Erectile dysfunction (ED) is often caused by endothelial dysfunction (END) and may indicate that the patient has other vascular disease. Risk factors for coronary heart disease such as lipid disorders, smoking, diabetes and hypertension are also risk factors for ED. Oral drugs for ED, such as sildenafil, inhibit phosphodiesterase 5 (PDE5) and the breakdown of cyclic guanosine monophosphate. PDE5 inhibitors are effective and safe in the treatment of ED, but their use is contraindicated when taking nitrates. These drugs are weak vasodilators and are currently being investigated for use in patients with pulmonary hypertension, heart failure, and END.
The early stages of atherosclerosis include END, a condition in which the inner layer of blood vessels loses its function. This includes the loss of normal endothelium-dependent vasodilation. When acetylcholine, an endothelium-dependent vasodilator, is injected into normal blood vessels, the endothelium releases nitric oxide (NO), which diffuses into the vascular smooth muscle cells, causing them to relax. The blood vessels dilate and blood flow increases. Similar phenomena occur when the brachial artery is occluded for several minutes (usually using a blood pressure cuff) followed by deflation of the cuff. When performing Doppler ultrasound, vasodilation is noted with an increase in the diameter of the brachial artery and blood flow velocity. This normal response is due to insufficient blood flow, leading to ischemia. However, with END, vascular response to acetylcholine or temporary compression of the brachial artery followed by restoration of blood flow is abnormal. Normal coronary arteries dilate in response to acetylcholine, which can be detected by angiography. The arteries affected by atherosclerosis do not expand in response to the administration of acetylcholine, or paradoxical narrowing is noted. In patients with vascular diseases caused by atherosclerosis itself or its risk factors, there is a decrease in the severity of vasodilation of the brachial artery after its temporary compression with subsequent reperfusion.
Endothelial damage can result from a wide variety of adverse effects. These include the following common risk factors for atherosclerosis: lipid disorders (increased total cholesterol, increased low-density lipoprotein (LDL) cholesterol, decreased high-density lipoprotein cholesterol), smoking, diabetes, and hypertension. In addition, inflammatory mediators, infectious agents, and other factors may also play a role. These effects can cause damage to the endothelium, leading to impaired synthesis / release of NO, an increase in endothelial permeability for lipids and an increase in endothelial thickness, which causes adhesion of neutrophils and monocytes to its surface. This dysfunction of the endothelium occurs before the formation of visible signs of atherosclerosis.
Research suggests that END is treatable. Lipid reduction with statins, treatment with ACE inhibitors and the use of the PDE5 inhibitor sildenafil can lead to a decrease in the severity of END, which is described in more detail in the next section.
Erectile dysfunction is a manifestation of endothelial dysfunction
There is an assumption that about 50% of cases of ED in men over 50 are due to vascular disease. A significant part of them can be associated with END. Experimental studies in rabbits have shown that END can lead to ED even before the development of atherosclerotic stenoses that obstruct blood flow in the arteries supplying the corpora cavernosa. Azadzoi et al. fed the rabbits with high cholesterol or normal foods. They then erected the rabbits by intracavernous administration of drugs such as phentolamine. Normally fed rabbits were able to achieve and maintain an erection with increased intracavernous pressure. Rabbits on a high cholesterol diet were unable to maintain an erection, as evidenced by a decrease in intracavernous pressure. ED also occurred in rabbits that developed angiographically detectable arterial stenosis, but the most important was the detection of ED in rabbits, which presumably developed END as a result of high blood cholesterol, even before the formation of atherosclerotic narrowing.
Many studies have shown that risk factors for the development of coronary artery disease and hypertension are also risk factors for ED. This is important due to the fact that these risk factors lead to the development of END in the entire vascular system. With its development, atherosclerosis affects various vascular beds. Lipid disorders, especially low high-density lipoprotein cholesterol and high total cholesterol, diabetes, smoking and hypertension (known as risk factors for coronary heart disease) are proven risk factors for ED. Obesity and physical inactivity are also risk factors for ED. Thus, patients with heart disease or risk factors for coronary artery disease are more likely to develop ED and should be asked questions about their erectile function. On the other hand, in some cases, patients turn to doctors in search of treatment for ED. It is important to ask such patients questions about cardiovascular risk factors: do they suffer from hypertension, lipid metabolism disorders, diabetes? Do they smoke? If these risk factors can be identified and treated, doctors can save the lives of many patients.
