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ARCHIVES OF HELLENIC MEDICINE 1999, 16(5):457–463 ÁÑ×ÅÉÁ ÅËËÇÍÉÊÇÓ ÉÁÔÑÉÊÇÓ 1999, 16(5):457–463 Erectile dysfunction
and cardiovascular disease
C.S. Thompson,2M.R. Dashwood,2R.J. Morgan,1D.P. Mikhailidis2 1Department of Urology2Department of Molecular Pathology & Clinical Biochemistry, Royal Freeand University College Medical School& The Royal Free Hampstead NHS Trust,London, UK ÓôõôéêÞ äõóëåéôïõñãßá Key words
êáé êáñäéáããåéáêÜ íïóÞìáôá Cardiovascular risk factorsDiabetes mellitus Ðåñßëçøç óôï ôÝëïò ôïõ Üñèñïõ EndothelinErectile dysfunctionHypercholesterolemiaHypertension Nitric oxide and penile erectile physiology Although erectile dysfunction (ED) is not life threaten- Penile erection is a hemodynamic process, involving ing, this common problem can significantly affect the increased arterial inflow and restricted venous outflow, quality of life and psychological well being.1 The Mass- coordinated by corpus cavernosum smooth muscle re- achusetts Male Aging study, on 1,290 men aged 40–70 laxation.8 Although this process is generally accepted to years, showed that 52% of men reported some degree be under neuroregulatory control,8–20 biochemical media- of ED (17.1% mild, 25.2% moderate, 9.6% total).2 ED tors released locally from the endothelium and/or s- becomes more common with advancing age and since mooth muscle also participate in initiating and main- the proportion of the older population is increasing, the taining erection.21–23 Nitric oxide (NO), which is pro- prevalence of ED should also rise.3 Data extrapolated duced both in cavernosal nerves and endothelium, has from the USA in the 1940s estimates that currently recently been recognized to play a key role in the physio- around 7 to 10 million men in that country have ED.4 Because ED is a sensitive issue it is likely that its preva- In this brief review we consider the evidence showing lence is under-reported4 but despite this, ED results in that men with ischemic heart disease (IHD) have a high more than 400,000 outpatient visits and 30,000 hospi-tal admissions in the USA per year.
prevalence of ED. We also consider that this association tudies carried out in Europe have demonstrated that may be related to the fact that the same risk factors (e.g.
39% of men aged 18–70 years in France have some de- hypertension, dyslipidemia, smoking and diabetes) pre- gree of ED and 11% have total ED6 and in the UK, an dict both erectile dysfunction and vascular disease.
estimated 17–19% of men are thought to suffer from The association between ED and IHD raises the im- portant question of whether vasculogenic ED is yet an- other manifestation of atherosclerosis. Impaired NO ac- products (AGEs)]38 or via inactivation by superoxide, tivity may provide a unifying explanation for such an as- plays a role in the pathogenesis of ED associated with sociation. There is convincing evidence that during erec- tion the local release of NO and/or related factors pro- Another link between ED and DM is the finding of duces relaxation of the corpus cavernosum.8–23 Nona- raised circulating levels of endothelin-1 (ET-1),39–41 a drenergic, noncholinergic (NANC) nerve-mediated NO peptide belonging to a family of potent vasoconstrictors.
