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

doi:10.21203/rs.3.rs-2963216/v1

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

https://doi.org/10.21203/rs.3.rs-2963216/v1

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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, PGE₂, and TXB₂ 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 PGE₂ 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

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 I₂ (PGI₂) and prostaglandin E₂ (PGE₂) (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).

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 PGI₂), PGE₂, and thromboxane B₂ (TXB₂) (stable metabolites of TXA₂) 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.

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 PGE₂ (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 TXB₂ (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 PGE₂ (p = 0.0097) concentration than control and BNCN group, while the TXB₂ (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).

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, PGI₂ 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, PGI₂ 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 PGE₂ exerts a similar relaxation effect by binding PGE receptor (EP) (Lin et al., 2013). According to these theory, PGI₂ and PGE₁ 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 PGI₂ and PGE₂ (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 TXA₂ could hydrolyze phosphoinositides to second messengers of inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) (J. Huang, 2004), while accumulated IP3 increased calcium (Ca²⁺) 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 TXA₂ 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 TXA₂ was inhibited when the relaxant PGI₂ and PGE₂ 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 (Ca²⁺) 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 PGE₁ 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.

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.

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

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No competing interests reported.

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

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Abstract

Figures

Background

Materials and methods

Erectile function measurement

Prostaglandins (PGs)

cAMP, cGMP and total NO

Statistical analysis

Result

Erectile function

PGs and cAMP

Total NO and cGMP

Erectile function

PGs and cAMP

Total NO and cGMP

Discussion

Conclusion

Declarations

References

Additional Declarations

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