Penile erection and cardiac risk: pathophysiologic and pharmacologic mechanisms

Penile Erection and Cardiac Risk: Pathophysiologic and Pharmacologic Mechanisms Karl-Erik Andersson,

MD, PhD,

and Christian Stief,

MD, PhD

Erection is initiated through the parasympathetic nervous system, activation of which overrides the sympathetic tone that maintains the penis in a nonerectile (flaccid) state. This state is maintained mainly through the release of norepinephrine from penile adrenergic nerves. Norepinephrine contracts the vasculature and cavernosal smooth muscle. Arousal/erection is associated with a decrease of norepinephrine release in the penis, with a release of nitric oxide, and with a reduction in penile smooth muscle tone. It is also associated with minor cardiovascular changes. Heart rate increases by 4 – 8 beats per minute, on average, and the rate–pressure product and oxygen consumption increase by approximately 25%. There may be no changes in systemic venous norepinephrine concentrations; systemic venous epinephrine concentrations increase by about 60%. Drugs initiating or enhancing erection act by inhibiting

norepinephrine-induced contraction (e.g., phentolamine) or by enhancing or directly inducing relaxation of the corpora cavernosa and the penile vasculature (e.g., sildenafil). Despite potentially negative hemodynamic actions when given parenterally, oral phentolamine—in doses required for enhancing erection—appears to produce few cardiovascular adverse effects. The hemodynamic effects of sildenafil are small, even in patients with coronary artery disease. However, the effects of the drug on human myocardium have not been conclusively established, and should be further investigated. As judged by available information, the cardiac risk associated with erection, with or without enhancement of drugs currently used for treatment of erectile dysfunction, is low. 䊚2000 by Excerpta Medica, Inc. Am J Cardiol 2000;86(suppl):23F–26F

vents and factors that may link sexual activity to cardiac risk include arousal/erection, physical acE tivity, drug effects, and underlying cardiac disease.

the adrenergic innervation, but also to release relaxant factors (e.g., nitric oxide [NO]) from nerves or endothelium to fill the corporeal sinusoids and to compress the venous outflow of the corpora. Stimulation of the cholinergic nerves in the penis causes relaxation of the corpora cavernosa and the vasculature by release of acetylcholine, which suppresses noradrenergic neurotransmission and induces release of NO from the endothelium. However, the cholinergic nerves contain NO synthase (NOS) and can also release NO, and possibly, vasoactive intestinal polypeptide and other relaxant peptides.3 Central in these processes is NO, released from nerves and/or the endothelium, which stimulates adenylate cyclase and increases the intracellular concentration of cyclic guanosine monophosphate.1,4 Even if increased parasympathetic activity may be expected to decrease heart rate, the events associated with erection stimulate the cardiovascular system. It has been shown by, among others, Bohlen et al5 that foreplay increases heart rate by 4 – 8 beats per minute, and increases the rate–pressure product and oxygen consumption by approximately 25% from basal values. Becker et al6 measured, in healthy volunteers, the concentrations of norepinephrine and epinephrine in peripheral venous and corporal blood during the different phases of erection: flaccidity, tumescence, rigidity, and detumescence. Penile erections were induced by audiovisual and tactile stimulation, and the plasma concentrations of norepinephrine and epinephrine were determined by means of radioimmunoassay. As expected, the norepinephrine concentration in corpora cavernosa plasma during flaccidity (362 ⫾ 173

