Current Pharmaceutical Design - Volume 11, Issue 31, 2005

It is widely accepted that nitric oxide plays an important role in the biology of the penis, serving most familiarly as the agent responsible for penile erection. Early investigation in the field led to the identification of the signaling function of the molecule in the penis which yields corporal smooth muscle relaxation fundamental for the erectile response. Ongoing study of this molecule and its signaling pathway in erectile tissue has served to revise and clarify its importance. Current information conveys the prerequisite of the nitric oxide signaling pathway for penile erection, the regulatory basis for the generation and actions of nitric oxide in the penis, the diverse roles of its synthetic enzyme isoforms in penile biology, and the interaction between nitric oxide and other molecular pathways operative in the broad context of erection physiology. Insight into these subject areas has therapeutic relevance for pathologic conditions of the penis. The purpose of this review is to highlight the latest areas of investigation related to the science of nitric oxide in the penis, as a gateway for considering novel therapeutic strategies for erectile disorders now and in the future.

Penile tumescence (erection) and detumescence (return to the flaccid state) are regulated by a complex neurophysiological process involving the relaxation and contraction, respectively, of smooth muscle (SM) within the two corpus cavernosum (CC) of the penis. Failure of the above SM-mediated process to function properly results in the inability to obtain an erection sufficient for sexual satisfaction and has been termed erectile dysfunction (ED). It is predicted that an estimated 322 million men worldwide will have ED by the year 2025 and, relevant to this review article, is that roughly 50% of men with diabetes also have ED. Furthermore, one of the largest classes of nonresponders to oral phosphodiesterase V (PDE5) inhibitors (the predominant pharmacological treatment for organic ED) are diabetics. This review article examines the current knowledge about the contractile pathways that fine-tune SM tone with particular emphasis on vascular SM including corpus cavernosum smooth muscle (CCSM). The role of the contractile apparatus, SM myosin phosphorylation/dephosphorylation pathways, calcium "sensitization" and "desensitization" pathways and the main neurotransmitters/modulators responsible for regulating CCSM contraction are outlined along with how they are modified or potentially may be modified in response to diabetes. The overall hypothesis generated from this review is that an increased CCSM tone, resulting from an enhancement of contractile mechanisms, may contribute to the higher than average nonresponse rate of diabetic men to PDE5 inhibitors. Knowledge gained from this review will hopefully lead to the generation of drugs that specifically target CCSM contractile pathways which may prove to have therapeutic usefulness in treating ED in diabetics either alone or in combination with existing PDE5 inhibitors.

The sinusoid anatomy of the penis is complex and requires complicated interaction between smooth muscle and endothelium in order to maintain homeostasis in the adult. The morphogen, Sonic hedgehog (Shh), is a crucial regulator of these processes, along with its down stream targets patched (Ptc), Hox, bone morphogenetic proteins (BMP's), vascular endothelial growth factor (VEGF) and nitric oxide synthase (NOS). Shh is critical for patterning and establishing tissue identity of the penis during embryonic development, is a crucial regulator of penile postnatal differentiation of the sinusoid morphology of the corpora cavernosa, and plays a fundamental role in maintaining sinusoidal structures pertinent to erectile function in the adult rat. Shh and its targets are active in human penes, and decreased in human diabetic penes in parallel with observations in the rat, thus lending clinical significance to the role of abnormal Shh signaling in erectile dysfunction (ED). Application of exogenous Shh protein to rat corpora cavernosa, induces VEGF and NOS proteins, suggesting a potential mechanism through which decreased Shh protein can cause ED. The studies outlined in this review provide in depth analysis of the Shh pathway and signal transduction, its role in penile development, how Shh signaling is altered in a rat model of ED and neuropathy, how abnormal Shh signaling can cause ED, and the clinical significance of the Shh pathway to human ED. These studies will provide valuable insight, at the molecular level, into understanding the mechanisms that under lie ED and lead to new treatment strategies for diabetic impotence.

