Last update:
   16-Jul-2000
 

Arch Hellen Med, 16(5), September-October 1999, 457-463

BRIEF REVIEW

Erectile dysfunction and cardiovascular disease

M.A. KHAN,1 M.E. SULLIVAN,1 C.S. THOMPSON,2
M.R. DASHWOOD,2 R.J. MORGAN,1 D.P. MIKHAILIDIS1
1Department of Urology, 2Department of Molecular Pathology & Clinical Biochemistry,
Royal Free and University College Medical School & The Royal Free Hampstead NHS Trust, London, UK

Key words: Cardiovascular risk factors, Diabetes mellitus, Endothelin, Erectile dysfunction, Hypercholesterolemia,
Hypertension, Nitric oxide

Introduction

Although erectile dysfunction (ED) is not life threatening, this common problem can significantly affect the quality of life and psychological well being.1 The Massachusetts Male Aging study, on 1,290 men aged 40–70 years, showed that 52% of men reported some degree of ED (17.1% mild, 25.2% moderate, 9.6% total).2 ED becomes more common with advancing age and since the proportion of the older population is increasing, the prevalence of ED should also rise.3 Data extrapolated from the USA in the 1940s estimates that currently around 7 to 10 million men in that country have ED.4 Because ED is a sensitive issue it is likely that its prevalence is under-reported4 but despite this, ED results in more than 400,000 outpatient visits and 30,000 hospital admissions in the USA per year.5 Epidemiological studies carried out in Europe have demonstrated that 39% of men aged 18–70 years in France have some degree of ED and 11% have total ED6 and in the UK, an estimated 17–19% of men are thought to suffer from ED.7

Nitric oxide and penile erectile physiology

Penile erection is a hemodynamic process, involving increased arterial inflow and restricted venous outflow, coordinated by corpus cavernosum smooth muscle relaxation.8 Although this process is generally accepted to be under neuroregulatory control,8–20 biochemical media tors released locally from the endothelium and/or smooth muscle also participate in initiating and maintaining erection.21–23 Nitric oxide (NO), which is produced both in cavernosal nerves and endothelium, has recently been recognized to play a key role in the physio logy of penile erection.8–23

In this brief review we consider the evidence showing that men with ischemic heart disease (IHD) have a high prevalence of ED. We also consider that this association may be related to the fact that the same risk factors (e.g. hypertension, dyslipidemia, smoking and diabetes) predict both erectile dysfunction and vascular disease.

The association between ED and IHD raises the important question of whether vasculogenic ED is yet another manifestation of atherosclerosis. Impaired NO activity may provide a unifying explanation for such an association. There is convincing evidence that during erection the local release of NO and/or related factors produces relaxation of the corpus cavernosum.8–23 Nonadrenergic, noncholinergic (NANC) nerve-mediated NO release appears to be the most important factor with respect to cavernosal smooth muscle relaxation.9–20 However, the erectile process may, at least in part, be acetylcholine (Ach)-mediated in the human and rabbit corpus cavernosum.21–23

To date, most of studies support the concept that NO derived from the autonomic innervation of the penis ope rates locally as a post-ganglionic neurotransmitter of NANC-mediated penile erection.8–20,24–32 Following its synthesis and release from nerve terminals, NO activates guanylate cyclase in vascular and trabecular smooth muscle.22 The increased intracellular accumulation of cyclic guanosine monophosphate (cGMP) is then believed to cause corporeal smooth muscle relaxation via a chemical cascade.26 Cyclic nucleotide phosphodiesterase enzymes (PDEs) present in the corpus cavernosum regulate the activity of cGMP.27,28 Experimental studies have shown that PDE III and V isoenzymes both play an important role in cavernosal smooth muscle tone.27,28 The inhibition of PDE V activity forms the basis of treating ED with sildenafil (ViagraTM).27,28

Molecular mechanisms and the risk factors for ED

1. Diabetes mellitus (DM). DM represents one of the major organic causes of ED. As many as 50% of men with DM suffer from ED.33 It is also well established that DM is associated with an increased incidence of vascular events.32 A link between the pathogenesis of ED and decreased local NO activity was suggested because in isolated corpus cavernosum strips from diabetic patients with ED, both neurogenic and endothelium-dependent relaxations were impaired.34 Similar findings were also apparent in rabbits with alloxan-induced DM.35 Reduced relaxation to electrical field stimulation in cavernosal tissue taken from diabetic patients with ED has also been demonstrated.36 This was associated with a lack of NO production (measured as the formation of nitrite) and not with the inability of the smooth muscle to relax.36 Further insight into the mechanisms involved was provided by studies which showed a significant increase in NO synthase (NOS) binding sites (putative receptors) in rat cavernosum two months post-induction of DM.37 This finding suggests that an impairment in NO bioavaila bility, either due to a lack of the substrate L-arginine, due to NO quenching [e.g. by advanced glycosylation end-products (AGEs)]38 or via inactivation by superoxi de, plays a role in the pathogenesis of ED associated with DM.

