JOURAA ISSN 0022-5347 olume141 June 1989 Number 6 The Journal of UROLOGY FOUNDED IN 1917 BY HUGH HAMPTON YOUNG

Official Journal of the American Urological Association, Inc.

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CONTENTS CLINICAL UROLOGY Review Article Nonoperative Management of Benign Prostatic Hyperplasia. H. Lepor 1283 Original Articles Selective Use of Excretory Urography in Women With Acute Pyelonephritis. T. Sandberg, Ε. Stokland, I. Brolin, G. Lidin-Janson and C. Svanborg Eden (Editorial Comments by Η. M. Pollack and Β. B. Garber) 1290 Elective Cholecystectomy During Major Urological Surgery. T. A. Rozanski, V. J. Kiesling, Jr., J. A. Vaccaro and W. D. Belville 1295 Impact of Endourology on Diagnosis and Management of Upper Urinary Tract Urothelial Cancer. M. L. Blute, J. W. Segura, D. E. Patterson, R. C. Benson, Jr. and H. Zincke (Editorial Comments by M. J. Droller and M. S. Soloway) 1298 Cardiovascular Evaluation Before Circulatory Arrest for Removal of Vena Caval Extension of Renal Car­ cinoma. J. A. Belis, W. E. Pae, Jr., T. J. Rohner, Jr., J. L. Myers, B. L. Thiele, G. S. Wickey and D. E. Martin (Editorial Comments by L. M. Zinman, J. A. Libertino, D. M. Shahian, F. F. Marshall and B. A. Reitz) 1302 Deoxyribonucleic Acid Content and Medroxyprogesterone Acetate Treatment in Metastatic Renal Cell Car­ cinoma. B. Ljungberg, R. Tomic and G. Roos 1308 Carcinoma of Renal Pelvis and Ureter Following Bladder Carcinoma. Frequency, Risk Factors and Clin- icopathological Findings. J. Oldbring, I. Glifberg, P. Mikulowski and S. Hellsten 1311 Semirigid Ureteroscopy: New Genre. S. P. Dretler and G. Cho 1314 Endoureteropyelotomy: Percutaneous Treatment of Ureteropelvic Junction Obstruction. P. J. Van Cangh, J. L. Jorion, F. X. Wese and R. J. Opsomer (Editorial Comments by R. V. Clayman and A. D. Smith) . . 1317 Continent Urinary Diversion. D. G. Skinner, G. Lieskousky and S. Boyd (Editorial Comments by R. G. Rowland, A. I. Sagalowsky and W. F. Whitmore, Jr.) 1323 Malacoplakia: 25-Year Experience With Review of Literature. J. P. Long, Jr. and A. F. Althausen 1328 Flow Cytometry as Predictor of Response and Progression in Patients With Superficial Bladder Cancer Treated With Bacillus Calmette-Guerin. P. R. Bretton, H. W. Herr, Μ. Kimmel, W. R. Fair, W. F. Whitmore, Jr. and M. R. Melamed (Editorial Comment by R. W. deVere White) 1332 Intravesical Mitomycin C Instillation as Prophylactic Treatment of Superficial Bladder Tumor. Η. H. Kim and C. Lee (Editorial Comments by M. S. Soloway and Τ. H. Stanisic) 1337 Complications of Whole Bladder Dihematoporphyrin Ether Photodynamic Therapy. J. I. Harty, M. Amin, Τ. J. Wieman, Μ. T. Tseng, D. Ackerman and W. Broghamer 1341 Late Occurrence of Urinary Tract Damage in Patients Successfully Treated by Radiotherapy for Cervical Carcinoma. J. Zoubek, E. J. McGuire, F. Noll and J. O. L. DeLancey 1347

Contents continued on page A6 Annual Meeting, American Urological Association, Inc., New Orleans, Louisiana, May 13-17, 1990 Contents continued from Cover 1

