J O U R A A ISSN 0022-5347

olume141 June 1989 Number 6

The Journal of

UROLOGY F O U N D E D I N 1917 B Y H U G H H A M P T O N Y O U N G

Official Journal of the Amer ican Urological Association, Inc.

)

CONTENTS CLINICAL UROLOGY

Review Article Nonoperative Management of Benign Prostatic Hyperplasia. H. Lepor 1283

Original Articles Selective Use of Excretory Urography in Women W i t h 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, J r . , 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, J r . 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 Car­cinoma. J . A. Belis, W. E. Pae, J r . , T. J . Rohner, J r . , 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 i n Metastatic Renal Cell Car­cinoma. B. Ljungberg, R. Tomic and G. Roos 1308

Carcinoma of Renal Pelvis and Ureter Following Bladder Carcinoma. Frequency, Risk Factors and Cl in -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 W i t h Review of Literature. J . P. Long, J r . and A. F. Althausen 1328 Flow Cytometry as Predictor of Response and Progression in Patients W i t h Superficial Bladder Cancer

Treated W i t h Bacillus Calmette-Guerin. P. R. Bretton, H. W. Herr, Μ. Kimmel, W. R. Fair, W. F. Whitmore, J r . and M. R. Melamed (Editorial Comment by R. W. deVere White) 1332

Intravesical Mitomycin C Insti l lat ion 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 E l . 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 W i t h 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 W i t h Advanced Adenocarcinoma of Pros­tate. 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 I n 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 W i t h 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 Tripl ication W i t h Crossed Ectopic Fused Kidneys Associated W i t h V A C T E R L Syn­

drome. J . Golomb and R. M. Ehrlich 1398 Retroiliac Ureter in Male Newborn W i t h Mult iple 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, I I I ) 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 W i t h 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

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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 I I H L A Antigen Expression by Transitional Cell Carcinoma of Bladder: Correlation W i t h

T-Cell Inf i l t rat ion 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

p H Analysis of Papaverine-Phentolamine and Prostaglandin El for Pharmacologic Erection. E. J . Seidmon and A. M. Samaha, J r 1458

I n Vivo Transfer of R-Plasmid in Urinary Tract Infection Model. D. E. Neal, J r . , Ε. Ε. M. Moody, V. L . Thomas, R. Gander and Η. M. Radwin 1460

Effects of A n t i - L i p i d A Human Monoclonal Antibody on Lipopolysaccharide-Induced Toxic ity to K i d ­ney. Β. M. Tune, C.-Y. Hsu, Μ. M. Bieber and Ν. Ν. H. Teng 1463

Immunoresponse of Tissue Inf i l t rat ing Lymphocytes in Bladder Tumors. H. Tsujihashi, H. Matsuda, S. Uejima, Τ Akiyama and T. Kurita 1467

I n Vitro Intravesical Insti l lat ion 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 I n 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 i n Follow-Up of Bladder Carcinoma. E. J . H. Meuleman and K. P. J . Delaere 1498

Impact of Hydronephrosis on Renal Function in Patients Treated W i t h 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 W i t h Stage I I I and I V 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 T r i a l of Etoposide + Cisplatin Versus Vinblastine + Bleomycin + Cisplatin + Cyclo­phosphamide + Dactinomycin in Patients W i t h 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, J r 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 W i t h Hypertension From Reflux or Obstructive Nephropathy. V. Braren, J . C.

West, J r . , 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 O K T 3 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 A n t i - 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

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Early Function as Principal Correlate of Graft Survival. Multivariate Analysis of 200 Cadaveric Renal Trans­plants Treated W i t h 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 W i t h Severe Cytomegalovirus Infec­t ion. 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 A n ­

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, J r . , Μ. H. McMullan, Η. B. Tyler, G. H. Mundinger, J r . and R. E. Kennedy 1507

Results of Renal Artery Balloon Angioplasty L i m i t 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 W i t h Spinal Cord Injury: Measurement W i t h 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, J r 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 T r i a l . 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 Art i f ic ia l Sphincter i n Complicated Salvage Radical Prostatectomy. S.