Another link between ED and DM is the finding of raised circulating levels of endothelin-1 (ET-1),39–41 a peptide belonging to a family of potent vasoconstrictors. To date, two major ET receptors have been identified and cloned: ETA and ETB.42 ET-1 is considered a physio logical antagonist of NO.43,44 Several studies have indicated the potential importance of ET-1 in the modulation of corpus cavernosum smooth muscle tone.39,45,46 Other studies have suggested that ET-1 may play a role in the development of MD.47 Moreover, the plasma levels of ET-1 are higher in diabetics with ED than in diabetics without ED.47

Animal and human corpus cavernosum produces a range of eicosanoids including prostaglandins (PGs) PGF2á, PGE2, PGI2 and TXA2.48–51 Muscarinic (but not adrenergic) stimulation of both animal and human penile tissue results in the release of PGI2.49,50 Since PGI2 is a vasodilator, it has been proposed that the release of this eicosanoid may be involved in the vasodilatory phenomenon associated with erection.53 As a potent inhibitor of platelet adhesion and aggregation, the acute release of PGI2 may also protect the penis from thrombosis during engorgement.53 DM is associated with abnormal PG synthesis.54–56 Streptozotocin-induced DM in the rat results in a marked inhibition of PGI2 synthesis by both penile and vascular tissues.57 Similarly, as we recently demonstrated in alloxan-induced diabetic rabbits there is impairment of cavernosal PGI2 formation.58 These effects relate to the duration rather than the severi ty of DM, thus mirroring the human situation.59 The reduced PGI2 synthesis reverts to normal following long-term administration of insulin.57 A reduction in PGE1 receptors has recently been reported in penile tissue obtained from diabetic men.60

2. Hypercholesterolemia. Hypercholesterolemia is a recognized risk factor for both vasculogenic ED61,62 and IHD. Studies using a genetic rabbit model of hypercho lesterolemia suggest that this lipid abnormality may account for ED because of changes in penile ET receptor distribution. These changes may, in turn, influence NOS-dependent mechanisms.63 Experiments using cholesterol-fed rabbits have demonstrated that inhibition of NO synthesis promotes the development of atheroma-like lesions, whereas supplementation with L-arginine prevents these changes.64

It has been demonstrated that high-density lipoprotein (HDL) decreases the risk of both ED and IHD,62 a further similarity between the risk factors for ED and IHD. There is also evidence that decreased cholesterol increases arterial vasodilator activity65 as well as cavernosal relaxation.7

3. Hypertension. Hypertension is also associated with both IHD and ED.61 Decreased endothelium-dependent relaxation of isolated blood vessels has been described in experimental animal models of systemic and pulmonary hypertension.66 These findings have been ascribed to either an attenuation of NO activity or augmented elaboration of an endothelium-derived contracting factor. More definitive date for a primary role of NO in the regulation of blood pressure has been shown in a mouse model with inactivation of the eNOS gene.67 This impairment of endothelial NO bioavailability could be one explanation why hypertension is a risk factor for vasculogenic ED.61

Studies have suggested that ET-1 may have a role in the development of hypertension68,69 as well as DM,47 both of which are cardiovascular risk factors that are also associated with ED.33–38,61,70 ET-1 potentiates the contractile response of vascular smooth muscle to other spa smogens.71–73 Therefore, the physiological relevance of ET-1 may be related to its ability to augment the contractile responses of other vasomodulators present in the human corpus cavernosum.

The link between hypertension and ED is illustrated by abnormal penile vascular responses, as shown by dynamic testing (e.g. using papaverine and duplex sonography).70 Hypertension acts synergistically with other vascular risk factors (e.g. DM and smoking) in terms of increasing the probability of ED.70 Hypertension-related ED could also result from the use of certain antihypertensive agents (e.g. thiazides or â-blockers). In contrast, doxazosin, a selective á1-antagonist, used in the treatment of mild hypertension, has been shown to have the lowest incidence of ED in a trial assessing the treatment of mild hypertension,74 where its effect did not dif fer significantly from that of placebo.

