Models of Urogenital Dysfunction: Benign Prostatic Hyperplasia (BPH)

Barry Kenny1, Alison Miller2, Neil Brunton2, Donald Newgreen2

1 Cambridge Drug Discovery, Ltd., Cambridge, United Kingdom, 2 Discovery Biology Pfizer Central Research, Sandwich, Kent, United Kingdom
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 5.10
DOI:  10.1002/0471141755.ph0510s01
Online Posting Date:  May, 2001
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Abstract

Bladder outlet obstruction can be associated with benign prostatic hyperplasia (BPH). A reduction in prostatic smooth muscle tone provides a means of improving the obstructive symptoms associated with BPH. This unit presents methods for studying prostatic pressure in both the anesthetized and conscious dog. In both models, the primary determinant is the measurement of experimentally induced changes in intra‐urethral prostatic pressure. The protocols allow measurement of the effects of compounds on agonist‐ or nerve‐stimulated prostatic contraction in vivo. Th conscious dog model has two potential advantages over the anesthetized preparation: it can be used for oral dosing of test compounds and it allows measurement of the effects of test compounds on postural hemodynamics under conditions where reflexes are not compromised by anesthesia. In all the protocols in this unit, measurement of Bladder outlet obstruction can be associated with benign prostatic hyperplasia (BPH)

     
 
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Table of Contents

  • Basic Protocol 1: Measurement of Prostatic Pressure and Blood Pressure in the Anesthethized Dog
  • Alternate Protocol 1: Hypogastric Nerve Stimulation to Produce Rises in Prostate Pressure in the Anesthetized Dog
  • Basic Protocol 2: Measurement of Prostatic Pressure and Blood Pressure in the Conscious Dog
  • Support Protocol 1: Measurement of Postural Reflexes in Conscious Dogs
  • Reagents and Solutions
  • Commentary
  • Figures
  • Tables
     
 
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Materials

Basic Protocol 1: Measurement of Prostatic Pressure and Blood Pressure in the Anesthethized Dog

  Materials
  • Mature male beagle dog, 12.5 to 14 kg
  • 60 mg/ml sodium pentobarbitone BP
  • 8 µg/kg/ml L‐phenylephrine hydrochloride solution (based on the weight of the animal; see recipe)
  • Test compound solution (see recipe)
  • Sterile saline (0.9% w/v NaCl)
  • Saturated KCl solution
  • Angiocath (0.8‐mm diameter, 2.5‐cm length)
  • Laryngoscope
  • Endotracheal tube, size 9 or 10
  • Thermostatically controlled large‐animal operating table
  • Unita S syringe pump (B. Braun Medical)
  • Cautery (Engel‐Löter 100S)
  • Cannulae, Portex nonsterile tubing: pp 240, coded 800/100/460/100, 1.67‐mm i.d., 2.42‐mm o.d.; pp 100, coded 800/100/280/100, 0.86‐mm i.d., 1.52‐mm o.d.
  • Expired air analyzer: Datex Normocap 200 (Instrumentarium)
  • Bird Mk 8 respirator (Viamed)
  • Grass model 7 polygraph with two 7P1 low‐level DC preamplifiers, one 7P6 EKG preamplifier, and one 7P44 tachograph unit (Stag Instruments)
  • Spectramed Model P23XL transducer (Stag Instruments)
  • Criticath 7 F cardiac thermodilution catheter (110 cm; Ohmeda catheter products, Ohmeda Medical Devices)
  • Rectal thermistor probe 2001 (Comark Electronics)
  • ABL500 blood‐gas analyzer (Radiometer)

Alternate Protocol 1: Hypogastric Nerve Stimulation to Produce Rises in Prostate Pressure in the Anesthetized Dog

  • Small‐animal platinum bipolar electrode (Harvard Instruments)
  • Grass S88 stimulator (Stag Instruments)

Basic Protocol 2: Measurement of Prostatic Pressure and Blood Pressure in the Conscious Dog

