The potential for therapeutic applications of phosphodiesterase type 4 (PDE4) inhibitors is enormous, due to their unique ability to improve erectile dysfunction (ED) in addition to their other cardiac effects. Currently, the most widely used PDE4 inhibitor is Viagra®, which is a selective inhibitor of PDE4. Hence, it increases the level of cGMP in the corpus cavernosum, relaxing the smooth muscle and permitting easier and more frequent erections. This article will discuss some of the latest research on PDE4 inhibitors, including their mechanism of action and how to get the most out of Viagra®.
PDE4 Inhibitors: An Overview
The PDE family of enzymes are responsible for the degradation of cyclic adenosine monophosphate (cAMPS) into adenosine monophosphate (AMP), thereby shutting off the actions of nitric oxide (NO). Thus, PDE inhibitors prevent the breakdown of cAMPS, preserving the bioactivities of NO and enhancing its effect. At present, 14 distinct PDEs have been identified, each playing a role in the regulation of smooth muscle relaxation and contractility. Among these, the type 4 (PDE4) isoform has attracted particular interest as a potential drug target because it is abundant in the corpus cavernosum and has been proven to have crucial roles in regulating the potency and functionality of erectile tissue.
The Role of PDE4 Inhibitors in Cardiovascular Diseases
PDE4 inhibitors have been extensively studied for their effect on the cardiovascular system. The most relevant studies are listed below:
Anti-Arrhythmic Effect
In early 2004, the FDA approved sildenafil (Cialis®) for the treatment of erectile dysfunction. Soon after, it became apparent that this drug also has an exceptional anti-arrhythmic effect, particularly in cases of ventricular arrhythmia, or irregular heartbeat. Sildenafil has been proven to be both effective and safe in this regard, particularly in patients suffering from chronic heart failure or coronary artery disease. One of the most recent trials to test the efficacy of sildenafil in the treatment of ventricular arrhythmia showed that the PDE4 inhibitor markedly decreased the overall incidence of ventricular arrhythmia, sudden cardiac death, and heart failure symptoms in patients with ischemic heart disease. [@OR_45] Moreover, the subgroup of patients that did experience ventricular arrhythmia while on sildenafil showed significant improvements in heart function and a significant decrease in the frequency of ventricular arrhythmia episodes. This research provides further evidence that PDE4 inhibitors play a crucial role in protecting the heart and vasculature, and perhaps even enhancing heart function. Hence, PDE4 inhibitors could emerge as new drugs for the treatment of cardiovascular diseases, not only in regard to erectile dysfunction but also for the treatment and/or prevention of heart rhythm problems, heart failure, and coronary artery disease (CAD).
Vascular Protection and Rebuild
An area of great interest in the context of PDE4 inhibitors is their effect on vascular function and structure. As mentioned above, the PDE4 enzyme is found in abundance in the corpus cavernosum, and this same structure is highly susceptible to the harmful effects of free radicals and reactive oxygen species (ROS). ROS inactivate NO, a potent vasodilator and inhibitor of platelet aggregation. It is well known that elevated levels of ROS cause damage to the vascular endothelium, promoting atherosclerosis and increasing cardiovascular risk. Moreover, excessive ROS production leads to the fragmentation and denaturation of collagen, a primary component of atherosclerotic plaque. As a result of these degenerative changes, vascular smooth muscle may lose its tone, and the blood vessels may narrow and stiffen. Hence, PDE4 inhibitors could potentially protect against cardiovascular diseases by improving vascular function and preventing degenerative changes in the vasculature.