The possible cardiac risks of arousal/erection, and the possibility that such risks are increased when erection is initiated or enhanced by drugs, have received increased attention with the introduction of new, orally active drugs for treatment of erectile dysfunction. Erection is initiated through the parasympathetic nervous system, whose activity overrides the sympathetic tone that maintains the penis in the flaccid state.1 It is known that both the autonomic and somatic nuclei in the spinal cord receive noradrenergic innervation. The sympathetic pathways to the periphery originate in the intermediolateral gray matter of the spinal cord, and reach the penis via several relay stations, including the sympathetic chain ganglia. These pathways also supply the heart and the vascular system. In the penis, both the smooth muscle of the corpora cavernosa and the penile vasculature receive a rich noradrenergic innervation, which is particularly dense around the helicinal vessels regulating flow to the lacunar spaces.2 To initiate an erection, it is necessary not only to reduce the contractile influences of From the Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden (K-EA); and Department of Urology, Hannover Medical School, Hannover, Germany (CS). This work was supported by grants from the Swedish Medical Research Council (grant no. 6837), and the Medical Faculty, University of Lund. Address for reprints: Karl-Erik Andersson, MD, PhD, Department of Clinical Pharmacology, Lund University Hospital, S-221 85 Lund, Sweden. ©2000 by Excerpta Medica, Inc. All rights reserved.

0002-9149/00/$ – see front matter PII S0002-9149(00)00887-0

23F

pg/mL) decreased significantly (p ⬍0.001) during tumescence and rigidity (to 248 ⫾ 122 pg/mL), and returned to baseline values (336 ⫾ 199 pg/mL) during detumescence. However, there were no changes in the norepinephrine concentration in peripheral venous blood, and during all phases, there were no significant changes in heart rate. There was a slight but significant (p ⬍0.001) increase in systemic plasma epinephrine concentration (flaccidity 69 ⫾ 55 pg/mL; tumescence 98 ⫾ 78 pg/mL), which was also found in the corpora cavernosa (flaccidity 47 ⫾ 41 pg/mL; tumescence 130 ⫾ 106 pg/mL). Taken together, these results suggest that arousal/erection per se causes little stress on the cardiovascular system. Do the recently introduced oral drugs for enhancing penile erection, phentolamine and sildenafil, increase this stress? Phentolamine, which selectively blocks nonsubtype ␣1- and ␣2-adrenoceptors, and sildenafil, which, by inhibiting phosphodiesterase 5 (PDE5) increases the intracellular concentration of cyclic guanosine monophosphate, represent different treatment principles7— on the one hand, the decrease in the effect of a contractile factor (norepinephrine), and on the other, the increase in the effect of a relaxant factor (NO). It should be noted that these drugs do not initiate erection—they are enhancers of the erectile responses initiated through normal mechanisms. Are they also enhancers of cardiovascular risk? When released, norepinephrine contracts the human corpora cavernosa by actions on postjunctional ␣1- and ␣2-adrenoceptors. This has been shown repeatedly by several investigators using different agents selective for ␣1- and ␣2-adrenoceptors.1 It is generally believed that ␣1-adrenoceptors are the most important for corpora cavernosa contraction. In the peripheral vasculature also, both ␣1- and ␣2-adrenoceptors can contribute to contractions, but it seems that ␣2-adrenoceptors may have a more important role in the vessels than in the corpora cavernosa. ␣1A-, ␣1B- and ␣1D-adrenoceptors have all been demonstrated in corporal smooth muscles,8,9 and functionally also the ␣1A/L-adrenoceptor.10 Which receptor subtype is the more important for contraction is unclear, although the ␣1A- and/or the ␣1A/L-adrenoceptor seem to be predominant. Among the ␣2-adrenoceptors, ␣2A␣2B-, and ␣2C-adrenoceptors have all been identified,11 and it was recently proposed that ␣2A-adrenoceptor predominates in the human corpora cavernosa.12 A significant recent observation was made by Simonsen et al.13 They suggested that norepinephrine stimulation of prejunctional ␣2-adrenoceptors may contribute to detumescence and flaccidity by inhibiting the release of NO. Because NOS is contained in cholinergic nerves, this would imply that these ␣2adrenoceptors are also located on cholinergic nerves. In the peripheral vascular system, both ␣1- and ␣2-adrenoceptors can contribute to vasoconstriction, and all the subtypes found in the corpora cavernosa have also been found in different vascular regions.14 In the human heart, ␣1A- and ␣1B-adrenoceptor subtypes can be found in the myocardium, both enhancing myocardial contractility.15 Both adrenoceptors 24F THE AMERICAN JOURNAL OF CARDIOLOGY姞

