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The Action of Morphine on the Urinary Bladder of the Unanesthetized Dog: A Comparison with the Action of Parasympathomimetic Drugs1
THE ACTION OF MORPHINE ON THE URINARY BLADDER OF THE UNANESTHETIZED DOG: A COMPARISON WITH THE ACTION OF PARASYMPATHQMIMETIC DRUGS 1 IRWIN C. WINTER From the Department of Pharmacology, The University of Oklahoma School of Medicine, Oklahoma City
Many of the actions of morphine have recently been shown to be peripheral and to meet the postulates of a parasympathomimetic substance. This peripheral parasympathomimetic action, as applied to the urinary bladder, is opposed to the clinically supported statement that morphine causes a spasm of the vesical sphincter with retention. According to the accepted theory, stimulation of the parasympathetic system results in an increased tone of the bladder musculature and a decreased tone of its sphincters, thus reducing bladder capacity. We have observed the stimulant action of morphine on the detrusor muscle and it was decided to investigate the possibility that the effect of morphine on the urinary bladder was entirely parasympathetic. Method. · Six normal female dogs were used. These animals were unanesthetized, but were trained to lie quietly under light restraint, thus preventing complicating anesthetic effects. As a means of measuring urinary bladder activity, the apparatus described by Langworthy et al. was employed to obtain a kymographic record of intravesical pressure during filling . Using this apparatus, normal saline at room temperature and under a constant head of pressure was allowed to flow into the bladder through a glass catheter. The inflow was continued until fluid was expressed around the catheter by bladder contractions, at which time the inflow and kymograph drum were stopped, and the bladder allowed to empty. The rate of inflow was adapted to each dog by means of a screw clamp placed on the inflow tube between the reservoir and the manometer, since the urinary bladders of some of the animals responded much more actively to stretch than did others. After adjustment, the inflow orifice was kept constant during the entire set of observations on each dog. 1 Presented before the Pharmacological Society, Federation of the American Societies of Experimental Biology and Medicine, New Orleans, March, 1940. Supported by a grant from the Legislature for Research in the University of Oklahoma School of Medicine. 388
ACTION OF MORPHINE ON URINARY BLADDER
389
The tonicity and capacity of the bladder and the urethral resistance to the outflow of urine were measured by means of the above procedure. As an expression of the tonicity of the detrusor muscle the acuteness of the angle made by the rising line drawn on the smoked drum the writing lever recording intravesical pressure was measured. This angle is recorded as degrees of "Slope" (figs. 2, 3, 4, 5). The greater the angle, the greater the tonicity. This value was much more conveniently measured than other possible indications of the bladder tone, such as intravesical pressure before the inflow was begun, the initial rise in pressure when the inflow was started, or the number of sharp contractions recorded during the filling process. The urethral resistance (using the terminology of Langworthy et al.) was determined as that pressure at which fluid first appeared around the
FIG. 1. Intravesical pressure during filling. Normal and following carbamylcholine chloride, 0.01 mg/kg.; signal magnet, time of beginning inflow; time marker, 5 seconds; scale at encl of tracing, each division equals 10 cm. ,Yater pressure above 0.
catheter, the fluid seen having traversed the entire urethra. This resistance is necessarily made up of a number of components: internal sphincter, urethral musculature, external sphincter and perinea! muscles, not all of which are under exclusively automatic control. The volume of saline needed to fill the bladder to the point where the urethral resistance was overcome was recorded as the capacity. In general, it may be said that a decrease in urethral resistance and an increase in tonicity of the detrusor caused a decrease in capacity, and vice versa. Of the two components, the activity of the detrusor muscle was by far the more potent in determining capacity, but no constant correlation between the two factors was noted. In figure 1 a typical recording of a complete experiment on 1 dog is reproduced to illustrate the above description. Procedure. In each experiment preliminary recordings were made of the intravesical pressure during filling, in the course of which the inflow
390
IRWIN C. WINTER
