Erectile dysfunction as the presenting symptom of a pheochromocytoma

We report the case of a 59-year-old man with a pheochromocytoma in which erectile dysfunction was the main symptom. Erectile function was related to the amount of noradrenaline secreted by the tumor, as was determined when recurrence of the malignancy was diagnosed twice. Erectile function could be restored by lowering the level of noradrenaline excretion, either by removal of the noradrenaline-producing tumor or by treatment with doxazosin. By stimulating alpha-1-adrenoceptors, high levels of noradrenaline are likely to result in excessive contraction of the corpus cavernosum and penile vessels and, thereby, cause erectile dysfunction.     

Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice

The generation of nitric oxide (NO) in penile erectile tissue and the subsequent elevation of cyclic GMP (cGMP) levels are important for normal penile erection. Current treatments of erectile dysfunction elevate either cGMP levels by blocking cGMP degrading phosphodiesterase 5 or cyclic AMP (cAMP) levels by intrapenile injection of prostaglandin E1. The molecular target or targets of cGMP in erectile tissue and the role of cAMP for normal penile erection are not known. Herein, we report that mice lacking cGMP-dependent kinase I (cGKI) have a very low ability to reproduce and that their corpora cavernosa fail to relax on activation of the NO/cGMP signaling cascade. Elevation of cAMP by forskolin, however, induces similar relaxation in normal and cGKI-null corpus cavernosum. In addition, sperm derived from cGKI-null mice is normal, can undergo acrosomal reactions, and can efficiently fertilize eggs. Altogether, these data identify cGKI as the downstream target of cGMP in erectile tissue and provide evidence that cAMP signaling cannot compensate for the absence of the cGMP/cGKI signaling cascade in vivo.     

The Role of Nitric Oxide in Erectile Dysfunction: Implications for Medical Therapy

Erectile dysfunction is a common, multifactorial disorder that is associated with aging and a range of organic and psychogenic conditions, including hypertension, hypercholesterolemia, diabetes mellitus, cardiovascular disease, and depression. Penile erection is a complex process involving psychogenic and hormonal input, and a neurovascular nonadrenergic, noncholinergic mechanism. Nitric oxide (NO) is believed to be the main vasoactive nonadrenergic, noncholinergic neurotransmitter and chemical mediator of penile erection. Released by nerve and endothelial cells in the corpora cavernosa of the penis, NO activates soluble guanylyl cyclase, which increases 3',5'-cyclic guanosine monophosphate (cGMP) levels. Acting as a second messenger molecule, cGMP regulates the activity of calcium channels as well as intracellular contractile proteins that affect the relaxation of corpus cavernosum smooth muscle. Impaired NO bioactivity is a major pathogenic mechanism of erectile dysfunction. Treatment of erectile dysfunction often requires combinations of psychogenic and medical therapies, many of which have been only moderately successful in the past. The advent of oral phosphodiesterase type 5 (PDE-5) inhibitors, however, has greatly enhanced erectile dysfunction treatment; patients have demonstrated high tolerability and success rates for improved erectile function. The efficacy of the PDE-5 inhibitors also serves to illustrate the importance of the NO-cGMP pathway in erectile function since these agents counteract the degradation of NO-generated cGMP. Because not all patients respond to PDE-5 inhibitors, additional therapies are being investigated, such as soluble guanylyl cyclase activators and NO donors, which act on NO-independent and NO-dependent pathways, respectively.     