4. Smoking. Smoking is a risk factor for both atherogenesis and ED.59,60 Smoking precipitates a number of acute changes which can affect normal erectile function, including impaired penile blood flow.75,76 Cigarette smoking results in a transient increase in blood levels of the catecholamines, adrenaline and noradrenaline,60 effects which appear to be mediated by nicotine.77 As á-adre noreceptor activation is associated with detumescence, this release of catecholamines may compromise normal erectile function. Smoking also produces profound acute morphological alterations in the vascular endothelium and enhances platelet and leukocytes adhesion to blood vessel walls.78 Adherent platelets and leukocytes are activated to release a plethora of vasoconstrictors such as TXA2, leukotrienes and serotonin79 which could contribute further to ED.

Apart from the acute effects on the vascular system, the chronic consequence from smoking of vascular disruption leads to an increased risk of atherosclerosis.60 This in turn leads to ED through atheroma formation in the pudendal arteries and possibly from altered function of the penile corporal smooth muscle itself.

5. Aging. Increasing age correlates with altered NO synthesis and erectile responses in the rat penis.80 This could be one explanation for the increasing incidence of ED with aging in man.80

6. Radiation effects. Radiation has been shown to reduce the number of penile NOS containing nerves in the rat, possibly providing an explanation for the development of ED in men following pelvic irradiation.81

ED and IHD: Does defective NO activity contribute to the pathogenesis of both conditions?

As discussed above, numerous studies have shown that IHD and ED share common risk factors.61,62 More recently, preliminary studies suggest that fibrinogen82 and lipoprotein are risk factors for ED as well as for IHD. The long-term follow up of the Massachusetts Male Aging epidemiological study concluded that the risk of moderate or complete ED in patients with cardiovascular risk factors was 31%, higher than in an age-matched disease free control cohort in which the incidence was 19.6%.39 It may also be relevant that the risk factors for IHD and ED behave synergistically in both conditions.61

Of equal interest are studies which show that the extent of IHD is related to the risk of concomitant ED. Two studies have shown a significant correlation between the presence of vasculogenic ED and clinically evident or subclinical IHD.83,84 A significant correlation was reported between ED and the number of coronary vessels occluded on angiography83 and patients with severe arteriogenic ED (assessed by duplex sonography) were shown to have a 16% risk of suffering from severe, although asymptomatic, IHD.84

Alterations in the endothelial L-arginine-NO pathway have been demonstrated in both atherosclerotic and hypercholesterolemic coronary arteries of humans and in animal models.85–89 These studies support the concept that there is a reduction in NO bioavailability in these conditions. These findings are similar to those observed in the penile L-arginine-NO pathway and support the concept that vasculogenic changes in the penile vascular bed in ED mirror those in the coronary arteries.

The role of NANC-mediated NO release in the coronary circulation is unclear, though NANC nerves have been implicated in coronary blood flow regulation.90 It has been found that NANC-mediated NO production causes vasodilation of human cerebral arteries,91 bovine basilar arteries92 and canine superficial temporal arteries,93 supporting a regulatory role in these vascular beds.

We have recently demonstrated that in the Watanabe rabbit model there is a significant decrease in ETÂ-receptor binding sites in corpus cavernosum tissue compared with age-matched healthy controls.63 This reduction, in part, involved endothelial ETB receptors63 which have been shown in other vascular beds to mediate ET-1-induced vasorelaxation by stimulating NO formation.94–96 However, the role of the ETB receptor in the corpus cavernosum remains unclear and further studies are awaited.

Hence, it appears that normal erectile function involves a delicate balance between vasodilating and vasoconstricting factors. When this balance is disrupted, erectile dysfunction may result. ED and ischemic heart disease may not occur in the same patients by coincidence but may have common etiological factors. Consequently, medical practitioners who treat ED need to be aware of the possibility of underlying IHD and its clinical rele vance in terms of "whole patient management".

Conclusions

NO plays a major role in the physiological regulation of penile erection, eliciting effects through the activation of guanylate cyclase and the subsequent production of cGMP. Impaired NO activity appears to play an important role in the pathogenesis of ED. This impaired NO activi ty may be similar to that which occurs in other forms of vascular disease or in the presence of cardiovascular risk factors (e.g. dyslipidemia, diabetes, smoking and hypertension).