was so adjusted that the rate of filling was just great enough to cause a smooth rise in pressure, but no so rapid as to obviously exceed the receptive properties of the detrusor muscle; a too rapid rate greatly decreasing the capacity of the bladder. When this adjustment was made, the orifice was kept constant throughout the remainder of the experiment. Additional determinations were made until at least 2 successive fillings were similar according to the measurements discussed above. The values from these similar recordings were averaged and taken as the "normal" for that experiment. Repeated fillings were necessary to obtain constant values since the reflex described by Rose and Deakin and Langworthy and his co-workers was definitely operative in causing a decreased capacity and urethral resistance following the first filling of the bladder and the expulsion of the fluid through the urethra. Once reached, however, the "normal" values did not change even after repeated fillings if no drugs were given. After constant values were obtained the drug to be studied was given subcutaneously (with massage) unless otherwise stated, and filling records were begun at 3, 10, 20 and 30 minutes after the administration of the drug. The measurements used are more closely related to the time of complete filling than to the start of the inflow, and were therefore plotted on time activity curves at the former interval (complete filling) after administration of the drug. Since these intervals varied in the different experiments, the values obtained on each dog were plotted separately and curves drawn. In this manner interpolated values for each dog at 5 minute intervals after the administrations of each drug were obtained. These individual 5 minute values were averaged and plotted against time to obtain the curves shown in figures 2 to 5. Since the "normal" values of the dogs varied considerably, the results are recorded as per cent of normal (capacity and urethral resistance) and as actual units of change from normal (slope). The dosages of the various drugs employed were adjusted by trial until roughly equivalent responses were obtained after each drug. Results. Morphine: Following the injection of 1.0 mg/kg. of morphine sulphate, an increased tonicity and reduced capacity of the bladder were obtained, the maximum effect occurring about half an hour after the drug was given. The urethral resistance, which was expected to rise in view of the usual statement that morphine causes a spasm of the vesical sphincter, showed a definite and prolonged fall after an early rise. The result was so at variance with the accepted theory of morphine action
391
ACTION OF MORPHINE ON URINARY BLADDER CAP·
ACITY 180
SLOPE
URETHRAL RESISTANCE
l-40
---·MORPHINE SULPHATE
R~t~ sLtittATE
160
130
140
120
120
110
o·················o
40
c.....
9 •••.••••• EPHED1 25.0 mg. I kg,
30
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100
········O.... 80
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60
60
40
70
-10
-20 0 0 fl.
URETHRAL RESISTANCE SLOPF.
CAPACITY
-30
DEGREES
20% OF 60o"-----.---,-o- --~,.---.~o~-~.~.--~,~o~-~,"".,~ c~~~~!E HOAMl'\L
MINUTES AFTER ADMINISTRATION
or
OAUG
t lORMAL
FIG. 2. Urinary bladder response to morphine and ephedrin. Side bars indicate limits of normal variation. Ul-l.ETHRAL
CAP• ACITY
SLOP!:::
RESISTANCE
180
140
160
130
-·-·AC(TYL BETA METHYLCHIJUNE CHLORIOE-O.Srng.l i-.g . .•.•••.•• CARt'All.'fL CHOL!Nt: CHLORIDE.> 0.CI mg. I k9. ---·Af.ETVLCHOLINE IODIDE-1•10,000 l't' DRIP• ·
r·-·-·-·<>-·-·-;·""'·g::·::·~:~·"'············ 0.04 mg. I kg. I min.
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MINUTES AFTER ADM1NISTAATION OF DRUG
NORMJl.L
FIG. 3. Urinary bladder response to acetylcholine, acetyl-beta-methylcholine and carbamylcholine. Side bars indicate limits of normal variation.
that another drug (ephedrin) said to cause an increased tone of the bladder sphincter was tried as a check on the method. Ephedrin: The urethral resistance after 25 mg/kg. of ephedrin sulphate
392
IRWIN C. WINTER CAP-
URETHAAL SLOPE R E S I S ; , . ; T ; - ' A C . , N C : , C E - - - - - - - - - - - - - - - - - - - -- - - ,
ACITV
,e·o
140
160
130
140
120
40
70
......... NICOTINE (ALKALOIO) 0.25 m9. I kg.
30
---- ATROPINE SULFATE 0.1 mg. I kg.
20
0 0 A
URETHRAL RESISTANCE SLOPE CAPACITY
-30 DEGREES
20% OF 60.,_o_ _ _s~--~,o---,~.---,-,,o~--,-.,s,------,,3,:-0---.:,,s~ c~:oN;_e NORMAL
MINUTES AFTER. A.OMINISTRATIOH OF DRUG
NORMAL
FIG. 4. Urinary bla,dder response to nicotine and atropine. Side bars indicate limits of normal variation. URETHRAL S· MINUTES AFTER ATROPINE SULFATE - 0.1 mq, I RESISTAl'!CE 140 -··-· ·-··- NO ADDITIONAL TREATMENT -- -- ---- M0'1.PHINE SULFATE-1.0mt;i.lkg .
:
$LOPE
40
................ CARBAMVL CHOLINC CH!.ORIOE-0.01 rng.lkg.