Topical Oxybutynin Chloride for Relaxation of Dysfunctional Bladders. C. B. Brendler, L. C. Radebaugh and J. L. Möhler 1350 Anatomy of Penile Venous Drainage in Potent and Impotent Men During Cavernosography. A. M. Fuchs, C. M. Mehringer and J. Rajfer 1353 Impotence Evaluated by Use of Prostaglandin El. T. I.-S. Hwang, C.-R. Yang, S.-J. Wang, C.-L. Chang, T.- S. Tzai, C.-H. Chang and H.-C. Wu (Editorial Comment by M. Marberger) 1357 Effect of Yohimbine Hydrochloride on Erectile Impotence: Double-Blind Study. J. G. Susset, C. D. Tessier, J. Wincze, S. Bansal, C. Malhotra and M. G. Schwacha 1360 Safety of Intracavernous Injections Using Alpha-Blocking Agent. J. Buvat, A. Lemaire, M. Buvat-Herbaut and G. Marcolin 1364 Malignant Lymphoma of Testis: Histological and Immunohistological Study of 28 Cases. N. Nonomura, Κ Aozasa, T. Ueda, A. Okuyama, M. Matsuda, S. Hida, 0. Yoshida, Y. Kobashi, N. Shima and H. Yamabe 1368 Incidence and Clinical Significance of Subclinical Scrotal Varicoceles. M. A. Yarborough, J. R. Burns and F. S. Keller 1372 Acute Urinary Retention Associated With Prostatic Carcinoma. J. W. Moul, R. Davis, J. A. Vaccaro, S. A. Sihelnik, W. D. Belville and D. G. McLeod 1375 Role of Prostatic Specific Antigen as Tumor Marker in Men With Advanced Adenocarcinoma of Pros­ tate. T. J. Maatman (Editorial Comment by P. H. Lange and M. Brawer) 1378 Candidal Antigenemia: Prognostic Determinant. T. Suits, G. J. Wise and B. Walters 1381 Urologists At Work New Technique of Using In Situ Appendix as Catheterizable Stoma in Continent Urinary Reserviors. Μ. M. Issa, J. E. Oester ling, D. A. Canning and R. D. Jeffs 1385 Adjunctive Endourological Technique for Transurethral Resection in Patients With Urethral Stricture. R. Κ Chiou, W. M. O'Brien and Κ P. O'Connor (Editorial Comment by W. Brannan) 1388 Urological Neurology and Urodynamics Bladder Hypocompliance in Spinal Cord Injury Population. R. H. Hackler, Μ. Κ Hall and T. A. Zampieri 1390 Urodynamic Studies in Patients Undergoing Bladder Replacement Surgery. B. Lytton and D. F. Green.... 1394 Pediatric Articles Bilateral Ureteral Triplication With Crossed Ectopic Fused Kidneys Associated With VACTERL Syn­ drome. J. Golomb and R. M. Ehrlich 1398 Retroiliac Ureter in Male Newborn With Multiple Genitourinary Anomalies: Case Report and Review of Literature. D. H. Nguyen, N. Koleilat and R. Gonzalez 1400 Bladder Compliance in Meningomyelocele Children. G. M. Ghoniem, D. A. Bloom, E. J. McGuire and K. L. Stewart (Editorial Comment by S. B. Bauer) 1404 Technical Challenge of Megameatus Intact Prepuce Hypospadias Variant: Pyramid Procedure. J. W. Duckett and M. A. Keating 1407 Incidence, Possible Causes and Followup of Idiopathic Prolonged Penile Erection in Newborn. P. Merlob and P. M. Livne (Editorial Comment by A. B. Belman) 1410 Infant Testicular Prostheses. J. S. Elder, M. A. Keating and J. W. Duckett (Editorial Comment by A. B. Belman) 1413 Orchiopexy of High Undescended Testis by Division of Spermatic Vessels: Critical Review of 38 Selected Transections. S. J. Kogan, B. Z. Houman, E. F. Reda and S. B. Levitt (Editorial Comment by H. McC. Snyder, III) 1416 Case Reports Acquired Intravesical Ureteral Diverticulum: Unusual Late Complication of Ureteroneocystostomy. F. Aragona, P. Bassi, G. Passerini Glazel and F. Pagano 1420 Treatment of Vesicouterine Fistula by Fulguration. L. R. Molina, C. M. Lynne and V. A. Politano 1422 Bladder Pheochromocytoma: Evaluation With Magnetic Resonance Imaging. J. Heyman, Y. Cheung, V. Ghali and E. Leiter 1424 Treatment of Persistent Penile Erection and Priapism Using Terbutaline. Τ. R. Shantha, D. P. Finnerty and A. P. Rodriquez 1427 Tuberculosis of Penis Presenting as Subcutaneous Nodule. L. S. Baskin and S. Mee 1430 Conservative Management of Seminal Vesicle Abscess. M. J. Kennelly and J. E. Oesterling 1432 Letter to the Editor Re: Dorsal Lumbotomy Incision in Pediatric Urological Surgery, by S. M. Orland, Η. M. Snyder and J. W. Duckett. J. M. Mallafre, R. Gutierrez del Pozo and J. A. Campos C 1434

