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. 2024 May 20;43(1):197–204. doi: 10.5534/wjmh.230362

The Effects of a Red-Light Controllable Nitric Oxide Donor, NORD-1, on Erectile Dysfunction in Rats with Streptozotocin Induced Diabetes Mellitus

Yuji Hotta 1,2,✉, Kyoya Oyama 2, Takuma Yoshida 2,3, Naoya Ieda 4, Taiki Mori 2, Yasuhiro Horita 1, Tomoya Kataoka 5, Yoko Furukawa-Hibi 1, Susumu Ohya 3, Hidehiko Nakagawa 4, Kazunori Kimura 1,2
PMCID: PMC11704171  PMID: 38772543

Abstract

Purpose

Patients with diabetes mellitus (DM) often exhibit refractory erectile dysfunction (ED). Red-light-controllable nitric oxide donor (NORD-1) and red-light irradiation have successfully enhanced erectile function in intact rats. In this study, we investigated whether the combination of NORD-1 and red-light irradiation effectively treated ED in streptozotocin (STZ)-treated rats with DM.

Materials and Methods

Seven-week-old male Sprague-Dawley rats were used in this study. Rats in the DM and sham groups received intravenous STZ (50 mg/kg) and saline, respectively. One week after treatment, the blood glucose level of rats in the DM group was >250 mg/dL. Five weeks after the treatment, we performed a functional study by measuring intracavernous pressure (ICP) under cavernous nerve stimulation before and after NORD-1 treatment with and without light irradiation. Additionally, we performed an isometric tension study using the corpus cavernosum of rats treated with NORD-1 or the control compound, SiR650.

Results

The ICP/mean arterial pressure (MAP) ratio was significantly lower in the DM group than in the sham group before and after NORD-1 treatment without light irradiation (both p<0.05). After NORD-1 treatment with light irradiation, the ICP/MAP ratio in the sham and DM groups was significantly enhanced than before and after NORD-1 treatment without light irradiation (all p<0.05). The ICP/MAP ratio in the DM group after NORD-1 with light irradiation was similar to that in the sham group under normal conditions before NORD-1 treatment. Moreover, the systemic blood pressure was not affected by NORD-1 or light irradiation. In the tension study, the corpus cavernosum of rats treated with SiR650 was not changed by red light in the sham or DM groups. However, the rats treated with NORD-1 were strongly relaxed by red light in both groups.

Conclusions

NORD-1 and red-light irradiation could improve ED in the presence of DM without lowering blood pressure.

Keywords: Diabetes mellitus, Erectile dysfunction, Nitric oxide, Red light, Relaxation

INTRODUCTION

Patients with diabetes mellitus (DM) are often affected by erectile dysfunction (ED) [1,2,3,4,5,6,7,8,9,10]. DMED prevalence ranges from 35% to 90% [2,4,5,6,7,8,9,10]. ED is mainly treated with phosphodiesterase-5 inhibitors; however, patients with DM are often less responsive to these treatments [3]. Various etiological mechanisms underlying DMED include decreased nitric oxide (NO) production, vascular dysfunction, and neuropathy [2,11,12].

NO is a key factor in erection [13]. Sexual stimuli induce nitrergic nerve activation in the penis and NO release. NO activates soluble guanylyl cyclase (sGC). Activated sGC enhances the production of cyclic guanosine monophosphate (cGMP) levels, which makes the penile corpus cavernosum smooth muscle relax and blood inflow into penis increase. The intracavernous pressure (ICP) increases, completing the erection. In a study of the human corpus cavernosum, the basal and acetylcholine-stimulated content of cGMP was significantly reduced in this tissue among diabetic men. This finding suggests that NO/cGMP signaling is reduced in the human corpus cavernosum of diabetic men [14]. Therefore, while NO supplementation is effective for the treatment of ED, it can affect the systemic vasculature, potentially causing problematic side effects such as reduced blood pressure. Additionally, the short half-life of NO and its gaseous nature make treatment difficult [15]. Therefore, we considered that light-controllable NO donors may be useful to address these problems.

In light-controllable NO donors, NO can only be released at the site and time of light irradiation [16]. Thus, light-controlled NO donors enable precise spatiotemporal control over the release. In our previous study, we successfully developed a light-controllable NO donor with various wavelengths [16,17,18,19,20,21,22,23]. Recently, a red-light-controllable NO donor, NORD-1, was developed, successfully enhancing erectile function in intact and neurogenic ED rats [17,19]. In this study, we investigated the effectiveness of NORD-1 and red-light irradiation against DMED using a streptozotocin (STZ)-induced DM model.

MATERIALS AND METHODS

1. Ethics statement

This animal study was performed after receiving approval from the Institutional Animal Care and Use Committee at Nagoya City University (approval No. H25-P-09). All animal experiments were conducted with consideration for animal ethics.

