cyclic-gmp and Penile-Induration

The FDA approval of Viagra (sildenafil) for the on demand treatment of erectile dysfunction (ED) through relaxation of the corporal and cavernosal vascular smooth muscle that results in an increase in blood flow to the corporal tissues stemmed from 2 decades of research, mainly at academic centers. This culminated in the finding of the nitric oxide/cGMP pathway as the mediator of penile erection, followed by some years of basic studies and clinical validation at Pfizer. Further on, new translational laboratory and animal research from our group initiated a second phase when we proposed an alternative therapeutic schedule and mechanism of action for PDE5 inhibitors (PDE5i) in both corporal veno-occlusive dysfunction (CVOD) and Peyronie's disease (PD), specifically, continuous long-term administration (CLTA) to achieve sustained levels of cGMP within the penis. Due to the extended half-life of the long-acting PDE5i, tadalafil, this new alternative encompasses preferentially daily administration, although shorter half-life PDE5i, like sildenafil and vardenafil work too, depending on the duration, dose, and frequency of their administration This novel use was initially supported by showing the antifibrotic/antioxidant effects of nitric oxide and cGMP, produced by the induction of iNOS, as a mechanism of defense against collagen deposition in the localized fibrotic plaque of PD in an avascular tissue, the tunica albuginea. Our studies on iNOS and the progressive diffuse fibrosis occurring in the smooth muscle in CVOD, led to proposing the CLTA of PDE5i for maintaining sustained cGMP levels both in PD and in CVOD in order to halt or regress the penile fibrosis. In CVOD, we showed that PDE5i protect the corporal smooth muscle and reduce myofibroblast activation and number, counteracting the underlying corporal tissue pathology that causes CVOD, and potentially ameliorating long-term CVOD or even curing it. This review is focused on this novel PDE5i anti-fibrotic therapeutic concept.

Topics: Animals; Arterial Occlusive Diseases; Cyclic GMP; Disease Models, Animal; Drug Evaluation, Preclinical; Erectile Dysfunction; Humans; Male; Muscle, Smooth; Nitric Oxide Synthase Type II; Penile Induration; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Translational Research, Biomedical

During the last decades it turned out that the NO/cGMP signaling cascade is one of the most prominent regulators of a variety of physiological and pathophysiological processes in a broad range of mammalian tissues. Thus cGMP is a key second messenger and targeting this pathway by increasing intracellular cGMP levels is a very successful approach in pharmacology as shown for nitrates, PDE5 inhibitors and more recently for stimulators of the guanylate cyclase. Besides the beneficial effects of cGMP elevation in cardiac, vascular, pulmonary, renal or liver disorders the launch of PDE5 inhibitors for the treatment of erectile dysfunction 10 years ago, has directed a lot of attention to the NO/cGMP signaling in the lower urinary tract. Triggered by the use of PDE5 inhibitors in ED it turned out that cGMP is a common regulatory mechanism for lower urinary tract function also beyond ED. In recent years intense research and development efforts were undertaken to elucidate the role of the NO/cGMP and to fully exploit the therapeutic implications of cGMP elevation in urological disorders in ED and beyond. Therefore we have summarized the effects of cGMP elevation for treatment of erectile dysfunction in males and in females. We have also reviewed the recent pre-clinical and clinical lines of evidence for treatment options of benign prostatic hyperplasia and lower urinary tract symptoms in male patients and overactive bladder and urinary incontinence in female patients. In addition we also touch more speculative concepts using cGMP elevating drugs for the treatment of premature ejaculation, peyornies disease and stone disease.

Topics: Animals; Cyclic GMP; Erectile Dysfunction; Female; Humans; Male; Nephrolithiasis; Nitric Oxide; Penile Induration; Prostatic Hyperplasia; Sexual Dysfunction, Physiological; Signal Transduction; Urinary Bladder, Overactive; Urinary Incontinence

