Penile erection and cardiovascular function: effects and pathophysiology

Abstract

Penile erection (PE) is a hemodynamic event that results from a neuroendocrine process, and it is influenced by the cardiovascular status of the patient. However, it may also modulate an individual’s cardiovascular events. The present study provides the mechanisms involved in the association of PE and cardiovascular function. Erection upsurges the cardiac rate, blood pressure, and oxygen uptake. Sex-enhancing strategies, such as phosphodiesterase inhibitors, alprostadil, and testosterone also promote vasodilatation and cardiac performance, thus preventing myocardial infarction. More so, drugs that are used in the treatment of hypertensive heart diseases (such as angiotensin system inhibitors and β-blockers) facilitate vasodilatation and PE. These associations have been linked with nitric oxide- and testosterone-dependent enhancing effects on the vascular endothelium. In addition, impaired cardiovascular function may negatively impact PE; therefore, impaired PE may be a pointer to cardiovascular pathology. Hence, evaluation of the cardiovascular status of an individual with erectile dysfunction (ED) is essential. Also, employing strategies that are used in maintaining optimal cardiac function may be useful in the management of ED.

Keywords:

• Cardiac function
• erectile dysfunction
• infertility
• nitric oxide
• penile erection
• sexual function

Introduction

Penile erection (PE) is a haemodynamic event [1] that results from a neuroendocrine process, involving the stimulation of elevated arterial blood flow and restricted venous return to the corpus cavernosum that culminates in the depolarization of the corpus cavernosum smooth muscle and erection [2]. This process is influenced by and may also influence cardiovascular function. There are convincing pieces of evidence linking PE and cardiovascular function. Optimal cardiac function is key in the maintenance of normal physiological processes, including vascular endothelial function and PE, while optimal PE is essential for sexual satisfaction and male fertility.

Sexual activity borders around the adaptation of metabolic and neural functions, as well as cardiovascular functions. Sexual activity alters cardiac function, such as heart rate, arterial blood pressure, and oxygen uptake; also, the cardiac status of an individual influences his sexual performance. This review provides an update on the relationship between PE and cardiovascular function. In addition, details of the associated mechanisms are discussed.

Physiological basis of penile erection

PE: a complex physiologic progression involving a series of vascular, neurologic, and humoral events initiated by stimuli such as visual, auditory, and olfactory signals and local stimulation of the penis. The process is initiated by elevated blood flow in the pudendal arteries, dilatation of the helicine arterioles as well as the cavernous arteries, and the depolarization of the smooth muscle in the trabecular complex. This leads to the torrent of blood in the corpora and the subtunical venules being compressed by the resistant tunica albuginea [3]. Hormonal signaling is also involved in the physiological process of an erection. Testosterone, the primary male sex hormone, is necessary for normal erectile function [4,5]. Testosterone promotes the depolarization of smooth muscle and the widening of blood vessels in the penis, which are required for an erection [6,7].

The core pudendal artery is the primary blood vessel that supplies blood to the penis. It branches off from the core iliac artery and develops into the common penile artery as it approaches the penis. The common penile artery possesses three components: bulbourethral, cavernous, and dorsal. The dorsal artery supplies blood to the glans of the penis for the period of an erection, while the bulbourethral artery provides the corpus spongiosum and bulb of the penis with blood. The cavernous artery provides the corpora cavernosa with blood and further bifurcates into helicine arteries that runs through each corporal body. The sinusoids of the erectile chambers and the trabecular tissue are vasculated by the helicine arteries [8]. These arteries are convoluted and restrained in a flaccid form, but they become straight and dilate during an erection, permitting blood to fill the corpora cavernosa. This engorgement triggers the veno-occlusive mechanism, significantly increasing blood flow by relaxing the small, cavernous arteries, essential for achieving and maintaining penile tumescence. The prominent veins that drain blood from the penis are the core pudendal veins. Blood from the outlying sinusoids flows through the trabecular complex and empties into the subtunical venous plexus, exiting the penis through the emissary’s veins. The emissary veins may drain directly into the core pudendal veins or connect with veins that meet on the deep dorsal vein and empty through the periprostatic plexus. In the course of an erection, the emissary’s veins are compacted between the sinusoids and tunica albuginea, which helps to reduce venous drainage from the sinusoids and preserve tumescence [8]. The cavernous and helicine arteries’ ability to dilate by up to 80%, compared to the 20% dilation seen in general body vessels, underscores the penile vasculature’s unique responsiveness. This substantial dilation facilitates the rapid influx of blood required for an erection, highlighting the potential for earlier erectile dysfunction (ED) manifestation in patients with underlying cardiovascular conditions, where vascular health is compromised [9].