The recent development of an effective, orally active, type V PDE inhibitor, sildenafil (Viagra) provides a novel method of therapy for patients with ED. It achieves this by inhibiting the hydrolysis of cGMP, produced via the L-arginine-NO pathway.

Further research in this area is needed to determine the precise pathophysiological role of NO, endothelin and possibly other mediators in this organ. This work may also provide further insights into the pathogenesis of cardiovascular diseases in general.

REFERENCES

  1. HANSON-DIVERS C, JACKSON SE, LUE TE, CRAWFORD SY, ROSEN RC. Health outcomes variables important to patients in the treatment of erectile dysfunction. J Urol 1998, 159:1541–1547
  2. FELDMAN HA, GOLDSTEIN I, HATZICHRISTOU DG, KRANE RJ, McKINLAY JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts male ageing study. J Urol 1994, 151:54–61
  3. RUBIN A, ABBOT D. Impotence and diabetes mellitus. JAMA 1958, 168:498–512
  4. NIH CONSENSUS CONFERENCE. Impotence. NIH Consensus Development Panel on Impotence. JAMA 1993, 270:83–90
  5. SHABSIGH R, FISHMAN IJ, SCOTT F. Evaluation of erectile impotence. Urology 1988, 32:83–90
  6. VIRAG R, BECK-ARCHLLY L. Nosology, epidemiology, clinical quantification of erectile dysfunction. Rev Med Interne 1997, 1:10S– 13S
  7. READ S, KING M, WATSON J. Sexual dysfunction in primary care. Prevalence, characteristics and detection by the general practitioner. J Public Health Med 1997, 19:387–391
  8. ANDERSSON K-E, WAGNER G. Physiology of penile erection. Physiol Rev 1997, 75:191–236
  9. BUSH PA, ARONSON WJ, BUGA GM, RAJFER J, IGNARRO LJ. Nitric oxide is a potent relaxant of human and rabbit corpus cavernosum. J Urol 1992, 147:650–665
  10. BUSH PA, ARONSON WJ, RAJFER J, BUGA GM, INGARRO LJ. Comparison of nonadrenergic, noncholinergic, and nitric oxide-mediated relaxation of corpus cavernosum. Int J Impot Res 1992, 4:85–93
  11. HOLMQUIST F, HEDLUND H, ANDERSSON K-E. L-NG-nitroarginine inhibits non-adrenergic, non-cholinergic relaxation of human isolated corpus cavernosum. Acta Physiol Scand 1991, 141:441– 442
  12. HOLMQUIST F, STIEF CG, JONAS U, ANDERSSON K-E. Effects of the nitric oxide synthase inhibitor NG-nitro-L-arginine on the erectile response to cavernous nerve stimulation in the rabbit. Acta Physiol Scand 1991, 143:299–304
  13. HOLMQUIST F, HEDLUND H, ANDERSSON K-E. Characterization of inhibitory neurotransmission in the isolated corpus cavernosum from rabbit and man. J Physiol 1992, 449:295–311
  14. HOLMQUIST F, FRIDSTRAND M, HEDLUND H, ANDERSSON K-E. Actions of 3-morpholinosydnonimin (SIN-1) on rabbit isolated penile erectile tissue. J Urol 1993, 150:1310–1315
  15. IGNARRO LJ, BUSH PA, BUGA GM, WOOD KS, FUKUTO JM, RAJFER J. Nitric oxide and cyclic GMP formation upon electrical field stimu lation cause relaxation of corpus cavernosum smooth muscle. Biochem Biophys Res Commun 1990, 170:843–850
  16. KIM JH, AZADZOI KM, GOLDSTEIN I, SAENZ DE TEJADA I. A nitric oxide-like factor mediates nonadrenergic, noncholinergic neurogenic relaxation of penile corpus cavernosum smooth muscle. J Clin Invest 1991, 88:112–118
  17. KNISPEL HH, GOESSL C, BECKMANN R. Nitric oxide mediates neurogenic relaxation induced in rabbit cavernous smooth muscle by electrical field stimulation. Urology 1992, 40:471–476
  18. PICKARD RS, POWELL PH, ZAR MA. The effect of inhibitors of nitric oxide biosynthesis and cyclic GMP formation on nerve-evoked relaxation of human cavernosal smooth muscle. Br J Pharmacol 1991, 104:755–759
