ACTA MàDICA PORTUGUESA Vol. 4 n.° 1, 1983 ORIGINAL

THE ROLE OF PROSTAGLANDINS IN THE LOWERURINARY TRACT DYNAMICS OFPROSTATECTOMIZED PATIENTS: A TRIAL WITHINDOMETHACIN AND ASPIRIN

A. MATOS FERREIRA AND J. M. REIS SANTOS

Serviço de Urologia do Hospital Curry Cabral (H.C.L.),Departamento de Urologia da Faculdade de Ciências Médicas (U.N.L.). LisboaPortugal

SUMMARY

Using 49 prostatectomized patients as experimental subjects, we studied the effects of Inclometnacinand acetylsalicylic acid — accredited prostaglandin synthetase inhibitors — from a urodynamic and clinicalstandpoint. Relevant urodynamic data was gathered 1 hr 30 mi after the patients had taken the drugs andplacebo. Clinical results were further scrutinized after 8 days of treatment, at which time a new urodynamicworkup was again performed on some patients. Results were again studied shortly after the end of treatment. The effect of the drugs on bladder and urethral structures was borne out by clear-ct!t clinical andurodynamic changes. After statistically analyzing such changes, we concluded that prostaglandin synthesisinhibition resulting in the inhibition of prostaglandin action had, at least in part, led to the changes noted.In the present report we shall discuss the role played by the highly complex mechanisms at work.

RESUMO

O PAPEL DAS PROSTAGLANDINAS NA DINÂMICA DO TRACTO URINÁRIOINFERIOR DE DOENTES PROSTATECTOMIZADOS: UM ENSAIO COMINDOMETACINA E ASPIRINA

Usando 59 doentes prostatectomizados como modelo experimental, os AA estudaram os efeitos da indometacina e do ácido acetilsalicílico — inibidores acreditados da sintetase prostaglandinica — sob o ponto de vista urodinâmico e clínico.

Os dados urodinâmicos foram colhidos 1 hora e 30 minutos depois de os doentes terem tomado Placeboou os medicamentos e os resultados clínicos depois de 8 dias de tratamento, ao fim dos quais foi feito umnovo estudo urodinâmico em alguns doentes. Os resultados clínicos foram analisados, de novo, pouco tempo depois determinado o tratamento. O efeito dos medicamentos na bexiga e nas estruturas uretrais foi demonstrado pelas nítidas alterações clínicas e urodinâmicas. Depois de analisar estatisticamente os resultados, os AA concluem que a inibição da sintetase prostaglandínica e consequente inibição da acção dasprostaglandinas conduziu, pelo menos em parte, às alterações verificadas, cujos mecanismos, altamentecomplexos, são discutidos.

INTRODUCTION

Research has already been carried out iii vitro and inexperimental animais in order to determine the effect ofprostaglandins on bladder and urethral structures.25’12282931’5267 The causes behind possibie synthesisstimuli182228’29’31’57587074 and activating mechanisms ofbladder and urethral structures have been the subi ect of several papers.11’2536-43’50’52’61”6-78 Only very spotty work hasbeen done, nevertheless, on human beings in ~j~~.1215~4

Our clinical study and thorough urodynamic researchproject, which begun in 1979, had as its aim the better understanding of the role of prostaglandins in normal and pathological vesico-sphincteric dynamics. The patients chosenas the target group of our study had ali undergone open sur

gery for benign hypertrophy of the prostate. Since such patients often display vesico-urethral dysfunctions,1’48183’85-87and exhibit a posterior urethra simplified and reduced tothe distal sphincters144559’65818286 (Fig. 1), we reasoned thatthe study of changes undergone in this area would be easierto chart.

Changes brought about by the synthesis inhibition ofendogenous prostaglandins and related substances providedus with the data we needed for our study. To effect the desired result, we used two drugs, indomethacin and aspirin,which despite their total chemical dissimilarity, both inhibitprostaglandin synthesis.21’75’88 The study of accumulated experimental and clinical data13’19’21’24’62’75’88 provided us withthe dosage of both drugs (sufficient to completely inhibitthe synthesis of prostaglandins and related substances) andthe spacing of administrations.