The sympathetic and parasympathetic nervous systems play a role in controlling PE through the nerves in the penis. The nerves in the penis are innervated by the S2–S4 nerve origin and form the hypogastric nerves as they enter the pelvic region. The hypogastric nerves are near the core iliac vessels and pass via the pelvic inlet. The pelvic plexuses, otherwise known as the inferior hypogastric plexuses, are produced by the hypogastric nerves connecting with the pelvic splanchnic nerves, which provide parasympathetic innervation and originate from the S2–S4 sacral spinal nerves [10]. Both sympathetic and parasympathetic fibers pass in the pelvic plexus, and their input is integrated into the penis. Branching pelvic plexus structures traverse the deep perineal pouch that makes up the prostatic plexus. The cavernous nerves, which originate from the prostatic plexus, transport parasympathetic fibers and innervate the helicine arteries in the cavernous spaces of the erectile tissue. These cavernous nerves largely intermediate vasodilation and contribute to the erection of the penis [10].

The tissue in the penis responsible for erections, including the smooth muscles in the walls of the arteries and arterioles, plays a crucial role in achieving an erection. During a flabby state, these muscles are repolarised due to sympathetic release and vasoconstrictors produced by the endothelium, which solitarily allows a minute quantity of blood flow for nourishment [11]. When a person is sexually stimulated, neurotransmitters are released from the cavernous nerve endings, resulting in the relaxation of the smooth muscles and the succeeding actions to occur: the arterioles and arteries dilate, allowing more blood flow during the diastolic and systolic phases; the expanding sinusoids trap the increased blood flow; the subtunical venular plexuses, flanked by the peripheral sinusoids and the tunica albuginea, are compressed, reducing venous outflow; the tunica albuginea expands to its maximum competence, enclosing the emissary veins between the inner circular and outer longitudinal layers and further reducing venous flow; intracavernous pressure upsurges to around 100 mm Hg, causing the penis to become erect; with the repolarization of the ischiocavernosus muscles, intracavernous pressure increases further, leading to a rigid erection [11,12]. Acetylcholine takes a crucial part in the relaxation of vascular smooth muscle and transmitting signals in the nervous system [13]. It is found in the cholinergic nerves of the human cavernous smooth muscle and neighbouring penile arteries. Research suggests that acetylcholine maintains the penile vascular endothelial function [13] and may stimulate the discharge of nitric oxide (NO) from endothelial cells, which leads to smooth muscle relaxation and erection [11]. It is believed that NO, or a similar substance, is the primary neurotransmitter responsible for causing an erection by increasing the releases of cyclic guanosine monophosphate (cGMP) and relaxing the cavernous smooth muscle [2,14]. However, it has been observed that the response to NO is impaired under low oxygen conditions, but normal oxygen levels can restore smooth muscle relaxation [11]. Apart from suppressing testosterone synthesis, hypoxia may impair PE via a testosterone-mediated downregulation of NO/cGMP signalling and upregulation of PGE1/TGF𝛽1-led penile endothelial dysfunction [15]. Hydrogen sulfide (H2S) has also been found to relax the smooth muscle in the penis, proposing that it may take part in the physiological process of an erection. Enzymes involved in the production of H2S have been identified in penile tissue, confirming the presence of the L-Cys/H2S system in the physiology of an erection [16]. Unlike NO, the primary way H2S relaxes smooth muscle is through the direct activation of KATP and KCa channels [16].

