Summary
The balance between contractant and relaxant factors controls the smooth muscle of the corpus cavernosum and determines the functional state of the penis (detumescence and flaccidity versus tumescence and erection). Noradrenaline contracts both the corpus cavernosum and penile vessels, mainly via stimulation ofα 1-adrenoceptors. Recent investigations have demonstrated the presence of several subtypes of α1-adrenoceptors (α 1A,α 1B, andα 1D) in the human corpus cavernosum and also that the noradrenaline-induced contraction in this tissue is probably mediated by two or, possibly, three receptor subtypes. Even if much of the available in vitro information suggests that endothelins (ETs) may be of importance for mechanisms of detumescene and flaccidity, the role of the peptides in the control of penile smooth-muscle tone in vivo is unclear, as is the question as to whether they can contribute to erectile dysfunction. For further evaluation of the clinical importance of ETs in penile physiology and pathophysiology, clinical studies on ET-receptor antagonists would be of interest. Neurogenic nitric oxide (NO) has been considered the most important factor for relaxation of penile vessels and the corpus cavernosum, but recent studies in mice lacking neurogenic NO synthase (NOS) have shown these animals to have normal erections. This focuses interest on the role of endothelial NOS and on other agents released from nerves or endothelium. For the time being the most effective means of inducing penile erection in men involves the intracavernous administration of prostaglandin Et (PGEI). PGE1 may act partly by increasing intracellular concentrations of cyclic adenosine monophosphate (cAMP).
Recent results obtained with the adenylate cyclase stimulator forskolin suggest that penile smooth-muscle relaxation leading to penile erection can be achieved through the cAMP pathway. Thus, transmitters and agents acting through this second-messenger system may significantly contribute to relaxation of penile smooth muscle and to erection.
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References
Adaikan PG, Kottegoda SR, Ratnam SS (1986) Is vasocative intestinal polypeptide the principal transmitter involved in human penile erection? J Urol 135: 638–640
Alm P, Larsson B, Ekblad E, Sundler F, Andersson K-E (1993) Immunohistochemical localization of peripheral nitric oxide synthase containing nerves using antibodies raised against synthetized C- and N-terminal fragments of cloned enzyme from rat brain. Acta Physiol Scand 148: 421–429
Andersson K-E (1993) The pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev 45: 253–308
Andersson K-E, Holmquist F (1990) Mechanisms for contraction and relaxation of human penile smooth muscle. Int J Impotence Res 2: 209–225
Andersson K-E, Wagner G (1995) Physiology of penile erection. Physiol Rev 75: 191–236
Argiolas A, Melis MR (1995) Neuromodulation of penile erection: an overview of the role of neurotransmitters and neuropeptides. Prog Neurobiol 47: 235–255
Ari G, Vardi Y, Hoffman A, Finberg PM (1996) Possible role for endothelins in penile erection. Eur J Pharmacol 307: 69–74
Azadzoi KM, Kim N, Brown LM, Goldstein I, Cohen RA, Saenz de Tejada I (1992) Edothelium-derived nitric oxide and cyclooxygenase products modulate corpus cavernosum smooth muscle tone. J Urol 147: 220–225
Bell CRW, Sullivan ME, Dashwood MR, Muddle JR, Morgan RJ (1955) The density and distribution of endothelin 1 and endothelin receptor subtypes in normal and diabetic rat corpus cavernosum. Br J Urol 76: 203–207
Boolell M, Allen M, Ballard S, Gepi-Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C (1996) Sildenafil: an orally active type 5 cyclic CMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impotence Res 8: 47–52
Burnett AL (1995) Nitric oxide control of lower genitourinary tract functions: a review. Urology 45: 1071–1083