-·-·-·-·- AC~BETA METHYLCHOLINE CHt.Or.:JDE - 0.5 mg.I k9. 130
30
120
20
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110
10
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MINUTES A FTER AOMlhllSTR,ATION OF DRUG
t-dORA\AL
FIG. 5. Urinary bladder response in atropinized dogs to morphine, acetyl-beta-methylcholine and carbamylcholine. Side bars indicate limits of normal variation.
showed a marked rise, while the bladder tonicity was lowered slightly. The observed capacity followed the change in tonicity more closely than in urethral resistimce, indicating, as stated above, that the activity of
ACTION OF MORPHINE ON URINARY BLADDER
393
the bladder musculature plays a much more important role than urethral, or sphincteric-resistance in determining capacity. Acetylcholine : Acetylcholine iodide given by continuous intravenous drip in amounts of approximately 0.04 mg/kg/min. caused a fall in urethral resistance, a decreased tonicity and a very slight increase in capacity of the bladder. It was noted at the start of the first filling after the acetylcholine was begun that the pressure in the bladder rose very rapidly for a short time, and then leveled off at less than the normal rate of rise. This effect is not shown in the figure. It is suggested that the drug caused a preliminary stimulation of the detrusor muscle but was not given in sufficiently large amounts to overcome the resulting compensation which the organism must have attempted. The end result, as far as tonicity is concerned, would therefore be a decreased tone of the bladder wall. The urethral resistance remained low as long as the acetylcholine was given. Salivation and miosis were seen, but no other parasympathetic effects were noted. Twenty minutes after the administration was begun, the acetylcholine was discontinued with a return of the urethral resistance to normal. Acetyl-Beta-Methylcholine:2 This compound, when given in quantities of 0.5 mg/kg., produced a rapid rise in bladder tonicity and a decrease in capacity, these effects reaching a maximum within 10 minutes and then returning gradually toward normal. The urethral resistance rose at first and then fell abruptly below normal, showing little tendency to rise again during the period of observation. These effects in every respect except the time relations are the same as those observed with morphine. Larger doses (0.75-1.0 mg/kg.) produced similar, but more marked effects, while smaller amounts (0.25 mg/kg.) resulted in inconstant changes. Carbamylcholine :2 This drug, in amounts of 0.01 mg/kg., while producing the increase in detrusor tonicity and decrease in capacity caused by acetyl-beta-methylcholine and morphine (except for the time necessary for the effects to be seen) caused an early rise in urethral resistance which, while showing a progressive decrease, never fell below normal. Doses of 0.05-0.10 mg/kg. produced marked systemic reactions as well as extreme motor stimulation of the bladder. In 1 case, 0.25 mg/kg. 2 The acetyl-beta-methylcholine chloride and carbamylcholine chloride were generously provided by Merck and Company, Rahway, New Jersey.
394
IRWIN C. WINTER
caused death by respiratory arrest; 0.005 mg/kg. produced consistently positive but less marked effects than the dosage used in this study. Nicotine: Since carbamylcholine has been reported to possess a strong "nicotine" action, it was thought that the failure of this choline derivative to reduce urethral resistance as had its homologues might be due to this property. Acetylcholine and its beta-methyl derivative should show no nicotine-like effects in the dosages given. Nicotine, in dosages of 0.25 mg/kg., was therefore tried, and was found to cause a slight fall in urethral resistance and bladder tonicity with a possible slight increase in capacity. This dose was sufficient to cause vomiting, but no marked hyperpnea was seen. Larger doses (0.5 mg/ kg.) gave too varied results to average. The results otained with nicotine therefore throw no light on the effect of carbamylcholine on urethral resistance. Atropine: To further test the parasympathetic action of morphine on the bladder the effect of atropine on that action was determined. First, atropine sulphate alone (0.1 mg/kg.) was tried. It will be seen from figure 4 that this substance when given alone caused no change in the tonicity of the bladder. A slight decrease in capacity was noted, probably resulting from an observed marked decrease in urethral resistance. Larger doses (2-5 mg/ kg.) only accentuated these effects on capacity and urethral resistance, and caused an increase in bladder tonicity. These results might be explained on the basis _that atropine is known not to prevent the effects of stimulation of the parasympathetic nerves to the bladder, and that the drug is a central stimulant. Marked excitement was always noted with the larger doses and frequently after 0.1 mg/kg. Therefore it may be that the central stimulation caused an outflow of unimpeded parasympathetic impulses to the bladder, producing the effect noted on the urethral resistance and tonicity of the detrusor. However, atropine is known to block the bladder effects of parasympathomimetic drugs (fig. 5). The urethral resistance following the administration of acetyl-beta-methylcholine 5 minutes after 0.1 mg/kg. of atropine sulphate is almost identical with that after atropine alone, while that of carbamylcholine is about midway between that drug alone and atropine alone; definitely reduced. Atropine prevents the rise in tonicity of the bladder musculature of both the beta-methyl and carbamylcholine compoµnds and, although not shown in figure 5, the capacity values after these two choline compounds combined with atropine were as expected from the decreased /
