madman
Super Moderator
Erectile dysfunction is increasingly affecting men, from the elderly to young adults, being a sexual disorder related to the inability to generate or maintain a penile erection. This disorder is related to psychosocial factors such as anxiety, depression, and low self-esteem, to organic factors such as the presence of preexisting conditions like hypertension, diabetes, and dyslipidemia. The pathophysiology of the disease is related to changes in the neurotransmission of the autonomic or the non-cholinergic nonadrenergic nervous system, as well as the release of local mediators, such as thromboxane A2 and endothelin, and hormonal action. These changes lead to impaired relaxation of cavernous smooth muscle, which reduces local blood flow and impairs penile erection. Currently, therapy is based on oral vasodilation, such as sildenafil, tadalafil, vardenafil, and iodenafil, or by direct administration of these agents into the corpus cavernosum or by intraurethral routes, such as alprostadil and papaverine. Despite this, studies that consolidate the understanding of its pathophysiological process contribute to the discovery of new more efficient drugs for the treatment of erectile dysfunction. In this sense, in the present work, an extensive survey was carried out of the mechanisms already consolidated and the most recent ones related to the development of erectile dysfunction.
INTRODUCTION
Erectile dysfunction is characterized by the inability to achieve and/or maintain a suitable penile erection for satisfactory sexual intercourse (NIH, 1993) and represents the sexual dysfunction most studied in men (Ückert et al., 2007). The first reports of this clinical disorder were found in ancient Egyptian writings dating back over 5,000 years, where reductions in both the number and quality of erections of different Egyptians were described (Smith, 1974; Shah, 2002).
The international consultation committee for sexual medicine on definitions, epidemiology, and risk factors for sexual dysfunction conducted an extensive analysis of the worldwide prevalence of erectile dysfunction. In this view, the prevalence of the disease was 1–10% in men under 40 years of age, 29% in those aged 40–49 years, 20–40% in men aged 60–69 years, and 50–100% in men over 70 years of age (Nicolosi et al., 2003). In addition, the worldwide prevalence of erectile dysfunction is estimated at 322 million men by 2025 (Costa and Potempa, 2012).
Data regarding erectile dysfunction incidence are less abundant. However, the number of new cases of the disease per year varies from 19 to 66 cases per 1,000 men, according to studies conducted in the United States, the Netherlands, and Brazil (Johannes et al., 2000; Moreira et al., 2003; Schouten et al., 2005).
Erectile dysfunction is, predominantly, a vascular and benign disease, but it affects both physical and psychological health and has a significant impact on the quality of life of men and their partners, mainly due to the reduction of self-esteem and the commitment to the interpersonal relationship. The prevalence of the disease increases with age and can be seen as a serious public health problem (Medeiros-Júnior et al., 2014). The etiology is multifactorial, and, among the risk factors, the presence of cardiovascular diseases, sedentary lifestyle, smoking, diabetes, depression, anxiety, and obesity are prominent (Alves et al., 2012).
Currently, erectile dysfunction is not limited to the reduction of sexual activity but acts as an indicator of systemic endothelial dysfunction. From the clinical point of view, this disease can precede cardiovascular events and can be used as an initial marker to identify men with high cardiovascular risk. In this case, patients with ED and no medical history of cardiovascular disease should be screened for cardiovascular disease (Gandaglia et al., 2014; Yafi et al., 2016; Hatzimouratidis et al., 2019).
*Therefore, since alterations in the cellular signaling of cavernous smooth muscle cells can lead to this disease, this review focused on both contraction and relaxation processes that regulate the penile erection, as well as highlights different targets as new approaches toward the development of new drugs for erectile dysfunction treatment.
PHYSIOLOGICAL CONTROL OF PENILE ERECTION
Penile erection is a neurovascular phenomenon modulated by psychological and hormonal factors, resulting in the relaxation of cavernous smooth muscles from the penis. This phenomenon involves a complex interaction between the central nervous system and local stimuli. It is basically mediated by spinal reflexes, by processing information in the hypothalamus and integrating tactile, visual, olfactory, auditory, and imaginary stimuli (Thomas, 2002).
Peripheral erection control depends on neuronal and local factors that ultimately influence the processes of cavernous smooth muscle contraction or relaxation. In this context, a muscle tone is generated and, thus, the functional state of the penis is maintained (Andersson, 2011).