Burnett AL, Lowenstein CJ, Bredt DS, Chang TSK, Snyder SH (1992) Nitric oxide: a physiologic mediator of penile erection. Science257: 401–403
Burnett AL, Tillman SL, Chang TSK, Epstein JI, Lowenstein CJ, Bredt DS, Snyder SH, Walsh PC (1993) Immunohistochemical localization of nitric oxide synthase in the autonomic innervation of the human penis. J Urol 150: 73–76
Burnett AL, Nelson RJ, Calvin DC, Liu J-X, Demas GE, Klein SL, Kriegsfeld LJ, Dawson VL, Dawson TM, Snyder SH (1996) Nitric oxide-dependent penile erection in mice lacking neuronal nitric oxide synthase. Mol Med 2: 288–296
Bush PA, Gonzalez NE, Ignarro LJ (1992) Biosynthesis of nitric oxide and citrulline froml-arginine by constitutive nitric oxide synthase present in rabbit corpus cavernosum. Biochem Biophys Res Commun 186: 308–314
Bylund DB, Eikenberg DC, Hieble JP, Langer SZ, Lefkowitz RJ, Minneman KP, Molinoff PB, Ruffolo RB Jr, Trendelenburg U (1994) International Union of Pharmacology nomenclature of adrenoceptors. Pharmacol Rev 46: 121–136
Cahn D, Melman A, Valcic M, Christ GJ (1996) Forskolin: a promising new adjunct to intracavernous pharmacotherapy. J Urol 155: 1789–1794
Christ GJ, Lerner SE, Kim DC, Melman A (1995) Endothelin-1 as a putative modulator of erectile dysfunction I. Characteristics of contraction of isolated corporal tissue strips. J Urol 153: 1998–2003
Costa P, Soulie-Vassal ML, Sarrazin B, Rebillard X, Navratil H, Bali JP (1993) Adrenergic receptors on smooth muscle cells isolated from human penile corpus cavernosum. J Urol 150: 859–863
Dail WG, Barba V, Leyba L, Galindo R (1995) Neural and endothelial nitric oxide synthase activity in rat penile erectile tissue. Cell Tissue Res 282: 109–116
Daley JT, Brown ML, Watkins MT, Traish AM, Huang Y-H, Moreland RB, Saenz de Tejada I (1996) Prostanoid production in rabbit corpus cavernosum I. Regulation by oxygen tension. J Urol 155: 1482–1487
Daley JT, Watkins MT, Brown ML, Martinez V, Cuevas P, Saenz de Tejada I (1996) Prostanoid production in rabbit corpus cavernosum II. Inhibition by oxidative stress. J Urol 156: 1169–1173
De Groat WC, Booth AM (1993) Neural control of penile erection. In: Maggi CA (ed) The autonomic nervous system, vol 6, ch 13. Nervous control of the urogenital system. Harwood London, pp 465–513
Derouet H, Eckert R, Trautwein W, Ziegler M (1994) Muscular cavernous single cell analysis in patients with venoocelusive dysfunction. Eur Urol 25: 145–150
Förstermann U, Schmidt HHHW, Pollock JS, Sheng H, Mitchell JA, Warner TD, Nakane M, Murad F (1991) Isoforms of nitric oxide synthase. Biochem Pharmacol 42: 1849–1857
Garland CJ, Plane F, Kemp BK, Cocks TM (1995) Endothelium-dependent hyperpolarization: a role in the control of vascolar tone. Trends Pharmacol Sci 16: 23–30
Giuliano FA, Rampin O, Benoit G, Jardin A (1995) Neural control of penile erection. Urol Clin North Am 22: 747–766
Hauser-Kronberger C, Hacker GW, Graf A-H, Mack D, Sundler F, Dietze O, Frick J (1994) Neuropeptides in the human penis: an immunobytochemical study. J Androl 15: 510–520
Hauser-Kronberger C, Hacker GW, Mack D, Dietze O, Arimura A, Sundler F, Frick J (1994) Pituitary adenylate cyclase activating peptide (PACAP), helospectin, peptide histidine methionine (PHM) and vasoactive intestinal polypetide (VIP) in the human penis: an immunocytochemical evaluation on the occurence of VIP-related peptides. Cell Vision 1: 319–323
Hedlund P, Alm P, Hedlund H, Larsson B, Andersson K-E (1994) Localization and effects of pituitary adenylate cyclaseactivating polypeptide (PACAP) in human penile erectile tissues. Acta Physiol Scand 150: 103–104
Hedlund P, Alm P, Ekström P, Fahrenkrug J, Hannibal J, Hedlund H, Larsson B, Andersson K-E (1995) Pituitary adenylate cyclase-activating polypeptide, helospectin, and vasoactive intestinal polypeptide in human corpus cavernosum. Br J Pharmacol 116: 2258–2266
Hedlund P, Larsson B, Alm P, Andersson K-E (1995) Distribution and function of nitric oxide-containing nerves in canine corpus cavernosum and spongiosum. Acta Physiol Scand 155: 445–455