In the unstimulated flabby penis, the smooth muscle in the cavernosal arterioles and sinusoids is in a state of high tonicity, leading to a high-resistance vascular bed with low blood flow. When the penis is stimulated to accomplish an erection, the smooth muscle relaxes through the increased activity of the parasympathetic nervous system, resulting in the discharge of nitric oxide from the endothelial cells in the cavernosal [17]. This relaxation of tone and vascular resistance leads to elevated blood flow in the cavernosal arteries throughout the cardiac cycle. The elevated blood flow in the cavernosal sinusoids causes the penis to lengthen and become turgid. The engorged sinusoids compress the exiting venules and emissary veins, which helps to limit venous outflow and increase intracorporal pressure. When the intracorporal pressure approaches systolic blood pressure, the inflow may also be reduced [17].

Three phases of detumescence (the process of the penis returning to a flaccid state) have been observed in animal reviews. The initial phase involves a temporary increase in intracorporeal pressure, signaling the start of smooth muscle repolarization with a closed venous system [11]. The succeeding stage expresses a gradual decline in pressure, indicating a sluggish reestablishment of the venous channels and the return of basal arterial flow. The third phase involves a swift decline in tension with total venous outflow volume restoration [11].

Cardiovascular changes during penile erection

In the context of the universal adaptation of autonomic roles, sexual activity depends on the adaptation of cardiac, neural, metabolic, and vascular roles. During sexual activity, cardiac function changes, as indicated by an increase in cardiac rate and arterial blood pressure. In a study of young male subjects, cardiac and metabolic outflows were quantified during four sexual actions. All activities (self-stimulation, partner stimulation, man-on-top coitus, and woman-on-top coitus) elevated the regular heart rate, rate–pressure results, and oxygen consumption. Man-on-top coitus showed the most significant and prolonged increases compared to other conditions and baseline. The autonomic nervous regulator of the genital organs in the course of sexual action also shifts from a relaxing to a dynamic state [18]. In the case of sexual action, studies suggest that copulation induces a systemic modification in cardiovascular yield, as well as regional blood flow modification that led to PE. The autonomic nervous system controls both targets, namely the cardiovascular system and the penis, including its arterial flow [18].

Events and variables that may connect sexual actions to cardiac risk comprises of physical activity, underlying cardiac disease, drug effects, and arousal/erection. The plausible cardiac risks of arousal/erection, and the probability that such perils are amplified when erection is introduced or boosted by drugs, have attracted greater awareness with the initiation of novel, orally dynamic drugs for the management of ED [19]. Functional reserve largely influences cardiovascular tolerance for sex which agrees to how proximal the cardiovascular retort to sex (in cases of cardiac rate, oxygen intake and blood pressure level) reaches the patient’s optimal retort to exercise [20].

Penile erection in cardiovascular disorders

Although there are several risk factors such as hormonal, neurogenic, iatrogenic, and psychogenic have been associated with ED, predisposing factors to cardiovascular disorders play significant roles in the development of ED. Hypertension [21], dyslipidaemia [22], diabetes [23,24], and obesity [25] alter penile function. Buranakitjaroen et al. [26] reported that about 67–68% of hypertensive men have ED. Hypertension-driven atherosclerosis is associated with endothelial damage by the sheer stress of raised blood pressure, leading to inflammatory changes, reduced nitric oxide, and increased migration of lipids into the media [27]. The endothelial injury is worsened by the generation of superoxide radicals by angiotensin 1 (AT1) [27], and may contribute to incident ED. Anti-hypertensive drugs also contribute to the development of ED. It has been reported that hypertensive patients on treatment had a higher incidence than untreated hypertensive patients [28,29].