Received: July 17, 1981 21

A. MATOS FERREIRA AND J. M. REIS SANTOS

POST-PRQSTATECTOMY STATUS

“lnt.rnalnon—tunctionol

lntrinhic striotedsphinct.r

lntrinsic distal aphinct.rm.chaflism lstriot.d and,.nooth muscl.—.lastictissue)

—Contin.nCe—Varying d.grees of inco~

tin.nct and obsiruction

C — Cholinergic receptoraa. — Alpha—adr.nergic receptora

9 — Beto—odrenergic receptora— Histamin. receptora

P — Prostaglandim receptors— Ganglia

Nerves tortuous course)

Fig. 1

Datrusor with varying de—grees ot hypertrophy andoth.r structural alterations

tntrinsic nsical and are—ttiral ínnervation — narylngdegrees ot lesion?

Bladder Idetrusar andinnervation) furictionallynormal unstabla or tiypcicantractile

—Frequency—Nocturia—Lkgency—Urge incontinence—Dribbling

Urinary retentian

De.p trigane

Post—prostatectomy caniiy

Smaoth muscle covering tirepast—prastotectomy cavitylPraproalatic UcNeal sptrincter—External circular ure—thral layer o~ Hulch andRombo) strawing varyingd.gre.s at damage

MATERIAL AND METHODS

59 patients were chosen on the basis of strict clinical, radiologicai and laboratorial criteria. When necessary, anI.V.P. was performed. Retrograde and micturition cystourethrograms were done on all patients and an endoscopywas performed whenever the presence of an organic lesionwas suspected. When confirmed, the patient was excluded.Also excluded were patients with diabetes, neurological orpsichiatric disorders, persistent organic bladder neck andurethral obstructions, total sphyncteric incontinence, andthose operated for simuitaneous vesical lesions. The use ofindomethacin and aspirin ied us to rule out patients withgastroduodenal ulcers as weii. Patients were not allowed totake any other type of medication starting at least a weekbefore and during the period of the trial.

A three-month post-operative time lapse was consideredthe minimum necessary for the probable eradication of residual infiarnmation and the epithelization of the area operated on. Given our interest in studying the clinical effects ofour therapy we tried to bring together ali patients we couldsuffering from functional disorders, that become rarer afterthat time period.4

A pre-operative and current ciinicai picture of each casewas formed, using a clinical protocoi that helped us to piacethe patients in two categories: normal (assymptomatic) with16 cases, and those suffering from a variery of functionaldisturbances — 43 cases. The patients were then divided into three main groups: placebo group with 12 patients, 8 ofwhom later became part of the indomethacin group whichhad 47 cases in ali, and 4 of whom later joined the aspiringroup composed of 12 cases.

At the onset ol our trial ail patients underwent a urodynamic work-up listed on Table 1, in which the terrninologyused is shown. A Disa (R) system was used. Urethral pressure profiles were not perfomed. International Continence Society4749 recomrnendations, terminology, units and symboiswere used whenever possibie. The procedure foliowed ineach urodynamic work-up and a few details not clearly inciuded in International Continence Society reports need tobe described.

With the patient supine, after having passed urine, a 1 2Fpoiyethylene urethrai catheter was introduced under localanesthesia and residual urine was measured. The bladderwas then filied at a continous rate of approximateiy 2 ml s-1with a room temperature normal saline soiution. In 39 cases, pressures (cm H2 O) were measured, with a suprapubic5 F poiyethyiene catheter and in the remaining cases with a6 F polyethylene urethrai catheter. Abdominal pressure wasmeasured using a rectal iatex baloon catheter. Detrusorpressures were indirectiy obtained, by subtracting abdominal from intravesical pressures. Maximum abdominal anddetrusor pressures were not measured. Detrusor post-micturition contraction pressure was obtained as indicatedfor the other detrusor pressures.

The slope’s tonus limb and colagen segment, when detectabie10’72’6° were mathernaticaiiy analysed (cm H2 O per100 mi), as prescribed by Merril et a16° and graphically represented. The sarne values which were directly measuredon the intravesical pressure curve, were used to caiculate thecompiiance in the muscular and colagen phases of biadderfiiling and are expressed in ml for cm H2 O.~

To detect possible detrusor instabiiity provocative stimuli such as coughing, standing and heei jouncing were empioyed during this phase.

22

THE ROLE OF PROSTAGLANDINS IN THE LOWER URINARY TRACf

Micturition pressures and flow (ml s-1) were then studied and either intermitent (1) or continous (C) patterns ofthe flow were noted along with cases of terminal dribble(D).

Urethral resistance (units) was measured using the formula:

The reiationship between pressure (intravesicai and detrusor, at maximum flow) and maximum flow was analysedusing the guidelines established by Abrams and Torrens,3Griffiths35 and adopted by the International Continence Society.49 The relationship was then depicted on graphs.

At the end of micturition, residual urine was again measured and figures confirmed by subtracting voided volumefrom maximum cystometric capacity.