Erectile dysfunction (ED) is a highly prevalent and often under-treated condition. Erection is basically a spinal reflex that can be initiated by recruitment of penile afferents but also by visual, olfactory and imaginary stimuli. The generated nervous signals will influence the balance between contractile and relaxant factors, which control the degree of contraction of penile corporal cavernosal smooth muscles and, thus, determine the erectile state of the penis. The different steps involved in neurotransmission, impulse propagation and intracellular transduction of neural signals may be changed in different types of ED. Recent studies have revealed important roles for the small GTPase RhoA and its effector, Rhokinase in regulating cavernosal smooth muscle tone. The RhoA/Rho-kinase pathway modulates the level of phosphorylation of the myosin light chain, mainly through inhibition of myosin phosphatase, and contributes to agonistinduced Ca2+-sensitization in smooth muscle contraction. Changes in this pathway may contribute to ED in various patient subgroups (e.g. hypertension, diabetes, hypogonadism). This review summarizes the importance of Rho-kinase signaling in the erectile response and introduces the evidence pointing to RGS-containing Rho-guanine nucleotide exchange factors (GEFs) as critical mediators of RhoA-GTPase activation in cavernosal smooth muscle and its possible compartmentalization in the caveolae. In addition, we suggest that the design of selective inhibitors of these GEFs might represent a novel class of pharmacological agents to treat ED.

The contribution of the neuronal and endothelial isoforms of nitric oxide synthase (nNOS and eNOS, respectively) in the synthesis of nitric oxide as a mediator of penile erection, at the levels of both the penile corpora cavernosa and the hypothalamic regions that control the erectile response, are well established. More recently, the role of the third NOS isoform, the inducible NOS (iNOS), has also started to be elucidated. iNOS does not appear to intervene directly in physiological penile erection or in its central control, but its transcriptional induction is postulated to be a key factor in two opposite related pathological processes, namely neurotoxicity in critical related regions of the hypothalamus during senescence, and as a defense mechanism against the aging or injury-associated fibrosis in the penile corpora cavernosa, the media of the penile arteries, and the tunica albuginea. By counteracting fibrosis that impairs cavernosal smooth muscle compliance, iNOS would protect the erectile tissue. However, further studies are needed to conclusively evaluate these putative roles in the two organs involved in reproductive function. In addition, whether iNOS induction during aging is a major cause in the net loss of trabecular smooth muscle in the corpora cavernosa through apoptosis, remains to be elucidated. The overall evaluation of these conflicting effects is important in order to decide whether pharmacological iNOS induction, or alternatively NO donors or L-arginine, may constitute a valid approach to prevent or treat penile fibrosis and vasculogenic erectile dysfunction.

Erectile function is determined by tight regulation of relaxation or contraction of corpus cavernosal smooth muscle, which is the result of a long and complex chain of molecular events. Control of erectile function resides in signaling pathways of the central and peripheral nervous system, as well as intracellular events in the penile smooth muscle. Vascular events resulting in erection have long been understood, and the role of the signaling pathways of the central and peripheral nervous systems in erectile function and dysfunction has become increasingly clear over the last decade. This knowledge has led to the development and current availability of effective oral treatments for erectile dysfunction, the selective phosphodiesterase type 5 (PDE5) inhibitors-sildenafil, vardenafil and tadalafil. In the past few years we have seen an elucidation of the molecular events involved in erectile function and dysfunction and the detailed mechanisms of action by which the specific PDE5 inhibitors work. A review of those mechanisms helps to explain the success of the currently available PDE5 inhibitors and the differences between them and suggests new approaches for developing potential future novel therapies or refinements to existing structures that may improve their efficacy, selectivity and safety profiles.