D.Boyd 1515 Radical Pelvic Surgery W i t h 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 W i t h 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 Arthr i t i s , Reiter's Disease, Multicentric Reticulohistiocytosis, and Progressive Systemic Scle­rosis. R. Η Gold, L W. Bassett and L . L . Seeger 1518

Demonstration of Rectovesical Fistula on Technetium-99m M D P 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 i i i

PROPRIETARY NAMES

Many of the words appearing in the J O U R N A L 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 i t is not the subject of proprietary rights.

A 1 6

0 0 2 2 - 5 3 4 7 / 8 9 / 1 4 1 6 - 1 4 4 4 $ 0 2 . 0 ( ) / 0 T H E J O U R N A L O F U R O L O G Y C o p y r i g h t © 1989 by W i l l i a m s & W i l k i n s

V o l . 141, J u n t Printed in U.S.A

A C E T Y L C H O L I N E AS A P O S S I B L E N E U R O T R A N S M I T T E R IN P E N I L E E R E C T I O N

C H R I S T I A N S T I E F , F R A N C O I S B E N A R D , R U U D B O S C H , S H E R I F A B O S E I F , L O R A N U N E S , T O M F . L U E * A N D E M I L A . T A N A G H O

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

A B S T R A C T

We investigated the erectile response to intracavernous injection of increasing doses of acetylcho­line (0.5 to 500 M g . ) in 10 monkeys. T o 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. H 2 0 ) . 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 stimula­t ion of pelvic parasympathetic nerves induces penile erection in the dog,1 many studies have confirmed these findings in different species.2"7 Based on the classic theory of autonomic neurotransmission, the muscarinic neurotransmitter was be­lieved to be acetylcholine (ACh). 8 However, penile erection has been shown to be atropine-resistant, 9 , 1 0 and organ bath studies of the effect of ACh on cavernous smooth muscle have been inconclusive. I n vitro , all possible responses to ACh have been observed: no e f fect ; 1 1 1 2 inconsistent effects; 1 1 and both contraction 1 4 and re laxat ion 1 5 , 1 6 of the cavernous smooth mus­cle. Our aim was to examine in vivo a possible role of ACh as a postganglionic parasympathetic neurotransmitter for penile erection.

M A T E R I A L S A N D M E T H O D S

Ten pigtail monkeys, weighing 4.3 to 10.5 kg., were used. After adequate anesthesia wi th ketamine (30 mg./kg. body-weight i.m.), the monkeys were placed in the supine position. Under sterile conditions, one 21-gauge scalp-vein needle was placed in each distal right and left cavernous body. One needle was connected to a Statham transducer (model P23 BC) for intracavernous pressure recording (Grass Polygraph; model 7); the other served for intracavernous injection or perfusion. Penile tumescence was visually monitored by at least two investigators and recorded. The flow through the cavernous arteries was measured in four monkeys (No. 7-10) by duplex ultrasound. 1 7 Pulse and blood pressure were monitored closely wi th the aid of a Doppler probe (Parks Medical Electronics) on the radial artery and a pediatric blood pressure cuff (fig. 1).

Intracavernous injection of ACh. A l l monkeys received doses of 0.5, 1 (5 x 10~9 mol.), 10, 100 and 500 Mg. ACh (Miocholine, Cooper Vision, Puerto Rico) by intracavernous injection. The effects of each dose were allowed to subside and a 10 to 15

Accepted for publ icat ion D e c e m b e r 15, 1988. * R e q u e s t s for repr ints : D e p t . of Urology, U n i v e r s i t y of C a l i f o r n i a

S c h o o l of M e d i c i n e , S a n F r a n c i s c o C A 94143. Supported by a grant from D e u t s c h e F o r s c h u n g s g e m e i n s c h a f t .

minute waiting period intervened before the next injection. To verify reproducibility, all injections were given twice.