External sphincter eiectromiography was performed onali patients.

The work-up was repeated 1 hr. 30 mm. after the administration with miik of a piacebo (12 cases), 150 mg of indomethacin in capsules (47 cases), or 2.000 mg of aspirin in tablet form (12 cases). The placebo administered, it may beadded, was identical in appearance to the drug to be takenby the patient iater on, when participating in the indomethacin or aspirin groups.

In the next stage, patients with clinical disturbances were singled out for 8 days of treatment, sufficient time for reliable results but not long enough to permit the natural tendency of this kind of patients to improve to significantly impair the conclusions. A placebo was administered to 12 patients (who between a week and a month later became partof the other two groups), 50 mg of indomethacin, 3 timesper day at approximate 8-hour mealtime intervais to 32 patients; or 1.000 mg of aspirin, 3 times a day at 8-hour mealtime intervals, to 9 patients. After 8 days were over, afourth group was formed with 5 patients from the indomethacin group. These patients underwent another identicalurodynamic work-up in order to note any further changesthat may have taken place.

Finally, doctors (unaware of what the patients had beengiven) analysed ali placebo, aspirin and indomethacin patients with clinical disturbances, after the 8 days were over,in order to note any changes in symptoms.

Of the 41 patients submitted to therapy for clinical disturbances (indomethacmn-32; aspirin-9), we succeeded incontacting 27 (indomethacin-23; aspirin-4) between 15 and45 days after the end of therapy, and were thus able to gather more useful information regarding the further evolution of symptoms in each case.

Clinical changes and urodynamic alterations were compared with the results gathered from studying the placebogroup.

The subjective nature of symptoms, the variability oftheir frequency in each group, the sparceness of certainsymptoms as a whole, and the need to qualify some resultsby grading them, thus avoiding the ali or nothing approach,led us to prefer the presentation of clinical results without astatistical analysis. Thus, changes noted are expressed interms of percentages.

The uniformity of ali 4 groups at the start was checkedstatistically using the Student’s t test, based on urodynamicfigures, obtained before medication had been given.

Urodynamic alterations underwent a statistical paired ttest analysis since the patients functioned as their own control. The graphs presented, show the means and standarderror of the means.

The following symbols were used on the graphs, depending on statistical significance:

0.05 < P0.01 < P

0.001 < P

The Fischer and Yates table23 was ijsed.

It is important to stress that both clinical and urodynamic results were analysed within each group through comparison of the results obtained before and after the administration of the drugs or placebo. We did not attempt to compare the groups; the placebo patients were used to give us an

TABLE 1. Urodynamic terminology.

First desire to void FS Continuous flow QCMaximum cystometric capacity Cap, max lntermittent 110w QIEffective cystometric capacity.. . Cap, ef Terminal dribbling QDInstability 1 Flow time QtInstability — detrusor pressure . . I(Pdet) Time to maximum 110w. . QtmaxSlope: Maximum flow Qmax

Smooth muscle segment Sm Voided volume VvSmooth colagen segment Sc Average flow rate Qmed

Compliance: Voiding time MtSmooth muscle phase Cm Residual urine ResColagen phase Cc ljrethral Resistance UR

Opening time opt

Intravesical Abdominal Detrusor

Pre-micturationpressureOpening pressureMaximum pressurePressure at maximum 110wContraction pressureat maximum flowPost-micturationcontraction

Pves,pm Pabd,pm Pdet,pmPves,op Pabd,op Pdet,opPves,max Pabd,max Pdet,maxPves,Qmax Pabd,Qmax Pdet,Qmax

Pdet,cQmaxCont Posm(Pdet)

Intravesicai pressure at maximum flow

(Maximum flow rate)2

non significant0.050.01

P 0.001

ns*

23

A. MATOS FERREIRA AND J. M. REIS SANTOS

idea of the natural evolution of the situation independent ofthe action of drugs and under the influence of the instrumentation for the urodynamic study.