  19. PICHARD RS, POWELL PH, ZAR MA. Nitric oxide and cyclic GMP formation following relaxant nerve stimulation in isolated human corpus cavernosum. Br J Urol 1995, 75:516–522
  20. RAJFER J, ARONSON WJ, BUSH PA, DOREY FJ, IGNARRO LJ. Nitric oxide as a mediator of relaxation of the corpus cavernosum on response to nonadrenergic, noncholinergic neurotransmission. N Engl J Med 1992, 326:90–94
  21. KNISPEL HH, GOESSL C, BECKMAN R. Basal and acetylcholine-stimu lated nitric oxide formation mediates relaxation of rabbit cavernous smooth muscle. J Urol 1991, 146:1429–1433
  22. KNISPEL HH, GOESSL C, BECKMAN R. Nitric oxide mediates relaxation in rabbit and human corpus cavernosum smooth muscle. Urol Res 1992, 20:253–257
  23. BURNETT AL, LOWENSTEIN CJ, BREDT DS, CHANG TSK, SNYDER SH. Nitric oxide: a physiologic mediator of penile erection. Science 1992, 257:401–403
  24. BUSH PA, GONZALEZ NE, IGNARRO LJ. Biosynthesis of nitric oxide and citrulline from L-arginine by constitutive nitric oxide synthase present in rabbit corpus cavernosum. Biochem Biophys Res Commun 1992, 186:308–314
  25. FEELISCH M. The biochemical pathways of nitric oxide formation form nitrovasodilators: appropriate choice of exogenous NO donors and aspects of preparation and handling of aqueous NO solutions. J Cardiovasc Pharmacol 1991, 17(Suppl 3):S25
  26. MARTINEZ-PINEIRO L, TRIGO-ROCHA LF, HSU GL, VON-HEYDEN B, LUY TF, TANAGHO EA. Cyclic guanosine monophosphate mediates penile erection in the rat. Urol Res 1993, 24:492–499
  27. BOOLELL M, ALLEN MJ, BALLARD SA, GEPI-ATTEE S, MUTRHEAD GJ, NAYLOR AM ET AL. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 1996, 8:47–52
  28. STIEF CG, UCKERT S, BECKER AJ, TRUSS MC, JONAS U. The effect of specific phosphodiesterase (PDE) inhibitors on human and rabbit cavernous tissue in vitro and in vivo. J Urol 1998, 159:1390– 1393
  29. SCHMIDT PS, GUPTA S, DALEY J, SAENZ DE TEJADA I. Mechanisms of nitric oxide-induced relaxation of rabbit corpus cavernosum smooth muscle. J Urol 1995, 153:442A
  30. GUPTA S, MORELAND RB, SCHMIDT PS, DALEY J, GOLDSTEIN I, SAENZ DE TEJADA I. Nitric oxide, Na+-K+-ATPase and human corpus cavernosum smooth muscle contractility. J Urol 1995, 153:42A
  31. SEFTEL AD, VIOLA KA, KASNER SE, GANZ MB. Nitric oxide relaxes rabbit corpus cavernosum smooth muscle via a potassium-conductive pathway. Biochem Biophys Res Commun 1996, 219: 382–387
  32. SULLIVAN ME, THOMPSON CS, DASHWOOD MR, KHAN MA, JEREMY JY, MORGAN RJ ET AL. Nitric oxide and penile erection: Is erectile dysfunction another manifestation of vascular disease? Cardiovasc Res 1999 (in press)
  33. McCULLOCH DK, CAMPBELL IW, FU FC, PRESCOTT RJ, CLARKE BF. The prevalence of diabetic impotence. Diabetologia 1980, 18:279– 283
  34. SAENZ DE TEJADA I, GOLDSTEIN I, AZADZOI KM, KRANE RJ, COHEN RA. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med 1989, 320:1025–1030
  35. AZADZOI KM, SAENZ DE TEJADA I. Diabetes mellitus impairs neurogenic and endothelium-mediated relaxation of rabbit corpus caver nosum smooth muscle. J Urol 1992, 148:1587–1591
  36. PICKARD RS, KING P, ZAR MA, POWELL PH. Corpus cavernosal relaxation in impotent men. Br J Urol 1994, 74:485–491
  37. SULLIVAN ME, BELL CRW, DASHWOOD MR, MILLER MA, THOMPSON CS, MIKHAILIDIS DP ET AL. Autoradiographic localisation of nitric oxide synthase binding sites in normal and diabetics rat corpus cavernosum. Eur Urol 1996, 30:506–511