release appears to be the most important factor with re- To date, two major ET receptors have been identified spect to cavernosal smooth muscle relaxation.9–20 How- ever, the erectile process may, at least in part, be acetyl- A and ETB.42 ET-1 is considered a physio- logical antagonist of NO.43,44 Several studies have indi- choline (Ach)-mediated in the human and rabbit corpus cated the potential importance of ET-1 in the modula- tion of corpus cavernosum smooth muscle tone.39,45,46 To date, most of studies support the concept that NO Other studies have suggested that ET-1 may play a role derived from the autonomic innervation of the penis ope- in the development of MD.47 Moreover, the plasma lev- rates locally as a post-ganglionic neurotransmitter of els of ET-1 are higher in diabetics with ED than in dia- NANC-mediated penile erection.8–20,24–32 Following its syn- thesis and release from nerve terminals, NO activates Animal and human corpus cavernosum produces a guanylate cyclase in vascular and trabecular smooth mus- range of eicosanoids including prostaglandins (PGs) cle.22 The increased intracellular accumulation of cyclic guanosine monophosphate (cGMP) is then believed to 2á, PGE2, PGI2 and TXA2.48–51 Muscarinic (but not a- drenergic) stimulation of both animal and human penile cause corporeal smooth muscle relaxation via a chemical cascade.26 Cyclic nucleotide phosphodiesterase enzymes vasodilator, it has been proposed that the release of this (PDEs) present in the corpus cavernosum regulate the ac- eicosanoid may be involved in the vasodilatory phe- tivity of cGMP.27,28 Experimental studies have shown that nomenon associated with erection.53 As a potent in- PDE III and V isoenzymes both play an important role in hibitor of platelet adhesion and aggregation, the acute cavernosal smooth muscle tone.27,28 The inhibition of PDE V activity forms the basis of treating ED with sildenafil (Vi- bosis during engorgement.53 DM is associated with ab- normal PG synthesis.54–56 Streptozotocin-induced DM inthe rat results in a marked inhibition of PGI Molecular mechanisms and the risk factors for ED by both penile and vascular tissues.57 Similarly, as we re- 1. Diabetes mellitus (DM). DM represents one of the cently demonstrated in alloxan-induced diabetic rabbits major organic causes of ED. As many as 50% of men there is impairment of cavernosal PGI2 formation.58 with DM suffer from ED.33 It is also well established that These effects relate to the duration rather than the severi- DM is associated with an increased incidence of vascu- ty of DM, thus mirroring the human situation.59 The re- lar events.32 A link between the pathogenesis of ED and duced PGI2 synthesis reverts to normal following long- decreased local NO activity was suggested because in term administration of insulin.57 A reduction in PGE1 re- isolated corpus cavernosum strips from diabetic patients ceptors has recently been reported in penile tissue ob- with ED, both neurogenic and endothelium-dependent relaxations were impaired.34 Similar findings were also 2. Hypercholesterolemia. Hypercholesterolemia is a apparent in rabbits with alloxan-induced DM.35 Reduced recognized risk factor for both vasculogenic ED61,62 and relaxation to electrical field stimulation in cavernosal tis- IHD. Studies using a genetic rabbit model of hypercho- sue taken from diabetic patients with ED has also been lesterolemia suggest that this lipid abnormality may ac- demonstrated.36 This was associated with a lack of NO count for ED because of changes in penile ET receptor production (measured as the formation of nitrite) and distribution. These changes may, in turn, influence NOS- not with the inability of the smooth muscle to relax.36 dependent mechanisms.63 Experiments using cholesterol- Further insight into the mechanisms involved was pro- fed rabbits have demonstrated that inhibition of NO syn- vided by studies which showed a significant increase in thesis promotes the development of atheroma-like le- NO synthase (NOS) binding sites (putative receptors) in sions, whereas supplementation with L-arginine pre- rat cavernosum two months post-induction of DM.37 Thisfinding suggests that an impairment in NO bioavailability, either due to a lack of the substrate L-arginine, due to It has been demonstrated that high-density lipoprotein NO quenching [e.g. by advanced glycosylation end- (HDL) decreases the risk of both ED and IHD,62 a fur- ERECTILE DYSFUNCTION AND CARDIOVASCULAR DISEASE ther similarity between the risk factors for ED and IHD.
and enhances platelet and leukocytes adhesion to blood There is also evidence that decreased cholesterol in- vessel walls.78 Adherent platelets and leukocytes are ac- creases arterial vasodilator activity65 as well as cavernosal tivated to release a plethora of vasoconstrictors such as TXA2, leukotrienes and serotonin79 which could con-tribute further to ED.
3. Hypertension. Hypertension is also associated with both IHD and ED.61 Decreased endothelium-dependent Apart from the acute effects on the vascular system, relaxation of isolated blood vessels has been described the chronic consequence from smoking of vascular dis- in experimental animal models of systemic and pul- ruption leads to an increased risk of atherosclerosis.60 monary hypertension.66 These findings have been as- This in turn leads to ED through atheroma formation in cribed to either an attenuation of NO activity or aug- the pudendal arteries and possibly from altered function mented elaboration of an endothelium-derived con- of the penile corporal smooth muscle itself.