RESULTS

Our findings showed that patients subjected to the influence of indomethacin and aspirin experienced a clinicialimprovement in symptoms that was not apparent in the piacebo group (Table 2). The fact that there was larger numberof subjects in the indomethacin group than in the aspiringroup undoubtedly conditioned results obtained. Although

= 100%

a)Numberof 4 16.7% 4 68.8% 4 44.4%micturitions par = 83.3% = 31.2% 55.6%night

Falte desire (n = 2) (n = 9)tovoid 4 55.6%

= 100% = 11.1%- 33.3%

(n = 6) (a = 15) (n 3)4 16.7% 4 66.7% 4 66.7%

tirgency = 83.3% = 6.7% = 33.3%— 26.6%

Stress (a = 1) (n = 1)incontinence 8 100% t 100%

Urge (n = 2)iucontinence — 100%

(a = 5) (a = 13) (n = 4)Terminal 415.4% 475%dribb)ing = 100%

— 84.6% — 25%

Initial (n = 1) (a = II)delay 4 81.8%

100% = 18.2%

(a = 1) (a = lO) (a = 1)Strainiag 1 70% 4 lOd%

= 100% = 20%— 10%

Stream: (a = 2) (a = 7) (a = 1)— calibreI t 50% 8 71.4% 8 100%

= 50% = 28,6%

—streagth) (a = 4) (n = II) (a = 4)8 81.8% 8 100%

100% = 18.2%

Tenesmus (n 1)— 400%

Seasation of (a = 6) (n = 14) (a = 3)bladder fullness 4 50%after micturition = 400% 28.6%

—24.4% —100%

Buraiagon (n = 4) (a 7) (a = 5)micturition 4 42.8% 4 33.3%

100% 14.4%— 42.8% — 66.7%

improvement of some symptorns was more noticeable in theformer group, the general tendency was the sarne in bothgroups. Initial disturbances tended, for the most part, toreapear after the end of treatment, although slight improvernent was maintained in some cases (Table 3).

Urodynamic values obtained, shown in detail in Fig. 2to 10 and Table 4, exhibit several statistically significant variations caused by both drugs and not by the placebo. Thevariation of values on the 8th day under indomethacin wassimilar and in certain aspects even more pronounced than at1 hr. 30 mi. The srnaller number of patients who tookpart in the 8th-day group prevents us from drawing any definite conclusions.

TABLE 3. Evolution ot symptoma alter the end ol therapy with indomeibacin and acetylsalicylic acid.

Indomethacin Acetylsalicylic(n = 23) acid (n = 4)

Diurnal interval “~ 26%ofmicturitions + 74% + 100%

Number of ‘~ 8.6%micturitions pernight + 91.4% + 100%

False desire (n = 6)tovoid

+ 66.7%

(n=11) (n=2)Urgency “~27.3% ~50%

+ 72.7% + 50%

(n=11) (n=2)Terminaldribbling + 72.7% + 100%

(n = 8)Initial “ 12.5%delay + 87.5%

(n=7) (n=1)Straining 28.6% ~o 100%

+ 71.4%

Sensation of (n = 6)bladder fullnessafter micturition + 100%

It should be noted that the variation in parameters forasymptomatic cases was identical to those which showed clinical disturbances. It is important to stress that the correiation between clinical and urodynamic data was frequentlypoor upon first inspeccion. Some symptoms frequently associated with instability 7 83. ~ (Table 2) were present in patients although the instability itself was not detectable onthe urodynamic curve, even under provocative tests. Theopposite was also true. In two patients, uninhibited contractions were present in the complete absence of symptoms, aphenomenon noted by other investigators.83 The correlationbetween clinical and urodynamic data was much clearerwith regard to micturition fenornena.

TABLE 2. Symptom changes ia 53 patieais sabjected tolhe infiueacc aI placebo, iadomethaciii and acetylsalicylic and.

Placebo Iadomethacta Acetylsalicylic(a = 42) (a = 32) acid(n = 9)

a)Diurnal intervalof micturitioas

8 25%75%

56.3%43.7%

Key: . . . Maintenancc of improvement; + . . . .return to pre-treatment tIa-te.

key;....population )aomber of cases); 8 ....iacrease; 4 ....decrease; = sarne

acate; — ....disappearaoce; * ....appearance.

a) «Frequeacy» and uNocturia» are nOt defined since concepta of normal va.ry widely.

24

THE ROLE OF PROSTAGLANDINS IN THE LOWER URINARY TRACr DYNAMI~S 06? PROSTATECEOMIZED PATIENTS

l°LACEBO1hr 30m1n

504540353025201510

o

60n~12

50

40

30

n~10~20

lo

Cm Cc

INDOMElHACINjhr30min

Fig. 3 — Compliances (Intravesical Pressure)

5045

PLACEBOo

E

1hr 30mnofter

Scn~10

15105o

INDOMETHACIN

Volume (ml)

504540

30~ 25• 20

1510

800

orE

Belo,.