Cavernous muscle tone modulation occurs through molecular mechanisms that depend on the action of agonists, such as neurotransmitters and endothelial-derived factors, and on the integrality of intracellular signaling. Specifically, an increase in intracellular Ca2+ concentration ([Ca2+]i) is the primary cause for the production of contraction, so the regulation of the intracellular levels of this ion and the sensitivity of contractile machinery are the key points for the regulation of smooth muscle cell (Maggi et al., 2000)
*PHYSIOLOGICAL DETERMINANTS OF PENILE FLACCIDITY
*PHYSIOLOGICAL DETERMINANTS OF PENILE ERECTION
*CAVERNOUS SMOOTH MUSCLE CELLS AS TARGETS FOR THE PHARMACOLOGICAL TREATMENT OF ERECTILE DYSFUNCTION
- Intracavernous and Intraurethral Therapies
-Oral Therapy
Targets Studied as an Alternative to the Use of Oral Therapy
Despite the use of oral therapy being the first line of treatment for erectile dysfunction, there are patients who are refractory to treatment, creating a field of research for new drugs. In this sense, there are different targets in the contractile machinery of the penile corpus cavernosum.
In clinical trials, the use of agents that act as activators of the soluble guanylyl cyclase enzyme has been shown to improve the development of a penile erection. Additionally, improvement in erectile dysfunction was also observed with the therapeutic use of Rho-kinase inhibitors. However, in terms of clinical efficacy and adverse effect profile, there was no superiority when compared to PDE inhibitors (Sanofi-Avenis, 2010; Bayer, 2017).
Another approach considered in the function of cavernous smooth muscle cells is to promote the opening of potassium channels, which would lead to a reduction in the intracellular concentration of calcium and, consequently, to relaxation. In this sense, the use of calcium-sensitive Maxi-K ion channel gene (hSlo cDNA) was evaluated in clinical phase I studies, demonstrating a good safety of use, however, there was no improvement to the use of PDE inhibitors, limiting clinical progress (Melman, 2006).
CONCLUSION
Balance among flaccidity and penile erection depends on the timing between the contraction and relaxation processes of cavernous smooth muscle cells. Thus, [Ca2+]i is the central point of regulation of smooth muscle tone. In this view, the increase in [Ca2+]i leads to contraction of these cavernous cells and, consequently, maintains the penis in the flaccid state, while relaxation, which promotes penile erection, is mediated by the reduction of [Ca2+]i. In this sense, the imbalance of these mechanisms is related to ED development.
Currently, the main therapeutic lines for ED present as targets steps of contraction and relaxation signaling in cavernous smooth muscle cells. Therefore, further research targeting different components of electro- and pharmacomechanical couplings of cavernous smooth muscle cells arise as new targets for the development of promising drugs for the treatment of this disease.
INTRODUCTION
Erectile dysfunction is characterized by the inability to achieve and/or maintain a suitable penile erection for satisfactory sexual intercourse (NIH, 1993) and represents the sexual dysfunction most studied in men (Ückert et al., 2007). The first reports of this clinical disorder were found in ancient Egyptian writings dating back over 5,000 years, where reductions in both the number and quality of erections of different Egyptians were described (Smith, 1974; Shah, 2002).
The international consultation committee for sexual medicine on definitions, epidemiology, and risk factors for sexual dysfunction conducted an extensive analysis of the worldwide prevalence of erectile dysfunction. In this view, the prevalence of the disease was 1–10% in men under 40 years of age, 29% in those aged 40–49 years, 20–40% in men aged 60–69 years, and 50–100% in men over 70 years of age (Nicolosi et al., 2003). In addition, the worldwide prevalence of erectile dysfunction is estimated at 322 million men by 2025 (Costa and Potempa, 2012).
Data regarding erectile dysfunction incidence are less abundant. However, the number of new cases of the disease per year varies from 19 to 66 cases per 1,000 men, according to studies conducted in the United States, the Netherlands, and Brazil (Johannes et al., 2000; Moreira et al., 2003; Schouten et al., 2005).
Erectile dysfunction is, predominantly, a vascular and benign disease, but it affects both physical and psychological health and has a significant impact on the quality of life of men and their partners, mainly due to the reduction of self-esteem and the commitment to the interpersonal relationship. The prevalence of the disease increases with age and can be seen as a serious public health problem (Medeiros-Júnior et al., 2014). The etiology is multifactorial, and, among the risk factors, the presence of cardiovascular diseases, sedentary lifestyle, smoking, diabetes, depression, anxiety, and obesity are prominent (Alves et al., 2012).