Testosterone (T) deficiency is associated with erectile dysfunction (ED). The relaxant response of T on the corporal smooth muscle through a non-genomic pathway has been reported; however, the in vitro modulating effects of T on human corpus cavernosum (HCC) have not been studied.. To compare the effects of various concentrations of T on nitric oxide (NO)-dependent and nitric oxide-independent relaxation in organ bath studies and elucidate its mode of action, specifically targeting the cavernous NO/cyclic guanosine monophosphate (cGMP) pathway.. Human corpus cavernosum (HCC) samples were obtained from men undergoing penile prosthesis implantation (n = 9). After phenylephrine (Phe) precontraction, the effects of various relaxant drugs of HCC strips were performed using organ bath at low (150 ng/dL), eugonadal (400 ng/dL), and hypergonadal (600 ng/dL) T concentrations. The penile tissue measurements of endothelial nitric oxide synthase (eNOS), neuronal (n)NOS, and phosphodiesterase type 5 (PDE5) were evaluated via immunostaining, Western blot, cGMP and nitrite/nitrate (NOx) assays.. Relaxation responses to ACh and EFS in isolated HCC strips were significantly increased at all T levels compared with untreated tissues. The sildenafil-induced relaxant response was significantly increased at both eugonadal and hypergonadal T levels. Normal and high levels of T are accompanied by increased eNOS, nNOS, cGMP, and NOx levels, along with reduced PDE5 protein expression.. This study reveals an important role of short-term and modulatory effects of different concentrations of T in HCC. T positively regulates functional activities, inhibition of PDE5 expression, and formation of cGMP and NOx in HCC. These results demonstrate that T indirectly contributes to HCC relaxation via downstream effects on nNOS, eNOS, and cGMP and by inhibiting PDE5. This action provides a rationale for normalizing T levels in hypogonadal men with ED, especially when PDE5 inhibitors are ineffective. T replacement therapy may improve erectile function by modulating endothelial function in hypogonadal men.

Topics: Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Hormone Replacement Therapy; Humans; Male; Middle Aged; Nitric Oxide; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Penile Induration; Penis; Sildenafil Citrate; Testosterone

Inducible nitric oxide synthase (iNOS) is expressed in both the fibrotic plaque of Peyronie's disease (PD) in the human, and in the PD-like plaque elicited by injection of TGFbeta1 into the penile tunica albuginea (TA) of the rat. Long-term inhibition of iNOS activity, presumably by blocking nitric oxide (NO)- and cGMP-mediated effects triggered by iNOS expression, exacerbates tissue fibrosis through an increase in: (a) collagen synthesis, (b) levels of reactive oxygen species (ROS), and (c) the differentiation of fibroblasts into myofibroblasts. We have now investigated whether: (a) phosphodiesterase (PDE) isoforms, that regulate the interplay of cGMP and cAMP pathways, are expressed in both the human and rat TA; and (b) L-arginine, that stimulates NOS activity and hence NO synthesis, and PDE inhibitors, that increase the levels of cGMP and/or cAMP, can inhibit collagen synthesis and induce fibroblast/myofibroblast apoptosis, thus acting as antifibrotic agents. We have found by immunohistochemistry, RT/PCR, and Western blot that PDE5A-3 and PDE4A, B, and D variants are indeed expressed in human and rat normal TA and PD plaque tissue, as well as in their respective fibroblast cultures. As expected, in the PD fibroblast cultures, pentoxifylline (non-specific cAMP-PDE inhibitor) increased cAMP levels without affecting cGMP levels, whereas sildenafil (PDE5A inhibitor) raised cGMP levels. Both agents and L-arginine reduced the expression of collagen I (but not collagen III) and the myofibroblast marker, alpha-smooth muscle actin, as determined by immunocytochemistry and quantitative image analysis. These effects were mimicked by incubation with 8-Br-cGMP, which in addition increased apoptosis, as measured by TUNEL. When L-arginine (2.25 g/kg/day), pentoxifylline (10 mg/kg/day), or sildenafil (10 mg/kg/day) was given individually in the drinking water for 45 days to rats with a PD-like plaque induced by TGF beta1, each treatment resulted in a 80-95% reduction in both plaque size and in the collagen/fibroblast ratio, as determined by Masson trichrome staining. Both sildenafil and pentoxiphylline stimulated fibroblast apoptosis within the TA. Our results support the hypothesis that the increase in NO and/or cGMP/cAMP levels by long-term administration of nitrergic agents or inhibitors of PDE, may be effective in reversing the fibrosis of PD, and more speculatively, other fibrotic conditions.

Topics: Animals; Apoptosis; Arginine; Blotting, Western; Cyclic GMP; Enzyme Inhibitors; Fibrosis; Humans; Male; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Penile Induration; Penis; Pentoxifylline; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Rats; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sildenafil Citrate; Sulfones