TABLE I Adverse Hemodynamic Effects of Oral Phentolamine (n ⬇700) Adverse Effect (%) Hypotension Tachycardia Hypertension

Phentolamine 40 mg

80 mg

Placebo

0.2 1.5 0

2.0 7.0 2.0

0 0.6 0.2

Adapted from Textbook of Erectile Dysfunction.21

(␣1, ␣2) are found in the coronary circulation mediating vasoconstriction.16 Phentolamine induces penile erection by blocking both ␣1- and ␣2-adrenoceptors, but seems also to have another action, possibly involving NO synthase activation.17 It is then unavoidable that phentolamine affects ␣-adrenoceptors of all types in the penis as well as in other parts of the body. According to textbooks,18 phentolamine use is associated with a considerable cardiac risk, producing hypotension, tachycardia, cardiac arrhythmia, and ischemic cardiac events. However, these actions refer to intravenous use of the drug. Oral phentolamine, in doses up to 150 mg seems to have moderate, beneficial hemodynamic short-term effects in patients with congestive heart failure.19,20 In the doses needed for enhancing erectile responses (20 – 40 mg), few adverse cardiovascular effects have been observed (Table I).21 Relaxation of the corpora cavernosa can be obtained by either increasing the formation of cyclic guanosine monophosphate and/or cyclic adenosine monophosphate, or by inhibiting their degradation. The cyclic nucleotides, cyclic adenosine monophosphate and cyclic guanosine monophosphate are synthesized from the corresponding nucleotide triphosphates by their respective membrane-bound or soluble adenylate or guanylate cyclases. Cyclic adenosine monophosphate and cyclic guanosine monophosphate are inactivated by PDEs via hydrolytic cleavage of the 3⬘-ribose phosphate bond. Presently, ⬎9 different families of PDE are known, which differ in their specificity for cyclic adenosine monophosphate and cyclic guanosine monophosphate, cofactor requirements, and kinetic properties.22–24 Each family can again be divided into subfamilies. Because of their central role in smooth muscle tone regulation, and the considerable variation of PDE isoenzymes with respect to species and tissues, PDEs have become an attractive target for drug development. PDE2, PDE3, PDE4, PDE5, and several other PDE isoforms have been identified in human cavernous tissue.25–30 Functionally, PDEs 3 and 5 seem to be the most important.28,31 PDE5 and PDE3 have been shown to be coexpressed in several tissues beside the penis. In line with this, Stief et al31 found that milrinone, selectively inhibiting PDE3, and sildenafil, selectively inhibiting PDE5,32,33 were equieffective and equipotent in relaxing norepinephrine-contracted human corpora cavernosa. The distribution of PDE5 activity is not restricted

VOL. 86 (2A)

JULY 20, 2000

FIGURE 1. Concentration of cyclic guanosine monophosphate (cGMP) in isolated human cardiac auricle in the presence of the phosphodiesterase (PDE)5 inhibitor, sildenafil, or the PDE3 inhibitor, milrinone (0.01, 0.05, 0.1, and 1 ␮mol/L). Each concentration was assayed using 6 strips. *p ⴝ 0.05– 0.01.

FIGURE 2. Concentration of cyclic adenosine monophosphate (cAMP) in isolated human cardiac auricle in the presence of the phosphodiesterase (PDE)5 inhibitor, sildenafil, or the PDE3 inhibitor, milrinone (0.01, 0.05, 0.1, and 1 ␮mol/L). Each concentration was assayed using 6 strips. *p ⴝ 0.05– 0.01, ns ⴝ not significant.