~

100 200 300 400 500 600 700

Volume (ml)INDOMETHACIN

Sc B.fore

eo~cE~~_”’

100 200 300 400 500 600 700 800

800

504540353025

Volume (ml)orE

8

5

100 200

Volume ml)

Fig. 2— Siope

ml for1cm H20

INDOMETHACIN

8 do»

ml for1 cm 130

ml for1cm H20

60

50

40

30

20

10

n-46 ~

n~33

CmCc

ACETVLSALICYLIC ACID1hr ~min

ml for1cm H20

60n~ 12

50 *040

30

20 n~l1

10 ::

Cm Cc

~::•( Before

i~z::::~—i Alter

Cm Cc

25

A. MATOS FERREIRA AND J. M. REIS SANTOS

The summarized analysis of graphs showing urodynamic results using a placebo and indomethacin and aspirinshows that the prostaglandin synthesis inhibitors broughtabout a decline in the slope (Fig. 2) (especially in the tonuslimb), increase in muscular compliance, (Fig. 3) delay infirst sensation and increase in bladder capacity (Fig. 4). Ins

ml500

400

300

200

100

PLACEBO 1hr 30m~n

1 In~5ns

FS Cap mix Cop .t-Vn Ris

INDOMETKACIN ~it~ 30min

n-47 ~**8

liiF , Capon o Cop • -Vo Ris

INDOMETHACIN—8 doyo8 *

n~5

~%Lí1j.n~i~~ACETYLSALICVLIC ACID _1hr30min

8~i

rfl~5 Cap mix Cap •t-Vv Ris

~~t:1 Befor.

1 ~] Alter

Fig. 4 — First desire to void, maximum and effective cystometriccapacities, voided volume and residual urine

INDOMETHACIN INDOMEtHACIN ACETYLSALICVLIC ACIO1hr 30m1n e doys 1hr 30min

cx, H20 cm H20

70 n~l 70

60 • 60

50 50

40 40

~ 30

20 20

10 10

tability disappeared in only a limited number of cases(21,3% in the indomethacin group). In cases in which instability was still present, after medication, we noted pressurevariations in the contractions which proved to be non significant when analysed statistically. (Fig. 5).

Greater ease in the onset of micturition, patent in shorter opening time, (Fig. 6), and lower intravesical openingpressure (Fig. 7A,B,C, and D), *as apparent, as was greater ease in the process of micturition as a whole. Maximumand average flow rates improved, (Fig. 8), with interruptedstreams becoming continuous in some cases (6 in the indomethacin group and 1 in the aspirin group) (Table 4). Oneof the most noteworthy changes was in terminal dribblewhich decreased in all cases submitted to medication (Tables 2 and 4). Urethral resistance decreased (Fig. 9) andpressure flow relationship improved (Fig. 10). In cases where it was present, residual urine decreased (Fig. 4) thus showing improved bladder emptying. Improved flow and vesical emptying were characterized by an overali drop in mieturition pressures (maximum intravesical pressure and intravesical pressure at maximum flow) (Fig. 7A,B,C and D).Post-micturition detrusor contraction suffered non-significant variations (Fig. 7A,B and C).

Side effects were infrequent with both drugo and theirintensity slight enough to have been considered unimportant by the patients.

10 20 30 40 50 60 70 90 90 100 o

INDOMETHACIN —6 do»

________________ os

—1— no

10 20 30 40 50 60 70 80 90 100 o

ACETYLSALICYLIC ACIO .1hr 30m1n

~:i B.tor.

1 Alter

Fig. 6— Opening time, time to maximum flow and voiding time

n~12no

500

400

300

200

100

ml500

400

300

200

100n~9 1

Cop m o Cop ei Ao Rei

ml500

400

300

200

100

n~12 e.