Contents continued on page A10

A6 Contents continued from page A6 INVESTIGATIVE UROLOGY This Month in Investigative Urology: Host Parasite Interaction in Pyelonephritis. J. A. Roberts 1436 Ureaplasma Urealyticum Upper Urinary Tract Infection: Persistence and Pathogenicity in Canine Model. J. N. Krieger, Ε. S. Boatman and G. E. Kenny 1437 Acetylcholine as Possible Neurotransmitter in Penile Erection. C. Stief, F. Benard, R. Bosch, S. Aboseif L. Nunes, Τ F. Lue and E. A. Tanagho 1444 Class I and Class II HLA Antigen Expression by Transitional Cell Carcinoma of Bladder: Correlation With T-Cell Infiltration and BCG Treatment. G. F. Stefanini, Ε. Bercovich, V. Mazzeo, W. F. Grigioni, E. Emili, A. D'Errico, M. Lo Cigno, N. Tamagnini and M. Mazzetti 1449 Suppression of Rat Urinary Bladder Carcinogenesis by Alpha-Difluoromethylornithine. Y. Homma, T. Kakizoe, S. Samma and R. Oyasu 1454

pH Analysis of Papaverine-Phentolamine and Prostaglandin El for Pharmacologic Erection. E. J. Seidmon and A. M. Samaha, Jr 1458 In Vivo Transfer of R-Plasmid in Urinary Tract Infection Model. D. E. Neal, Jr., Ε. Ε. M. Moody, V. L. Thomas, R. Gander and Η. M. Radwin 1460 Effects of Anti-Lipid A Human Monoclonal Antibody on Lipopolysaccharide-Induced Toxicity to Kid­ ney. Β. M. Tune, C.-Y. Hsu, Μ. M. Bieber and Ν. Ν. H. Teng 1463 Immunoresponse of Tissue Infiltrating Lymphocytes in Bladder Tumors. H. Tsujihashi, H. Matsuda, S. Uejima, Τ Akiyama and T. Kurita 1467 In Vitro Intravesical Instillation of Anticholinergic Antispasmodic and Calcium Blocking Agents (Rabbit Whole Bladder Model). K. Kato, S. Kitada, A. Chun, A. J. Wein and R. M. Levin 1471 Regeneration of Canine Urinary Bladder Mucosa After Complete Surgical Denudation. Κ. I. Wishnow, D. E. Johnson, D. J. Grignon, D. M. Cromeens and A. G. Ayala 1476 Prostatic Specific Antigen: Immunoreactivity in Urachal Remnants. R. Golz and G. E. Schubert 1480 Characterization and Localization of In Vivo Phospholipid Methylation in Hamster Testis. P. N. Schlegel, W. W. Wright and Τ S. K. Chang 1483 Investigative Grammar 1488

UROLOGICAL SURVEY Subject Index to Abstracts in Volume 141 1490

Diagnostic Efficacy of Combination of Urine Cytology, Urine Analysis and History in Follow-Up of Bladder Carcinoma. E. J. H. Meuleman and K. P. J. Delaere 1498 Impact of Hydronephrosis on Renal Function in Patients Treated With Cisplatin-Based Chemotherapy for Metastatic Nonseminomatous Germ Cell Tumors. C. Barton, G. Duchesne, M. Williams, C. Fisher and A. Horwich 1498 Results of Adjuvant Surgery in Patients With Stage III and IV Nonseminomatous Testicular Tumors After Cisplatin-Vinblastine-Bleomycin Chemotherapy. W. A. H. Gelderman, H. Schraffordt Koops, D. Th. Sleijfer, J. W. Oosterhuis, J. Ν. H. Van Der Heide, Ν. Η. Mulder, J. Marrink, Η. W. Α. De Bruyn and J. Oldhoff 1498 Cisplatin-Based Combination Chemotherapy for Disseminated Germ Cell Tumors: Long-Term Follow- Up. B. J. Roth, A. Greist, P. S. Kubiiis, S. D. Williams and L. H. Einhorn 1499 Randomized Trial of Etoposide + Cisplatin Versus Vinblastine + Bleomycin + Cisplatin + Cyclo­ phosphamide + Dactinomycin in Patients With Good-Prognosis Germ Cell Tumors. G. J. Bosl, N. L. Geller, D. Bajorin, S. P. Leitner, A. Yagoda, R. B. Golbey, H. Scher, Ν. J. Vogelzang, J. Auman, R. Carey, W. R. Fair, Η Herr, Μ. Morse, P. Sogani and W. Whitmore, Jr 1499 Surveillance for Stage I Non-Seminomatous Germ Cell Tumours of Testis: Optimal Protocol Has Not Yet Been Defined. D. Raghavan, B. Colls, J. Levi, B. Fitzharris, Μ. Η. N. Tattersall, C. Atkinson, R. Woods, G. Coorey, C. Farrell and R. Wines 1500 Clinical Stage I Nonseminomatous and Mixed Germ Cell Tumors of Testis: Clinicopathologic Study of 93 Patients on Surveillance Protocol After Orchiectomy Alone. C. H. Dunphy, A. G. Ayah, D. A. Swanson, J. Y. Ro and C. Logothetis 1500 Stage I Nonseminomatous Germ Cell Testicular Tumor: Prediction of Metastatic Potential by Primary Histopathology. C. Y. Fung, L. A. Kalish, G. L. Brodsky, J. P. Richie and Μ. B. Garnick 1501 Renal Acidification Defects in Medullary Sponge Kidney. P. J. Osther, A. B. Hansen and H. F. R0hl 1501 Improvement of Renal Function in Azotaemic Hypertensive Patients After Surgical Revascularization. C. A. Mestres, J. M. Campistol, S. Ninot, A. Botey, C. Abad, M. Guerola, A. Cases, L. Revert and J. Mulet. . 1501 Management of Children With Hypertension From Reflux or Obstructive Nephropathy. V. Braren, J. C. West, Jr., R. C. Boerth and C. M. Harmon 1502 New Approach to Treatment of Polycystic Kidneys. D. Frang, I. Czvalinga and L. Polyak 1502 Renal Pathology in von Hippel-Lindau Disease. D. Solomon and A. Schwartz 1502 Renewed Role of Nuclear Medicine in Renovascular Hypertension. M. D. Blaufox and L. M. Freeman .... 1502 Cadaveric Renal Transplantation in Cyclosporine and OKT3 Eras. R. J. Stratta, A. M. D'Alessandro, R. M. Hoffmann, H. W. Sollinger, Μ. Kalayoglu, D. F. Lorentzen, J. D. Pirsch and F. O. Beizer 1503 Effectiveness of Second Course of OKT3 Monoclonal Anti-T Cell Antibody for Treatment of Renal Allograft Rejection. D. J. Norman, C. F. Shield, III, Κ R. Henell, J. Kimball, J. M. Barry, W. M. Bennett and M. Leone 1503