Hempelmann RG, Papadopoulos I, Herzig S (1995) Non-synergistic relaxant effects of vasoactive intestinal polypeptide and SIN-1 in human isolated cavernous artery and corpus cavernosum. Eur J Pharmacol 276: 277–280
Hieble JP, Bylund DB, Clarke DE, Eikenburg DC, Langer SZ, Lefkowitz RJ, Minneman KP, Ruffolo RR Jr (1995) International Union of Pharmacology X. Recommendation for nomenclature of al-adrenoceptors: consensus update. Pharmacol Rev 47: 267–270
Holmquist F, Andersson K-E, Hedlund H (1990) Actions of endothelin on isolated corpus cavernosum from rabbit and man. Acta Physiol Scand 139: 113–122
Holmquist F, Kireby HJ, Larsson B, Forman A, Andersson KE (1992) Functional effects, binding sites and immunolocalization of endothelin-1 in isolated penile tissues from man and rabbit. J Pharmacol Exp Ther 261: 795–802
Holmquist F, Persson K, Garcia-Pascual A, Andersson K-E (1992) Phospholipase C activation by endothelin-1 and noradrenaline in isolated penile erectile tissue from rabbit. J Urol 147: 1632–1635
Huang PL, Dawson T, Bredt DS, Snyder SH, Fishman MC (1993) Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75: 1273–1286
Jünemann K-P, Ehmke H, Kummer W, Mayer B, Bührle CP, Alken P (1993) Coexistence of nitric oxide synthase and vasoactive intestinal polypeptide in nerve terminals of human corpus cavernosum. (abstract 127) J Urol 149: 245A
Kim YC, Kim JH, Davies MG, Hagen PO, Carson CC (1995) Modulation of vasoactive intestinal polypeptide (VIP)-mediated relaxation by nitric oxide and prostanoids in the rabbit corpus cavernsoum. J Urol 153: 807–810
Kimoto Y, Kessler R, Constantinous CE (1990) Endothelium dependent relaxation of human corpus cavernosum by bradykinin. J Urol 144: 1015–1017
Kirkeby HJ, Fahrenkrug J, Holmquist F, Ottesen B (1992) Vasoactive intestinal polypeptide (VIP) and peptide histidine methionine (PHM) in human penile corpus cavernosum tissue and circumflex veins: localization and in vitro effects. Eur J Clin Invest 22: 24–30
Kirkeby HJ, Svane D, Populsen J, Tottrup A, Forman A, Andersson K-E (1993) Role of thel-argininelnitric oxide pathway in relaxation of human penile cavernous tissue and circumflex veins. Acta Physiol Scand 149: 385–392
Klinge E, Sjöstrand NO (1994) Smooth muscle of the male reproductive tract. In: Szekers L, Papp JG (eds) Pharmacology of smooth muscle. (Handbook of experimental pharmacology series, vol 111) Springer, Heidelberg Berlin New York, pp 533–573
Lerner SE, Melman A, Christ GJ (1993) A review of erectile dysfunction: new insights and more questions. J Urol 149: 1246–1255
Levin RM, Wein AJ (1980) Adrenergic alpha-receptors outnumber beta-receptors in human penile corpus cavernosum. Invest Urol 18: 225–226
Lin JS-N, Lin J-M, Jou Y-C, Cheng J-T (1995) Role of cyclic adenosine monophosphate in prostaglandin Et-induced penile erection in rabbits. Eur Urol 28: 259–265
Linet OI, Ogrine FG (1996) Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction. N Engl J Med 334: 873–877
Martinez-Pineiro L, Trigo-Rocha F, Hsu GL, Heyden B von, Lue TF, Tanagho EA (1993) Cyclic guanosine monophosphate mediates penile erection in the rat. Urol Res 24: 492–499
Michel MC, Kenny B, Schwinn DA (1995) Classification of aladrenoceptors. Naunyn Schmiedebergs Arch Pharmacol 352: 1–10
Miller MAW, Morgan RJ (1994) Eicosianoids, erections and erectile dysfunction. Prostaglandins Leukotrienes Essent Fatty Acids 51: 1–9
Modin A, Weitzberg E, Lundberg JM (1995) Nitric oxide regulates peptide release from parasympathetic nerves and vascular reactivity to vasoactive intestinal polypeptide in vivo. Eur J Pharmacol 261: 185–197
Molderings GJ, Ahlen H van, Göthert M (1992) Modulation of noradrenaline release in human corpus cavernosum by presynaptic prostaglandin receptors. Int J Impotence Res 4: 19–26