2. Animals and NORD-1

Fig. 1 describes the experimental protocol. This study included 42 male seven-week-old Sprague-Dawley rats (Japan SLC, Inc.). The rats in the sham group (n=21) were intravenously administered saline, while those in the DM group were intravenously administered STZ (50 mg/kg). STZ (Enzo Life Sciences Inc.) was dissolved in saline immediately before administration. Body weight and blood glucose (BG) levels were measured before and after five weeks of treatment. Additionally, BG levels were evaluated one week after treatment, and we confirmed that the levels were over 250 mg/dL among rats in the DM group. Five weeks after treatment, erectile function was evaluated (n=9 in each group), and an isometric tension study was performed (n=12 in each group). NORD-1 was synthesized according to the previous method [19].

Fig. 1. Experimental protocols. DM: diabetes mellitus, BW: body weight, BG: blood glucose.

Fig. 1

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3. Evaluation of erectile function

The ICP measurements were used to evaluate erectile function, as in previous studies [17,24]. A schematic diagram of the ICP measurements is described in Fig. 2A. Anesthesia was induced and maintained using 3% and 1% isoflurane (Pfizer Inc.), respectively. Blood pressure was monitored via a catheter inserted into the left carotid artery. Subsequently, the penis was fully exposed, and a catheter was inserted into the left penile crus to monitor ICP measurements. All routes were filled with heparinized saline (50U heparin/mL), and a T-shaped stopcock was connected to inject NORD-1. The major pelvic ganglion and the cavernous nerve on the prostate were then identified and exposed carefully. Cavernous nerve electrostimulation was performed using bipolar electrodes (Unique Medical) and a pulse generator (Nihon Kohden). The stimulus conditions were 1 minute at 5 V, 8 Hz, and a 5 ms square wave pulse width. Systemic arterial pressure and ICP were recorded and analyzed using the LabChart8 software (AD Instruments Pty. Ltd.). The maximum ICP and the mean arterial pressure (MAP) during stimulation were obtained; then a ratio of the maximum ICP to MAP was calculated to determine the erectile function index.

Fig. 2. Images of intracavernous pressure (ICP) measurements. A schematic diagram of the ICP measurements (A) and the timing of stimulation, NORD-1 injection and light irradiation (B).

Fig. 2

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The experimental protocol is described in Fig. 2B. ICP was measured during electrostimulation before NORD-1 treatment without light irradiation. Subsequently, 100 µL (10-4 M) NORD-1 was injected into the penile corpus cavernosum from the T-shape stopcock slowly to prevent ICP increase and damage to the penile corpus cavernosum due to high pressure. After injecting NORD-1, we confirmed no change in baseline ICP compared with that before injection. The ICP was measured during electrostimulation without light irradiation 5 minutes after the NORD-1 injection. The ICP was then measured during electrostimulation with redlight (630–690 nM) and irradiation (146 mW) using a CL-1501 LED light source (Asahi Spectra Co.) at a 2-cm distance. Additionally, arterial pressure changes during electrostimulation were evaluated by comparing the MAP at the end of the electrostimulation (End-MAP) with that at its initiation (Start-MAP).

4. Isometric tension study

Twelve rats from each group were used for the isometric tension study. Under isoflurane anesthesia, six rats were administered the 100 µL (10-4 M) control compound (SiR650), and six other rats were administered 100 µL (10-4 M) NORD-1. Penes were obtained 20 minutes after treatment and stored in a chilled Krebs solution. The urethra, artery, vein, and adipose tissue were carefully removed, and the penile corpus cavernosum was obtained. The cavernous sinus of the penile corpus was placed in a Magnus tube. One side was fixed with cellufin, while the other side was fixed using a thread to a force transducer (ULA-10GR; MinebeaMitsumi Inc.). In Magnus tubing, 37 ℃ Kreb solutions were filled with gas (95% O2, 5% CO2). Tension was recorded using PowerLab and LabChart8 software (AD Instruments Pty. Ltd.). The resting tension was 0.6 g, and more than one hour of equilibration was set. Subsequently, noradrenaline (3×10-6 M) was added to the precontract. After reaching the plateau, red-light tissue irradiation was performed 2 cm away. The ratio of maximum relaxation during irradiation to noradrenaline contraction was calculated.

5. Statistical analysis

Data are presented as mean±standard deviation, and Welch’s t-tests were used for two-group comparisons. One-way analysis of variance and Bonferroni’s multiple comparison tests were used to compare different conditions in the same group. Statistical significance was set at p<0.05.

RESULTS

1. Body weight and BG levels

The body weights and BG levels at the initial and final time points are presented in Table 1. No body weight differences between the sham and DM groups were observed at the initial time point. Body weights in the DM group were significantly lower than those in the sham group at the final time point (p<0.01). No significant BG level differences between the sham and DM groups were observed at the initial time point. The BG levels in the DM group were significantly higher than those in the sham group at the final time point (p<0.01).

