Extracorporeal Shock Waves Therapy Delivered by Aries Improves Erectile Dysfunction in Spontaneously Hypertensive Rats Through Penile Tissue Remodeling and Neovascularization

Abstract

Background: Low-intensity extracorporeal shock wave therapy (Li-ESWT) has been reported to improve erectile function in patients with moderate-to-severe erectile dysfunction (ED) or even convert phosphodiesterase type 5 inhibitors nonresponders to responders. ED is highly prevalent in hypertensive patients. The effect of Li-ESWT on an animal model of hypertension-associated ED has not been reported.

Aim: To investigate the effect of Li-ESWT on hypertension-associated ED and provide plausible mechanisms of action of Li-ESWT on local mechanisms of penile erection.

Methods: Spontaneously hypertensive rats (SHRs) in the active group (n = 13) received Li-ESWT at energy flux density 0.06 mJ/mm² (Aries; Dornier MedTech, Wessling, Germany) twice weekly for 6 weeks. The emitter was set to zero for SHRs in the sham group (n = 12). Erectile function was assessed 4 weeks post-treatment by monitoring intracavernosal pressure (ICP) in response to electrical stimulation of cavernous nerve before and after single dose of 0.3 mg/kg intravenous sildenafil. Cavernosal tissue was then evaluated for collagen/smooth muscle content, neuronal nitric oxide synthase (nNOS), and vascular endothelial factor (CD31) expression.

Outcomes: Erectile function was assessed with ICP, erectile tissue remodeling was studied by smooth muscle/collagen ratio, nNOS and CD31 were semiquantitatively evaluated on cavernosal sections.

Results: The improvement of ICP parameters was greater in Li-ESWT-treated rats compared with controls with and without sildenafil. Sildenafil led to 20% increase in area under the intracavernosal pressure curve measured during the entire response/mean arterial pressure at 10 Hz in ESWT_SHR + sildenafil compared with ESWT_SHR. The smooth muscle/collagen ratio increased 2.5-fold in Li-ESWT compared with sham. Expression of CD31 tended to be increased whereas nNOS was unchanged.

Conclusions: Li-ESWT by Aries may represent an effective noninvasive therapeutic alternative and a relevant add-on therapy to phosphodiesterase type 5 inhibitors for ED in hypertensive patients, and it is suggested that it acts via remodeling of the penile tissue and promoting cavernosal vascularization. Assaly R, Giuliano F, Clement P, et al. Extracorporeal Shock Waves Therapy Delivered by Aries Improves Erectile Dysfunction in Spontaneously Hypertensive Rats Through Penile Tissue Remodeling and Neovascularization. Sex Med 2019;7:441-450.

Keywords: Erectile Dysfunction; Fibrosis; Hypertension; Low-Intensity Extracorporeal Shock Wave Therapy.

Figure 1

Representative tracings of ICP and MAP. ESWT = extracorporeal shock wave therapy; ICP = intracavernosal pressure; MAP = mean arterial pressure.

Figure 2

Effect of Li-ESWT protocol delivered by Aries on erectile function in SHRs. Erectile responses to ES CN of varying frequency were obtained in anesthetized rats who received (SHR_ESWT) or not (sham) the Li-ESWT protocol. The first series of ES CN was performed in absence of sildenafil and the second one after intravenous delivery of 0.3 mg/kg sildenafil (sild). Erectile responses are expressed as ICP/MAP (Panel A), AUC45/MAP (Panel B), and erectile detumescence as AUCtot/MAP (Panel C). Data are mean ± standard error of the mean. Statistics: 2-way analysis of variance; **P < .01, ***P < .001, ****P <.0001 overall significance. AUC45 = area under the intracavernosal pressure curve measured during the 45 seconds of electrical stimulation; AUCtot = area under the intracavernosal pressure curve measured during the entire response; ES CN = electrical stimulation of cavernous nerve; ICP = intracavernosal pressure; Li-ESWT = low-intensity extracorporeal shock wave therapy; MAP = mean arterial pressure; SHR = spontaneously hypertensive rat.

Figure 3

Representative images of SHR corpus cavernosum sections stained with Masson’s trichrome. Sections of penis were obtained in sham rats (Panel A) or rats who received the Li-ESWT protocol delivered by Aries (Panel B). Collagen fibers stained blue and smooth muscle fibers stained red. Magnification ×400. Li-ESWT = low-intensity extracorporeal shock wave therapy; SHR = spontaneously hypertensive rat.

Figure 4

Representative images of SHR corpus cavernosum sections immunostained for CD31 and semiquantitative evaluation of CD31. Sections of penis were obtained in sham rats (Panel A) or rats who received the Li-ESWT protocol delivered by Aries (Panel B). Immunopositive cells stained brown (arrows). Magnification: ×40 (left panel), ×400 (right panel). The mean number of dots is presented in Panel C. Li-ESWT = low-intensity extracorporeal shock wave therapy; SHR = spontaneously hypertensive rat.

Figure 5

Representative images of SHR corpus cavernosum sections immunostained for nNOS. Sections of penis were obtained in sham rats (left panel) or rats who received the Li-ESWT protocol delivered by Aries (right panel). Immunopositive cells stain brown (arrows) were found in dorsal arteries and dorsal nerves (Panel A) and corpus cavernosum (Panel B). Magnification: ×400. Li-ESWT = low-intensity extracorporeal shock wave therapy; nNOS = neuronal nitric oxide synthase; SHR = spontaneously hypertensive rat.