ACTION OF MORPHINE ON URINARY BLADDER
395
urethral resistance noted above; i.e., reduced. Since the bladder tonicity after the beta-methyl compound in the atropinized dog was slightly reduced, the capacity here was not lowered as much as after carbamylcholine, in which case the detrusor tonicity showed little change from normal. The table also shows that atropine was effective in preventing or reducing the effects of morphine on the bladder. The increase in tonicity caused by 1.0 mg/kg. of morphine sulphate after atropine (0.1 mg/kg.) was much less than that seen after morphine alone, while the decrease in urethral resistance is practically the same as that for atropine alone. The initial rise of the urethral resistance after morphine is abolished by atropine. Discussion. It is apparent from the data presented in this paper that the typical action of parasympathomimetic drugs on the urinary bladder is to cause a marked rise in the tonicity of the bladder musculature and a decrease in that poorly defined group of reactions termed the " urethral resistance." This urethral resistance underwent an initial rise in most cases, subsequently falling below normal, although in 1 case this decrease did not reach or fall below normal values. Usually, the fall of urethral resistance below normal was prolonged and marked. In the main, this conclusion is in accord with the usual statement of parasympathetic action on the bladder. Atropine abolished or decreased the effects of these drugs on the bladder. The increase in tonicity was prevented, and the change in urethral resistance followed exactly that produced by atropine alone or was reduced. In any case, the initial rise was prevented. The actions of morphine, as described above, in every respect are similar to those produced by known parasympathomimetic drugs, and morphine may therefore be classed as a typical parasympathomimetic drug in its action on the urinary bladder. Further, atropine prevents the action of morphine much as the effects of the other drugs are blocked. Morphine must therefore act peripherally. The most striking fact observed was that no confirmation could be made of the statement appearing in the textbooks that morphine causes a spasm of the sphincters of the urinary bladder. In fact , in every case the final effect noted was a definitely decreased urethral resistance. The observed decrease in urethral resistance, increased detrusor tonicity and reduced capacity gives no explanation of the mechanism by which urinary retention following morphine administration can be produced.
396
IRWIN C. WINTER SUMMARY AND CONCLUSIONS
The characteristic actions of parasympathomimetic drugs on the urinary bladder as determined by cystometric study on trained unanesthetized female dogs are: (a) an increase in tonicity of the detrusor muscle; (b) a fall in urethral resistance, which may be preceded by an initial rise; (c) a marked decrease in bladder capacity. Atropine prevents the increase in tonicity and the initial rise in urethral resistance produced by such drugs, and itself causes a characteristic fall in urethral resistance. Morphine, as judged by the above criteria, is a peripherally acting parasympathomimetic drug. The change in capacity caused by any drug or combination of drugs used is a function of the change in tonicity of the bladder and urethral resistance. REFERENCES LANGWORTHY, ORTHELLO R., REEVES, DAVID L., AND TAUBER, EDWARD S. : Autonomic control of urinary bladder. Brain, 57: 266, 1934. - -- , DREW, J. EDWIN, AND VEST, SAMUEL A.: Urethral resistance in relation to vesical activity. J. Urol., 43: 123, 1940. MOLITOR, H.: A comparative study of effects of 5 choline compounds used in therapeutics: acetylcholine chloride, acetyl beta-methylcholine chloride, carbaminoyl choline, ethyl ether beta-methylcholine chloride, carbaminoyl beta-methylcholine chloride. J. Pharm. Exp. Therap., 58: 337, 1936. RosE, D. K., AND DEAKIN, ROGERS: A cystometric study of pharmacology of bladder. Surg., Gynec. and Obst., 46: 221, 1928. SLAUGHTER, DONALD, AND GRoss, E.G.: Some new aspects of morphine action. Effect on intestine and blood pressure; toxicity studies. J. Pharm. Exp. Therap., 68: 96, 1940. VAN DuzEN, R. E., SLAUGHTER, DONALD, AND WINTER, I. C.: Effect of trasentin and morphine on urinary bladder of unanesthetized dog. In press.