tracting factor. More definitive date for a primary role of 5. Aging. Increasing age correlates with altered NO NO in the regulation of blood pressure has been shown synthesis and erectile responses in the rat penis.80 This in a mouse model with inactivation of the eNOS gene.67 could be one explanation for the increasing incidence of This impairment of endothelial NO bioavailability could be one explanation why hypertension is a risk factor forvasculogenic ED.61 6. Radiation effects. Radiation has been shown to re- duce the number of penile NOS containing nerves in the Studies have suggested that ET-1 may have a role in rat, possibly providing an explanation for the develop- the development of hypertension68,69 as well as DM,47 ment of ED in men following pelvic irradiation.81 both of which are cardiovascular risk factors that are al-so associated with ED.33–38,61,70 ET-1 potentiates the con- ED and IHD: Does defective NO activity contribute tractile response of vascular smooth muscle to other spa- smogens.71–73 Therefore, the physiological relevance ofET-1 may be related to its ability to augment the con- As discussed above, numerous studies have shown tractile responses of other vasomodulators present in the that IHD and ED share common risk factors.61,62 More re- cently, preliminary studies suggest that fibrinogen82 andlipoprotein are risk factors for ED as well as for IHD. The The link between hypertension and ED is illustrated by long-term follow up of the Massachusetts Male Aging epi- abnormal penile vascular responses, as shown by dy- demiological study concluded that the risk of moderate namic testing (e.g. using papaverine and duplex sonog- or complete ED in patients with cardiovascular risk fac- raphy).70 Hypertension acts synergistically with other tors was 31%, higher than in an age-matched disease vascular risk factors (e.g. DM and smoking) in terms of free control cohort in which the incidence was 19.6%.39 increasing the probability of ED.70 Hypertension-related It may also be relevant that the risk factors for IHD and ED could also result from the use of certain antihyper- ED behave synergistically in both conditions.61 tensive agents (e.g. thiazides or â-blockers). In contrast, Of equal interest are studies which show that the ex- doxazosin, a selective á1-antagonist, used in the treat- tent of IHD is related to the risk of concomitant ED. T- ment of mild hypertension, has been shown to have the wo studies have shown a significant correlation between lowest incidence of ED in a trial assessing the treatment the presence of vasculogenic ED and clinically evident or of mild hypertension,74 where its effect did not differ sig- subclinical IHD.83,84 A significant correlation was report- ed between ED and the number of coronary vessels oc- 4. Smoking. Smoking is a risk factor for both athero- cluded on angiography83 and patients with severe arte- genesis and ED.59,60 Smoking precipitates a number of a- riogenic ED (assessed by duplex sonography) were cute changes which can affect normal erectile function, shown to have a 16% risk of suffering from severe, al- including impaired penile blood flow.75,76 Cigarette smok- ing results in a transient increase in blood levels of the Alterations in the endothelial L-arginine-NO pathway catecholamines, adrenaline and noradrenaline,60 effects have been demonstrated in both atherosclerotic and which appear to be mediated by nicotine.77 As á-adre- hypercholesterolemic coronary arteries of humans and in noreceptor activation is associated with detumescence, animal models.85–89 These studies support the concept this release of catecholamines may compromise normal that there is a reduction in NO bioavailability in these erectile function. Smoking also produces profound acute conditions. These findings are similar to those observed morphological alterations in the vascular endothelium in the penile L-arginine-NO pathway and support the concept that vasculogenic changes in the penile vascu- ly, medical practitioners who treat ED need to be aware lar bed in ED mirror those in the coronary arteries.
of the possibility of underlying IHD and its clinical rele- The role of NANC-mediated NO release in the coro- vance in terms of "whole patient management".
nary circulation is unclear, though NANC nerves havebeen implicated in coronary blood flow regulation.90 It has been found that NANC-mediated NO productioncauses vasodilation of human cerebral arteries,91 bovine NO plays a major role in the physiological regulation of basilar arteries92 and canine superficial temporal arter- penile erection, eliciting effects through the activation of ies,93 supporting a regulatory role in these vascular beds.