Although ED is often associated with many cardiovascular risk factors, it is widely accepted that most cardiologists do not ask their patients about sexual dysfunction. The same is true in other medical specialties, including urologists. Kloner et al. conducted a pilot study in collaboration with a large private heart center in Los Angeles to determine the prevalence of ED in men with stable chronic coronary artery disease. The study included 66 patients with proven coronary artery disease, many of whom had previously undergone surgical treatment (balloon dilatation with or without stenting or coronary artery bypass grafting). Typically, patients answered the questionnaire while waiting for an appointment or at home by sending the answers by mail. This questionnaire, which is an abbreviated version of the IIEF, contains 5 questions that determine a man’s ability to achieve and maintain an erection. All questions were scored from 0 to 5 points, and the results were summarized. A result less than or equal to 21 was considered as a sign of ED. ED was present in 75% of men. In addition, 25% of men with ED had severe ED. Thus, ED is often associated with coronary artery disease. Similar results were observed in patients with hypertension (regardless of the antihypertensive drug intake).
Erectile dysfunction as a prognostic factor for the development of coronary artery disease
The results of several studies suggest that patients with ED, even if they do not have angina pectoris and do not have a history of heart attacks, are more likely to show signs of myocardial ischemia during exercise testing. They are also more likely to have risk factors for ED. In this connection, Pritzker coined the term “penile stress test”. In other words, the development of ED may be an early sign of the presence of risk factors for CHD in men.
Inhibition of phosphodiesterase-5 in the treatment of erectile dysfunction in cardiac patients
PDE-5 inhibitors are a group of effective drugs for the treatment of ED. Sildenafil is the only oral ED drug available in the United States, and tadalafil and vardenafil have recently been approved in Europe. Since sildenafil is the only PDE5 inhibitor used in the United States, this article will focus on its use in cardiac patients.
Sildenafil works by inhibiting the enzyme PDE5, which breaks down cyclic guanosine monophosphate (cGMP). It is cGMP that leads to relaxation of the smooth muscle cells of the arteries, arterioles and sinusoids in the cavernous body of the penis. NO released by non-adrenergic non-cholinergic nerves and endothelium during sexual stimulation leads to the activation of the enzyme guanylate cyclase, which catalyzes the formation of cGMP. It may be inadequate in men with ED. Thus, the PDE-5 inhibitor sildenafil prevents the breakdown of cGMP, which leads to greater vasodilation in the corpora cavernosa and better erections. Tadalafil and vardenafil act through similar mechanisms.
Taking 100 mg of sildenafil leads to improved erections in 82% of patients with ED. The drug is effective in patients with organic and psychogenic ED. In patients with ED and coronary artery disease (and, presumably, atherosclerotic or vascular causes of ED), sildenafil was effective in about 70% of cases. In studies of the efficacy of sildenafil in hypertensive patients, sildenafil was safe and improved erection in 70–72% of patients. Moreover, it was effective in patients who received one, two, three or more drugs for the treatment of hypertension. This is important because some antihypertensive medications can impair erectile function. Thiazide diuretics, b-blockers, and centrally acting drugs are the most likely examples of these drugs. Calcium channel blockers and ACE inhibitors are less likely to cause ED. Recently, there have been several interesting studies suggesting that angiotensin receptor antagonists may actually improve erectile function. There was no evidence of an increase in the incidence of serious cardiovascular complications such as angina pectoris, myocardial infarction or cardiac death in patients with coronary artery disease or hypertension taking sildenafil.
The enzyme PDE-5 is localized in the smooth muscle cells of the vessels of the corpora cavernosa, as well as in the smooth muscle cells of the systemic arteries and veins, the smooth muscle cells of the gastrointestinal tract and in platelets. Due to the fact that PDE-5 is located in the smooth muscle cells of the systemic arteries and veins, with its inhibition, slight vasodilation is noted, while the hemodynamic effect resembles the action of weak nitrates. Therapeutic doses of sildenafil reduce blood pressure by about 8 mmHg. and diastolic by about 5-6 mm Hg. In most cases, this decrease is not felt by the patients themselves. Sildenafil reduces systemic vascular resistance and does not significantly affect heart rate. It does not increase myocardial contractility and, when taken in therapeutic dosages, does not adversely affect the QT interval. In a study of patients with severe coronary artery disease who received sildenafil in the laboratory for cardiac catheterization, sildenafil did not change the diameter of the coronary arteries and the blood flow velocity in them. It had a weak positive effect on increasing the coronary vasodilatory reserve in response to the action of adenosine and did not induce it.