Intracavernous injection of ACh after muscarinic blockade. The above injection protocol was followed after intracavernous injection of 0.1 mg. atropine (1.4 Χ 10" 7 mol.) (Elkins-Sim Inc., Cherry H i l l , N.Y.) . This dosage was chosen after 0.01 mg. intracavernously proved to be sufficient for complete musca­rinic blockade in dogs (unpublished data). Although the size of the cavernous bodies in monkeys and dogs is comparable, a ten-fold increase (0.1 mg.) was selected to ensure complete local muscarinic blockade.

Erections induced by neurostimulation before and after atro­pine. I n monkeys 1-6, cuff electrodes were placed around the cavernous nerve as previously described. 1 8 After three erections had been induced by neurostimulation (20 Hz, six to eight V, stimulation time = one minute), 0.1 mg. atropine was injected intracavernously and neurostimulation was repeated five times w i t h an eight-minute interval between each stimulation.

Intracavernous injection of ACh after nicotinic blockade. To investigate the effect of ACh after nicotinic blockade, the six monkeys w i t h implanted electrodes were given an intracaver­nous injection of 1.6 mg. trimethaphan camsylate (Roche Lab­oratories, Nutley, N.J.), the lowest dosage shown to block neurostimulation-induced erections in all monkeys. The drug's intrinsic activity resulted in penile tumescence wi th venous occlusion for 180 to 290 seconds (mean 235 seconds). However, during this period and for the next 180 to 200 seconds, the erectile response to neurostimulation was completely abolished. Acetylcholine (0.5 mg.) was injected intracavernously after trimethaphan camsylate's intrinsic activity had subsided (by direct vasodilation and smooth muscle relaxation) but during maintenance of nicotinic blockade.

Injection of trimethaphan camsylate and ACh was repeated after 0.1 mg. atropine.

The effect of ACh on the cavernous outflow. I n five monkeys, a flow probe was placed around the pudendal artery and the aorta was dissected for intermittent clamping w i t h a Satinsky clamp. W i t h the aorta clamped and the intracavernous pressure at baseline (mean 11 cm. H 2 0 ) , the penis was perfused w i t h

A C E T Y L C H O L I N E A S N E U R O T R A N S M I T T E R 1445

0.5 μς injection

Pressure Recording

F l G . 1. E r e c t i o n was induced in m o n k e y s by cavernous nerve s t i m ­u l a t i o n or i n t r a c a v e r n o u s inject ion . A r t e r i a l response was measured by D u p l e x u l t r a s o u n d or by flow probe placed a r o u n d pudendal artery , or both . I n t r a c a v e r n o u s pressure response was recorded v i a needle i n ­serted i n cavernous body.

saline (37C) at increasing rates (3.8, 7.6, 15.3 and 26.6 m l . / min.) before and after 0.5 mg. ACh intracavernously. When the perfusion had continued for 60 seconds or the intracavernous pressure surpassed 200 cm. H 2 0 , i t was stopped. After intervals of 90, 60 and 60 seconds the penis was re-perfused. The clamp on the aorta was then released.

Histologic staining for acetylcholinesterase. I n five monkeys in which no neurotransmitter studies had been performed (i.e. animals to be sacrificed by other departments at our inst i tu ­t ion) , the aorta was clamped and the distal aorta was perfused w i t h two liters of saline to wash the red blood cells from the penile tissue. The penis was then immediately frozen and stained for acetylcholinesterase (AChE). 1 9

R E S U L T S

Intracavernous injection of ACh. Intracavernous injection of ACh induced a dose-dependent increase in penile tumescence, intracavernous pressure, and flow through the internal puden­dal artery (fig. 2). The lowest dosage that induced penile tumescence was 0.5 μg. in three monkeys, one μg. in six, and 10 μg. in one. The first observable change was an increase in arterial flow, followed by penile tumescence, and then, after some seconds, by an increase in intracavernous pressure. The duration of tumescence increased w i t h increasing dosages: from a mean of nine seconds (zero to 14 seconds) after 0.5 ^g. to a mean of 82 seconds (60 to 96) after 500 μg. ACh.