Contents continued on page A16

A10 Contents continued from page A10

Early Function as Principal Correlate of Graft Survival. Multivariate Analysis of 200 Cadaveric Renal Trans­ plants Treated With Protocol Incorporating Antilymphocyte Globulin and Cyclosporine. P. F. Halloran, M. A. Aprile, V. Farewell, D. Ludwin, Ε. Κ. Smith, S. Y. Tsai, R. A. Bear, Ε. H. Cole, S. S. Fenton and D. C. Cattran 15C4 Efficacy of Ganciclovir in Liver and Kidney Transplant Recipients With Severe Cytomegalovirus Infec­ tion. C. V. Paya, P. E. Hermans, Τ F. Smith, J. Rakela, R. Η Wiesner, R. Α. F. Krom, V. E. Torres, S. Sterioff and C. J. Wilkowske 15C5 Renal Artery Stenosis After Renal Transplantation. M. Lacombe 15C5 Recurrent Pulmonary Oedema in Hypertension Due to Bilateral Renal Artery Stenosis: Treatment by An­ gioplasty or Surgical Revascularisation. Τ G. Pickering, L. Herman, R. B. Devereux, J. E. Sotelo, G. D. James, Τ A. Sos, M. F. Silane and J. H. Laragh 1506 Aortorenal Arterial Autografts: Last Two Decades. R. J. Stoney and P. A. Olofsson 1507 Simultaneous Aortic Reconstruction and Bilateral Renal Revascularization: Is This Safe and Effective Pro­ cedure? C. S. O'Mara, M. D. Maples, Τ L. Kilgore, Jr., Μ. H. McMullan, Η. B. Tyler, G. H. Mundinger, Jr. and R. E. Kennedy 1507 Results of Renal Artery Balloon Angioplasty Limit its Indications. H. G. Beebe, K. Chesebro, F. Merchant and W. Bush 1508 Surgical Renal Artery Reconstruction After Percutaneous Transluminal Angioplasty. R. L. McCann, R. R. Bollinger and G. E. Newman 1509 Urinary-Bladder Management After Total Joint-Replacement Surgery. J. D. Michelson, P. A. Lothe and M. E. Steinberg 1509 Treatment of Urinary Complications After Total Joint Replacement in Elderly Females. V. L. Carpiniello, T. R. Malloy, Μ. Cendron, R. Booth and Η G. Altman 1509 Can Transabdominal Ultrasound Estimation of Postvoiding Residual (PVR) Replace Catheterization. C. G. Roehrborn and P. C. Peters 1510 Residual Urine Volumes in Patients With Spinal Cord Injury: Measurement With Portable Ultrasound Instrument. D. D. Cardenas, E. Kelly, J. N. Krieger and W. H. Chapman 1510 Effect of Pelvic Floor Exercises in Treatment of Genuine Urinary Stress Incontinence in Women at Two Hospitals. S. M. Henalla, P. Kirwan, C. M. Castleden, C. J. Hutchins and A. J. Breeson 1511 Pelvic-Floor Musculature Exercises in Treatment of Anatomical Urinary Stress Incontinence. D. C. H. Tchou, C. Adams, R. E. Varner and B. Denton 1511 Clinical and Urodynamic Effects of Anterior Vaginal Repair and Burch Colposuspension. J. M. van Geelen, A. G. M. Theeuwes, Τ Κ. Α. Β. Eskes and C. Β. Martin, Jr 1512 Estrogens and Phenylpropanolamine in Combination for Stress Urinary Incontinence in Postmenopausal Women. A.-C. Kinn and M. Lindskog 1512 Norfenefrine in Treatment of Female Stress Incontinence: Double-Blind Controlled Trial. G. Lose, P. Rix, Ε. Diernoes and N. Alexander 1513 Urinary Incontinence During Sexual Intercourse: Common, but Rarely Volunteered, Symptom. P. Hilton 1513 Long-Term Follow-Up of Selective Sacral Neurectomy. M. G. Lucas, D. G. Thomas, S. Clarke and D. M. C. Forster 1514 Acupuncture in Treatment of Bladder Instability. T. Philp, P. J. R. Shah and P. H. L. Worth 1514 Role of Urethral Reconstruction and Artificial Sphincter in Complicated Salvage Radical Prostatectomy. S. D.Boyd 1515 Radical Pelvic Surgery With Preservation of Sexual Function. P. C. Walsh and P. N. Schlegel 1515 Pelvic Fracture and Injury to Lower Urinary Tract. J. P. Spirnak 1516 Save Prepuce. Painless Separation of Preputial Adhesions in Outpatient Clinic. G. A. MacKinlay 1517 Do You Favor Routine Neonatal Circumcision? Yes. Τ Ε. Wiswell 1517 Fracture of Penis—Review With Case Report. J. Τ. Κ Tiong, A. Taylor, E. Engfand and R. Hirsch 1517 Other Arthritides: Roentgenologic Features of Osteoarthritis, Erosive Osteoarthritis, Ankylosing Spondylitis, Psoriatic Arthritis, Reiter's Disease, Multicentric Reticulohistiocytosis, and Progressive Systemic Scle­ rosis. R. Η Gold, L W. Bassett and L. L. Seeger 1518 Demonstration of Rectovesical Fistula on Technetium-99m MDP Bone Image. Κ Higashi, M. Ohguchi, Τ Okimura, T. Miyamura and I. Yamamoto 1518 Volume Index and Contents Index, Volume 141 1519 Table of Contents, Volume 141 iii