  38. HOFFMAN D, SEFTEL AD, HAMPEL N, RESNICK MI. Advanced glycation end-products quench cavernosal nitric oxide. J Urol 1995, 153: 441A
  39. KHAN MA, THOMPSON CS, SULLIVAN ME, DASHWOOD MR, MORGAN RJ, MIKHAILIDIS DP. Endothelin and erectile dysfunction: a target for pharmacological intervention? Expert Opin Invest Drugs 1998, 7:1759–1767
  40. JAGROOP IA, BERWANGER C, STANSBY G, MIKHAILIDIS DP. Plasma endothelin-1 concentrations in non-insulin dependent diabetes mellitus and non-diabetic patients with chronic arterial obstructive disease of the lower limbs. Int Angiol 1999 (in press)
  41. LERMAN A, EDWARDS BS, HALLETT JW, HUBLEIN DM, SANDBERG SM, BURNETT JC. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med 1991, 325:997– 1001
  42. MASAKI T, KIMURA S, YANAGISAWA M, GOTO K. Molecular and cellular mechanism of endothelial regulation: implications for vascular function. Circulation 1991, 84:1457–1468
  43. VANHOUTTE PM, RUBANYI GM, MILLER VM, HOUSTON DS. Modulation of vascular smooth muscle contraction by the endothelium. Annu Rev Physiol 1986, 48:307–320
  44. TAYLOR SG, WESTON AH. Endothelium-derived hyperpolarizing factor: a new endogenous inhibitor from the vascular endothelium. Trends Pharmacol Sci 1988, 9:272–274
  45. SAENZ DE TEJADA I, CARSON MP, GOLDSTEIN I, TRAISH AM. Endothelin: localization, synthesis, activity and receptor types in human penile corpus cavernosum. Am J Physiol 1991, 261:H1078– H1085
  46. CHRIST GJ, LERNER SE, KIM DC, MELMAN A. Endothelin as a putative modulator of erectile physiology and dysfunction. I. Characteristics of ET-1-induced contractions in isolated corporal smooth muscle strips. J Urol 1995, 153:1998–2003
  47. FRANCAVILLA S, PROPERZI G, BELLINI C, MARINO G, FERRI C, SANTUCCI A. Endothelin-1 in diabetic and nondiabetic men with erectile dysfunction. J Urol 1997, 158:1770–1774
  48. ROY AC, TANN SM, KOTTEGODA SR, RATNAM SS. Ability of the human corpora cavernosa muscle to generate prostaglandins and thromboxanes in vitro. IRCS J Med Sci 1984, 12:608–609
  49. JEREMY JY, MORGAN RJ, MIKHAILIDIS DP, DANDONA P. Prostacyclin synthesis by the corpora cavernosa of the human penis: evidence for muscarinic control and pathological implications. Prostagl Leukotr Essentl Fatty Acids 1986, 23:211–216
  50. JEREMY JY, MORGAN RJ, MIKHAILIDIS DP, DANDONA P. Muscarinic stimulation of prostacyclin synthesis by the rat penis. Eur J Pharmacol 1986, 123:67–71
  51. SAENZ DE TAJEDA I, GOLDSTEIN I, KRANE RJ. Local control of penile erection. Nerves smooth muscle and endothelium. Urol Clin North Am 1988, 15:9–15
  52. JEREMY JY, MIKHAILIDIS DP. Prostaglandins and the etiology and treatment of erectile dysfunction. In: Ledda A (ed) Vascular Andrology. Springer-Verlag, Berlin, 1996:1–47
  53. JEREMY JY. Smoking and vascular defense mechanisms. J Smok Rel Disord 1994, 5:49–54
  54. MIKHAILIDIS DP, JEREMY JY, DANDONA P. The role of prostaglandins, leukotrienes and essential fatty acids in the pathogenesis of the complications associated with diabetes mellitus. Prostagl Leukotr Essentl Fatty Acids 1988, 33:205–206
  55. HENDRA T, BETTERIDGE DJ. Platelet function, platelet prostanoids and vascular prostacyclin synthesis in diabetes mellitus. Prostagl Leukotr Essentl Fatty Acids 1988, 35:197–212
  56. HORROBIN DF. The role of fatty acids in the development of diabetic neuropathy and other complications of diabetes mellitus. Prostagl Leukotr Essentl Fatty Acids 1994, 31:181–197