Dyslipidemia is accompanied by reduced integrity of the vascular endothelium, which alters vasodilatory properties of vessels such as the pudendal arteries. Lipoproteins migrate into the arteries through transcytosis, and in the background of endothelial inflammation and hyperlipoproteinemia, they rapidly move into the media and intima [30]. Also, modified low-density lipoproteins prevents the synthesis of nitric oxide in addition to promoting its destruction through enhanced superoxide generation [31]. These events culminate in reduced circulatory nitric-oxide and by extension, impaired nitric oxide-dependent vasodilation effect, leading to atherosclerosis, endothelial injury [27], and ED.

In addition, diabetes is a major play in the development of ED. It is been reported that more than two-thirds of diabetic patients would develop ED [32]. Diabetes is associated with neurological and vasculogenic ED through the induction of autonomic neuropathy and atherosclerosis [33]. The incidence of cardiovascular diseases such as hypertension and atherosclerosis is increased in diabetes, leading to inflammation [27,34]. Also, elevated glucose levels in diabetes induce apoptosis of the endothelial cells [35]. These events enhance ROS generation, lower nitric oxide levels, and promote lipid migration into the media, thus causing endothelial injury and impairing erectile function [32]. Obesity exerts a similar effect on endothelial function. It is a low-grade inflammatory state and promotes accumulation of lipids in the intima [27], leading to impaired vascular compliance and incident ED. Obesity is also associated with increased aromatase activity that converts testosterone to oestrogen [36], thus preventing the pro-sexual effect of testosterone.

Several cardiovascular disorders such as congestive cardiac failure and coronary artery disease also alter endothelial integrity and cause ED. Chronic cardiovascular diseases reduces libido, the frequency of sexual activity, and causes ED [37]. About three-quarter of patients with cardiac failure have ED [38]. The association of cardiovascular diseases with ED may be attributed to the observed peripheral venous stasis, reduced venous return, stroke volume and cardiac output, which are causes of physical inactivity, in patients with cardiovascular diseases [37]. Drugs used in the management of cardiac failure like beta blockers, digoxin, and diuretics have also been reported to worsen ED by reducing vascular compliance [36]. Endothelial dysfunction remains a common denominator in coronary artery disease and ED, although ED may precede coronary artery disease for years; hence, ED is a sentinel occurrence and may be a pointer of incident coronary artery disease. It has been reported that 56% of men with ED have asymptomatic myocardial ischemia, while 75% of men with coronary artery disease have ED and 91% of men suffering from ED have cardiovascular risks [39].

Effects of therapeutic agents used in enhancing penile erection on cardiovascular function

Pharmacological agents that promote PE may also modulate cardiovascular function. These effects may be positive, although they may also exert negative effects. Common pharmacological agents that are used to enhance PE and also modulate cardiovascular function include phosphodiesterase Type 5 (PDE-5) inhibitors (PDE-5i), alprostadil, testosterone, and Vacuum Erection Devices.

PDE5-i

Phosphodiesterases (PDEs) are isoenzymes whose chief biological action is to kerb intracellular levels of cyclic nucleotides such as cGMP and cyclic adenosine monophosphate (cAMP) [40]. PDE-5 degrades cGMP, thus inactivating it [40]. Hence, inhibition of this enzyme by PDE-5i preserves optimal levels of cGMP, leading to improved PE.

Aside the penile corpus cavernosum, PDE-5 isoform is also represented in other tissues, such as skeletal, visceral as well as tracheobronchial muscles, brain, retina, platelets, arterial and venous vasculature, and myocardium [41], Therefore PDE5 and PDE5i may affect the functions of these tissues/organs, including the heart. Common PDE5i include avanafil, vardenafil, tadalafil and sildenafil, which are FDA sanctioned and commercially available. PDE5i inhibitors inhibit the actions of PDE-5 in the smooth muscle cells of the vessels, thus thwarting the breakdown of cGMP by PDE-5, resulting in the stimulation of protein kinase G, depolarization of the vascular smooth muscle, and dilatation of the blood vessels by phosphorylation of different downstream effector molecules [42]. Dilatation of the penile arteries results in improved erection. In addition, PDE-5 inhibitors enhance endothelial roles and decrease apoptosis of vascular smooth muscle cells in the corpus cavernosum [43].