Erectile dysfunction: from biochemical pharmacology to advances in medical therapy

Research on penile smooth muscle physiology has increased the number of drugs available for treating erectile dysfunction (ED). Penile erection involves the relaxation of smooth muscle in the corpus cavernosum. The key mediator of smooth muscle relaxation is nitric oxide (NO), which acts by increasing the cellular level of cGMP. Another cyclic nucleotide, cAMP, is involved in smooth muscle cell relaxation; cAMP formation is stimulated by a number of compounds, such as alprostadil. An increase in cAMP and/or cGMP levels can also be induced by inhibition of phosphodiesterases (PDEs), the enzymes involved in cyclic nucleotide breakdown. Both papaverine and sildenafil are PDE inhibitors. Papaverine is a non-specific inhibitor of these enzymes; sildenafil is an orally active, potent and selective inhibitor of GMP-specific PDE5, the predominant isoenzyme metabolizing cGMP in the cells of the corpus cavernosum. Penile smooth muscle contraction, induced by adrenergic fibers through alpha(1) adrenoceptors, produces detumescence, thus making alpha adrenoceptor antagonists suitable for maintenance of penile erection. The orally active drug yohimbine is a mixed alpha(1)-alpha(2) adrenoceptor antagonist that works by a dual mechanism; it facilitates sexual arousal by acting on alpha(2) adrenoceptors in the central nervous system and blocks adrenergic influences at peripheral level.     

Treatment with hypotensive agents affects the impaired relaxation of the penile corpus cavernosum in hypertensive rats.

Treatment of erectile dysfunction (ED) in hypertensive subjects remains to be formally established. There is currently no standardized treatment for ED in hypertensive subjects. In this study, we tested our hypothesis that hypotensive drugs would improve impaired relaxation in the corpus cavernosum of spontaneously hypertensive rats (SHR). Ten-week-old SHR was treated with amlodipine, imidapril or hydralazine for 4 weeks. Although all three drugs achieved an equivalent decrease in systolic blood pressure (SBP), only amlodipine and imidapril induced an increase in relaxation in response to electrical field stimulation (EFS) of the corpus cavernosum. In the case of amlodipine, this effect was dose- and SBP-dependent. Nitric oxide (NO)-dependent relaxation was increased by amlodipine over a wide range of EFS frequencies, was increased by imidapril at low EFS frequencies, and was decreased by hydralazine. Carbon monoxide (CO)-dependent relaxation was only increased by hydralazine, and this increase occurred over a wide range of frequencies. The NOx and cGMP levels in the EFS-stimulated corpus cavernosum were increased by amlodipine. Amlodipine did not affect the thiobarbituric acid-reacting substance levels in the serum and the corpus cavernosum, but did decrease superoxide dismutase activity in the tissue. Imidapril and hydralazine inhibited the acetylcholine-induced relaxation in the corpus cavernosum. Sodium nitroprusside-induced relaxation in the tissue was increased by amlodipine. All three agents similarly inhibited the phenylephrine-induced contraction. These results suggest that impaired neurogenic relaxation in the corpus cavernosum of SHR is improved by amlodipine and imidapril through an increase in the synthesis and/or release of neuronal NO, but not CO, and presumably the inhibited detumescence of erection, which is induced by norepinephrine being released from sympathetic neuron. These findings indicate that amlodipine and imidapril may ameliorate the decreased relaxation of cavernous smooth muscle in the setting of hypertension.     

Adenosine signaling: good or bad in erectile function?

The erectile status of penile tissue is governed largely by the tone of cavernosal smooth muscle cells, which is determined by the balance of vascular relaxants and constrictors. Vascular relaxants play a key role in regulating the tone of cavernosal smooth muscle and thus the initiation and maintenance of penile erection. Early studies drew attention to the potential role of adenosine signaling in this process. However, the serendipitous discovery of the effect of sildenafil on erectile physiology drew more attention toward nitric oxide (NO) as a vasodilator in the process of penile erection, and a recently discovered, unexpected erectile phenotype of adenosine deaminase-deficient mice reemphasizes the importance of adenosine as a key regulatory of erectile status. Adenosine, like NO, is a potent and short-lived vasorelaxant that functions via cyclic nucleotide second messenger signaling to promote smooth muscle relaxation. Recent studies reviewed here show that adenosine functions to relax the corpus cavernosum and promote penile erection. Excess adenosine in penile tissue contributes to the disorder called priapism, and impaired adenosine signaling is associated with erectile dysfunction. More recent research summarized in this review reveals that adenosine functions as a key endogenous vasodilator in the initiation and maintenance of normal penile erection. This new insight highlights adenosine signaling pathways operating in penile tissue as significant therapeutic targets for the treatment of erectile disorders.     