A characteristic tri-phasic response was seen in seven mon­keys with dosages up to 100 μg. and two monkeys up to 500 μg. Acetylcholine first induced penile tumescence and a rise in intracavernous pressure. This was followed by penile contrac­t ion and a plateau in intracavernous pressure at a level above baseline (fig. 2). During penile contraction, the arterial flow wi th in the cavernous artery was markedly greater than in the flaccid state. This contraction was followed by another increase in tumescence and intracavernous pressure, both less dramatic than those in the first phase (table 1).

Intracavernous Pressure (cm H20)

1.0 μς

10 μ ς

100 μς

Flow (ml/min)

500 μς Intracavernous

Pressure (cm H20)

Flow (ml/min)

mBH20) \f ( c m

F I G . 2. E r e c t i l e responses to i n t r a c a v e r n o u s inject ion of A C h at different doses.

A multi-peaked, wave-shaped intracavernous pressure re­sponse was seen after 100 μg. in three monkeys and after 500 μg. in four (fig. 2). I n the majority, 0.5 μg. ACh caused the systemic blood pressure to fall below 40 mm. Hg for about 20 to 40 seconds.

Intracavernous injection of ACh after muscarinic blockade by atropine. Intracavernous injection of 0.1 mg. atropine was not followed by changes in heart rate or systemic blood pressure. I t induced an increase in the arterial flow of brief duration (five to 10 seconds) and slight tumescence lasting 10 to 25 seconds. The subsequent response to ACh remained dose-dependent: 0.5 and one μg. did not result in tumescence, but only in penile contraction with a subsequent intracavernous pressure increase (table 1). Compared w i t h the effect induced by ACh alone, the response to ACh after atropine injection was markedly differ­ent: the duration of tumescence and the increase in intracav­ernous pressure and arterial flow were less; the contraction phase was more pronounced (high intracavernous pressure) and more prolonged; no second tumescence phase occurred. I n the monkeys wi th wave-shaped erectile responses to 100 and 500 μg. ACh, the same doses after atropine induced a continu­ous, sustained erectile response.

Erection induced by neurostimulation before and after atro­pine. I n all six monkeys w i t h electrodes around the cavernous nerve, electrical stimulation induced a reproducible ful l erec­t ion. After 0.1 mg. atropine, the first neurostimulation produced the same full erection as before. I n the subsequent neurosti-mulated erections, the phase u n t i l attainment of maximal i n ­tracavernous pressure was prolonged by 10 to 34% (mean 28%; a mean delay of four seconds; ρ <0.001 [Student's t test]) and

1446 S T I E F A N D A S S O C I A T E S

T A B L E 1. Erectile response to acetylcholine before and after atropine

A CU F i r s t T u m e s c e n c e C o n t r a c t i o n S e c o n d T u m e s c e n c e A L n t .. tr \ D u r a t i o n P r e s s u r e * D u r a t i o n P r e s s u r e D u r a t i o n P r e s s u r e

( m i n . ) ( c m . H , 0 ) ( m i n . ) ( c m . H 2 0 ) ( m i n . ) ( c m . H , 0 )

0.5 15 3 5 t 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

A f t e r 0.1 mg. a t r o p i n e 0.5 - - 40 60 1 - - 62 60

10 14 42 165 90 100 22 60 210 100 500 30 75 260 100

* I n t r a c a v e r n o u s p r e s s u r e . t N u m b e r s r e p r e s e n t m e a n v a l u e s for a l l m o n k e y s t h a t r e s p o n d e d (3 to 0.5 ^ g . , 6 to 1.0 ßg. 7 to 10 ^g . , a n d a l l 10 to 100 a n d 500 ßg).

the ful l erection pressure was decreased by 12 to 20% (mean 16% or 25 cm. H 2 0 ; ρ <0.05). The detumescence phase was unchanged. The immediate, strong increase in flow with in 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 tr imetha­phan camsylate was followed by a mean reduction in systemic blood pressure of 12 cm. H 2 0 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 intracav­ernous pressure in five.