Ame

pLACEBO_1hr30~nopt ,,~

Otmoo

01 - —

Mi _________________

10 20 30 40 50 60 70 80 90 100 o

INDOMETIIACIN_lhr 30,,,inopi

n~ 47

÷ *8

-f-~ 8•

O tomo01

Mi

opi

O tomo

01

Mi

opi

O tmis

Qt

Mi

n~5PLACEBO1hr 30min

cm H20 cm H20

70 ~,_4 70 n~14

E 60no

5C 50

40 40 no

E 30

21 20

10 lO

1 1

• Bel ir. O Aft.r No coses ai ir,siobility lfl thio 9roup

Fig. 5 — Instability

—O--

n~12

+ no

+ no

10 20 30 40 50 60 70 80 90 100 o

26

THE ROLE OF PROSTAGLANDINS JN THE LOWER URJNARY TRACE DYNAMICS OF PROSTATECEOMIZED PATIENTS

A

c

H20

30

20

10

630

70

60

50

40

30

20

lo

INDOI4ETUACIN

1 n~2

e

NDOMETHACIN

o~“

70

60

56

40

30

20

lo

n~47 n~4

0

Pd.t, p01 1 Pd.1,op 1 Pd.l, ‘~ 1 Pd.l Q.oO,l Conl p..n

ACETYLSALICVLIC ACIO

P.bd, pe 1 P.bd,Op 1 P060,... 1 P.bd O ‘eo 1

Not ,010u100

No 00.. 11 th~,,0~p

001 620

70

60

50

40

30

20

lo

010 620

70

60

50

40

30

20

lo

630

50

40

1 P0... op 1 P000.fllOO 1 PV~O, 0,10” 1

011630 n.l2 n~2’

40

30 .4 O 30

20 ,,, 20

10 lo

Po.o, P11 1 P0~, 60 1 P...,n~.x 1 Pv.., Q~oo 1

Pd.l,p11 Pd.t.op 1 Pd~l ~ 1 Pd.l.’Q,,oo 1 Coni p0~fll

n.12

o

1120

30

20

lo

47

Pobd, p0’ Pobd,op 1 Pobd.n,oo Pobd.Q,no.

•—• 6~lor.

~ 6, 30’~’~ olt.,

P.bd.p,,. 1 PObd .p 1 Pobd,,.oo Pobd.0’,lOo

._—.

~ 1hr 3o0”oi, 6o1 ,e.,~r.d

12

Pv.., pm 1 Pv.,, °e Pvn,m.x Pvn.Q,,,ox

~-nt

010 620

60

50

40

30

20

lo

H20

30

20

lo

P000, op 1 p,,,,~0 1 ~~ 1

n. 12010 630

P001, P11 1 Pd.t,.p

62030 ~ n.12

Pd.I,p,. 1 P001. OP 1 PdOI.,000 1 P001. Q’noo 1 Coni poo,o

n±__—__--~ o1 Pobd.op 1 PObd.0l00 1 Pobd.6..00 1

e__e Bolo,. (~) •4çf 1740$gr•d

0.—O O dopo alto,

1 Pd.t,nlo, 1 Pd.t,Q,,.00 1 Cont ~ 1

20

lo

.—. _,o1.

o -o 1N30ob10 ,f).,

Fig. 7 — A, B, C, D. Micturition Pressures

A. MATOS FERREIRA AND J. M. REIS SANTOS

a’z*:•:i setore1 Alter

FIO. 8 — Maximum and average flow rates

PLACEBO — 1hr aomin INDOMET HACIN_traomn INDOMETHACIN-6 doye ACETYLSALICYLIC ACID_1h1 ~min

ml

PLACEBO INDOI4ETIIACIN INDOI4ETHACIN ACETYLSALICYLIC ACIDlhrxmin 1hr 3groin 6 doys 15r 30m1n