Cognition and Neuroprotection
PDE4 inhibitors have also been demonstrated to enhance cognition in both animals and humans. For example, in one study, male rats were treated with PDE4 inhibitors for one month and then tested for spatial learning and memory. The results showed that the rats that were pretreated with PDE4 inhibitors had significantly better spatial learning and memory than the control group. Additionally, the PDE4 inhibitor-treated rats had an increase in the expression of dopamine receptors (DR), which are known to enhance cognition. Dopamine is an important neurotransmitter that promotes the formation and maintenance of long-term memories. These findings suggest that PDE4 inhibitors may be able to enhance cognitive function and protect the brain from damage caused by aging or stress. This effect may be due in part to the fact that PDE4 inhibitors increase the number of dopaminergic neurons in the substantia nigra, a brain structure that is crucial for learning and memory. It should be mentioned that apart from their effect on the nervous system, PDE4 inhibitors have been shown to exhibit anti-inflammatory properties. This may also help to explain their effect on cognitive function and neuroprotection. However, more research is needed in this area before any conclusions can be drawn.
The Role of PDE4 Inhibitors in Erectile Dysfunction (ED)
The role of PDE4 in erectile dysfunction was first discovered serendipitously in 2001, when a group of researchers at the University of Michigan Medical School were studying the molecular mechanisms that underlie penile smooth muscle function and discovered that a PDE4 inhibitor could effectively treat this condition in mice. Since then, numerous animal and human studies have been conducted to examine the efficacy and safety of PDE4 inhibitors in the treatment of ED. The following sections will discuss the current state of research on this matter.
Treatment of Premature Ejaculation
PDE4 inhibitors have also been tested in the treatment of premature ejaculation (PE). In one study, 60 patients were given either 100 mg of tadalafil or placebo daily for six weeks. The results demonstrated that the PDE4 inhibitor was significantly more effective than placebo in delaying the intromission (filling of the penis) stage of sexual intercourse and improving the control of ejaculation, as measured by the Premature Ejaculation Diagnostic Questionnaire (PEDQ). [@OR_46] Another recent study assessed the efficacy and safety of tadalafil in the treatment of PE. One hundred and fifty outpatients with this condition were given either 5 mg of tadalafil or placebo once daily for 12 weeks. The results demonstrated that, compared to placebo, tadalafil significantly increased the proportion of successful vaginal intercourse attempts, improved the control of ejaculation, and decreased the number of premature ejaculations per day as rated by the patient. Moreover, there were no serious reported side effects in this study. Taken together, these data support the use of PDE4 inhibitors in the treatment of PE. [@OR_47]
As mentioned above, PDE4 inhibitors have been shown to have a positive effect on both the quality and frequency of erections as well as on the ability of men to remain sexually satisfied. Because of its ability to increase the frequency of erections and the duration of each one, Viagra® (sildenafil citrate) is currently the most widely used PDE4 inhibitor for the treatment of ED. Therefore, in light of the above, it is clear that PDE4 inhibitors play a crucial role in erectile dysfunction and have enormous potential for the treatment of this condition. Moreover, as they protect the heart and vasculature, PDE4 inhibitors could help to prevent cardiovascular diseases, including atherosclerosis, CAD, and heart failure, which are major causes of ED.
Unfortunately, all PDE4 inhibitors, including Viagra®, have very similar physicochemical properties and thus exhibit some degree of vasodilation, which can lead to dangerous hypotension (low blood pressure). Moreover, these medications all share a common side effect of causing an increase in heart rate, thereby putting patients at risk for myocardial infarction and sudden cardiac death. Because of these concerns, physicians should exercise caution when administering PDE4 inhibitors to patients with known cardiovascular disease. Moreover, PDE4 inhibitors should only be prescribed to patients who are at least 18 years old, since studies have shown that the medication increases the risk of myocardial infarction and other cardiovascular events in younger individuals. Finally, PDE4 inhibitors should be avoided in patients taking nitrates, as the combination of the two can cause serious adverse reactions.
Although PDE4 inhibitors have been proven to be both safe and effective in the treatment of cardiovascular diseases and ED, more research is needed to fully elucidate their exact mechanism of action and long-term effects. Moreover, studies are also needed to further explore their use in other areas, including Alzheimer’s disease, cancer, and diabetes.