Apart from the maintenance of PE, PED5 inhibitors exert mild systemic vasodilatory effects and may thus control cardiac function. Although PDE5 gene is expressed in human heart, enzyme activity and protein appearance were originally assumed to be physiologically negligible [41]. The systemic vasodilatory characteristics hypothetically make these drugs appropriate for managing hypertension as initially believed [44]. PDE-5 inhibitors also improve arterial rigidity and endothelial dysfunction, two early vascular abnormalities depicting essential hypertension [45]. The repercussions of this are vital, as it is unanimously accepted that dropping blood pressure also depresses cardiovascular risk and is a possible mechanism for reduced myocardial infarction rates seen with steady dosing regimens. Thus, improvement of PE may also improve cardiac function.

Current reviews established that PDE5 signaling looks to be classified within the myocyte and its limitation can modulate myocyte and cardiac role [46–48]. This does not transpire on basal cardiac role but only when the heart is stimulated, that is by adrenergic agonists or pressure overload [40]. PDE5 inhibition by sildenafil can reduce the systolic feedback to acute β-adrenergic contractile stimulation and neutralize multiple ventricular hypertrophies signaling pathways activated by pressure overload [48]. A current review on hypertrophied right ventricular myocardium model demonstrated a noticeable increase in cAMP and primary inotropic action through restriction of noticeably up-regulated PDE5 [46]. Thus, PDE5 inhibition may enhance right ventricular function, which has frequently been illustrated to be an important element of the efficient status in many cardiovascular diseases.

Tadalafil has been reported to augment the blood pressure-lowering effects of antihypertensive agents with no risk of hypotension, although there was no significant difference in the adverse events observed in patients taking tadalafil with or without antihypertensive medications [49]. Santos et al. [50] also revealed that tadalafil enhances left ventricular relaxation via direct effects of PDE-3-mediated actions on the cardiomyocytes in subjects with left ventricular hypertrophy and diastolic dysfunction.

Alprostadil

Alprostadil is an artificial analogue of prostaglandin E1 (PGE1) and expresses a multidimensional pharmacologic action. It results in vasodilation by a direct effect on the vascular and ductus arteriosus smooth muscle [51]. Alprostadil binds as an agonist to prostaglandin receptors, such as EP2, which in turn triggers adenylate cyclise, resulting into the build-up of 3′ 5′-cAMP that is responsible for the pharmacologic effects of the treatment, including bronchodilation, inhibition of platelet aggregation, smooth muscle relaxation and vasodilation [52].

Intracavernous alprostadil is beneficial for its vasodilating characteristics, which acts by depolarization of the smooth muscle of the corpus cavernosum, consequently enlarging the span of the cavernous arteries resulting in an erection. After intracavernous injection of alprostadil, it is either absorbed locally or via the lungs after being absorbed systematically. Short-term trials have proven that intracavernous administration of alprostadil is equivalent to if not more effective in inducing erection in comparison to supplementary drugs administered intracavernously, such as papaverine or the mixed therapy of phentolamine with papaverine, topical nitroglycerine (glyceryl trinitrate) with linsidomine [53].

Although alprostadil may cause hemodynamic instability [51], it results in vasodilation by a direct effect on vascular and ductus arteriosus smooth muscle. In babies presenting with limited systemic blood flow, alprostadil upsurges systemic blood pressure and down-regulates the pulmonary artery pressure to aortic pressure ratio. However, Lipo-PGE1 may efficiently increase the neural function of patients with diabetic neuropathy [54].