Many of the actions of morphine have recently been shown to be peripheral and to meet the postulates of a parasympathomimetic substance. This peripheral parasympathomimetic action, as applied to the urinary bladder, is opposed to the clinically supported statement that morphine causes a spasm of the vesical sphincter with retention. According to the accepted theory, stimulation of the parasympathetic system results in an increased tone of the bladder musculature and a decreased tone of its sphincters, thus reducing bladder capacity. We have observed the stimulant action of morphine on the detrusor muscle and it was decided to investigate the possibility that the effect of morphine on the urinary bladder was entirely parasympathetic. Method. · Six normal female dogs were used. These animals were unanesthetized, but were trained to lie quietly under light restraint, thus preventing complicating anesthetic effects. As a means of measuring urinary bladder activity, the apparatus described by Langworthy et al. was employed to obtain a kymographic record of intravesical pressure during filling . Using this apparatus, normal saline at room temperature and under a constant head of pressure was allowed to flow into the bladder through a glass catheter. The inflow was continued until fluid was expressed around the catheter by bladder contractions, at which time the inflow and kymograph drum were stopped, and the bladder allowed to empty. The rate of inflow was adapted to each dog by means of a screw clamp placed on the inflow tube between the reservoir and the manometer, since the urinary bladders of some of the animals responded much more actively to stretch than did others. After adjustment, the inflow orifice was kept constant during the entire set of observations on each dog. 1 Presented before the Pharmacological Society, Federation of the American Societies of Experimental Biology and Medicine, New Orleans, March, 1940. Supported by a grant from the Legislature for Research in the University of Oklahoma School of Medicine. 388
ACTION OF MORPHINE ON URINARY BLADDER
389
The tonicity and capacity of the bladder and the urethral resistance to the outflow of urine were measured by means of the above procedure. As an expression of the tonicity of the detrusor muscle the acuteness of the angle made by the rising line drawn on the smoked drum the writing lever recording intravesical pressure was measured. This angle is recorded as degrees of "Slope" (figs. 2, 3, 4, 5). The greater the angle, the greater the tonicity. This value was much more conveniently measured than other possible indications of the bladder tone, such as intravesical pressure before the inflow was begun, the initial rise in pressure when the inflow was started, or the number of sharp contractions recorded during the filling process. The urethral resistance (using the terminology of Langworthy et al.) was determined as that pressure at which fluid first appeared around the
FIG. 1. Intravesical pressure during filling. Normal and following carbamylcholine chloride, 0.01 mg/kg.; signal magnet, time of beginning inflow; time marker, 5 seconds; scale at encl of tracing, each division equals 10 cm. ,Yater pressure above 0.
catheter, the fluid seen having traversed the entire urethra. This resistance is necessarily made up of a number of components: internal sphincter, urethral musculature, external sphincter and perinea! muscles, not all of which are under exclusively automatic control. The volume of saline needed to fill the bladder to the point where the urethral resistance was overcome was recorded as the capacity. In general, it may be said that a decrease in urethral resistance and an increase in tonicity of the detrusor caused a decrease in capacity, and vice versa. Of the two components, the activity of the detrusor muscle was by far the more potent in determining capacity, but no constant correlation between the two factors was noted. In figure 1 a typical recording of a complete experiment on 1 dog is reproduced to illustrate the above description. Procedure. In each experiment preliminary recordings were made of the intravesical pressure during filling, in the course of which the inflow
390
IRWIN C. WINTER
was so adjusted that the rate of filling was just great enough to cause a smooth rise in pressure, but no so rapid as to obviously exceed the receptive properties of the detrusor muscle; a too rapid rate greatly decreasing the capacity of the bladder. When this adjustment was made, the orifice was kept constant throughout the remainder of the experiment. Additional determinations were made until at least 2 successive fillings were similar according to the measurements discussed above. The values from these similar recordings were averaged and taken as the "normal" for that experiment. Repeated fillings were necessary to obtain constant values since the reflex described by Rose and Deakin and Langworthy and his co-workers was definitely operative in causing a decreased capacity and urethral resistance following the first filling of the bladder and the expulsion of the fluid through the urethra. Once reached, however, the "normal" values did not change even after repeated fillings if no drugs were given. After constant values were obtained the drug to be studied was given subcutaneously (with massage) unless otherwise stated, and filling records were begun at 3, 10, 20 and 30 minutes after the administration of the drug. The measurements used are more closely related to the time of complete filling than to the start of the inflow, and were therefore plotted on time activity curves at the former interval (complete filling) after administration of the drug. Since these intervals varied in the different experiments, the values obtained on each dog were plotted separately and curves drawn. In this manner interpolated values for each dog at 5 minute intervals after the administrations of each drug were obtained. These individual 5 minute values were averaged and plotted against time to obtain the curves shown in figures 2 to 5. Since the "normal" values of the dogs varied considerably, the results are recorded as per cent of normal (capacity and urethral resistance) and as actual units of change from normal (slope). The dosages of the various drugs employed were adjusted by trial until roughly equivalent responses were obtained after each drug. Results. Morphine: Following the injection of 1.0 mg/kg. of morphine sulphate, an increased tonicity and reduced capacity of the bladder were obtained, the maximum effect occurring about half an hour after the drug was given. The urethral resistance, which was expected to rise in view of the usual statement that morphine causes a spasm of the vesical sphincter, showed a definite and prolonged fall after an early rise. The result was so at variance with the accepted theory of morphine action
391
ACTION OF MORPHINE ON URINARY BLADDER CAP·
ACITY 180
SLOPE
URETHRAL RESISTANCE
l-40
---·MORPHINE SULPHATE
R~t~ sLtittATE
160
130
140
120
120
110
o·················o
40
c.....