Moreland RB, Traish A, McMillan MA, Smith B, Goldstein I, Saenz de Tejada I (1995) PGE1 suppresses the induction of collagen synthesis by transforming growth factor-β1 in human corpus cavernosum smooth muscle. J Urol 153: 826–834
Muramatsu I, Ohmura T, Hashimoto S, Oshita M (1995) Functional subclassification of vascular α1-adrenoceptors. Pharmacol Commun 6: 23–28
Palmer LS, Valcic M, Giraldi AM, Wagner G, Christ GJ (1994) Characterization of cyclic AMP accumulation in cultured human corpus cavernosum smooth muscle cells. J Urol 152: 1308–1314
Parkkisenniemi U-M, Klinge E (1996) Functional characterization of endothelin receptors in the bovine retractor penis and penile artery. Pharmacol Toxicol 79: 73–79
Pickard RS, Powell PH, Zar MA (1993) Evidence against vasoactive intestinal polypeptide as the relaxant neurotransmitter in human cavernosal smooth muscle. Br J Pharmacol 108: 497–500
Porst H (1996) A rationale for prostaglandin E1 in erectile failure: a survey of worldwide experince. J Urol 155: 802–815
Price DT, Schwinn DA, Kim JH, Carson CC III, Caron MG, Lefkowitz RJ (1993) Alpha, adrenergic receptor subtype mRNA expression in human corpus cavernosum. (abstract 287) J Urol 149: 285A
Rubanyi GM, Polokoff MA (1994) Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Physiol Rev 46: 325–341
Saenz de Tejada I, Carson MP, De las Morenas A, Goldstein I, Traish AM (1991) Endothelin: localization, synthesis, activity, and receptor types in human penile corpus cavernosum. Am J Physiol 261: H1078-H1085
Simonsen U, Prieto D, Saenz de Tejada I, Garcia-Sacristan A (1995) Involvement of nitric oxide in the non-adrenergic noncholinergic neurotransmission of horse deep penile arteries: role of charybdotoxin-sensitive K+-channels. Br J Pharmacol 116: 2582–2590
Stief CG, Ückert S, Truss M, Becker AJ, Taher A, Jonas U (1995) Cyclic nucleotide phosphodiesterase (PDE) isoenzymes in human cavernos smooth muscle: characterization and functional effects of PDE-inhibitors in vitro and in vivo. Int J Impotence Res 7 [Suppl] 1: 6–7
Tamura M, Kagawa S, Kimura K, Kawanishi Y, Tsuruo Y, Ishimura K (1995) Coexistence of nitric oxide synthase, tyrosin hydroxylase and vasoactive intestinal polypeptide in human penile tissue-a triple histochemical and immunohistochemical study. J Urol 153: 530–534
Taub HC, Lerner SE, Melman A, Christ GJ (1993) Relationship between contraction and relaxation in human and rabbit corpus cavernosum. Urology 42: 698–704
Traish A, Netsuwan N, Daley J, Padman-Nathan H, Goldstein I, Saenz de Tejada I (1995) A heterogeneous population of α1-adrenergic receptors mediates contraction of human corpus cavernosum smooth muscle [in response] to norepinephrine. J Urol 153: 222–227
Traish A, Gupta S, Toselli P, Saenz de Tejada I, Goldstein I, Moreland RB (1996) Identification of α1-adrenergic receptor subtypes in human corpus cavernosum tissue and in cultured trabecular smooth muscle cells. Receptor 5: 145–157
Trigo-Rocha F, Hsu GL, Donatucci CF, Lue TF (1993) The role of cyclic adenosine monophosphate, cyclic guanosine monophosphate, endothelium and nonadrenergic, noncholinergic neurotransmission in canine penile erection. J Urol 149: 872–877
Trigo-Rocha F, Hsu G-L, Donatucci CF, Marinez-Pineiro L, Lue TF, Tanagho EA (1994) Intracellular mechanism of penile erection in monkeys. Neurourol Urodyn 13: 71–80
Yiangou Y, Christofides ND, Gu J, Blank MA, Polak JM, Bloom SR (1985) Peptide histidine methionine (PHM) and the human male genitalia. Neuropeptides 6: 133–142
Zhao W, Christ GJ (1995) Endothelin-1 as a putative modulator of erectile dysfunction. II. Calcium mobilization in cultured human corporal smooth muscle cells. J Urol 154: 1571–1579
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Andersson, KE., Stief, C.G. Neurotransmission and the contraction and relaxation of penile erectile tissues. World J Urol 15, 14–20 (1997). https://doi.org/10.1007/BF01275151
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DOI: https://doi.org/10.1007/BF01275151