Currently, erectile dysfunction is not limited to the reduction of sexual activity but acts as an indicator of systemic endothelial dysfunction. From the clinical point of view, this disease can precede cardiovascular events and can be used as an initial marker to identify men with high cardiovascular risk. In this case, patients with ED and no medical history of cardiovascular disease should be screened for cardiovascular disease (Gandaglia et al., 2014; Yafi et al., 2016; Hatzimouratidis et al., 2019).
*Therefore, since alterations in the cellular signaling of cavernous smooth muscle cells can lead to this disease, this review focused on both contraction and relaxation processes that regulate the penile erection, as well as highlights different targets as new approaches toward the development of new drugs for erectile dysfunction treatment.
PHYSIOLOGICAL CONTROL OF PENILE ERECTION
Penile erection is a neurovascular phenomenon modulated by psychological and hormonal factors, resulting in the relaxation of cavernous smooth muscles from the penis. This phenomenon involves a complex interaction between the central nervous system and local stimuli. It is basically mediated by spinal reflexes, by processing information in the hypothalamus and integrating tactile, visual, olfactory, auditory, and imaginary stimuli (Thomas, 2002).
Peripheral erection control depends on neuronal and local factors that ultimately influence the processes of cavernous smooth muscle contraction or relaxation. In this context, a muscle tone is generated and, thus, the functional state of the penis is maintained (Andersson, 2011).
Cavernous muscle tone modulation occurs through molecular mechanisms that depend on the action of agonists, such as neurotransmitters and endothelial-derived factors, and on the integrality of intracellular signaling. Specifically, an increase in intracellular Ca2+ concentration ([Ca2+]i) is the primary cause for the production of contraction, so the regulation of the intracellular levels of this ion and the sensitivity of contractile machinery are the key points for the regulation of smooth muscle cell (Maggi et al., 2000)
*PHYSIOLOGICAL DETERMINANTS OF PENILE FLACCIDITY
*PHYSIOLOGICAL DETERMINANTS OF PENILE ERECTION
*CAVERNOUS SMOOTH MUSCLE CELLS AS TARGETS FOR THE PHARMACOLOGICAL TREATMENT OF ERECTILE DYSFUNCTION
- Intracavernous and Intraurethral Therapies
-Oral Therapy
Targets Studied as an Alternative to the Use of Oral Therapy
Despite the use of oral therapy being the first line of treatment for erectile dysfunction, there are patients who are refractory to treatment, creating a field of research for new drugs. In this sense, there are different targets in the contractile machinery of the penile corpus cavernosum.
In clinical trials, the use of agents that act as activators of the soluble guanylyl cyclase enzyme has been shown to improve the development of a penile erection. Additionally, improvement in erectile dysfunction was also observed with the therapeutic use of Rho-kinase inhibitors. However, in terms of clinical efficacy and adverse effect profile, there was no superiority when compared to PDE inhibitors (Sanofi-Avenis, 2010; Bayer, 2017).
Another approach considered in the function of cavernous smooth muscle cells is to promote the opening of potassium channels, which would lead to a reduction in the intracellular concentration of calcium and, consequently, to relaxation. In this sense, the use of calcium-sensitive Maxi-K ion channel gene (hSlo cDNA) was evaluated in clinical phase I studies, demonstrating a good safety of use, however, there was no improvement to the use of PDE inhibitors, limiting clinical progress (Melman, 2006).
CONCLUSION
Balance among flaccidity and penile erection depends on the timing between the contraction and relaxation processes of cavernous smooth muscle cells. Thus, [Ca2+]i is the central point of regulation of smooth muscle tone. In this view, the increase in [Ca2+]i leads to contraction of these cavernous cells and, consequently, maintains the penis in the flaccid state, while relaxation, which promotes penile erection, is mediated by the reduction of [Ca2+]i. In this sense, the imbalance of these mechanisms is related to ED development.
Currently, the main therapeutic lines for ED present as targets steps of contraction and relaxation signaling in cavernous smooth muscle cells. Therefore, further research targeting different components of electro- and pharmacomechanical couplings of cavernous smooth muscle cells arise as new targets for the development of promising drugs for the treatment of this disease.