The effect of ACh on the cavernous outflow. W i t h the aorta clamped, saline perfusion after ACh injection resulted in a perfusion-dependent plateau in intracavernous pressure w i t h ­out penile tumescence. Immediately after injection of 0.5 mg. ACh, perfusion rates of 3.8 m l . / m i n . and higher induced full penile erection (intracavernous pressure > 200 cm. H 2 0 ) . Re-perfusion after 90 seconds produced the same result. However, w i th the th i rd perfusion, flow rates up to 26.6 m l . / m i n . did not induce any tumescence, although, at the fourth perfusion, flow rates > 15.3 m l . / m i n . again induced ful l erection (fig. 3 ) . Thus, this perfusion study shows that intracavernous injection of ACh induced cavernous smooth muscle relaxation and subse­quent cavernous outflow occlusion during the first two perfu­sions, but no cavernous occlusion (or smooth muscle relaxation) during the th i rd . W i t h the fourth perfusion, cavernous occlu­sion was again demonstrated, although i t was not as pro­nounced as immediately after ACh injection (probably owing to a lesser degree of smooth muscle relaxation). Thus, the perfusion study confirmed the above-described findings of a triphasic erectile response to intracavernous ACh.

Histologic findings. I n the histologic sections from the five monkeys, dense staining for acetylcholinesterase was seen around the cavernous artery, w i th in nerves near the cavernous artery, and wi th in the cavernous erectile tissues. No staining was found in the tunica albuginea (fig. 4).

D I S C U S S I O N

Intracavernous injection of ACh in the monkey induced a triphasic, dose-dependent erectile response: a first phase of penile tumescence and rigidity; a phase of penile contraction; and a second phase of penile tumescence, not as pronounced as the first. This triphasic reaction wi th contraction between two phases of tumescence may be explained by an immediate or reflexogenic release of noradrenaline from noradrenergic nerves. 2 0 Carbachol has been reported to induce a similar effect in vitro: cavernous smooth muscle relaxation followed by con-

11 min I

F I G . 3. W i t h aorta c l a m p e d a n d 500 μg. A C h injected i n t r a c a v ­ernously , sa l ine perfusion induced venous occ lus ion at minutes 0 a n d 1 (first tumescence phase ) . A t minute 3, no venous occlusion could be induced by perfusion rates below 26.6 m l . / m i n . (contract ion p h a s e ) . T h e n , at minutes 5 a n d 7, venous occlusion w a s produced by flow rates of 15.3 m l . / m i n . a n d greater.

tract ion. 1 5 After the effect of noradrenaline on its receptors has subsided, the second phase of tumescence could be explained by the ongoing effect of ACh on the cavernous smooth muscles in combination wi th the ongoing increase in arterial flow. The init ia l small dip in the intracavernous pressure at the beginning of this second phase of tumescence (fig. 2) can easily be ex­plained by the elongation of the penis at this time.