PROPRIETARY NAMES

Many of the words appearing in the JOURNAL OF UROLOGY are proprietary names even though no reference to this fact is made in the text. The appearance of any name without designation as proprietary is, therefore, not to be regarded as a representation by the editorial committee or publisher that it is not the subject of proprietary rights.

A16 0022-5347/89/1416-1444$02.0()/0 THE JOURNAL OF UROLOGY Vol. 141, Junt Copyright © 1989 by Williams & Wilkins Printed in U.S.A

ACETYLCHOLINE AS A POSSIBLE NEUROTRANSMITTER IN PENILE ERECTION

CHRISTIAN STIEF, FRANCOIS BENARD, RUUD BOSCH, SHERIF ABOSEIF, LORA NUNES, TOM F. LUE* AND EMIL A. TANAGHO

From the Department of Urology, University of California School of Medicine, San Francisco, California

ABSTRACT

We investigated the erectile response to intracavernous injection of increasing doses of acetylcho­ line (0.5 to 500 Mg.) in 10 monkeys. To differentiate between nicotinic (ganglionic) and muscarinic (parasympathetic postganglionic) effects, acetylcholine was likewise administered after 1.6 mg. trimethaphan camsylate and 0.1 mg. atropine, alone or sequentially. Erections were induced by cavernous nerve stimulation before and after atropine. Acetylcholine induced a dose-dependent, triphasic erectile response: a first tumescence phase followed by contraction and a subsequent second phase of tumescence. Atropine reduced but did not abolish the erectile response to acetylcholine: attainment of maximal intracavernous pressure

after neurostimulation was both delayed and reduced (mean 25 cm. H20). Only after combined nicotinic and muscarinic blockade was the erectile response to acetylcholine completely abolished. Histologic staining for acetylcholinesterase in five additional monkeys that had not received acetylcholine showed dense staining within the cavernous erectile tissue and around the cavernous arteries. Our data suggest that acetylcholine is a possible neurotransmitter for penile erection in monkeys. (J. Urol, 141: 1444-1448, 1989)