The erectile-endothelial dysfunction nexus: new opportunities for cardiovascular risk prevention

Erectile and endothelial dysfunction are common in individuals with multiple cardiovascular risk factors and are longitudinal predictors of cardiovascular events. The pathogenesis of both endothelial and erectile dysfunction is intimately linked through increased expression and activation of endothelial nitric oxide synthase, and the subsequent physiological actions of nitric oxide. Endothelial production of nitric oxide by endothelial nitric oxide synthase in the corpus cavernosum is involved in the maintenance of penile erection. Erectile dysfunction can be detected clinically using systematic questioning and could potentially be employed as an independent predictor of cardiovascular risk to target treatment of cardiovascular risk factors. Both erectile and endothelial dysfunction respond to lifestyle modifications, particularly in individuals with the metabolic syndrome. Drugs that improve endothelial dysfunction can also improve erectile dysfunction, but responses are not always concordant. Phosphodiesterase type 5 inhibitors, however, are powerful agents that commonly improve erectile and endothelial dysfunction, with potential cardiac applications. The recent Princeton consensus requires more extensive implementation and evaluation in clinical practice. The judicious diagnosis of erectile dysfunction, nevertheless, provides a unique opportunity for the prevention of cardiovascular disease.     

Sildenafil Citrate,a Selective Phosphodiesterase Type 5 Inhibitor:: Research and Clinical Implications in Erectile Dysfunction

Under normal physiological conditions, following sexual stimulation, release of nitric oxide (NO) from penile non-adrenergic, non-cholinergic nerves and the endothelium activates guanylyl cyclase and induces intracellular cGMP synthesis in erectile tissue trabecular smooth muscle cells. Increased cGMP levels reduce intracellular Ca²⁺ concentrations, inhibiting smooth muscle contractility and thereby initiating the erectile response. Phosphodiesterase type 5 (PDE type 5) is the predominant enzyme responsible for cGMP hydrolysis in trabecular smooth muscle. Activation of PDE type 5 terminates NO-induced, cGMP-mediated smooth muscle relaxation, resulting ultimately in restoration of basal smooth muscle contractility and penile flaccidity. Sildenafil citrate is a potent PDE type 5 reversible and selective inhibitor that blocks cGMP hydrolysis effectively (K_i ∼3 nM). Under conditions of excessive adrenergic tone or impaired neurovascular status, following sexual stimulation, sildenafil acts to enhance NO-mediated smooth muscle relaxation, resulting in improved penile erection in men with erectile dysfunction. In this review, we summarize the current state of knowledge of the physiology of penile erection and the pharmacology, metabolism and clinical experience with sildenafil citrate in the management of erectile dysfunction.     

The pathophysiology of erectile dysfunction related to endothelial dysfunction and mediators of vascular function

The incidence of erectile dysfunction increases with diabetes, hypertension, hypercholesterolaemia, cardiovascular disease and renal failure. All these conditions are associated with endothelial dysfunction. This review addresses the pathophysiology of erectile dysfunction with a special focus on new insights into nitric oxide (NO)-mediated pathways, oxidative stress and parallels to endothelial dysfunction. NO appears to be the key mediator promoting endothelium-derived vasodilation and penile erection. The possibility is discussed that elevated plasma concentrations of asymmetrical dimethylarginine (ADMA), an endogenous NO synthase inhibitor, may provide an additional pathomechanism for various forms of erectile dysfunction associated with cardiovascular risk factors and disease. Likewise, the role of endothelium-derived factors mediating NO-independent pathways is evaluated.     