guanylate cyclase and the subsequent production ofcGMP. Impaired NO activity appears to play an important We have recently demonstrated that in the Watanabe rabbit model there is a significant decrease in ET role in the pathogenesis of ED. This impaired NO activi- ceptor binding sites in corpus cavernosum tissue com- ty may be similar to that which occurs in other forms of pared with age-matched healthy controls.63 This reduc- vascular disease or in the presence of cardiovascular risk tion, in part, involved endothelial ETB receptors63 which factors (e.g. dyslipidemia, diabetes, smoking and hyper- have been shown in other vascular beds to mediate ET- 1-induced vasorelaxation by stimulating NO forma- The recent development of an effective, orally active, tion.94–96 However, the role of the ETB receptor in the cor- type V PDE inhibitor, sildenafil (Viagra) provides a nov- pus cavernosum remains unclear and further studies are el method of therapy for patients with ED. It achieves this by inhibiting the hydrolysis of cGMP, produced via Hence, it appears that normal erectile function in- volves a delicate balance between vasodilating and vaso- Further research in this area is needed to determine constricting factors. When this balance is disrupted, erec- the precise pathophysiological role of NO, endothelin tile dysfunction may result. ED and ischemic heart dis- and possibly other mediators in this organ. This work ease may not occur in the same patients by coincidence may also provide further insights into the pathogenesis but may have common etiological factors. Consequent- of cardiovascular diseases in general.
ÓôõôéêÞ äõóëåéôïõñãßá êáé êáñäéáããåéáêÜ íïóÞìáôá
M.A. KHAN,1 M.E. SULLIVAN,1 C.S. THOMPSON,2 R.J. MORGAN,1 D.P. MIKHAILIDIS2 1Department of Urology, 2Department of Molecular Pathology & Clinical Biochemistry, Royal Free and University College Medical School & The Royal Free Áñ÷åßá ÅëëçíéêÞò ÉáôñéêÞò 1999, 16(5):457–463 Óôïõò áóèåíåßò ìå éó÷áéìéêÞ êáñäéïðÜèåéá (ÉÊ) ðáñáôçñåßôáé áõîçìÝíç åðßðôùóç óôõôéêÞò äõóëåéôïõñãßáò(ÓÄ). Ç óõó÷Ýôéóç áõôÞ ìðïñåß íá áðïäïèåß óôïõò ðáñÜãïíôåò êéíäýíïõ, ðïõ åßíáé êïéíïß êáé óôéò äýïêáôáóôÜóåéò (ð.÷. õðÝñôáóç, äõóëéðéäáéìßá, äéáâÞôçò, êÜðíéóìá). Ç äñáóôçñéüôçôá ôïõ ïîåéäßïõ ôïõ áæþôïõ(ÍÏ) óôïõò éóôïýò ôïõ ðÝïõò êáé ôùí áããåßùí åðçñåÜæåôáé áñíçôéêÜ áðü áõôïýò ôïõò ðáñÜãïíôåò êáé, êáôÜóõíÝðåéá, ïé äéáôáñá÷Ýò ôçò åßíáé ðéèáíü íá äéáäñáìáôßæïõí ðáèïãåíåôéêü ñüëï, ôüóï óôç ÓÄ, üóï êáé óôçíÉÊ. Ïé äéáôáñá÷Ýò ôçò ÍÏ-äñáóôçñéüôçôáò, óå óõíäõáóìü ìå äéáôáñá÷Ýò ôçò óýíèåóçò ôùí åéêïóáíïåéäþíêáé ôçí áýîçóç ôçò óõãêÝíôñùóçò ôçò êõêëïöïñïýóáò åíäïèçëßíçò-1, åíäÝ÷åôáé íá áðïôåëïýí åêäÞëùóçåíüò åíéáßïõ âéï÷çìéêïý ìç÷áíéóìïý, ï ïðïßïò åõèýíåôáé ãéá ôç óõó÷Ýôéóç ôçò ÉÊ ìå ôç ÓÄ. Ç óõíÝ÷éóç ôçòÝñåõíáò ó' áõôÞ ôçí ðåñéï÷Þ åßíáé ðéèáíü íá óõìâÜëåé óôçí êáôáíüçóç ôçò ðáèïãÝíåéáò ôùí êáñäéáããåéáêþííïóçìÜôùí, ãåíéêþò.
ËÝîåéò åõñåôçñßïõ: Åíäïèçëßíç, ÊáñäéáããåéáêÜ íïóÞìáôá, Ïîåßäéï ôïõ áæþôïõ, Óáê÷áñþäçò äéáâÞôçò, ÓôõôéêÞ
äõóëåéôïõñãßá, ÕðÝñôáóç, Õðåñ÷ïëçóôåñïëáéìßá
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