9 •••.••••• EPHED1 25.0 mg. I kg,
30
10
1
6.····
100
········O.... 80
90
60
60
40
70
-10
-20 0 0 fl.
URETHRAL RESISTANCE SLOPF.
CAPACITY
-30
DEGREES
20% OF 60o"-----.---,-o- --~,.---.~o~-~.~.--~,~o~-~,"".,~ c~~~~!E HOAMl'\L
MINUTES AFTER ADMINISTRATION
or
OAUG
t lORMAL
FIG. 2. Urinary bladder response to morphine and ephedrin. Side bars indicate limits of normal variation. Ul-l.ETHRAL
CAP• ACITY
SLOP!:::
RESISTANCE
180
140
160
130
-·-·AC(TYL BETA METHYLCHIJUNE CHLORIOE-O.Srng.l i-.g . .•.•••.•• CARt'All.'fL CHOL!Nt: CHLORIDE.> 0.CI mg. I k9. ---·Af.ETVLCHOLINE IODIDE-1•10,000 l't' DRIP• ·
r·-·-·-·<>-·-·-;·""'·g::·::·~:~·"'············ 0.04 mg. I kg. I min.
.--ACETYLCliOLIHE DlSCO~;rJHl)l:.l> 30
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110
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~~~:~!TY
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MINUTES AFTER ADM1NISTAATION OF DRUG
NORMJl.L
FIG. 3. Urinary bladder response to acetylcholine, acetyl-beta-methylcholine and carbamylcholine. Side bars indicate limits of normal variation.
that another drug (ephedrin) said to cause an increased tone of the bladder sphincter was tried as a check on the method. Ephedrin: The urethral resistance after 25 mg/kg. of ephedrin sulphate
392
IRWIN C. WINTER CAP-
URETHAAL SLOPE R E S I S ; , . ; T ; - ' A C . , N C : , C E - - - - - - - - - - - - - - - - - - - -- - - ,
ACITV
,e·o
140
160
130
140
120
40
70
......... NICOTINE (ALKALOIO) 0.25 m9. I kg.
30
---- ATROPINE SULFATE 0.1 mg. I kg.
20
0 0 A
URETHRAL RESISTANCE SLOPE CAPACITY
-30 DEGREES
20% OF 60.,_o_ _ _s~--~,o---,~.---,-,,o~--,-.,s,------,,3,:-0---.:,,s~ c~:oN;_e NORMAL
MINUTES AFTER. A.OMINISTRATIOH OF DRUG
NORMAL
FIG. 4. Urinary bla,dder response to nicotine and atropine. Side bars indicate limits of normal variation. URETHRAL S· MINUTES AFTER ATROPINE SULFATE - 0.1 mq, I RESISTAl'!CE 140 -··-· ·-··- NO ADDITIONAL TREATMENT -- -- ---- M0'1.PHINE SULFATE-1.0mt;i.lkg .
:
$LOPE
40
................ CARBAMVL CHOLINC CH!.ORIOE-0.01 rng.lkg.