to the human corpora cavernosa, but the enzyme can be found in, for example, platelets, arteries, and veins.34,35 Wallis et al34 were unable to demonstrate PDE5 activity in the human myocardium, where they found PDE1 to be predominant. Others have demonstrated PDE3 in human myocardium.36 The possible absence of PDE5 in human myocardium needs further confirmation (see below). The identification of PDE families has been paralleled by the synthesis of selective or partially selective inhibitors. As mentioned above, sildenafil is a highly selective inhibitor of PDE5.32,33 It enhances NO-mediated relaxation of rabbit and human corpus cavernosum in vitro28,29,31,37 and dose dependently increases the intracavernous pressure in anesthetized dogs.38 Sildenafil increases the intracellular concentrations of cyclic guanosine monophosphate in rabbit corpora cavernosa,37,39 but can also significantly increase the cyclic adenosine monophosphate concen¨ ckert et al40 trations in human corpora cavernosa.40 U found that in the concentration of 0.01–1 ␮mol/L, sildenafil had a minor effect on cyclic guanosine monophosphate levels in isolated human cavernous and cardiac tissues. In contrast, sildenafil was found to increase cyclic adenosine monophosphate significantly in both cavernous and cardiac tissue. The stimulation of cyclic adenosine monophosphate generation by sildenafil was more pronounced in cavernous than in cardiac tissue. In the cardiac strips, the concentrations of cyclic guanosine monophosphate were unaltered by milrinone (Figure 1), whereas the drug at a concentration of 0.05 ␮mol/L increased the cyclic adenosine monophosphate levels (Figure 2). In the

concentration of 0.1–1.0 ␮mol/L, sildenafil increased the cyclic adenosine monophosphate levels in the cardiac samples almost as effectively as milrinone in the same concentrations (Figure 2). The hypothesized mechanism responsible for the increase in cyclic adenosine monophosphate was suggested to be an increased concentration of cyclic guanosine monophosphate associated with inhibition of PDE5 in the myocardium by sildenafil. Because PDE3 is inhibited by cyclic guanosine monophosphate, there may be a secondary increase in the levels of cyclic adenosine monophosphate. This would imply that sildenafil has the potential to influence cardiac activity by increasing the myocardial concentration of cyclic adenosine monophosphate. Whether this effect is clinically relevant, and whether it increases the cardiac risk in patients taking sildenafil, remains to be shown.

CONCLUSION Arousal/erection is associated with few cardiovascular changes. Despite potential negative cardiac effects when given parenterally, oral phentolamine, in doses required for enhancing erection, appears to produce few cardiovascular adverse effects. The hemodynamic effects of sildenafil are small. However, the myocardial effects of the drug have not been definitely established, and should be further investigated. Overall, as judged by available information, the cardiac risk associated with erection, with or without enhancement of drugs currently used for treatment of erectile dysfunction, is low. A SYMPOSIUM: SEXUAL ACTIVITY AND CARDIAC RISK