Several studies have confirmed the safety of sildenafil in patients with coronary artery disease undergoing stress testing. One study even suggested that sildenafil increased exercise tolerance and increased ischemic threshold. The importance of these studies lies in the fact that the patients performed exercise with a load comparable to the load that occurs during intercourse. Several similar studies have confirmed the safety of tadalafil and vardenafil in patients with coronary artery disease when performing exercise tests.
Early analyzes of the incidence of myocardial infarction and death in double-blind, placebo-controlled studies were comparable in patients treated with sildenafil and placebo. Open-label studies have shown lower rates with sildenafil compared to placebo. A British prescription drug study found no evidence of an increased incidence of cardiovascular complications with sildenafil in thousands of men compared with the general male population in England. Similar, but smaller-scale studies of tadalafil also showed no increase in the incidence of myocardial infarction or death among patients receiving this drug, compared with patients receiving a placebo or with a similar age group in the general population. Published FDA data also show that mortality among men taking sildenafil was within the expected range for men of this age. Thus, despite individual reports of the development of cardiovascular complications in patients taking sildenafil, a careful analysis of the frequency of such events among patients receiving sildenafil, compared with patients of a similar age who may develop ED, shows that sildenafil does not lead to similar phenomena. Although sexual activity in rare cases can cause the development of myocardial infarction, the absolute number of such cases is small. Given that sildenafil can allow a man to resume sexual activity, various societies such as the American College of Heart and the American Heart Association have created guidelines for prescribing sildenafil for cardiac patients. In addition to contraindications for prescribing sildenafil to patients taking nitrates (eg, nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate), these societies and the authors of the Prinsenton Consensus Guidelines suggest that caution should be exercised when prescribing sildenafil in patients with unstable heart disease. It should be noted that this is a highly controversial assumption, especially given the fact that patients with truly unstable heart disease (for example, unstable angina pectoris, myocardial infarction, and severe heart failure) rarely see a doctor for the treatment of sexual dysfunctions.
PDE-5 inhibitors and antihypertensive drugs
Due to the fact that PDE-5 inhibitors are weak vasodilators, some doctors are afraid to prescribe them to patients taking antihypertensive drugs, for fear of hypotension. Most studies have shown no or insignificant additional pressure reduction when PDE5 inhibitors are prescribed in combination with antihypertensive drugs. The drug from the a-blocker group doxazosin, taken together with the PDE-5 inhibitor sildenafil, led to orthostatic hypotension in only a small number of patients, which required the abolition of contraindications to the joint administration of these drugs within 4 hours. Tadalafil does not lead to an additional decrease in blood pressure when taken together with amlodipine, but a decrease in pressure was noted when combined with angiotensin receptor blockers. It also led to mild reductions in blood pressure when taken in conjunction with diuretics, b-blockers and ACE inhibitors. Small reductions in blood pressure also occurred when vardenafil was taken together with various antihypertensive drugs. Thus, PDE-5 inhibitors can lead to small reductions in blood pressure. PDE-5 inhibitors are effective in treating ED in hypertensive patients. In general, there is no significant increase in the frequency and severity of side effects of PDE-5 inhibitors in patients receiving antihypertensive drugs compared with those who do not.