-·-·-·-·- AC~BETA METHYLCHOLINE CHt.Or.:JDE - 0.5 mg.I k9. 130
30
120
20
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110
10
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0
UR.t:THRA.L RES!STAt~CE
0
SLOPE
-10
-20
-30
DEGREES CfoOF 600.,..__ _-:15!'-~-~,o---~,s---,~.0---2~9---3~0--~35--' CF~~E NORA\AL
MINUTES A FTER AOMlhllSTR,ATION OF DRUG
t-dORA\AL
FIG. 5. Urinary bladder response in atropinized dogs to morphine, acetyl-beta-methylcholine and carbamylcholine. Side bars indicate limits of normal variation.
showed a marked rise, while the bladder tonicity was lowered slightly. The observed capacity followed the change in tonicity more closely than in urethral resistimce, indicating, as stated above, that the activity of
ACTION OF MORPHINE ON URINARY BLADDER
393
the bladder musculature plays a much more important role than urethral, or sphincteric-resistance in determining capacity. Acetylcholine : Acetylcholine iodide given by continuous intravenous drip in amounts of approximately 0.04 mg/kg/min. caused a fall in urethral resistance, a decreased tonicity and a very slight increase in capacity of the bladder. It was noted at the start of the first filling after the acetylcholine was begun that the pressure in the bladder rose very rapidly for a short time, and then leveled off at less than the normal rate of rise. This effect is not shown in the figure. It is suggested that the drug caused a preliminary stimulation of the detrusor muscle but was not given in sufficiently large amounts to overcome the resulting compensation which the organism must have attempted. The end result, as far as tonicity is concerned, would therefore be a decreased tone of the bladder wall. The urethral resistance remained low as long as the acetylcholine was given. Salivation and miosis were seen, but no other parasympathetic effects were noted. Twenty minutes after the administration was begun, the acetylcholine was discontinued with a return of the urethral resistance to normal. Acetyl-Beta-Methylcholine:2 This compound, when given in quantities of 0.5 mg/kg., produced a rapid rise in bladder tonicity and a decrease in capacity, these effects reaching a maximum within 10 minutes and then returning gradually toward normal. The urethral resistance rose at first and then fell abruptly below normal, showing little tendency to rise again during the period of observation. These effects in every respect except the time relations are the same as those observed with morphine. Larger doses (0.75-1.0 mg/kg.) produced similar, but more marked effects, while smaller amounts (0.25 mg/kg.) resulted in inconstant changes. Carbamylcholine :2 This drug, in amounts of 0.01 mg/kg., while producing the increase in detrusor tonicity and decrease in capacity caused by acetyl-beta-methylcholine and morphine (except for the time necessary for the effects to be seen) caused an early rise in urethral resistance which, while showing a progressive decrease, never fell below normal. Doses of 0.05-0.10 mg/kg. produced marked systemic reactions as well as extreme motor stimulation of the bladder. In 1 case, 0.25 mg/kg. 2 The acetyl-beta-methylcholine chloride and carbamylcholine chloride were generously provided by Merck and Company, Rahway, New Jersey.
394
IRWIN C. WINTER
caused death by respiratory arrest; 0.005 mg/kg. produced consistently positive but less marked effects than the dosage used in this study. Nicotine: Since carbamylcholine has been reported to possess a strong "nicotine" action, it was thought that the failure of this choline derivative to reduce urethral resistance as had its homologues might be due to this property. Acetylcholine and its beta-methyl derivative should show no nicotine-like effects in the dosages given. Nicotine, in dosages of 0.25 mg/kg., was therefore tried, and was found to cause a slight fall in urethral resistance and bladder tonicity with a possible slight increase in capacity. This dose was sufficient to cause vomiting, but no marked hyperpnea was seen. Larger doses (0.5 mg/ kg.) gave too varied results to average. The results otained with nicotine therefore throw no light on the effect of carbamylcholine on urethral resistance. Atropine: To further test the parasympathetic action of morphine on the bladder the effect of atropine on that action was determined. First, atropine sulphate alone (0.1 mg/kg.) was tried. It will be seen from figure 4 that this substance when given alone caused no change in the tonicity of the bladder. A slight decrease in capacity was noted, probably resulting from an observed marked decrease in urethral resistance. Larger doses (2-5 mg/ kg.) only accentuated these effects on capacity and urethral resistance, and caused an increase in bladder tonicity. These results might be explained on the basis _that atropine is known not to prevent the effects of stimulation of the parasympathetic nerves to the bladder, and that the drug is a central stimulant. Marked excitement was always noted with the larger doses and frequently after 0.1 mg/kg. Therefore it may be that the central stimulation caused an outflow of unimpeded