Flow-dependent dilatation of the cavernous artery. A potential test of penile NO content

BACKGROUND: Nitric oxide (NO) is now considered as the main contributor to elicit and maintain erection. It is also established that flow-dependent dilatation of conduit arteries is mediated by NO. The present study was designed to verify the possibility of assessing the penile NO content when measuring the post occlusive vasodilatation of the cavernous arteries.PATIENTS AND METHODS: Ninety five subjects, 22 with normal erections (control group) and 73 with various degrees of erectile dysfunction (ED), measured with the international index of erectile function (IIEF) and erectile activity index (IAE). Multidisciplinary evaluation helped to separate two subgroups: mainly organic (n=47) and mainly psychologic (n=26). The diameter of one of the two cavernous arteries was measured by duplex-scan before and after a five-minute complete occlusion of penile vascular flow. The criterion retained was the maximum percentage of dilatation achieved within 45 to 90 sec after the release of the occlusion. Means were compared in the clinical groups. Influences of IIEF, IAE, age, arterial risk factors, preocclusive diameter of the artery, testosterone and DHEA levels were evaluated.RESULTS: The mean percentage of increase in the control group was 65.2 +/- 26.3% vs 34.9 +/- 34.9% for the ED group (p=0.0003). The psychologic subgroup with 68.2 +/- 40% was similar to the control group as opposed to the organic group which showed a highly-significant difference (16.4 +/- 8.4; p=0.0001). In the control group and the psychological sub-group, subjects with arterial risk factors exhibited a less pronounced response (53.7 +/- 22) as compared to those free of any risk factors (80.3 +/- 30%) p=0.007. Age (r=0.29), preocclusion arterial diameter (r=0.3) and DHEA-S (r=0.56) as well as IIEF and IAE were correlated with the magnitude of the reaction. Sensitivity (100%) and specificity (92%) have been achieved in discriminating organic from psychologic DE.CONCLUSION: Flow-dependent vasodilatation of the cavernous artery is extremely strong. It is much stronger in control subjects and in patients with predominantly psychological ED. An increase of 30% seems to be a critical level since only patients in the organic group were below that level. Thus, organic ED seems to be linked to the decrease of NO production by the cavernous bodies. If these results were confirmed post occlusive vasodilatation of the cavernous artery might be proposed as a fully non-invasive diagnostic and prognostic test in the study of ED. We propose to call it PNORT (penile NO release test).     

Pharmacology of phosphodiesterase 5 inhibitors

The phosphodiesterase enzymes, of at least 11 types, are ubiquitous throughout the body, and perform a variety of functions. Phosphodiesterase type 5 (PDE5) is the predominant enzyme in the corpus cavernosum, and plays a crucial role in penile erection. Inhibitors of PDE5 are the most effective oral agents in the treatment of erectile dysfunction. Sildenafil, tadalafil, and vardenafil are all potent inhibitors of PDE5 and show the same mechanism of action, although they have some pharmacological differences that may translate into varying clinical effects.     

Etiology and treatment of erectile failure in diabetes mellitus

Men with diabetes are especially prone to neuronal and endothelial disease and are afflicted with erectile dysfunction (ED) at a much higher incidence and prevalence than normal men, with a consequent reduction in quality of life. ED in diabetes results from combinations of impairments from nearly every step in the production of a penile erection. These include the failed transmission of neural signals to and from the spinal cord due to neuropathy resulting in reduced neural nitric oxide (NO) delivery to cavernosal smooth muscle, impaired sinusoidal endothelial cell NO release because of endothelial dysfunction, reduced arterial and arteriolar inflow due to peripheral vascular disease, and failure of relaxation of the corpora from glycation of the elastic fibers. The evaluation of men with diabetes and ED is similar to that in nondiabetic men. It includes assessment of gonadal, neural, arterial, and on occasion, venous function, along with marital and psychological status. Although treatment options for diabetic men with ED have fortunately expanded, the risk factors for ED are the same as those for cardiovascular disease; a flagging penis should raise a red flag of warning to evaluate and treat the risk factors for coronary, cerebral, and peripheral vascular disease, which are common in persons, of either sex, afflicted by diabetes.     