  57. JEREMY JY, MIKHAILIDIS DP, THOMPSON CS, DANDONA P. Experimental diabetes mellitus inhibits prostacyclin synthesis by the rat penis: pathological implications. Diabetologia 1985, 28:365–368
  58. SULLIVAN ME, THOMPSON CS, MIKHAILIDIS DP, MORGAN RJ, ANGELINI DG, JEREMY JY. Differential alterations of prostacyclin, cyclic AMP and cyclic GMP formation in the corpus cavernosum of the dia betic rabbit. Br J Urol 1998, 82:578–584
  59. KRANE RJ, GOLDSTEIN I, DE TEJADA IS. Impotence. N Engl J Med 1990, 321:1648–1659
  60. JEREMY JY, MIKHAILIDIS DP. Cigarette smoking and erectile dysfunction. J Roy Soc Health 1998, 118:151–155
  61. FELDMAN HA, McKINLAY JB, GOLDSTEIN I, LONGCOPE C. Erectile dysfunction, cardiovascular disease and cardiovascular risk factors: prospective results in a large random sample of Massachusetts men. J Urol 1998, 159:91
  62. WEI M. Total cholesterol and high density lipoprotein cholesterol as important predictors of erectile dysfunction. Am J Epidemiol 1994, 140:930–937
  63. SULLIVAN ME, DASHWOOD MR, THOMPSON CS, MIKHAILIDIS DP, MORGAN RJ. Decreased endothelin B receptor binding sites on corpus cavernosa of hypercholesterolaemic rabbits. Br J Urol 1998, 1:128–134
  64. GIRERD XJ, HIRSCH AT, COOKE JP, DZAU VJ, CREAGER MA. L-arginine augments endothelium-dependent vasodilation in cholesterol-fed rabbits. Circ Res 1990, 67:1301–1308
  65. SIMONS LA, SULLIVAN D, SIMONS J, CELERMAJER DS. Effects of atorvastatin monotherapy and simvastatin plus cholestyramine on arterial endothelia function in patients with severe primary hypercholesterolaemia. Atherosclerosis 1998, 137:197–203
  66. CALVER A, COLLIER J, VALLANCE P. Nitric oxide and cardiovascular control. Exp Physiol 1993, 78:303–326
  67. HUANG PL, HYANG Z, MASHIMO H. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 1995, 377: 239–242
  68. RANDALL MD. Vascular activities of endothelins. Pharmacol Ther 1991, 50:73–93
  69. TABUSHI Y, NAKAMARU M, RAKUGI H, NAGANO M, HIGASHIMORI K, MIKAMI H ET AL. Effect of endothelin on neuroeffector junction in mesenteric arteries of hypertensive rat. Hypertension 1990, 15:739–743
  70. VIRAG R, BOUILLY P, FRYDMAN D. Is impotence an arterial disorder? A study of arterial risk factors in 440 impotent men. Lancet 1985, i:181–184
  71. YANG ZH, RICHARD V, VON SEGESSER L, BAUER E, STULZ P, TURINA M ET AL. Threshold concentrations of endothelin-1 potentiate contractions to norepinephrine and serotonin in human arteries. Circulation 1990, 82:188–195
  72. ITOH H, HIRAOKA N, HIGUCHI H, ITO M, KONISHI T, NAKANO T. Contractile actions of endothelin-1 in isolated helical strips from rat pulmonary artery: potentiation of serotonin-induced contraction. J Cardiovasc Pharmacol 1992, 20:1–6
  73. HENRION D, LAHER I. Potentiation of norepinephrine-induced contraction by endothelin-1 in the rabbit aorta. Hypertension 1993, 22:78–83
  74. GRIMM RH, GRANDITS GA, PRINEAS RJ, McDONALD RH, LEWIS CE, FLACK JM ET AL. Long-term effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hyper tensive men and women. Treatment of mild hypertensive study (TOMHS). Hypertension 1997, 29:8–14
  75. GLINA R, REICHELT AC, LEAO PP, DOSREIS JM. Impact of cigarette smoking on papaverine induced erections. J Urol 1988, 140: 523–524
  76. LEVINE LA, GERGER GS. Acute vasospasm of penile arteries in response to cigarette smoking. Urology 1990, 36:99–100
  77. BENOWITZ NL, KUYT F, JACOB P. Influence of nicotine on cardiovascular and hormonal effects of cigarette smoking. Clin Pharmacol Ther 1984, 36:74–81