parasympathetic impulses to the bladder, producing the effect noted on the urethral resistance and tonicity of the detrusor. However, atropine is known to block the bladder effects of parasympathomimetic drugs (fig. 5). The urethral resistance following the administration of acetyl-beta-methylcholine 5 minutes after 0.1 mg/kg. of atropine sulphate is almost identical with that after atropine alone, while that of carbamylcholine is about midway between that drug alone and atropine alone; definitely reduced. Atropine prevents the rise in tonicity of the bladder musculature of both the beta-methyl and carbamylcholine compoµnds and, although not shown in figure 5, the capacity values after these two choline compounds combined with atropine were as expected from the decreased /
ACTION OF MORPHINE ON URINARY BLADDER
395
urethral resistance noted above; i.e., reduced. Since the bladder tonicity after the beta-methyl compound in the atropinized dog was slightly reduced, the capacity here was not lowered as much as after carbamylcholine, in which case the detrusor tonicity showed little change from normal. The table also shows that atropine was effective in preventing or reducing the effects of morphine on the bladder. The increase in tonicity caused by 1.0 mg/kg. of morphine sulphate after atropine (0.1 mg/kg.) was much less than that seen after morphine alone, while the decrease in urethral resistance is practically the same as that for atropine alone. The initial rise of the urethral resistance after morphine is abolished by atropine. Discussion. It is apparent from the data presented in this paper that the typical action of parasympathomimetic drugs on the urinary bladder is to cause a marked rise in the tonicity of the bladder musculature and a decrease in that poorly defined group of reactions termed the " urethral resistance." This urethral resistance underwent an initial rise in most cases, subsequently falling below normal, although in 1 case this decrease did not reach or fall below normal values. Usually, the fall of urethral resistance below normal was prolonged and marked. In the main, this conclusion is in accord with the usual statement of parasympathetic action on the bladder. Atropine abolished or decreased the effects of these drugs on the bladder. The increase in tonicity was prevented, and the change in urethral resistance followed exactly that produced by atropine alone or was reduced. In any case, the initial rise was prevented. The actions of morphine, as described above, in every respect are similar to those produced by known parasympathomimetic drugs, and morphine may therefore be classed as a typical parasympathomimetic drug in its action on the urinary bladder. Further, atropine prevents the action of morphine much as the effects of the other drugs are blocked. Morphine must therefore act peripherally. The most striking fact observed was that no confirmation could be made of the statement appearing in the textbooks that morphine causes a spasm of the sphincters of the urinary bladder. In fact , in every case the final effect noted was a definitely decreased urethral resistance. The observed decrease in urethral resistance, increased detrusor tonicity and reduced capacity gives no explanation of the mechanism by which urinary retention following morphine administration can be produced.
396
IRWIN C. WINTER SUMMARY AND CONCLUSIONS
The characteristic actions of parasympathomimetic drugs on the urinary bladder as determined by cystometric study on trained unanesthetized female dogs are: (a) an increase in tonicity of the detrusor muscle; (b) a fall in urethral resistance, which may be preceded by an initial rise; (c) a marked decrease in bladder capacity. Atropine prevents the increase in tonicity and the initial rise in urethral resistance produced by such drugs, and itself causes a characteristic fall in urethral resistance. Morphine, as judged by the above criteria, is a peripherally acting parasympathomimetic drug. The change in capacity caused by any drug or combination of drugs used is a function of the change in tonicity of the bladder and urethral resistance. REFERENCES LANGWORTHY, ORTHELLO R., REEVES, DAVID L., AND TAUBER, EDWARD S. : Autonomic control of urinary bladder. Brain, 57: 266, 1934. - -- , DREW, J. EDWIN, AND VEST, SAMUEL A.: Urethral resistance in relation to vesical activity. J. Urol., 43: 123, 1940. MOLITOR, H.: A comparative study of effects of 5 choline compounds used in therapeutics: acetylcholine chloride, acetyl beta-methylcholine chloride, carbaminoyl choline, ethyl ether beta-methylcholine chloride, carbaminoyl beta-methylcholine chloride. J. Pharm. Exp. Therap., 58: 337, 1936. RosE, D. K., AND DEAKIN, ROGERS: A cystometric study of pharmacology of bladder. Surg., Gynec. and Obst., 46: 221, 1928. SLAUGHTER, DONALD, AND GRoss, E.G.: Some new aspects of morphine action. Effect on intestine and blood pressure; toxicity studies. J. Pharm. Exp. Therap., 68: 96, 1940. VAN DuzEN, R. E., SLAUGHTER, DONALD, AND WINTER, I. C.: Effect of trasentin and morphine on urinary bladder of unanesthetized dog. In press.