25F

1. Andersson K-E, Wagner G. Physiology of penile erection. Physiol Rev 1995; 75:191–236. 2. Andersson K-E, Hedlund P, Alm P. Identification and localization of sympathetic pathways to and adrenergic innervation of the penis. Int J Impot Res 2000; in press. 3. Hedlund P, Alm P, Ekstro¨m P, Fahrenkrug J, Hannibal J, Hedlund H, Larsson B, Andersson K-E. Pituitary adenylate cyclase-activating polypeptide, helospectin, and vasoactive intestinal polypeptide in human corpus cavernosum. Br J Pharmacol 1995;116:2258 –2266. 4. Burnett AL. Nitric oxide in the penis: physiology and pathology. J Urol 1997;157:320 –324 5. Bohlen JG, Held JP, Sanderson MO, Patterson RP. Heart rate, rate-pressure product, and oxygen uptake during four sexual activities. Arch Intern Med 1984;144:1745–1748. ¨ ckert S, Stief CG, Truss MC, Machtens S, Scheller F, Knapp WH, 6. Becker AJ, U Hartmann U, Jonas U. Plasma levels of cavernous and systemic norepinephrine and epinephrine in men during different phases of penile erection. Akt Urologie Urologe [A] 1999;38:S124. 7. Andersson K-E, Steers WD. The pharmacological basis of sexual therapeutics. In: Morales A, ed. Erectile Dysfunction. Issues in Current Pharmacotherapy. London: Martin Dunitz Ltd, 1998:97–124. 8. Traish A, Netsuwan N, Daley J, Padman-Nathan H, Goldstein I, Saenz de Tejada I. A heterogeneous population of ␣1 adrenergic receptors mediates contraction of human corpus cavernosum smooth muscle to norepinephrine. J Urol 1995;153:222–227. 9. Traish A, Gupta S, Toselli P, Saenz de Tejada I, Goldstein I, Moreland RB. Identification of ␣1-adrenergic receptor subtypes in human corpus cavernous tissue and in cultured trabecular smooth muscle cells. Receptor 1996;5:145–157. 10. Davis B, Chapple C, Chess-Williams R. The a1 L-adrenoceptor mediates contraction in human erectile tissue. (Abstr.) Eur Urol 1999;35(suppl 2):102. 11. Traish AM, Moreland RB, Huang YH, Goldstein I. Expression of functional alpha2-adrenergic receptor subtypes in human corpus cavernosum and in cultured trabecular smooth muscle cells. Recept Signal Transduct 1997;7:55– 67. 12. Michel MC, Krege S, Sperling H, Goepel M. ␣1- and ␣2-adrenoceptors in the human penis: affinities of trazodone. (Abstr.) Eur Urol 1999;35(suppl 2):102. 13. Simonsen U, Prieto D, Hernandez M, Saenz de Tejada I, Garcı´a-Sacrista´n A. Prejunctional alpha 2-adrenoceptors inhibit nitrergic neurotransmission in horse penile resistance arteries. J Urol 1997;157:2356 –2360. 14. Muramatsu I, Ohmura T, Hashimoto S, Oshita M. Functional subclassification of vascular ␣1-adrenoceptors. Pharmacol Commun 1995;6:23–28. 15. Hattori Y, Kanno M. Role of alpha1-adrenoceptor subtypes in production of the positive inotropic effects in mammalian myocardium: implications for the alpha1-adrenoceptor subtype distribution. Life Sci 1998;62:1449 –1453. 16. Baumgart D, Haude M, Gorge G, Liu F, Ge J, Grosse-Eggebrecht C, Erbel R, Heusch G. Augmented alpha-adrenergic constriction of atherosclerotic human coronary arteries. Circulation 1999;99:2090 –2097. 17. Traish A, Gupta S, Gallant C, Huang YH, Goldstein I. Phentolamine mesylate relaxes penile corpus cavernosum tissue by adrenergic and non-adrenergic mechanisms. Int J Impot Res 1998;10:215–223. 18. Hoffman BB, Lefkowitz RJ. Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In: Harman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG, eds. Goodman and Gilman⬘s The Pharmacological Basis of Therapeutics, 9th edition. New York: McGraw-Hill, 1996:199 –248. 19. Gould LA, Reddy CV. Oral therapy with phentolamine in chronic congestive heart failure. Chest 1979;75:487– 491. 20. Schreiber R, Maier PT, Gunnar RM, Loeb HS. Hemodynamic improvement following single dose of oral phentolamine: administration in patients with chronic low output cardiac failure. Chest 1979;76:571–575. 21. Wyllie MG, Andersson K-E. Orally actve agents: the potential of alphaadrenoceptor antagonists. In: Carson C, Kirby R, Goldstein I, eds. Isis Textbook of Erectile Dysfunction. Oxford: Medical Media, 1999:317–322.