Table 1. Body weight and blood glucose levels (n=21).

Body weight (g) Blood glucose levels (mg/dL)
Initial Final Initial Final
Sham 260±14.1 404±23.1 110±7.0 109±9.8
DM 263±15.3 274±17.7** 108±10.0 479±93.7**
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Values are presented as mean±standard deviation.

DM: diabetes mellitus.

Welch’s t-test. **p<0.01 vs. sham group at final.

2. Evaluation of erectile function

The representative charts are outlined in Fig. 3A. Before treatment, the ICP increase was lower among rats in the DM group than in the sham group. After NORD-1 treatment without light irradiation, the ICP increase was unchanged and remained lower in the rats in the DM group than in the sham group. After NORD-1 treatment with light irradiation, the ICP increase was enhanced compared to that before and after NORD-1 treatment without light irradiation in the DM and sham groups. The ICP/MAP ratio was significantly lower in the DM group than in the sham group before NORD-1 treatment (p<0.05) and after NORD-1 treatment without light irradiation (p<0.01) (Fig. 3B). In both groups, the ratio after NORD-1 treatment with light irradiation was significantly increased compared to that before and after NORD-1 treatment without light irradiation (Fig. 3B). The ratio in the DM group was significantly lower than that in the sham group after NORD-1 treatment with light irradiation (p<0.01) (Fig. 3B). However, the ratio in the DM group after NORD-1 treatment with light irradiation was similar to that in the sham group before and after NORD-1 treatment without light irradiation (Fig. 3B).

Fig. 3. Erectile function in three conditions before NORD-1 treatment, after NORD-1 treatment without light irradiation, and after NORD-1 treatment with light irradiation (n=9). (A) Representative charts of the sham and DM groups in three conditions. The red line represents the blood pressure. The blue line demonstrates the ICP. The bold line describes the stimulation period (1 minute). (B) Results of the max ICP/MAP analysis. DM: diabetes mellitus, ICP: intracavernous pressure, MAP: mean arterial pressure. Welch‘s t-test (†p<0.05 vs. sham, ††p<0.01 vs. sham). ANOVA and Bonferroni’s multiple comparison test (*p<0.05, **p<0.01).

Fig. 3

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Additionally, we evaluated the effects of the combination of NORD-1 and light irradiation on blood pressure, calculating the End-MAP/Start-MAP ratio. The results are expressed relative to those before the NORD-1 treatment (Table 2). The End-MAP/Start-MAP ratio did not change between the three conditions in the sham or DM groups.

Table 2. Effects of NORD-1 and red-light irradiation on blood pressure.

NORD-1 (-) NORD-1 (+)
Light (-) Light (-) Light (+)
Sham 100 99.4±3.1 95.6±2.8
DM 100 99.0±2.8 101.9±1.5
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Values are presented as mean±standard deviation.

The End-MAP/Start-MAP ratios in the NORD-1 (-) and light (-) groups were 100% (n=9). ANOVA and Bonferroni’s multiple comparison test.

DM: diabetes mellitus, MAP: mean arterial pressure.

3. Isometric tension study

Fig. 4A describes the representative charts. In the sham+SiR650 and DM+SiR650 groups, light irradiation did not alter the penile corpus cavernosum tension. However, in the sham+NORD-1 and DM+NORD-1 groups, light irradiation caused obvious penile corpus cavernosum relaxation, and the tension recovered soon after the light irradiation stopped (Fig. 4A). When calculating the maximum penile corpus cavernosum relaxation, the relaxation induced by NORD-1 and light irradiation was significantly higher than that induced by SiR650 (p<0.05) and light irradiation, with almost 100 percent relaxation (Fig. 4B).

Fig. 4. Results of isometric tension study (n=5). (A) Representative charts in each group. (B) Maximum relaxation to NA ratio in each group. DM: diabetes mellitus, NA: noradrenaline, NS: not significant. ANOVA and Bonferroni’s multiple comparison test *p<0.01 vs. SiR650 group.

Fig. 4

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DISCUSSION

This study found that NORD-1 and red-light irradiation effectively treated ED in rats with STZ-induced DM. Additionally, irradiation of the penis did not alter the blood pressure, suggesting that the effects exclusively affected irradiation site and that NORD-1 and red-light irradiation could avoid systemic side effects. A previous study also found no blood pressure changes due to NORD-1 or irradiation using intact rats and those with ED induced by bilateral cavernous nerve injury [17,19]. In addition, NORD-1 existed only in the penile corpus cavernosum and was not transferred to the urethra, dorsal arteries or vein [17]. Therefore, NORD-1 and red-light irradiation could release NO only in the penile corpus cavernosum and improve DMED.