Since the report of Eckhardt in 1863 that galvanic stimula­ minute waiting period intervened before the next injection. To tion of pelvic parasympathetic nerves induces penile erection verify reproducibility, all injections were given twice. in the dog,1 many studies have confirmed these findings in Intracavernous injection of ACh after muscarinic blockade. different species.2"7 Based on the classic theory of autonomic The above injection protocol was followed after intracavernous neurotransmission, the muscarinic neurotransmitter was be­ injection of 0.1 mg. atropine (1.4 Χ 10"7 mol.) (Elkins-Sim Inc., lieved to be acetylcholine (ACh).8 However, penile erection has Cherry Hill, N.Y.). This dosage was chosen after 0.01 mg. been shown to be atropine-resistant,9,10 and organ bath studies intracavernously proved to be sufficient for complete musca­ of the effect of ACh on cavernous smooth muscle have been rinic blockade in dogs (unpublished data). Although the size of inconclusive. In vitro, all possible responses to ACh have been the cavernous bodies in monkeys and dogs is comparable, a observed: no effect;1112 inconsistent effects;11 and both ten-fold increase (0.1 mg.) was selected to ensure complete local contraction14 and relaxation15,16 of the cavernous smooth mus­ muscarinic blockade. cle. Our aim was to examine in vivo a possible role of ACh as Erections induced by neurostimulation before and after atro­ a postganglionic parasympathetic neurotransmitter for penile pine. In monkeys 1-6, cuff electrodes were placed around the erection. cavernous nerve as previously described.18 After three erections had been induced by neurostimulation (20 Hz, six to eight V, MATERIALS AND METHODS stimulation time = one minute), 0.1 mg. atropine was injected Ten pigtail monkeys, weighing 4.3 to 10.5 kg., were used. intracavernously and neurostimulation was repeated five times After adequate anesthesia with ketamine (30 mg./kg. body- with an eight-minute interval between each stimulation. weight i.m.), the monkeys were placed in the supine position. Intracavernous injection of ACh after nicotinic blockade. To Under sterile conditions, one 21-gauge scalp-vein needle was investigate the effect of ACh after nicotinic blockade, the six placed in each distal right and left cavernous body. One needle monkeys with implanted electrodes were given an intracaver­ was connected to a Statham transducer (model P23 BC) for nous injection of 1.6 mg. trimethaphan camsylate (Roche Lab­ intracavernous pressure recording (Grass Polygraph; model 7); oratories, Nutley, N.J.), the lowest dosage shown to block the other served for intracavernous injection or perfusion. neurostimulation-induced erections in all monkeys. The drug's Penile tumescence was visually monitored by at least two intrinsic activity resulted in penile tumescence with venous investigators and recorded. The flow through the cavernous occlusion for 180 to 290 seconds (mean 235 seconds). However, arteries was measured in four monkeys (No. 7-10) by duplex during this period and for the next 180 to 200 seconds, the ultrasound.17 Pulse and blood pressure were monitored closely erectile response to neurostimulation was completely abolished. with the aid of a Doppler probe (Parks Medical Electronics) on Acetylcholine (0.5 mg.) was injected intracavernously after the radial artery and a pediatric blood pressure cuff (fig. 1). trimethaphan camsylate's intrinsic activity had subsided (by Intracavernous injection of ACh. All monkeys received doses direct vasodilation and smooth muscle relaxation) but during of 0.5, 1 (5 x 10~9 mol.), 10, 100 and 500 Mg. ACh (Miocholine, maintenance of nicotinic blockade. Cooper Vision, Puerto Rico) by intracavernous injection. The Injection of trimethaphan camsylate and ACh was repeated effects of each dose were allowed to subside and a 10 to 15 after 0.1 mg. atropine. The effect of ACh on the cavernous outflow. In five monkeys, a flow probe was placed around the pudendal artery and the Accepted for publication December 15, 1988. aorta was dissected for intermittent clamping with a Satinsky * Requests for reprints: Dept. of Urology, University of California School of Medicine, San Francisco CA 94143. clamp. With the aorta clamped and the intracavernous pressure

Supported by a grant from Deutsche Forschungsgemeinschaft. at baseline (mean 11 cm. H20), the penis was perfused with ACETYLCHOLINE AS NEUROTRANSMITTER 1445

0.5 μς injection

1.0 μς Intracavernous Pressure

(cm H20)

10 μς

100 μς

Flow (ml/min)

500 μς Intracavernous Pressure

(cm H20)

Pressure Recording Flow FlG. 1. Erection was induced in monkeys by cavernous nerve stim­ (ml/min) ulation or intracavernous injection. Arterial response was measured by Duplex ultrasound or by flow probe placed around pudendal artery, or both. Intracavernous pressure response was recorded via needle in­

serted in cavernous body. B (cm H20) \f

saline (37C) at increasing rates (3.8, 7.6, 15.3 and 26.6 ml./ min.) before and after 0.5 mg. ACh intracavernously. When the

