cyclic-gmp and Priapism

Penile detumescence depends on the hydrolysis of cyclic guanosine monophosphate (cGMP) by phosphodiesterase type 5 (PDE5). It is hoped that a review of publications relevant to the regulation of PDE5 in the penis will be helpful to both scientists and clinicians who are interested in the sciences of erectile function/dysfunction.. The aim of this article is to comprehensively review the mechanisms by which PDE5 activity and expression in the penis are regulated. All published studies relevant to PDE5 regulation in the penis or penile cells will be reviewed.. Entrez (PubMed) was used to search for publications relevant to the topics of this review. Keywords used in the searches included vascular, cavernous, penis, smooth muscle, signaling molecules, erection, priapism, and PDE5. Articles that are dedicated to the study of erectile function/dysfunction were prioritized for citation.. Regulation of PDE5 can occur at both protein and gene levels. At protein level, PDE5 is activated by phosphorylation and/or allosteric cGMP binding. Deactivation is carried out by protein phosphatase 1 and thus linked to the Rho-kinase signaling pathway. Cleavage of PDE5 into an inactive form has been shown as carried out by caspase-3. At the gene level, PDE5 expression is regulated at two alternative promoters, PDE5A and PDE5A2, both of which are positively regulated by cyclic adenosine monophosphate and cGMP. Downregulation of PDE5 has been observed in the penis of castrated animals; however, proof of androgen regulation of PDE5 gene requires examination of the smooth muscle content. Hyperoxia and hypoxia, respectively, regulate PDE5 expression positively and negatively. Hypoxic downregulation of PDE5 is a possible mechanism for the development of priapism.. PDE5 can be regulated at protein and gene levels. In the penis, changes of PDE5 activity have been linked to its phosphorylation status, and downregulation of PDE5 expression has been associated with hypoxia.

Topics: Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Humans; Male; Muscle, Smooth; Nitric Oxide Synthase; Penis; Priapism; rho-Associated Kinases; Up-Regulation

Phosphodiesterase 5 (PDE5) has been identified in many species. The three isoforms, PDE5A1, PDE5A2, and PDE5A3, differ only in their N-terminal sequence. PDE5A1 and PDE5A2 are ubiquitous, but PDE5A3 is specific to smooth muscle. The initial three exons (A1-A3-A2) of PDE5A, located on chromosome 4q26, are alternative first exons encoding the isoform-specific sequences. The PDE5A promoter overlaps with the A1-specific exon, while the PDE5A2 promoter is located between the A3- and A2-specific exons. Both respond to cyclic guanosine monophosphate (cGMP) or cyclic adenosine monophosphate (cAMP) stimulation. The PDE5A2 promoter contains an Sp1-binding sequence critical for basal and cGMP/cAMP-inducible promoter activities. PDE5A is induced by adjacent sequences (enhancers) containing Sp1-binding sites. The potential role of PDE5A promoters in the tachyphylaxis effect of PDE5 inhibitors is currently being investigated. Preliminary data suggest that hypoxia might down-regulate PDE5A promoters, implying an involvement of PDE5 in stuttering priapism.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Binding Sites; Chromosomes, Human, Pair 4; Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Exons; Gene Expression Regulation; Humans; Isoenzymes; Male; Muscle, Smooth; Organ Specificity; Priapism; Promoter Regions, Genetic; Tissue Distribution; Transcription Factors

Nitric oxide has been identified as an Endothelium-Derived Relaxing Factor (EDRF). Non adrenergic-non cholinergic nerves synthesise and release nitric oxide, thus modulating the arterial tone. Nitric oxide synthase exists either as a constitutive enzyme in many cell types and as an inducible form expressed under immunological stimulation. Nitric oxide is also involved in the non adrenergic-non cholinergic neurotransmission that leads to smooth muscle relaxation in the corpus cavernosum. Similarly nitric oxide induces reduction of cytosolic free Ca++ as a result of activation of the soluble form of guanylyl cyclase. VIP and nitric oxide may function as co-transmitters. Relaxation of the corpus cavernosum is blocked by methylene blue which inhibits cyclic GMP synthesis; so, high flow priapism refractory to medical and surgical treatments can be managed successfully by intracavernous methylene blue. Moreover it is suggested that enhanced alpha 1-adrenergic mediated constrictor tone and penile flaccidity in diabetic men may respond to exogenous generators of nitric oxide. We postulate that relaxation of the corpus cavernosum, started by nitric oxide in response to non adrenergic-non cholinergic neurotransmission, could be amplified and maintained by nitric oxide production as a result of platelet trapping in the corpus cavernosum during the first phase of the penile erection.