Relaxation effect of nitric oxide-donor on diabetic penile smooth muscle in vitro

The primate model has been used for investigations on the physiology and pharmacology of erection. Recent in vitro investigations indicate that nitric oxide (NO)-donor act as the mediator of penile erection, but it is unclear whether NO-donor could enhance the relaxation effect of sildenafil on diabetic penile smooth muscle. To determine the relaxation effect of NO-donor on diabetic penile smooth muscle, we studied strips of corpus cavernosum tissue obtained from 15 diabetic cynomolgus monkey (Macaca fascicularis). Contraction was induced on isolated strips of corporal smooth muscle by norepinephrine; then relaxation was assessed with the administration of two agents: selective phosphodiesterase type 5 (PDE5) inhibitor (sildenafil citrate) and S-nitroso-N-acetylpenicillamine (SNAP), an NO-donor, and combination of both agents. Analysis of variance was used to compare the responses to the different agents under various treatments. It was concluded that NO-donor could not enhance the relaxation effect of sildenafil on corpus cavernosum of diabetic monkey.     

Erectile dysfunction: expectations beyond phosphodiesterase type 5 inhibition

In the last few years the pathophysiological mechanisms of erection have been partially clarified, and the molecular machinery of the cellular components of the corpus cavernosum (CC) has been widely investigated. Since erection is a vascular event and the penis is a vascular organ, there must be an intact endothelium for an erection to occur. The regulation of penile tumescence inside the CC involves a balance between contracting and relaxing factors which regulate the functional state of smooth muscle cells. Recent studies have highlighted the importance of new local factors (i.e. phosphodiesterases, rho-kinases and endothelins), and pharmacological agents are available in the armamentarium of the specialist which are targeted to modulate the function of those mediators of erection. It is now well understood that male erectile dysfunction (ED) is a symptom rather than a disease; for this reason in the near future both general practitioners and specialists in internal medicine would have to interplay with sexual medicine. This review is intended to give the clinician some basic concepts of the pathophysiology of erection with relevance to the clinical practice, and to discuss the newest therapeutic approaches for those patients who do not respond to the treatment with oral inhibitors of phosphodiesterase Type 5.     

Cyclic AMP-dependent phosphorylation of neuronal nitric oxide synthase mediates penile erection

Nitric oxide (NO) generated by neuronal NO synthase (nNOS) initiates penile erection, but has not been thought to participate in the sustained erection required for normal sexual performance. We now show that cAMP-dependent phosphorylation of nNOS mediates erectile physiology, including sustained erection. nNOS is phosphorylated by cAMP-dependent protein kinase (PKA) at serine(S)1412. Electrical stimulation of the penile innervation increases S1412 phosphorylation that is blocked by PKA inhibitors but not by PI3-kinase/Akt inhibitors. Stimulation of cAMP formation by forskolin also activates nNOS phosphorylation. Sustained penile erection elicited by either intracavernous forskolin injection, or augmented by forskolin during cavernous nerve electrical stimulation, is prevented by the NOS inhibitor l-NAME or in nNOS-deleted mice. Thus, nNOS mediates both initiation and maintenance of penile erection, implying unique approaches for treating erectile dysfunction.     