n=12

ml

0=4730

25

20no

mlml ~

30 -

25 -

20

15-

10 -

5-

Gmoo Qmed amox Qmed Qmoo Qmed

n = 12

Un0.6

0.7-0=47

UnUn0.6

0.7

0.64

0.5

0.4

0.3

0.2

0.1

Un0.6

0.7

0.6-

as-

0.4

0.3-

0.2-

0.1

n= 12

UR UR UR

~~~t:-~I Belore

1 Alter

Fig. 9 — Urethral resistance

28

THE ROLE OF PROSTAGLANDINS IN THE LOWER URINARY TRACE DYNAMICS OF PROSTATECfOMIZED PATIENTS

PLACEBO

5.12

INDOMETHACIN

nC47

PLACEBO

12

INDOMETHACIN

77C47

5 70 75 20 25 30 35 40 - 5 ~

Orno, Orno,

P6.?, 5,,,,. . P,.,,, Q,,o.—.rn 030Q,,,o,—rnl .1

Fig. 10— Pressure-flow relationships

TABLE 4. FIow variations during urodynamic stndy.

Acetylsalicylicacid

1h 30m(n = 12)

0.7Cr.jhr 30rnIfl ~ o

5 70 25 20

750

700l~’ 30”' oito, O

50

250

00

50

25 30 35 40

S.!Or. •9~r 30rn,n ,1t.r O

5 30 75 20 25 30 35 40

80

60

40

E 20

o

80

601~ 40

E 20

o

00

601

40

E 20

o

++

+

9.,,,.;ltr 3onfln 011., O

+

5 70 75 20 25 30 35 40

NDOI4ET HACIN

“5

O 607. 0/?~~ O 700

±5°

5 70 75 20 25 30 35 40

250 INDOMErI4ACIN

no 59.l.r. •

O dpln 01t~ O

++

5 70 75

ACETYLSALICYLIC ACID

no 12

20 25 30 35 40 5 70 75 20 25 30 35 40

00

60

E 20

ii,, 30”oit.,

+

750

700

E 50

ACETYLSALICYLIC ACIO

129.9r.,hry0rnrn.fg., O

±±

75 20 25 30 35 40

Indomethacin

1h 30m(n = 47)

8 days(n = 5)

(n=8) (n= 1) (n= 1)QI —E QC 75% 100% 100%

QD-°- (n=2)100%

29

A. MATOS FERREIRA AND .1. M. REIS SANTOS

DISCUSSION

Two chemically dissimilar drugs — indomethacin andaspirin — known to be potent prostagiandin synthesis inhibitors since Vane’s pioneer study,88 were used in our trial.Though we admit the possibiity that these NSAID (non-steroid anti-inflammatory drugs) can act directly on certainstructures through mechanisms that are stili pooriy understood” ~ ~ 63. 64. 66 it is our opinion that the changes inbladder and urethrai dynamics we noted, were, at least partly due to the synthesis inhibition of prostaglandins whichthrough complex mechanisms act on specific receptors.52’ 76

The dosage of the drugs, the spacing between administrations, and the anaiysis of main urodynamic resuits (1 hr. 30mm.) were based on pharmacoiogicai knowledge and previous studies using prostagiandin synthesis inhibitors.19 24

Consuitation of other sources13’ ~ 21. 62. 75. 88 ieads us to believe, with little margin of doubt, that the inhibition ofprostagiandin and reiated substances (tromboxanes) wasprobabiy complete in ali cases.

Frequent relapse after the end of treatment was taken asfurther substantiation of the fact that good results wereprobably due to the action mentioned. Inhibitor action isknown to be praticaliy immediate,12’ 52 and since the tissuesdo not store prostaglandins to any significant degree, it isclear that synthesis inhibition represents an inhibition of theeffects.66 89. 90-92 Given this fact, it is likely that inhibitorssuch as indomethacin and aspirin, will oniy show any significant action during the actual period of administration.

We must not disregard the possible effect of the drugson central55’ ~ or peripheral sensitivity;9’ 71. 73. ~ and thismight well have been prostaglandin synthesis inhibition aswell.16’ 20, 93 This effect could have had a complementary action on bladder and urethral structures thus contributing tothe improvement of certain symptoms such as burning uponmicturition, sensation of bladder fuliness after micturition,deia~ of first sensation with consequent decrease of frequency of micturitions, and decrease of biadder sensitivity,(a possible factor of increased capacity of the organ). Weknow however that the pressure at which the micturition reflex is triggered is the pre-micturition pressure. Since themicturition reflex appeared when greater bladder capacitieswere brought about but under lower pre-micturition pressures, it is logical to suppose that local muscular or neuromuscular action was predominant over a possibie depressive action on the sensitive sphere.

The analysis of the results in the filling and micturitionphases showed us that both prostaglandin synthetase inhibitors brought about diffuse and non-specific muscle relaxation.

Contrary to Ruch’s findings72 the absence of any declinein the slope for our piacebo group (which, in fact exhibitedsome statistically non-significant increase (Fig. 2)), makes itclear that the distension of the bladder caused by thepre-medication examination was not a factor in slope decline in patients submitted to the drugs. Bladder hypertonus,probably due to muscular hypertrophy from pre-operativeobstruction and sometimes patent in high pressures, couldbe ascribed, at least to a certain degree, to prostaglandins.Decrease in bladder hypertonus, caused by the inhibitors,wouid thus be easy to understand. Slope figures obtained byus were generally higher than those mentioned by Merril etai.6° This was taken as au indicator of hipertonus of purelymuscular origin found in somewhat hipertrophied and damaged detrusors.72 Detrusor action in the fiiling phase isknow to be non-neural.6’72’8° Thus, it is likely that factorsaffecting the detrusor during this phase were of a directmuscular nature.

We know that several stimuii affect prostaglandins synthesis:1822’31’3251’57’58’69’70’74 among them is bladder distension.28’31 Thus, it is altogether possible that prostagiandinproduction may be increased in cases like ours. Besides thementioned direct muscular action, tissue reaction to neuro-transmitters may be altered by higher prostaglandin leveis,which would influence neurovegetative action.36’37’3943

