however aspirin did not strength or deteriorate normal erectile function, whether with bigger dosage or longer duration. In addition, aspirin also did not preserve impaired erectile function, as shown on BCNC-induced ED model.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTao Li, Yiting Jiang, and Gang Shan conceived and designed the experiments. Chao Luo, Guangshi Du, Xinzhu Qi, and Ye Tian performed the experiments. Yiting Jiang and Fu Luo analyzed data. Tao Li and Yiting Jiang wrote the manuscript. Yuan Tian and Jiang Gu revised it. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis manuscript was funded by The Science and Technology Department of Guizhou Province (QianKeHe LH Zi【2016】7148) and the National Natural Science Foundation of China (Grant No. 82060276).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u0026nbsp;\u003c/strong\u003eThis study was approved by the Animal Ethics Committee of Guizhou Medical University (2304361).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e This is an animal study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eAll authors agree to publish.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare no competing interests\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAzadzoi, K. 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Cancer Prev Res (Phila), \u003cem\u003e10\u003c/em\u003e(7), 410\u0026ndash;420. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1158/1940-6207.capr-17-0033\u003c/span\u003e\u003cspan address=\"10.1158/1940-6207.capr-17-0033\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Aspirin, Erectile function, Prostaglandin, Chronic inflammation","lastPublishedDoi":"10.21203/rs.3.rs-2963216/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2963216/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAspirin is the most widely used medicine since its synthesis, we aim to investigate the controversial relationship between aspirin and erectile function.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThirty-six healthy young rats were grouped and administrated with small (10 mg/kg/d) and big (150 mg/kg/d) dose aspirin for 1 and 3 months, respectively; eighteen rats with bilateral cavernous nerve crush (BCNC) process were gavaged with small dose aspirin for 1 month. The 6-keto PGF\u003csub\u003e1a\u003c/sub\u003e, PGE\u003csub\u003e2\u003c/sub\u003e, and TXB\u003csub\u003e2\u003c/sub\u003e in corpus cavernosum were detected to verify the bioactivity of aspirin. The mICP, mICP/MAP ratio, and concentrations of total NO, cAMP, as well as cGMP were selected to determine the erectile function.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eFor the healthy young rats, aspirin significantly decreased the 6-keto PGF\u003csub\u003e1a\u003c/sub\u003e and PGE\u003csub\u003e2\u003c/sub\u003e levels than control group, however, mICP, mICP/ MAP, total NO, cAMP, and cGMP levels was similar, whether with bigger dosage or longer duration. In BCNC groups, aspirin also significantly inhibited prostaglandin productions, however, it did not improve the impaired erectile function as well.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eLong-term aspirin (even with higher dosage or longer duration) administration did not strength nor deteriorate erectile function for healthy young rats, while it did not improve the BCNC-induced erectile dysfunction as well.\u003c/p\u003e","manuscriptTitle":"Aspirin Administration can not Improve Erectile Dysfunction, whether with Higher Dosage or Longer Duration","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-05-30 17:13:10","doi":"10.21203/rs.3.rs-2963216/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b32e0916-1fab-4324-baad-8e2e7a27cfb1","owner":[],"postedDate":"May 30th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-07-11T09:31:38+00:00","versionOfRecord":[],"versionCreatedAt":"2023-05-30 17:13:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2963216","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2963216","identity":"rs-2963216","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}