Testosterone replacement therapy

Testosterone is the principal male sex hormone and is crucial for the preservation of male secondary sexual properties and fecundity. It plays an unswerving role in erectile physiology. It triggers the central pathways, including libido and neurological signals that descend the spinal cord to impact their stimulus on the penis [55]. Testosterone also has an impact on the peripheral pathway of erectile function, and these include endothelial production of nitric oxide and endothelial-independent pathway that are still to be explored [55]. Testosterone may also enhance libido and sexual performance by upregulating dopamine and dopamine receptor expression [4,56], hence it is not surprising that sexual dysfunction is acknowledged as one of the most vital indications accompanying a decline in testosterone levels [57]

Sexual dysfunction manifests in various ways, such as reduced sexual activity and frequency, lower libido, less spontaneous erections, difficulties with ejaculation or orgasm, and poorer erectile quality [58]. Due to an existing connection between testosterone deficiency and sexual dysfunction, supplementation of testosterone can be of added advantage in grown-ups as well as younger hypogonadal men. A rise in testosterone levels may enhance libido and upturn sexual function (such as a rise in the amount of spontaneous erections), also reducing body fat, elevating lean body mass and increasing muscle mass [58]. Feldman et al. [34] documented that there is approximately 35–40% improvements in both primary and secondary hypogonadism in ED as a result of testosterone supplementary therapy, and the unyielding response in 60–65% of men was likely caused from other underlying diseases or treatments adding to the ED. In addition, testosterone replacement therapy improves the reaction to PDE-5 inhibitors [55]. Testosterone replacement is essential in men who fail on phosphodiesterase type-5 inhibitors because the slightest plasma concentration of testosterone is necessary for the effective refurbishment of erectile function with these agents. Gagliano-Juca and Basaria [59] reported that testosterone replacement is beneficial in young men with androgen insufficiency due to organic disease of the pituitary gland, hypothalamus, or testes without adverse cardiovascular events. Testosterone supplementary therapy improves a lot of the impact of hypogonadism, such as energy levels, mood, sexual function, lean body mass, sense of welfare and muscle strength, erythropoiesis and bone mineral density, cognition, and cardiovascular risk factors [60]. Testosterone plays a crucial role in erectile health, influencing sexual desire and maintaining penile tissue integrity. It regulates nocturnal penile tumescence, essential for erectile tissue health, and prevents tissue fibrosis by promoting smooth muscle over collagen formation. Testosterone also enhances the differentiation of cells within the penile tissue and supports the veno-occlusive mechanism necessary for maintaining erections by fortifying perineal muscles and improving vascular endothelial function [9]. It is pivotal in facilitating the relaxation of the corpora cavernosa, highlighting its importance in both the normal erectile process and in the management of ED [9].

In males, testosterone concentration starts a decline after age 40, and this decline is related to an escalation in all-cause death and cardiovascular risks. Low testosterone concentration in men may escalation the risk of incident metabolic syndrome, coronary artery disease, and type II diabetes [61]. More so, a decline in testosterone concentration in men with congestive heart failure portends a poor prognosis and is linked with amplified mortality [61]. Human studies revealed that testosterone therapy improves myocardial ischemia in men with coronary artery disease and extends the period to exercise-induced ST-segment depression [62–64]. Testosterone also exerts a direct vasodilatory effect on the coronary arteries in men with coronary artery disease [64].

Vacuum erection device (VED)

VED is one of the most communal choices of non-invasive treatment for erection. It consists of a cylindrical element and a suction device that the patient puts around the penis to generate a negative pressure and attain an erection. Sustenance of erection is then achieved with an elastic compression ring positioned at the base of the penis [65].

VED, because of their capacity to direct blood into the penis irrespective of nerve interference, have become the focus of penile recuperation procedures. Even nerve–sparing radical prostatectomy harms the cavernous nerves and results in momentary ED in men recuperating from prostate cancer surgery. Patients with considerable peripheral vascular disease, those getting anticoagulants, and diabetics are usually not suitable candidates for the VED. Patient approval and gratification with VED in all types of ED (including diabetic ED), have been stated to be 68–83%, while the most recurrent impediments remain struggle with ejaculation, hematomas, penile pain, petechiae, and ecchymoses [65]. Patients consuming aspirin or warfarin are more susceptible to complications associated to vascular delicacy [65].