Topics: Amino Acid Oxidoreductases; Calcium; Cyclic GMP; Endothelium, Vascular; Erectile Dysfunction; Humans; Male; Methylene Blue; Neurotransmitter Agents; Nitric Oxide; Nitric Oxide Synthase; Penile Erection; Penis; Priapism; Signal Transduction; Vasodilation

Sildenafil citrate revolutionized the practice of sexual medicine upon its federal regulatory agency approval approximately 15 years ago as the prototypical phosphodiesterase type 5 inhibitor indicated for the treatment of male erectile dysfunction. We now provide scientific support for its alternative use in the management of priapism, a clinical disorder of prolonged and uncontrolled penile erection. Sildenafil administered continuously to sickle cell mice, which show a priapism phenotype, reverses oxidative/nitrosative stress effects in the penis, mainly via reversion of uncoupled endothelial nitric oxide synthase to the functional coupled state of the enzyme, which in turn corrects aberrant signaling and function of the nitric oxide/cyclic GMP/protein kinase G/phosphodiesterase type 5 cascade. Priapism tendencies in these mice are reverted partially toward normal neurostimulated erection frequencies and durations after sildenafil treatment in association with normalized cyclic GMP concentration, protein kinase G activity and phosphodiesterase type 5 activity in the penis. Thus, sildenafil exerts pleiotropic effects in the penis that extend to diverse erection disorders.

Topics: Anemia, Sickle Cell; Animals; Blotting, Western; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Male; Mice; Mice, Knockout; Mice, Transgenic; Nitric Oxide; Nitric Oxide Synthase Type III; Nitrosation; Oxidative Stress; Penis; Phosphodiesterase 5 Inhibitors; Piperazines; Priapism; Purines; Reactive Oxygen Species; Signal Transduction; Sildenafil Citrate; Sulfones

The inducible isoform of heme oxygenase (HO)-1 regulates the vascular smooth muscle tone and responds to hypoxia.. To investigate the role of HO-1 in a low-flow priapism.. Sixty male Sprague-Dawley rats were divided into five groups of six rats each. Each group of rats was sacrificed at 0 hour (group 1, control), 4 hours (group 2), 8 hours (group 3), 12 hours (group 4), and 24 hours (group 5) after inducing an artificial veno-occlusive priapism. The changes of the expression and activity of HO-1, and the expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS), and levels of cyclic guanosine monophosphate in the penis were examined in a low-flow priapism. In addition, the HO-1 expression level in the aortas from each group was simultaneously measured to determine whether the changes in HO-1 were systemic.. The expression and activity of HO-1 was examined in artificially induced veno-occlusive priapism in rat penile tissues.. The expression of the HO-1 protein and the HO-1 enzyme activities in the penile tissues were gradually increased as time increased from 0 to 24 hours (P < 0.01). HO-1 immunoreactivities were localized in the endothelial layer of the cavernosal sinusoids. The expression of iNOS were also increased at 12 and 24 hours. The cyclic guanosine monophosphate level was also significantly increased at 24 hours (P < 0.05). However, the expression of the eNOS protein showed no statistically significant change with time, and the expression of the HO-1 protein in the aorta also showed no significant change with time.. A higher induction of HO-1 with time was observed in artificially induced veno-occlusive priapism, which might play a protective role against hypoxic injury. However, this may also play an important role in the vicious circle observed in a low-flow priapism.

Topics: Animals; Blotting, Western; Cyclic GMP; Endothelium, Vascular; Heme Oxygenase-1; Male; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Penis; Priapism; Rats; Rats, Sprague-Dawley

Nitrergic neurons are important for erectile responses in the corpus cavernosum and impaired signalling results in erectile dysfunction, today treated successfully by oral administration of the selective phosphodiesterase 5 (PDE 5) inhibitors sildenafil, tadalafil and vardenafil. Although the importance of nitrergic neurons in urogenital function has become evident, it has not been investigated if the PDE 5 inhibitors affect the nerve-induced release of nitric oxide (NO). In a previous study we found that the soluble guanylate cyclase (sGC)/cyclic guanosine 3',5'-monophosphate (cGMP) pathway might modulate nerve-induced release of NO in isolated cavernous tissue.. Electrical field stimulation (EFS 5 Hz, 40 V, 0.3 ms pulse duration, 25 pulses at intervals of 2 min) of rabbit isolated cavernous tissue elicited reproducible, nerve-mediated relaxations in the presence of scopolamine (10(-5) M), guanethidine (10(-5) M) and phenylephrine (3 x 10(-6) M). In superfusion experiments, nerve stimulation (20 Hz, 40 V, 1 ms) of the cavernous tissue evoked release of NO/NO2-, measured by chemiluminescence.. Sildenafil, tadalafil and vardenafil decreased the muscular tone and prolonged the relaxations to nerve stimulation. The evoked release of NO decreased to 72+/-11%, 55+/-16% and 61+/-14% of control, respectively after addition of sildenafil, tadalafil or vardenafil (all 10(-4) M, n=6-8, p<0.05).. Selective PDE 5 inhibitors influence the nerve-induced release of NO, probably via cGMP-mediated negative feedback. This negative feedback might explain why priapism is not seen during monotherapy with the PDE inhibitors.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Carbolines; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Imidazoles; In Vitro Techniques; Male; Muscle, Smooth; Nitrergic Neurons; Nitric Oxide; Penis; Phosphodiesterase Inhibitors; Piperazines; Priapism; Purines; Rabbits; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride

The molecular mechanism for priapism is not well characterized. Although the nitric oxide (NO) pathway is known to mediate penile erection under normal conditions, we hypothesized that the mechanism of priapism rests in aberrant downstream signaling of this pathway based on our previous findings that mice lacking the gene for endothelial nitric oxide synthase (eNOS-/-) and mice lacking both neuronal NOS (nNOS) and eNOS (nNOS-/-, eNOS-/-) have a tendency for priapic activity. We investigated the role of downstream guanylate cyclase and phosphodiesterase type 5 (PDE5A) expression and function in mediating these responses in eNOS-/- and nNOS-/-, eNOS-/- mice. Erectile responses to both cavernous nerve stimulation and intracavernosal injection of the NO donor diethylamine-NONOate were augmented in eNOS-/- and nNOS-/-, eNOS-/- mice but not in WT or nNOS-/- mice. PDE5A protein expression and activity and cGMP levels were significantly lower in eNOS-/- and nNOS-/-, eNOS-/- mice, and this effect was reproduced in WT corpus cavernosum exposed to NOS inhibitors. Moreover, cavernous nerve stimulation was associated with a marked augmentation of cavernosal cGMP levels, suggesting that, although lower at baseline, the production of cGMP is unchecked in eNOS-/- and nNOS-/-, eNOS-/- mice upon neurostimulation. Transfection of eNOS-/- mice with an adenovirus encoding eNOS resulted in a normalization of PDE5A protein and activity as well as a correction of priapic activity. Coupled with the observation that sickle cell disease mice (which show a priapism phenotype) evince dysregulated PDE5A expression/activity, these data suggest that PDE5A dysregulation is a fundamental mechanism for priapism.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Enzyme Inhibitors; Gene Deletion; Gene Expression Regulation; Kinetics; Male; Mice; Mice, Knockout; Nerve Tissue Proteins; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Penile Erection; Priapism; Reverse Transcriptase Polymerase Chain Reaction

To investigate the effects of a purified scorpion toxin (Ts3) on human corpus cavernosum (HCC) in vitro. Scorpion venoms cause a massive release of neurotransmitters that contribute to the clinical symptoms resulting from envenomation.. HCC strips were mounted in organ baths containing Krebs solution. After equilibration, the tissues were precontracted with phenylephrine (10 micromol/L). The relaxations caused by Ts3 (30 nmol/L) were compared with those induced by electrical field stimulation (1 to 20 Hz) and nitric oxide (NO, 1 to 100 micromol/L).. The addition of Ts3 evoked long-lasting relaxations of precontracted HCC strips, and exogenously applied NO and electrical field stimulation caused short-lived responses. The NO synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME; 100 micromol/L) reduced by 87% +/- 2% the Ts3-induced relaxations; this inhibition was reversed by pretreating the tissues with L-arginine (1 mmol/L). The relaxant responses mediated by Ts3 were blocked to a similar degree by the soluble guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3,-alquinoxalin-1-one] (10 micromol/L). In contrast, the addition of the phosphodiesterase type 5 inhibitor sildenafil (0.1 micromol/L) significantly enhanced Ts3-evoked relaxations by 78% +/- 4%. The sodium channel blocker tetrodotoxin (1 micromol/L) completely blocked the relaxant responses elicited by both Ts3 and electrical field stimulation, without significantly affecting those elicited by NO.. The results indicate that Ts3 relaxes the HCC through the release of NO from nitrergic nerves. The elucidation of this mechanism is useful for the development of new therapeutic strategies to treat priapism after scorpion envenomation or to modulate sodium channel activity in the case of penile dysfunction.

Topics: Adolescent; Adult; Child; Cyclic GMP; Drug Evaluation, Preclinical; Electric Stimulation; Enzyme Inhibitors; Humans; In Vitro Techniques; Male; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Neurotoxins; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oxadiazoles; Penis; Phenylephrine; Piperazines; Priapism; Purines; Quinoxalines; Scorpion Venoms; Second Messenger Systems; Sildenafil Citrate; Sodium Channel Blockers; Sulfones; Tetrodotoxin

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Male; Muscle, Smooth, Vascular; Penis; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Priapism; Purines; Sickle Cell Trait; Sildenafil Citrate; Sulfones