Basic science research on erectile physiology has been devoted to investigating the pathogenesis of erectile dysfunction (ED) and has led to the conclusion that ED is predominately a disease of vascular origin. It is well recognized that the incidence of ED dramatically increases in men who suffer from diabetes mellitus, hypercholesterolemia, and cardiovascular disease. Endothelial nitric oxide synthase (eNOS) is an important factor in cardiovascular homeostasis, angiogenesis, and erectile function. Given the impact of endothelial-derived nitric oxide (NO) in vascular biology, a great deal of research over the past decade has focused on the role of NO synthesis from the endothelium in normal erectile physiology as well as in disease states. Loss of the functional integrity of the endothelium and subsequent endothelial dysfunction plays an integral role in the occurrence of ED. Therefore, a likely target of gene therapy for the treatment of ED is eNOS. This communication reviews the role of eNOS in erectile physiology and discusses the alterations in eNOS expression in various vascular diseases of the penis. Putative gene therapy interventions to restore eNOS expression and subsequent endothelial function may represent an exciting new therapeutic strategy for the future treatment of ED.

Premature ejaculation is generally regarded the most frequent male ejaculatory complaint and has been considered a psychosexual disorder with psychogenic aetiology. The efficacy of various antidepressants, however, to delay ejaculation in men and to pharmacologically treat premature ejaculation suggests a strong neurobiological involvement. Most of our current understanding of the neurobiology and neuroanatomy of sexual behavior and ejaculatory function has been derived from preclinical studies using several laboratory species. In the present paper we will review the various animal models that have been developed to further study ejaculatory function in the laboratory rat. In addition, we will briefly review the effects of serotonergic antidepressants and serotonergic compounds on sexual and ejaculatory behavior. Together, these preclinical studies may contribute to a better understanding of the neurobiology of ejaculation and help the development of novel drug targets to treat ejaculatory disorders such as premature ejaculation.

Magnetic Resonance Imaging is gaining a prominent role in the routine clinical investigation. To further improve this technique it is crucial that contrast agents are developed with more optimal organ specificity. This will not only result in a better diagnostic efficiency but also in a reduction of the amount of the agent administered. A combination of techniques has been employed to increase the target selectivity of the contrast agent and thereby the feasibility to visualize different organs. The organ targeting is based on the understanding of the mechanisms involved in the interaction of the agent with plasma proteins (albumin in particular) as well as the different membrane transporters involved in the uptake and in the excretion of the agent from the organ. The physicochemical properties of the contrast agents play a major role in the interaction with these various proteins. In this review we address the relationship between the structure of the contrast agents and their binding to different plasma proteins and membrane transporters in different organs, with special reference to the liver and kidney. The present and potentially future applications of these concepts in the clinical setting are also discussed.

Donor blood is a limited resource and its transfusion is associated with significant adverse effects. Therefore, alternatives have been searched, the ultimate being artificial oxygen (O2) carriers. There are two main groups of artificial O2 carriers: hemoglobin based and perfluorocarbon emulsions. The hemoglobin molecule in hemoglobin based artificial O2 carriers needs to be stabilized to prevent dissociation of the α2β2-hemoglobin tetramer into ab-dimers in order to prolong intravascular retention and to eliminate nephrotoxicity. Other modifications serve to decrease O2 affinity in order to improve O2 off-loading to tissues. In addition, polyethylene glycol may be surface conjugated to increase molecular size. Finally, certain products are polymerized to increase the hemoglobin concentration at physiologic colloid oncotic pressure. Perfluorocarbons are carbon-fluorine compounds characterized by a high gas dissolving capacity for O2 and CO2 and chemical and biologic inertness. Perfluorocarbons are not miscible with water and therefore need to be brought into emulsion for intravenous application. Development, product specification, physiologic effects, efficacy to decrease the need for donor blood in surgery and side effects of the following products are described: Diaspirin cross-linked hemoglobin (HemAssist), human recombinant hemoglobin (rHb1.1 and rHb2.0), polymerized bovine hemoglobin-based O2 carrier (HBOC-201), human polymerized hemoglobin (PolyHeme®), hemoglobin raffimer (Hemolink™), maleimide-activated polyethylene glycol-modified hemoglobin (MP4) and perflubron emulsion (Oxygent™). In addition, enzyme cross-linked poly-hemoglobin, hemoglobin containing vesicles (nano-dimension artificial red blood cells) and an allosteric modifier (RSR13) are discussed. The most advanced products are in clinical phase III trials but no product has achieved market approval yet in the US, Europe or Canada.