Involvement of beta 3-adrenergic receptor activation via cyclic GMP- but not NO-dependent mechanisms in human corpus cavernosum function

The beta(3)-adrenoreceptor plays a major role in lipolysis but the role and distribution of beta(3)-receptors in other specific sites have not been extensively studied. beta(3)-adrenergic receptors are present not only in adipose tissue but also in human gall bladder, colon, prostate, and skeletal muscle. Recently, beta(3)-adrenergic receptor stimulation was shown to elicit vasorelaxation of rat aorta through the NO-cGMP signal transduction pathway. Here we show that beta(3)-receptors are present in human corpus cavernosum and are localized mainly in smooth muscle cells. After activation by a selective beta(3)-adrenergic receptor agonist, BRL 37344, there was a cGMP-dependent but NO-independent vasorelaxation that was selectively blocked by a specific beta(3)-receptor antagonist. In addition, we report that the human corpus cavernosum exhibits basal beta(3)-receptor-mediated vasorelaxant tone and that beta(3)-receptor activity is linked to inhibition of the RhoA/Rho-kinase pathway. These observations indicate that beta(3)-receptors may play a physiological role in mediating penile erection and, therefore, could represent a therapeutic target for treatment of erectile dysfunction.     

Gene transfer of endothelial nitric oxide synthase to the penis augments erectile responses in the aged rat

Nitric oxide (NO), a mediator involved in penile erection, is synthesized by the nitric oxide synthase (NOS) family of enzymes. It has been shown that NOS activity decreases with age. To determine whether adenoviral-mediated overexpression of endothelial NOS (eNOS) could enhance erectile responses, we administered a recombinant adenovirus containing the eNOS gene (AdCMVeNOS) into the corpora cavernosum of the aged rat. Adenoviral expression of the beta-galactosidase reporter gene was observed in cavernosal tissue 1 day after intracavernosal administration of AdCMVbetagal; 1 day after administration of AdCMVeNOS, transgene expression was confirmed by immunoblot staining of eNOS protein, and cGMP levels were increased. The increase in cavernosal pressure in response to cavernosal nerve stimulation was enhanced in animals transfected with eNOS, and erectile responses to acetylcholine and zaprinast were enhanced at a time when the erectile response to the NO donor sodium 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate was not altered. These results suggest that in vivo gene transfer of eNOS, alone or in combination with a type V phosphodiesterase inhibitor, may constitute a new therapeutic intervention for the treatment of erectile dysfunction.     

Alpha7-nicotinic acetylcholine receptors on cerebral perivascular sympathetic nerves mediate choline-induced nitrergic neurogenic vasodilation

It has been suggested in isolated porcine cerebral arteries that stimulation by nicotine of alpha7-nicotinic acetylcholine receptors (alpha7-nAChRs) on sympathetic nerves, but not direct stimulation of parasympathetic nitrergic nerves, caused nitrergic neurogenic dilation. Direct evidence supporting this hypothesis has not been presented. The present study, which used in vitro tissue bath and confocal microscopy techniques, was designed to determine whether choline, a selective agonist for alpha7-nAChRs, induced sympathetic-dependent nitrergic dilation of porcine basilar arterial rings. Choline and several nAChR agonists induced exclusive relaxation of basilar arterial rings without endothelium. The relaxation was blocked by tetrodotoxin, nitro-L-arginine, guanethidine, and beta2-adrenoceptor antagonists. Furthermore, the relaxation was blocked by methyllycaconitine and alpha-bungarotoxin (preferential alpha7-nAChR antagonists) and mecamylamine but was not affected by dihydro-beta-erythroidine (a preferential alpha4-nAChR antagonist). Confocal microscopic study demonstrated that choline and nicotine induced significant calcium influx in cultured porcine superior cervical ganglionic cells but failed to affect calcium influx in cultured sphenopalatine ganglionic cells, providing direct evidence that choline and nicotine did not act directly on the parasympathetic nitrergic neurons. The increased calcium influx in superior cervical ganglionic cells was attenuated by alpha-bungarotoxin and methyllycaconitine but not by dihydro-beta-erythroidine. These results support our hypothesis that activation of alpha7-nAChRs on cerebral perivascular sympathetic nerves causes calcium influx and the release of norepinephrine, which then act on presynaptic beta2-adrenoceptors located on the neighboring nitrergic nerve terminals, resulting in NO release and vasodilation. Endogenous choline may play an important role in regulating cerebral sympathetic activity and vascular tone.