  78. PITTILO RM, WOOLF N. Cigarette smoking, endothelial cell injury and atherosclerosis. J Smok Rel Disord 1993, 4:17–25
  79. JEREMY JY, MEHTA D, BRYAN AJ, LEWIS D, ANGELINI GD. Platelets and saphenous vein graft failure following coronary artery bypass graft surgery. Platelets 1997, 8:295–309
  80. GARBAN H, VERNET D, FREEDMAN A, RAJFER J, GONZALEZ-CADAVID NF. Effect of aging on nitric oxide-mediated penile erection in rats. Am J Physiol 1995, 268:H467–H475
  81. CARRIER S, HRICAK H, LEE S, BABA K, MORGAN DM, NUNEL L ET AL. Radiation-induced decrease in nitric oxide synthase-containing ner ves in the rat penis. Radiology 1995, 195:95–99
  82. SULLIVAN M, MILLER M, BELL R, JEREMY JY, THOMPSON CS, MIKHAILIDIS DP ET AL. The effects of cigarette smoking on vascular risk factors in patients with erectile dysfunction. Eur Urol 1996, 30(Suppl 2):250
  83. GREENSTEIN A, CHEN J, MATZKIN H, VILLA Y, BRAF Z. Does severity of ischaemic coronary disease correlate with erectile function? Int J Impot Res 1997, 9:123–126
  84. ANDERSON M, NICHOLSON B, LOUIE E, MULHALL JP. An analysis of vasculogenic erectile dysfunction as a potential predictor of occult cardiac disease. J Urol 1998, 159:30
  85. BOSSALLER C, HABIB GB, YAMAMOTO H, WILLIAMS C, WELL S, HENRY PD. Impaired muscarinic endothelium-dependent relaxation and cy clic guanosine-5-monophosphate formation in atherosclerotic human coronary artery and rabbit aorta. J Clin Invest 1987, 79:170–182
  86. CHESTER AH, O'NEIL GS, MONCADA S, TADJKARIMI S, YACOUB MH. Low basal and stimulated release of nitric oxide in atherosclerotic epicardial coronary arteries. Lancet 1990, 336:897–900
  87. NABEL EG, SELWYN AP, GANZ P. Large coronary arteries in humans are responsive to changing blood flow: An endothelium-dependent mechanism that fails in patients with atherosclerosis. J Am Coll Cardiol 1990, 16:349–356
  88. TANNER FC, NOLL G, BOULANGER CM, LUSCHER TF. Oxidised low-density lipoproteins inhibit relaxants of porcine coronary arteries: Role of scavenger receptor and endothelium-derived nitric oxide. Circulation 1991, 83:2012–2020
  89. EGASHIRA K, INOU T, HIROOKA Y, YAMADA A, MARUOKA Y, KAI H ET AL. Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. J Clin Invest 1993, 91:29–37
  90. YAOITA H, SATO E, KAWAGUCHI M, SAITO T, MAEHARA K, MARUYAMA Y. Nonadrenergic noncholinergic nerves regulate coronary flow via capsaicin-sensitive neuropeptides in the rat heart. Circ Res 1994, 75:780–788
  91. TODA N. Mediation by nitric oxide of neurally induced human cerebral artery relaxation. Experientia Basel 1993, 49:51–53
  92. AYAJIKL K, OKAMURA T, TODA N. Nitric oxide mediates and acetylcholine modulates neurally-induced relaxation of bovine cerebral arteries. Neuroscience 1993, 541:819–825
  93. TODA N, OKAMURA T. Reciprocal regulation by putatively nitroxidergic and adrenergic nerves of monkey and dog temporal arterial tone. Am J Physiol 1992, 261:H1740–H1745
  94. BATRA VK, McNEILL JR, XU Y, WILSON TW, GORALAKRISHMAN V. ET-B receptors on aortic smooth muscle cells of spontaneously hypertensive rats. Am Phys Soc 1993, 264:C479–C484
  95. DURHAM SK, GOLLER NL, LYNCH JS, FISHER SM, ROSE PM. Endothelin receptor B expression in the rat and rabbit lung as determined by in situ hybridization using nonisotopic probes. J Cardiovasc Pharmacol 1993, 22:S1–S3
  96. MASAKI T, VANE JR, VANHOUTTE PM. International Union of Pharmacology Nomenclature of endothelin receptors. Pharmacol Rev 1994, 46:137–142

 

© 2000, Archives of Hellenic Medicine