Intracavernous ACh provoked an immediate, strong increase in arterial flow, which subsided somewhat but remained at moderately increased levels during the three phases. These pressure and flow effects were not due solely to a muscarinic cholinergic effect because they could not be completely blocked by atropine. Only after the additional intracavernous injection of a nicotinic blocker did ACh induce no erectile response. These observations correspond to the findings of Adaikan and

A C E T Y L C H O L I N E A S N E U R O T R A N S M I T T E R 1447

F l G . 4. D e n s e acety lchol inesterase -posi t ive areas (dark spots) were found A, a r o u n d cavernous arteries a n d B, w i t h i n cavernous erectile t issue. ( M a g n i f i c a t i o n X 200 a n d X 400 for A a n d B, respectively . )

coworkers, 1 3 who demonstrated muscarinic and nicotinic chol-inoreceptors in human cavernous tissue. This overlapping of muscarinic and nicotinic effects after the intracavernous injec­t ion of ACh, together w i t h an increasing effect on the systemic blood pressure wi th doses of 0.1 and 0.5 mg., can explain the two (or more) wave-shaped erectile responses to high doses of ACh in seven monkeys.

Atropine modulated but did not abolish the erectile response to neurostimulation. The reduction of the immediate increase in arterial flow led to a prolongation of the tumescence phase. This and the decreased intracavernous pressure were supported as signs of incomplete cavernous relaxation by the staining of AChE around the cavernous artery and wi th in the cavernous smooth muscles on histologic examination.

Our findings of the erectile response to intracavernous injec­t ion of ACh are in agreement wi th other in vivo studies: partial or fu l l erections have been described after ACh in the rabbit" 1

I and dog; 2 2 atropine has been shown to reduce significantly the erectile response to pelvic and hypogastric nerve stimulation in the dog,4 cat 2 3 and rabbit ; 2 1 AChE-containing nerve fibers have been found in the cavernous tissue and around the cavernous

I artery in man and different animal species. 1 1 , 1 2 ' 2 4" 2 6

A t variance, Henderson et al. observed no erectile response ! after intraaortic injection of ACh. 3 This lack of effect may be

due to the immediate inactivation of ACh by the AChE in the blood, to the pronounced lowering of the systemic blood pres­sure after high doses of ACh, or to the fact that the pressure in

I the glans instead of in the cavernous bodies was recorded. The abil ity of atropine to antagonize penile erection in man could

I not be proven in two studies . 9 1 0 However, intracavernous pres­sure was not monitored by invasive means and a 15 or 20%

j lowering of the maximal pressure could have been easily missed. Results of in vitro studies of the effect of ACh on the

cavernous smooth muscle have been contradictory, showing a range of results: no e f fect ; 1 1 1 2 inconsistent effects; 1 3 contrac­t i o n ; 1 4 and r e l a x a t i o n . 1 5 1 6 These contradictory findings may have several causes. To prove a relaxing effect, the cavernous smooth muscle must first be contracted by electrical or phar­macologic means. I n the studies in which the smooth muscles were contracted by norepinephrine before ACh was given, a relaxing effect could be shown. Secondly, the human cavernous smooth muscle, like the monkey's, w i l l probably react to intra ­cavernous injection of ACh in a triphasic manner, but the dog responds w i t h a single phase of tumescence and rigidity (un­published data). Third ly , the action of ACh may be dependent on an intact cavernous endothelium (Goldstein, I . : personal communication). I n the studies in which no effect was observed, the cavernous endothelium may have been damaged during preparation of the tissue.

Our study showed that intracavernous injection of ACh in

the monkey induces a dose-dependent erectile response by increasing the arterial flow, relaxing the cavernous smooth muscles, and occluding the cavernous outflow. These in vivo results, together wi th the histologic findings of AChE-positive fibers around the cavernous artery and wi th in the cavernous erectile tissue, suggest that ACh may be a neurotransmitter for penile erection. The fact that atropine could only diminish, but not abolish, the erectile response to neurostimulation suggests the presence of additional postganglionic parasympathetic neu­rotransmitters for erection. There is strong evidence that vas­oactive intestinal polypeptide (VIP) may be one of these. 2 7 - 3 0

We have observed that the combination of atropine and ant i -V I P likewise only reduces the erectile response to neurostim­ulation (unpublished data), and therefore further studies are needed to uncover additional neurotransmitters involved in penile erection.

R E F E R E N C E S

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