Separate or Combined Treatments with Daily Sildenafil, Molsidomine, or Muscle‐Derived Stem Cells Prevent Erectile Dysfunction in a Rat Model of Cavernosal Nerve Damage

Abstract

Introduction. Long‐term daily administration of phosphodiesterase type 5 (PDE5) inhibitors in the rat prevents or reverses corporal veno‐occlusive dysfunction (CVOD) and smooth muscle cell (CSMC) loss and fibrosis, in both aging and bilateral cavernosal nerve resection (BCNR) models for erectile dysfunction. In the aging rat model, corporal implantation of skeletal muscle‐derived stem cells (MDSC) reverses CVOD. Nitric oxide (NO) and cyclic guanosine monophosphate can modulate stem cell lineage. Aim. To investigate in the BCNR model the effects of sildenafil at lower doses, alone or in combination with MDSC or the NO donor molsidomine, on CVOD and the underlying corporal histopathology. Main Outcomes Measures. CVOD, histological, and biochemical markers in rat corporal tissue. Methods. Rats subjected to BCNR were maintained for 45 days either untreated, or received sildenafil in the water or retrolingually at 10, 2.5, and 1.25 mg/kg/day (medium, low, and very low doses), or intraperitoneal molsidomine, or MDSC implantation into the corpora cavernosa separately or in combination. Cavernosometry evaluated CVOD. Histopathology was assessed on penile sections by Masson trichrome, immunohistochemistry for α‐smooth muscle actin (ASMA), or immunofluorescence for neuronal nitric oxide synthase (nNOS)/neurofilament 70, and in fresh tissue by Western blot for various markers and picrosirius red for collagen. Results. All treatments normalized erectile function (drop rate), and most increased the CSMC/collagen ratio and ASMA expression in corporal tissue sections, and reduced collagen content in the penile shaft. MDSC also increased nNOS and brain‐derived neurotrophic factor. The combination treatment was not superior to MDSC or sildenafil given alone, and upregulated PDE5. Conclusions. Lowering the dose of a continuous long‐term sildenafil administration still maintained the prevention of CVOD in the BCNR rat previously observed, but it was less effective on the underlying histopathology. As in the aging rat model, MDSC also counteracted CVOD, but supplementation with very low‐dose sildenafil did not improve the outcome. Kovanecz I, Rivera S, Nolazco G, Vernet D, Segura D, Gharib S, Rajfer J, and Gonzalez‐Cadavid NF. Separate or combined treatments with daily sildenafil, molsidomine, or muscle‐derived stem cells, prevent erectile dysfunction in a rat model of cavernosal nerve damage. J Sex Med 2012;9:2814–2826.

Implanted Muscle-Derived Stem Cells Ameliorate Erectile Dysfunction in a Rat Model of Type 2 Diabetes, but Their Repair Capacity Is Impaired by Their Prior Exposure to the Diabetic Milieu

“…No non-diabetic MDSC were isolated and tested, since this would require a different non-allogeneic strain as a source, the LZ rats, thus complicating the comparison and also the statistics and the study itself if a sixth experimental group would have been added. So, the ED-SC was taken as a control, considering that in addition, the non-diabetic MDSC have already been shown by us to ameliorate corporal SMC loss and fibrosis and CVOD in non diabetic rats (31,32,47). …”

“…MDSC were isolated from the hind limb muscles from the two OZ rat groups (n=2/group), using the preplating procedure, a validated method for MDSC isolation, as in our previous reports for mice and Fisher 344 rats (31–35). Preplate fraction 6 (pP6) is the cell population containing MDSCs, that was subjected to Sca 1 selection and flow cytometry as described.…”

“…Our group applied them as therapy for erectile dysfunction (31,32) and for other conditions (33–35), but they have not been tested in T2D. A major obstacle for their clinical translation, as well as for stem cells in general, is that if they are used as autologous implants from the same patient they would have been subjected in the muscle to the same T2D milieu that in the corpora cavernosa damages the SMC and other differentiated cells.…”

Current Perspectives on Stem Cell Therapy for Erectile Dysfunction

“…71 A study performed by Kovanecz et al combined the current treatment strategy for postprostatectomy ED, the daily use of a PDE5i, with stem cells. 72 Specifically, they investigated the effects of sildenafil at low doses, alone or in combination with MDSCs or the nitric oxide donor, molsidomine, in treating veno-occlusive disease in the bilateral cavernous nerve resection rat model. The results of the study indicated that a sustained administration of sildenafil at medium and low doses prevents veno-occlusive disease after nerve resection, and reduces collagen deposition in the corpora cavernosa.…”

Radiation-induced erectile dysfunction: Recent advances and future directions

“…Later, Qiu et al established RiED as a target for SC therapy and showed that IC injection of stem cells was able to treat both acute and chronic CN injury-induced ED 65, 67. Kovanecz et al showed that IC injection of SkMSC (xenogeneic mouse mesenchymal stem cells) alone or in combination with oral sildenafil was able to normalize erectile function in rats with CN injury 68 . There has been a lot of progress in this field of research.…”