Muscle relaxation caused by the drugs, affected predominantly those muscles that make up the intrinsic distalsphincteric mechanism(Fig. 1). The predominant relaxationof these muscies(the only functional ones in the posteriorurethra of a prostatectomized patient) would be the oniyfeasible explanation for improved flows and emptying where low intravesical pressures are present.

Decrease in micturition pressures was probabiy due bothto a direct action on the detrusor whose sensivity to prostaglandin action is experimentally proved,2’5125267 and to thedecrease brought about in urethrai resistance. Is is a knownfact that a decrease in intravesicai pressure, is a normal consequence of better urethrai permeablility.

The relaxation of urethrai musculature mentioned,which is responsible for continence in prostatectomized patients,14 was taken as the cause of heighened sphincteric incontinence.

Cases of ciinicaily and urodynamicaily detected obstruction that improved with treatment were attributed to a probable hypertonic intrinsic striated sphyncter798186 counteracted by the medication given, which, as experiments have proved possible, acted directiy on muscularfunction.2’5’12’5267 Some improvement may also be ascribedto more complex and difficult-to-analyse neuro-muscularmechanisms 12.40.46

Fig. 1 shows the structures on which the protaglandinshad to act in order to cause the changes described. Ghoneimet ai28 found that the detrusor distension releases PGE2which, when inhibited by indomethacin, does not exerciseits rela.xing effect on the urethra. Our experience demonstrated a different effect, since we obtained a relaxing effecton the urethral muscies with thë prostaglandin synthetaseinhibitors. If we keep the multiple and frequently opposingactions of ali prostaglandins in mmd, it is easy to understand the different results obtained. Analysis of pertinent bibliography5’2852’67 only seems to demonstrate the differencebetween the results obtained by several investigators. SincePGF2 contracts the urethral muscles5’53’67 while PGE2 relaxes them,528’67 it is obvious that the results noted will depend on which prostaglandin is acting at any given moment.

The correlation between clinical and urodynamic factors, unclear when first approached, became obvious whenwe analysed the improvement of symptoms from the standpoint of the urodynamic changes found. These changes,though non-specific(appearing identically in asymptomaticcases and those with clinical disturbances alike), were obviously responsible for counteracting those physiopathoiogical mechanisms behind the clinical dysfunctions wefound.

Instability, a pooriy understood phenomenon,26’83 underwent changes detected in our urodynamic study. Thesechanges though minor, are considered by us to be noteworthy, given the generaily poor results obtained with even themost aggressive types of treatment.5664’85 The decrease inurethral resistance may have had an influence on the improvement.83’86 It is important to stress that evento the most astute observer, there often seems to be no correlation between certain symptoms such as frequency, urge incontinence, etc., and urodynamic instability. This occurs not onlyupon first approach but also when trial results are analysed.With the use of indomethacin and aspirin, improvement of

30

THE ROLE OF PROSTAGLANDINS IN THE LOWER URINARY TRACE DYNAMICS OF PROSTATECTOMIZED PATJENTS

symptoms was more frequent than improvement of instability in the urodynamic study.

Some authors7 do not distinguish between long post-micturition detrusor contractions, which obviously do notshow up in normal urodynamic studies, and those veryshort-acting post-micturition contractions, detectable inthese studies. The former type of contraction is a possiblecause of certain symptoms such as sensation of bladderfullness after micturition. Both types are detrusor contractions3° and possibly signify instability. The causes of thesecontractions have been widely interpreted.830’44 In our cases, the short-acting, urodynamically detectable form wasencountered Iess frequently than by other authors827, andchanges resulting from the use of the drugs proved to becontradictory and inconclusive.

The marked improvement in micturition efficacy easilyexpIam the improvement os symptoms such as poor stream,hesitancy, etc., we obtained in our cases.

Improvement of terminal dribbling, which some investigators associated with instability,1 was ascribed to improved emptying of the bladder and a decrease in intravesicalpressure after micturition.

The knowledge we have about the complex action ofprostaglandins on physiological and pathological phenomena is still very incomplete. This information gap prevents usat this time from delving deeper into the discussion of precise mechanisms involved in the vesico-sphincteric changesfound in our cases.

Up to now, little research has been done into the relationship between prostaglandins and lower urinary tract dynamics — a field that opens up whole new realm of possibilities for the treatment of vesico-sphincteric dysfunctions.

It is our hope that this project, to our knowledge thefirst to be done on human subjects in vivo, will provide thestimulus for further research into this necessary, yet relatively unexplored field.

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Pedido de Separatas: A. Matos FerreiraServiço de Urologia do Hospital Curry CabralRua da Beneficência1000 LisboaPortugal

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