DM often causes systemic vascular dysfunction and neuropathy, often inducing ED as a complication. This complication occurs because of the crucial roles of normal neurotransmission from the central nervous system to the penis and peri-penile vascular functions [2,11,12]. Additionally, PDE-5 inhibitors are not effective in treating DMED [3]. In the present study, the ICP increase induced by cavernous nerve stimulation in DM rats was impaired. This finding suggests that in DM rats, neurotransmission from the cavernous nerve to the penis, hemodynamic conditions around the penis, and/or organic damage of the penile structure may be impaired. However, NORD-1 treatment and light irradiation increased the ICP/MAP ratio in DM rats, similar to that observed in the sham group before the NORD-1 treatment. Additionally, the isometric tension study results revealed that almost 100% relaxation was induced in DM rats by NORD-1 and red-light irradiation. These findings suggest that penile organic damage may not be substantial among DM rats in this study and that the penile corpus cavernosum smooth muscle function may still be maintained. Thus, the ICP/MAP ratio decrease may be due to cavernous nerve neuropathy from the nerve to the penis. In cases of DMED with no severe organic dysfunction and only mild neuropathy, NORD-1 and light irradiation were considered very effective.

Our previous study found that NORD-1 and red-light irradiation enhanced erectile function against ED in a bilateral cavernous nerve injury model [17]. Additionally, tissue permeability to red light was confirmed using pig meat [17]. These findings support that this light-based therapy is also useful for treating DMED. NO is a key molecule for erection. Therefore, NORD-1 and red-light irradiation may be useful in various ED forms, particularly when there is preservation of the penile corpus cavernous smooth muscle and hemodynamics around the penis to some extent. In other words, this novel therapy may be ineffective for severe organic ED or arteriogenic ED. The effect of NO is relatively short. Regarding the clinical use, we considered that this NORD-1 and red-light irradiation therapy could be used in combination with a PDE-5 inhibitor or daily use to improve the hemodynamic condition of the penis.

This study had some limitations. First, DMED was considered mild in this study, and we did not check whether NORD-1 and red-light irradiation could enhance erectile function in rats with more severe forms. Second, we used STZ as the experimental DM model. This model mimics type 1 DM [25]. Thus, future studies should use a type 2 DM model. Finally, we evaluated the effects by on-demand use and did not investigate the usefulness of daily NORD-1 and red-light irradiation therapy as a rehabilitation therapy. Some reports indicate that red-light irradiation increases NO production in human umbilical vein endothelial cells or that near-infrared light improved erectile function in rats with DMED. However, it is unknown whether additive or synergistic effects are observed when we use NORD-1 in addition to red-light mono-therapy [26,27,28]. Long-term effects of NORD-1 and red-light irradiation, particularly repeated usage, may be expected to be the effects of penile rehabilitation to improve hemodynamic conditions around the penis and maintain the penile structure; however, the safety of the use remains unknown. In addition, we did not evaluate the safety of NORD-1 or red-light irradiation. Excessive NO release induces oxidative stress and apoptosis and causes tissue damage [29]. In addition, we should pay attention to carcinogenic risks due to NO-related metabolites. Unfortunately, it may be difficult to use this compound in a clinical setting as it is, and we may need to improve the compound to resolve this problem and use it in clinical situations. Of course, carefully assessing the safety of any compounds is necessary before conducting clinical trials. However, in this study, we showed the potential of light-based therapy using a photo-regulated compound for DMED. We believe that this is an important insight.

CONCLUSIONS

In conclusion, NORD-1 and red-light irradiation could be effective in treating DMED without lowering systemic blood pressure. Of course, DM treatment is crucial for preventing the progression of DMED and averting the emergence of severe complications, including cardiovascular events, as NORD-1 and red-light irradiation did not improve DM but only addressed its complications.

Acknowledgements

None.

Footnotes

Conflict of Interest: The authors have nothing to disclose.

Funding: This work was supported by JSPS KAKENHI grant number 23K08766 (YH), 20K09583 (YH), and 21K19576 (KK).

Author Contribution:
  • Conceptualization: Y Hotta, NI, HN, KK.
  • Data curation: Y Hotta, KO, TY, TM, Y Horita.
  • Formal analysis: Y Hotta, KO, TY, TM, Y Horita, TK.
  • Funding acquisition: Y Hotta, NI, TK, KK.
  • Investigation: Y Hotta, KO, Y Horita, TY, TM.
  • Methodology: Y Hotta, KO, TY, TM.
  • Project administration: Y Hotta, NI.
  • Resources: NI, HN.
  • Software: Y Hotta, KK.
  • Supervision: YF, SO, HN, KK.
  • Validation: Y Hotta, KK.
  • Visualization: Y Hotta, KO.
  • Writing – original draft: Y Hotta.
  • Writing – review & editing: all authors.

Data Sharing Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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