VED uses negative pressure to amplify blood inflow into the corpora cavernosum, with a ring at the base of the penis to uphold erection for copulation or without a ring for penile restoration [66]. It may be a beneficial option in cases of failed pharmacotherapies and in individuals with a stable relationship. Although younger patients may present partial reception because of its alleged “unnatural” erection, VED is widely more received among elderly patients with intermittent sexual relationship [67].

Effects of therapeutic agents for maintaining optimal cardiovascular function on penile erection

ED is a highly predominant medical state affecting a notable proportion of men globally. It is identified by the incompetence to realize or sustain an erection adequate for satisfactory sexual performance, resulting in various degrees of distress and diminished quality of life. Recent estimates suggest that approximately 150 million men worldwide are currently experiencing ED to some extent, with this number projected to increase significantly by the year 2025, reaching more than 300 million men globally [68].

ED affects nearly 40% of men over 40 years of age, increasing with age. ED and cardiovascular disease (CVD) share risk elements such as age, hypertension, diabetes, insulin resistance, metabolic syndrome, smoking, hypercholesterolemia, obesity, metabolic syndrome, sedentary lifestyle, and depression, as well as a mutual pathophysiological basis. Risk factors for ED include hypertension, depression, diabetes, heart disease, smoking, and age. ED is postulated to be a sentry indication in patients with occult CVD due to the shared aetiologies and pathophysiology, including endothelial dysfunction, and evidence suggesting the level of ED compares with CVD seriousness [69,70]. Several reviews have proven that ED (i) is regular in men with known CVD, (ii) co-exists with occult coronary artery disease (CAD) and (iii) is an autonomous risk factor for impending cardiovascular events both in men with known CVD and in men with no recognized CVD [70].

The connection between ED and CVD is inevitably complicated by using concurrent medications. It is challenging to differentiate the impact of a drug on ED from the impact of the disease itself. According to the recent findings of Shiri et al. [29], the utilization of cardiovascular medications is linked to an elevated risk of ED. Among the utmost probable medications identified in this association were calcium channel inhibitors, non-selective β-blockers, angiotensin II antagonists, and diuretics. Conversely, no significant association was observed between ED and the usage of organic nitrates, angiotensin-converting enzyme inhibitors, selective β-blockers, and serum lipid-lowering agents. ED is often classified as a vascular disorder, with a proposed association between the condition and CVD intermediated by the nitric oxide (NO) pathway. Endothelial dysfunction, a critical component of the pathogenesis of both ED and coronary artery disease (CAD), has been identified as a key contributor to this relationship [71].

The prevalence of ED associated with medication side effects was found to be up to 25%, with antihypertensive drugs being the most frequently implicated class. Recent chains of proof have recommended that β-blockers may pose an elevated risk of ED. Nebivolol, a freshly established, extremely choosy b1-blocker, has demonstrated the capacity to induce vasodilation by potentially augmenting nitric oxide (NO) production. The functions of NO in erectile function is believed to be significant as it intercedes the easing of the trabecular muscle of the corpus cavernosum, thus promoting PE [72]. The impact of cardiovascular drugs on erectile function has been a subject of scrutiny. A review of the available literature indicates that only thiazide diuretics and beta-blockers have compelling evidence supporting their adverse effect on erectile function, while nebivolol may potentially have a favourable impact. Conversely, ACE inhibitors, angiotensin-receptor-blockers, and calcium-channel-blockers are either neutral or, in the case of ARBs, possibly beneficial to erectile function [73].

Several studies suggest that the management of hypertension may add to the growth of ED, with diuretics having been revealed to destruct sexual function. Specifically, chlorthalidone is associated with an amplified prevalence of ED, which disappears after 24 months of management. Among calcium-antagonists, nifedipine shows higher decline in ejaculation and tuminescence than diuretics, ACE-I, or beta-receptor-blockers, although data on the novel groups of calcium channel antagonists are deficient. Furthermore, beta-receptor blockers, which are believed to induce ED due to their beta1/beta2 selectivity, have been stated to demonstrate a decline in erectile function. However, clinical reviews have been abortive to endorse a connection between the use of these drugs and ED. Regarding elements inhibiting the renin–angiotensin system, both ACE-I and ARB have been revealed to improve erectile function [74]. Medications with established risk-reducing properties, namely ramipril and telmisartan, either in isolation or in combination, demonstrated comparable effects on ED. Notably, neither treatment was found to exert a detrimental impact on erectile function [75].