perfusion had continued for 60 seconds or the intracavernous FIG. 2. Erectile responses to intracavernous injection of ACh at pressure surpassed 200 cm. H20, it was stopped. After intervals different doses. of 90, 60 and 60 seconds the penis was re-perfused. The clamp on the aorta was then released. Histologic staining for acetylcholinesterase. In five monkeys A multi-peaked, wave-shaped intracavernous pressure re­ in which no neurotransmitter studies had been performed (i.e. sponse was seen after 100 μg. in three monkeys and after 500 animals to be sacrificed by other departments at our institu­ μg. in four (fig. 2). In the majority, 0.5 μg. ACh caused the tion), the aorta was clamped and the distal aorta was perfused systemic blood pressure to fall below 40 mm. Hg for about 20 with two liters of saline to wash the red blood cells from the to 40 seconds. penile tissue. The penis was then immediately frozen and Intracavernous injection of ACh after muscarinic blockade by stained for acetylcholinesterase (AChE).19 atropine. Intracavernous injection of 0.1 mg. atropine was not followed by changes in heart rate or systemic blood pressure. RESULTS It induced an increase in the arterial flow of brief duration (five Intracavernous injection of ACh. Intracavernous injection of to 10 seconds) and slight tumescence lasting 10 to 25 seconds. ACh induced a dose-dependent increase in penile tumescence, The subsequent response to ACh remained dose-dependent: 0.5 intracavernous pressure, and flow through the internal puden­ and one μg. did not result in tumescence, but only in penile dal artery (fig. 2). The lowest dosage that induced penile contraction with a subsequent intracavernous pressure increase tumescence was 0.5 μg. in three monkeys, one μg. in six, and (table 1). Compared with the effect induced by ACh alone, the 10 μg. in one. The first observable change was an increase in response to ACh after atropine injection was markedly differ­ arterial flow, followed by penile tumescence, and then, after ent: the duration of tumescence and the increase in intracav­ some seconds, by an increase in intracavernous pressure. The ernous pressure and arterial flow were less; the contraction duration of tumescence increased with increasing dosages: from phase was more pronounced (high intracavernous pressure) a mean of nine seconds (zero to 14 seconds) after 0.5 ^g. to a and more prolonged; no second tumescence phase occurred. In mean of 82 seconds (60 to 96) after 500 μg. ACh. the monkeys with wave-shaped erectile responses to 100 and A characteristic tri-phasic response was seen in seven mon­ 500 μg. ACh, the same doses after atropine induced a continu­ keys with dosages up to 100 μg. and two monkeys up to 500 μg. ous, sustained erectile response. Acetylcholine first induced penile tumescence and a rise in Erection induced by neurostimulation before and after atro­ intracavernous pressure. This was followed by penile contrac­ pine. In all six monkeys with electrodes around the cavernous tion and a plateau in intracavernous pressure at a level above nerve, electrical stimulation induced a reproducible full erec­ baseline (fig. 2). During penile contraction, the arterial flow tion. After 0.1 mg. atropine, the first neurostimulation produced within the cavernous artery was markedly greater than in the the same full erection as before. In the subsequent neurosti- flaccid state. This contraction was followed by another increase mulated erections, the phase until attainment of maximal in­ in tumescence and intracavernous pressure, both less dramatic tracavernous pressure was prolonged by 10 to 34% (mean 28%; than those in the first phase (table 1). a mean delay of four seconds; ρ <0.001 [Student's t test]) and 1446 STIEF AND ASSOCIATES

TABLE 1. Erectile response to acetylcholine before and after atropine

A CU First Tumescence Contraction Second Tumescence ALn Pressure* Duration t .. tr \ Duration Pressure Duration Pressure

(min.) (cm. H,0) (min.) (cm. H20) (min.) (cm. H,0)

0.5 15 35t 90 60 60 32 1 24 40 120 60 60 40 10 32 65 120 60 70 40 100 54 105 150 60 90 25 500 84 120 180 75 90 25

After 0.1 mg. atropine 0.5 - - 40 60 1 - - 62 60 10 14 42 165 90 100 22 60 210 100 500 30 75 260 100

* Intracavernous pressure. t Numbers represent mean values for all monkeys that responded (3 to 0.5 ^g., 6 to 1.0 ßg. 7 to 10 ^g., and all 10 to 100 and 500 ßg). the full erection pressure was decreased by 12 to 20% (mean