  Materials
  • Mature male beagle dog, 12 to 18 kg
  • 1:750 detergicide in distilled water (USCI)
  • Sterile saline (0.9% w/v NaCl)
  • 25 IU/ml heparin in sterile saline
  • Xylocaine (optional)
  • Lubricating jelly
  • 60 µg/ml L‐phenylephrine hydrochloride solution (see recipe)
  • Test compound solution (see recipe)
  • Canvas support sling (length 80 cm, width 45 cm) with holes cut out for hind legs and 15‐cm slit for genitals
  • Two Micron model MP15D miniature pressure transducers (Micron Instruments)
  • Two 20‐G, 2‐in. Angiocath over‐the‐needle catheter units (Becton Dickinson Vascular Access)
  • 3‐way taps (Baxter Healthcare)
  • Extension set, 76‐cm length × 1.4‐mm i.d. (Baxter Healthcare)
  • HSE Plugsys Type 603 with 1 × DVM Digital Volt Meter Type 666, 1 × BPA Bio Potential Amplifiers Type 675, and 2 × DBA DC Bridge Amplifiers Type 660 (Hugo Sachs Electronik)
  • Po‐ne‐mah Digital acquisition, analysis, and archive system (Gould Instrument Systems)
  • Criticath 7 F thermodilution catheter (110 cm; Ohmeda catheter products, Ohmeda Medical Devices)
  • ECG connecting lead
  • Adapted 14 Fr. urethral catheter
  • Gavage tube
NOTE: Surgical gloves should be worn throughout the preparation process to minimize the risk of infecting the dog.NOTE: It is advisable to acclimatize dogs to the procedure before experimental use through sessions during which the dog is placed in the canvas sling in the laboratory without any procedures being carried out.
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Figures

Videos

Literature Cited

Literature Cited
  Arunlakshana, O. and Schild, H.O. 1959. Some quantitative uses of drug antagonists. Br. J. Pharmacol. Chemother. 14:48‐52.
   Blue, D.R., Ford, A.P.D.W., Morgans, D.R., Padilla, F., and Clarke, D.E. 1996. Preclinical pharmacology of a novel α1A/1L‐adrenoceptor antagonist, RS‐100975. Neurourol. Urodyn. 15:345‐346.
  Breslin, D., Fields, D.W., Chou, T.‐C., Marion, D.N., Kane, M., Vaughan, E.D., and Felson, D. 1993. Medical management of benign prostatic hyperplasia: A canine model comparing the in vivo efficacy of α1 adrenergic antagonists in the prostate. J. Urol. 149:395‐399.
   Brune, M.E., Buckner, S.A., Polakowski, J., Kerwin, J.F., and Hancock, A.A. 1995. harmacological antagonism of α adrenergic agonist induced increases in canine intraurethral pressure in vivo. Drug Dev. Res. 34:267‐275.
   Goetz, A.S., Lutz, M.W., Rimele, T.J., and Saussy, D.L. 1994. Characterization of α1 adrenoceptor subtypes in human and canine prostate membranes. J. Pharmacol. Exp. Ther. 271:1228‐1233.
   Kenny, B.A., Naylor, A.M., Carter, A.J., Read, A.M., Greengrass, P.M., and Wyllie, M.G. 1994. Effect of α1 adrenoceptor antagonists on prostatic pressure and blood pressure in the anaesthetized dog. Urology 44:52‐57.
   Kenny, B.A., Miller, A.M., Williamson, I.J.R., O'Connell, J., Chalmers, D.H., and Naylor, A.M. 1996. Evaluation of the pharmacological selectivity profile of α1 adrenoceptor antagonists at prostatic α1 adrenoceptors: Binding, functional and in vivo studies. Br. J. Pharmacol. 118:871‐878.
  Shibasaki, M., Sudoh, K., Inagaki, O., Uchida, W., and Honda, K. 1992. Effect of the optical isomers of YM‐12617 on increased intra‐urethral pressure induced by phenylephrine in anaesthetized dogs. J. Autonom. Pharmacol. 12:263‐268.
   Sudoh, K., Tanaka, H., Inagaki, M., and Takenaka, T. 1996. Effect of tamsulosin, a novel α1 adrenoceptor antagonist, on urethral pressure profile in anaesthetized dogs. J. Autonom. Pharmacol. 16:147‐154.
   Taniguchi, N., Hamada, K., Ogasawara, T., Ukai, Y., Yoshikuni, Y., and Kimura, K. 1996. NS‐49, an α1A adrenoceptor agonist, selectively increases intraurethral pressure in dogs. Eur. J. Pharmacol. 318:117‐122.
   Testa, R., Sironi, G., Colombo, D., Greto, L., and Leonardi., A. 1994. Rec 15/2739, a new α1‐adrenoceptor antagonist selective for the lower urinary tract: In vivo studies. Neurourol. Urodyn. 13:471‐473.
Key References
   Kenny et al., 1994. See above.
  An assessment of the selectivity exhibited by α1 adrenoceptor antagonists using the anesthetized dog protocol. Shows quantifiable effects of the compounds against blood pressure and prostate pressure responses.
   Sudoh et al., 1996. See above.
  An extension of the methodology described in the anesthetized dog in which urethral pressure profiles have been obtained along the entire urethra, and drug effects evaluated at the points of highest pressure.
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