Losartan, an AT1 receptor blocker, can kerb the modifying procedure in vascular structures and inhibit cavernous tissue fibrosis. Its communication against the local renin–angiotensin system may assist penile enlargement in patients with arterial hypertension [76]. Valsartan, an angiotensin receptor blocker (ARB), advances several areas of sexual function in hypertensive males. The pathway(s) underlying this impact stay(s) uncertain and may involve both peripheral and central components [77]. Treatment with irbesartan, either alone or in collaboration with hydrochlorothiazide, is connected to improvements in sexual desire, frequency of sexual contacts, and erectile function in hypertensive patients with metabolic syndrome [78]. Treatment with sildenafil, a selective inhibitor of phosphodiesterase type 5, significantly improves erectile function in hypertensive patients suffering from ED and also helps to lower blood pressure. Sexual stimulation discharges nitric oxide into the penile smooth muscle, and the inhibition of phosphodiesterase advances smooth-muscle relaxation and erection. Furthermore, nebivolol enhances vascular nitric oxide discharge and meaningfully improves its impact on vascular dilatation [79].

Cardiovascular drugs have varying impact on erectile function, with diuretics and β-blockers having the most detrimental profiles and renin–angiotensin–aldosterone system inhibitors and nebivolol having the most favourable profiles. However, the pharmacological management of ED has an uncertain impact on the risk of CVD, indicating a complex relationship between ED and medications used for treating CVD [80]. The inhibition of angiotensin-converting enzyme (ACE) activity leads to a reduction in angiotensin II discharge and a rise in tissue concentration of bradykinin, indicating that patients with ED and associated vascular diseases may profit from the administration of ACE inhibitors. Furthermore, ACE inhibitors and angiotensin II receptor antagonists symbolise an antihypertensive management that does not damage male erectile function and libido [81]. Among antihypertensive drugs, diuretics and beta-blockers have a deleterious impact on sexual function, with the exclusion of nebivolol, which has favourable properties by increasing nitric oxide bioavailability. Conversely, renin-angiotensin system inhibitors and calcium-channel blockers have a neutral effect on sexual activity. Although the effect of hypoglycaemic drugs on erectile function has not been well studied, data on metformin, pioglitazone, and liraglutide show promising results. However, the effects of statins on sexual activity have not been consistent. Observational studies demonstrate a detrimental effect, while randomized studies reveal a neutral or even beneficial impact on erectile function [82]. Losartan was found to improve erectile function, as well as both satisfaction and frequency of sexual activity. Given that side effects are among the most significant factors in hypertension management, the positive impact of losartan therapy on quality of life may be an added benefit [83].

Conclusion and future perspectives

Available evidence from the literature demonstrate that PE modulates cardiovascular function, and cardiovascular variability also influences PE. Furthermore, drugs that are used to enhance PE may alter cardiovascular function, vice versa. Although the impacts of these physiological functions on the other may not be detrimental, impaired cardiovascular function may negatively impact on PE; hence, impaired PE may be a pointer to cardiovascular pathology. It is thus essential to evaluate the cardiovascular status of males with ED. Also, employing strategies that are used in maintaining optimal cardiac function may be useful in the management of ED.

Authors’ contributions

Conceptualization and design: ARE. Funding acquisition: ABA, HAS, and ARE. Investigation: ABA, HAS, and ARE. Methodology: ARE. Project administration: ABA, HAS, and ARE. Supervision: ARE. Validation: ARE. Writing-original draft: ABA, HAS, and ARE. Writing-review and editing and final approval: ABA, HAS, and ARE.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data used to support the findings of the present study are available from the corresponding author upon request.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.