ABSTRACT
We compared the activity of a new phosphodiesterase-5 inhibitor (PDE5i) avanafil with sildenafil and tadalafil in human and rat corpus cavernosum (CC) tissues. The effect of avanafil with several inhibitors and electrical field stimulation (EFS) was evaluated on CC after pre-contraction with phenylephrine. With the PDE5i, sildenafil and tadalafil, concentration-response curves were obtained and cyclic guanosine monophosphate (cGMP) levels were measured in tissues. Avanafil induced relaxation with maximum response of 74 ± 5% in human CC. This response was attenuated by NOS inhibitor and soluble guanylate cyclase (sGC) inhibitor. Avanafil potentiated relaxation responses to acetylcholine and EFS in human CC and enhanced SNP-induced relaxation and showed 3-fold increase in cGMP levels. When compared with sildenafil, avanafil and tadalafil were effective at lower concentrations in human CC. In addition, Sprague-Dawley rats underwent in vivo intracavernosal pressure (ICP) and mean arterial pressure (MAP) measurements. Avanafil increased ICP/MAP that was enhanced by SNP and cavernous nerve (CN) stimulation in rat CC tissues. Also avanafil showed maximum relaxation response of 83 ± 7% in rat CC with 3-fold increase in cGMP concentration. Taken together, these results of our in vivo and in vitro studies in human and rat suggest that avanafil promotes the CC relaxation and penile erection via NO-cGMP pathway.
Subject(s)
Penis/drug effects , Phosphodiesterase 5 Inhibitors/pharmacology , Pyrimidines/pharmacology , Animals , Blood Pressure/drug effects , Cyclic GMP/analysis , Dose-Response Relationship, Drug , Humans , Male , Penis/blood supply , Penis/chemistry , Rats , Rats, Sprague-Dawley , Sildenafil Citrate/pharmacology , Tadalafil/pharmacology , Vasodilation/drug effectsABSTRACT
Peyronie's disease (PD) is a localized connective tissue disorder that involves the tunica albuginea (TA) of the penis. While surgical correction remains the gold standard, the search for an effective and less invasive therapy continues. The objective of this study was to evaluate the effects of intratunical injection of adipose tissue-derived stem cells (ADSCs) for the prevention and treatment of erectile dysfunction in a rat model of PD. Twenty-four male Sprague-Dawley rats (300-350 g) were randomly divided into four groups: sham, PD, PD + ADSC (prevention) and PD + ADSC (treatment). All rats underwent penile injections into the TA with 50 µL vehicle (sham) or 0.5 µg transforming growth factor (TGF)-ß1 (remaining groups). The ADSC groups received intratunical injections with 0.5 million rat-labelled ADSCs on day 0 (prevention) or day 30 (treatment). Forty-five days following TGF-ß1 injection, rats underwent cavernous nerve stimulation (CNS) with total intracavernous-to-mean arterial pressure ratio (ICP/MAP) and total ICP recorded to measure response to therapy. Tissues were evaluated histologically and for mRNA expression of tissue inhibitors of metalloproteinases (TIMPs), matrix metalloproteinases (MMPs) and zymographic activity of MMPs. Statistical analysis was performed by analysis of variance followed by the Tukey test for post hoc comparisons. In both prevention and treatment groups, intratunical injection of ADSCs resulted in significantly higher ICP/MAP and total ICP in response to CNS compared with the PD group. Local injection of ADSCs prevented and/or reduced Peyronie's-like changes by decreasing the expression of TIMPs, and stimulating expression and activity of MMPs. This study documents the preventive and therapeutic benefits of ADSC on penile fibrosis and erectile function in an animal model of PD.