26F THE AMERICAN JOURNAL OF CARDIOLOGY姞

22. Beavo JA. Cyclic nucleotide phosphodiesterases: functional implications of mutiple isoforms. Physiol Rev 1995;75:725–748. 23. Polson JB, Strada SJ. Cyclic nucleotide phosphodiesterases and vascular smooth muscle. Annu Rev Pharmacol Toxicol 1996;36:403– 427. 24. Dousa TP. Cyclic-3⬘,5⬘-nucleotide phosphodiesterase isozymes in cell biology and pathophysiology of the kidney. Kidney Int 1999;55:29 – 62. 25. Taher A, Stief CG, Raida M, Jonas U, Forssmann WG. Cyclic nucleotide phosphodiesterase activity in human cavernous smooth muscle and the effect of various selective inhibitors. (Abstr.) Int J Impot Res 1992;4(suppl 2):11. ¨ ckert S, Meyer M, Schulz-Knappe P, Forss26. Stief CG, Taher A, Truss M, U mann WF, Jonas U. Die Phosphodiesterase-Isoenzyme des humanen corpus cavernosum penis und deren funktionelle Bedeutung. Akt Urol 1995;26(suppl I):58 – 61. ¨ ckert S, Broderick GA, Jonas U. Phosphodiesterases in 27. Stief CG, Ku¨the A, U human cavernous smooth muscle: expression and possible clinical significance. Dallas, TX: American Urological Association Postgraduate Course: 1999;in press. 28. Ballard SA, Gingell CJ, Tang K, Turner LA, Price ME, Naylor AM. Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. J Urol 1998;159: 2164 –2171. 29. Ballard SA, Turner LA, Naylor AM. Sildenafil, a potent selective inhibitor of type 5 phosphodiesterase enhances nitric oxide-dependent relaxation of rabbit corpus cavernosum. (Abstr.) Br J Pharmacol 1996;118:153. ¨ ckert S, Forssmann W-G, Jonas U. 30. Ku¨the A, Stief CG, Ma¨gert H-J, U Molecular biological characterisation of phosphodiesterases 3 and 5 in human corpus cavernosum penis (Abstr.) Eur Urol 1999;35(suppl 2):102. ¨ ckert S, Becker AJ, Truss MC, Jonas U. The effect of the specific 31. Stief CG, U phosphodiesterase (PDE) inhibitors on human and rabbit cavernous tissue in vitro and in vivo. J Urol 1998;159:1390 –1394. 32. Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C. 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. 33. Boolell M, Gepi-Attee S, Gingell JC, Allen MJ. Sildenafil, a novel oral therapy for male erectile dysfunction. Br J Urol 1996;78:257–261. 34. Wallis RM, Corbin JD, Francis SH, Ellis P. Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. Am J Cardiol 1999;83(suppl):3C–12C. ¨ ckert S, Forssmann W-G, 35. Ku¨the A, Wiedenroth A, Stief CG, Ma¨gert H-J, U Jonas U. Identification of 13 phosphodiesterase isoforms in human cavernous tissue. (Abstr.) Eur Urol 1999;35(suppl 2):101. 36. Meacci E, Taira M, Moos JRM, Smith CJ, Movesesian A, Degerman E, Belfrage P, Manganiello V. Molecular cloning and expression of human myocardial cGMP-inhibited cAMP phosphodiesterase. Proc Natl Acad Sci USA 1992;89:3721–3725. 37. Chuang AT, Strauss JD, Murphy RA, Steers WD. Sildenafil, a type-5 cGMP phosphodiesterase inhibitor, specifically amplifies endogenous cGMP-dependent relaxation in rabbit corpus cavernosum smooth muscle in vitro. J Urol 1998;160: 257–261. 38. Carter AJ, Ballard SA, Naylor AM. Effect of the selective phosphodiesterase type 5 inhibitor sildenafil on erectile function in the anesthetized dog. J Urol 1998;160:242–246. 39. Jeremy JY, Ballard SA, Naylor AM, Miller MAW, Angelini GD. Effects of sildenafil, a type-5 cGMP phosphodiesterase inhibitor, and papaverine on cyclic GMP and cyclic AMP levels in the rabbit corpus cavernosum in vitro. Br J Urol 1997;79:958 –963. ¨ ckert S, Becker AJ, Stief CG, Truss MC, Harringer W, Forssmann W-G, 40. U Jonas U. Effects of sildenafil on cyclic AMP and cyclic GMP levels in isolated human cavernous and cardiac tissue. Urology 2000;55:146 –150.

VOL. 86 (2A)

JULY 20, 2000