Interactions with nitrates
Organic nitrates such as nitroglycerin are NO donors and increase cGMP production. PDE-5 inhibitors prevent the breakdown of cGMP. When both drugs are taken together, it is possible to increase the level of cGMP, sufficient for the development of significant hypotension in some patients. As a result, nitrates are the only contraindication to taking sildenafil in the United States. Some deaths in patients taking sildenafil have been attributed to the concomitant use of nitrates. Interaction with nitrates has also been described for tadalafil, and it is very likely that the contraindication regarding the intake of nitrates will be common to the entire class of PDE inhibitors as a whole. If a patient has taken sildenafil and develops an episode of chest pain, the American College of Heart and American Heart Association consensus guidelines indicate that nitrates cannot be used within 24 hours of taking sildenafil in order for the drug to be cleared from the body over a period equal to six half-lives. New preliminary data suggest that interactions with nitrates may disappear within 4 hours of taking sildenafil. It is possible that the possibility of interaction with nitrates will be longer when taking tadalafil, since the half-life of this drug is 17.5 hours. If a patient has taken a PDE5 inhibitor and develops chest pain, there are other antianginal / antiischemic drugs that can be used instead of nitrates. These include b-blockers, calcium channel blockers, oxygen, acetylsalicylic acid, and morphine. Patients with myocardial infarction who have taken a PDE-5 inhibitor can receive the usual treatment (acetylsalicylic acid, thrombolysis, percutaneous intervention) with the exception of nitrates.
Possible indications for the use of PDE-5 inhibitors in the future
Sildenafil has been shown to improve endothelial function in two studies. In one study of diabetic patients, sildenafil rapidly improved reduced brachial artery dilatation. In addition, daily administration of sildenafil for several weeks resulted in improved vasodilatation rates, suggesting that long-term administration may lead to long-term vascular protection in diabetic patients. In another study, Katz et al. showed that patients with congestive heart failure have a decrease in the degree of expansion of the brachial artery after compression. Sildenafil improved this indicator, while the effect was dose-dependent.
PDE-5 is common in the vessels of the lungs. Several studies have shown that sildenafil reduces pulmonary vascular resistance and pulmonary artery pressure and improves cardiac output in patients with primary and secondary pulmonary hypertension (such as scleroderma and other collagen diseases). Given that pulmonary hypertension is difficult to treat, the emergence of new drugs is received with enthusiasm. Sildenafil has an additional positive effect on pulmonary hemodynamics when taken together with the pulmonary vasodilator iloprost or inhalation of NO. Large-scale multicenter studies are currently in the planning stage.
Recent studies suggest that sildenafil has additional benefits for improving END in patients with heart failure. Bocchi et al. investigated the effect of oral sildenafil in 23 patients with congestive heart failure (in most cases class 2 and 3) during exercise tests. Sildenafil reduced heart rate and blood pressure before and during the 6-minute treadmill test. Sildenafil increased maximal oxygen consumption during exercise and improved exercise time from 12.3 to 13.7 minutes (p = 0.003). In a preliminary report, Lachmann et al. describe patients with heart failure who exercise on a stationary bike at maximum intensity. The next day, they underwent catheterization of the right heart. Sildenafil improved work efficiency, maximal oxygen consumption and cardiac output during exercise. It also decreased peripheral resistance during rest and increased stroke volume during rest and exercise. These data, combined with data from Katz et al. Showing improvements in vascular function with sildenafil, suggest that long-term studies of sildenafil or other PDE5 inhibitors are warranted in patients with heart failure.
Erectile dysfunction is often a consequence of END. Smoking, lipid disorders, diabetes, hypertension (the same risk factors as for CHD) are also associated with ED. ED can be an early sign of coronary artery disease. PDE-5 inhibitors can effectively treat patients with ED, including patients with atherosclerosis, coronary artery disease and hypertension. It has not been proven that PDE-5 inhibitors can directly lead to cardiovascular complications. They should not be used concomitantly with nitrates. They are safe for most patients on antihypertensive therapy. PDE-5 inhibitors were originally created for the treatment of angina pectoris, however, in the course of studies of sildenafil in such patients, improvement of erections, which was primarily considered as a side effect, eventually became an indication for prescribing the drug. Apparently, we have gone through a full cycle, since now there is interest in the use of sildenafil in cardiac patients and especially patients with heart failure and pulmonary hypertension. In addition, there are other potential uses, since sildenafil restores endothelial function and, possibly, has a vasoprotective effect. Sildenafil can be prescribed for long-term use in patients with peripheral vascular disease and coronary artery disease, as well as as a new antihypertensive drug.
Since this writing, vardenafil has been approved for use in the United States. Due to the possibility of hypotension, α-blockers and nitrates are contraindications to its use.
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