16% or 25 cm. H20; ρ <0.05). The detumescence phase was unchanged. The immediate, strong increase in flow within the internal pudendal artery at cavernous nerve stimulation was decreased by a mean of 29%. Intracavernous injection of ACh after nicotinic blockade by trimethaphan camsylate. Intracavernous injection of trimetha­ phan camsylate was followed by a mean reduction in systemic blood pressure of 12 cm. H20 for two to three minutes. After nicotinic blockade, intracavernous injection of 0.5 mg. ACh induced a similar erection to the one before trimethaphan camsylate, but attainment of maximal intracavernous pressure was delayed by a mean of nine seconds. The injection of 0.5 mg. ACh after 0.1 mg. atropine and nicotinic blockade induced slight penile tumescence in one of the six monkeys, but no tumescence or increase in intracav­ ernous pressure in five. The effect of ACh on the cavernous outflow. With the aorta clamped, saline perfusion after ACh injection resulted in a perfusion-dependent plateau in intracavernous pressure with­ out penile tumescence. Immediately after injection of 0.5 mg. ACh, perfusion rates of 3.8 ml./min. and higher induced full penile erection (intracavernous pressure > 200 cm. H20). Re- perfusion after 90 seconds produced the same result. However, with the third perfusion, flow rates up to 26.6 ml./min. did not induce any tumescence, although, at the fourth perfusion, flow rates > 15.3 ml./min. again induced full erection (fig. 3). Thus, this perfusion study shows that intracavernous injection of ACh induced cavernous smooth muscle relaxation and subse­ quent cavernous outflow occlusion during the first two perfu­ sions, but no cavernous occlusion (or smooth muscle relaxation) during the third. With the fourth perfusion, cavernous occlu­ 11 min I sion was again demonstrated, although it was not as pro­ FIG. 3. With aorta clamped and 500 μg. ACh injected intracav­ nounced as immediately after ACh injection (probably owing ernously, saline perfusion induced venous occlusion at minutes 0 and to a lesser degree of smooth muscle relaxation). Thus, the 1 (first tumescence phase). At minute 3, no venous occlusion could be induced by perfusion rates below 26.6 ml./min. (contraction phase). perfusion study confirmed the above-described findings of a Then, at minutes 5 and 7, venous occlusion was produced by flow rates triphasic erectile response to intracavernous ACh. of 15.3 ml./min. and greater. Histologic findings. In the histologic sections from the five monkeys, dense staining for acetylcholinesterase was seen traction.15 After the effect of noradrenaline on its receptors has around the cavernous artery, within nerves near the cavernous subsided, the second phase of tumescence could be explained artery, and within the cavernous erectile tissues. No staining by the ongoing effect of ACh on the cavernous smooth muscles was found in the tunica albuginea (fig. 4). in combination with the ongoing increase in arterial flow. The initial small dip in the intracavernous pressure at the beginning DISCUSSION of this second phase of tumescence (fig. 2) can easily be ex­ Intracavernous injection of ACh in the monkey induced a plained by the elongation of the penis at this time. triphasic, dose-dependent erectile response: a first phase of Intracavernous ACh provoked an immediate, strong increase penile tumescence and rigidity; a phase of penile contraction; in arterial flow, which subsided somewhat but remained at and a second phase of penile tumescence, not as pronounced as moderately increased levels during the three phases. These the first. This triphasic reaction with contraction between two pressure and flow effects were not due solely to a muscarinic phases of tumescence may be explained by an immediate or cholinergic effect because they could not be completely blocked reflexogenic release of noradrenaline from noradrenergic by atropine. Only after the additional intracavernous injection nerves.20 Carbachol has been reported to induce a similar effect of a nicotinic blocker did ACh induce no erectile response. in vitro: cavernous smooth muscle relaxation followed by con- These observations correspond to the findings of Adaikan and ACETYLCHOLINE AS NEUROTRANSMITTER 1447

FlG. 4. Dense acetylcholinesterase-positive areas (dark spots) were found A, around cavernous arteries and B, within cavernous erectile tissue. (Magnification X 200 and X 400 for A and B, respectively.)

coworkers,13 who demonstrated muscarinic and nicotinic chol- the monkey induces a dose-dependent erectile response by inoreceptors in human cavernous tissue. This overlapping of increasing the arterial flow, relaxing the cavernous smooth muscarinic and nicotinic effects after the intracavernous injec• muscles, and occluding the cavernous outflow. These in vivo tion of ACh, together with an increasing effect on the systemic results, together with the histologic findings of AChE-positive blood pressure with doses of 0.1 and 0.5 mg., can explain the fibers around the cavernous artery and within the cavernous two (or more) wave-shaped erectile responses to high doses of erectile tissue, suggest that ACh may be a neurotransmitter for ACh in seven monkeys. penile erection. The fact that atropine could only diminish, but Atropine modulated but did not abolish the erectile response not abolish, the erectile response to neurostimulation suggests to neurostimulation. The reduction of the immediate increase the presence of additional postganglionic parasympathetic neu• in arterial flow led to a prolongation of the tumescence phase. rotransmitters for erection. There is strong evidence that vas• This and the decreased intracavernous pressure were supported oactive intestinal polypeptide (VIP) may be one of these.27-30 as signs of incomplete cavernous relaxation by the staining of We have observed that the combination of atropine and anti- AChE around the cavernous artery and within the cavernous VIP likewise only reduces the erectile response to neurostim• smooth muscles on histologic examination. ulation (unpublished data), and therefore further studies are Our findings of the erectile response to intracavernous injec• needed to uncover additional neurotransmitters involved in tion of ACh are in agreement with other in vivo studies: partial penile erection. or full erections have been described after ACh in the rabbit"1 I and dog;22 atropine has been shown to reduce significantly the erectile response to pelvic and hypogastric nerve stimulation in REFERENCES

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