VESICOTROPIC LARRY T. WELCH, NABIL JOHN

ACTION OF DIGITALIS* PH.D.

K. BISSADA, F. REDMAN,

M.D. M.D.

From the Department University of Arkansas

of Pharmacology, Medical Center,

Division of Urology, Little Rock, Arkansas

ABSTRACT - Digitalis was investigatedfor its potential effect on pressure-volume relationships in the bladder of monkeys. This drug reproducibly decreased bladder capacity and increased intravesical pressure. This effect appears to be mediated by an increase in tension of the bladder wall. These changes were prevented by prior treatment with atropine which was given to produce pharmacologic impairment of the parasympathetic innervation to the bladder. Digitalis may represent a potentially useful drug fm the treatment of some types of hypotonic, neurogenic bladder or bladders with persistent decompensation following correction of associated distal urinary tract obstruction.

Historically, the clinical utility of digitalis preparations has been related to their cardiotonic effects. More recent observations have suggested a possible uropharmacologic action of these drugs.’ For example, in some patients with congestive heart failure and urinary retention, a dimiwtion of urinary symptoms following digitalization was noted.’ Other evidence for a vesicotropic action of digitalis comes from studies which have utilized the isolated bladder preparation as an experimental system. In these studies digitalis has been shown to affect tissue ion transport2B3 and metabolism,4,5 two factors which are associated with the function of all excitable tissues. Because of the potential clinical significance of vesicotropic action of digitalis, we examined its effects on pressure-volume relations in the bladder of a series of primates. Material

and Methods

Monkeys ranging in weight from 2 to 8 Kg., of either sex, and ofthe strains Macaca arctoides, M. fascicularis, M. mulatta, M. nemistrina, and Cercocebus torquatus were anesthetized by in*Supported in part by the John T. Haskins Urologic Research Fund 329-405-050, University of Arkansas Medical Center.

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tramuscular administration of 25 mg. per kilogram pentobarbital sodium. The bladder was catheterized via the urethra with a no. 5 vinyl infant feeding tube. The bladder was emptied, and the catheter was connected to a two-way system which permitted infusion of 0.9 per cent saline or measurement of intravesical pressure. The latter was performed by means of a Statham pressure transducer and a Sanbom Twin-Viso recorder. The bladder was filled in increments with saline at a rate of 6 ml. per minute, and pressure was recorded after infusion of each 10 or 25 ml. aliquot until voiding occurred. Preliminary observations showed that thirty seconds should be allowed before pressure readings were recorded to allow readings to reach 95 per cent of their steady-state value. Cystometrograms were plotted from the resulting data. Control studies were performed following the intravenous administration of a placebo solution of 0.9 per cent saline. All experiments were done in duplicate. At the end of control studies, 30 micrograms per kilogram of a rapidly acting preparation of digitalis (ouabain) in 0.9 per cent saline was given by slow intravenous administration. One-half hour later the pressure-volume measurements were repeated. In another group, atropine sulfate 0.4 mg. per kilogram was given intravenously

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A0

50

100

150

VOLUME

200

0 B

(ml)

20

40

60

0

C

CONTROL PRESSURE (cm H20 J

100

200

300

VOLUME

400

500

(ml)

FIGURE 1. Effects of digitalis on (A) pressure-volume relations in bladder of representative animal; (B) intravesical isovolemicpressure in normal animals; and (C) pressure-volume relations in bladder of representative animal given a&-opine.

Effect of digitalis on maximum intravesical pressure

TABLE II.

Effect of digitalis on maximum bladder capacity

TABLE I.

Monkey Number

Control (Milliliters)

1 2 3 4 5

200 90 75 73 94

Treated (Milliliters)

Change

175 -25 80 -10 -10 65 -13 60 -14 80 Mean f S.E.M. (-)14.4+ 2.7”

*Significantly different from zero (p < 0.05).

following control observations but prior to administration of digitalis. The bladder was evaluated fifteen minutes after administration of atropine. Digitalis was then given and bladder function was reevaluated thirty minutes later. The following values were compared under the conditions described: resting intravesical pressure and difference in intravesical pressure at equal filling volumes. In addition the bladder capacity at which voiding occurred and the corresponding maximum pressure were observed. Statistical evaluation ofthe measured parameters from control and experimental studies were performed by use of the student T test. Results Initial experiments were performed to evaluate the basic question: does digitalis aifect pressure-volume relations of the bladder in vivo? Data from a representative experiment are shown in Figure 1A. The most apparent effect ofdigitalis was a shift to the left of the pressure-volume curve in the area of the sharp, upward inflection. The point on the abscissa at which voiding occurred (MBC [maximum bladder capacity]) has shifted toward a lower value (Table I). This shift represented a statistically significant (p < 0.05) decrease of 13.9 per cent. The effect of digitalis on

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Monkey Number

Control (Centimeters Water)

1 2 3 4 5

26 29 38 28 38

*Not

Treated (Centimeters Water)

Change

27.5 1.5 1.0 30 43 5.0 -8.0 20 -12.0 26 Mean + S.E.M. (-)2.5 + 3.2*

statisticallydifferentfrom zero (p > 0.05).

MBC suggested that the reflex-mediated excitation resulting from a given increase in volume also resulted in a greater increase in pressure. Figure 1B shows the relationship of intravesical pressure during the control period and after digitalis. In all animals the largest difference in pressure was recorded at a volume equal to bladder capacity during treatment with the drug. All data points are observed to lie above the identity line, which suggests that the drug increased IP (intravesical isovolemic pressure). These data show an average increase of 76.8 per cent (p < 0.05) in the IP. It was not immediately apparent whether or not digitalis caused a change in MP (maximum intravesical pressure) at the point of voiding compared to control experiments. The shift to the left of the value for MP appeared to be virtually horizontal (Fig. 1A). Table II depicts a summary comparison of MP in all animals with and without digitalis. No significant difference (p > 0.05) in MP was observed following administration of the drug. A further question arose concerning the possible effect of digitalis on resting intravesical pressure. Pressures were measured and compared following evacuation of the bladder. No significant change (p > 0.05) in resting pressures was discernable following treatment with the drug (Table III).

UROLOGY / MARCH 1975 / VOLUME V, NUMBER 3

TABLE III.

Monkey Number

of digitalis

Effect intravesical

Control (Centimeters Water)

Treated (Centimeters Water)

1

10

2

12

7

3

10

10

4

8

8

5

12

7

-

different

therefore, probably mediated parasympathetic nerves.

Change 0 -5 0 0 -5

S.E.M.

from zero

through

+ 1.2*

(-)2

(p > 0.05).

Additional experiments were performed to evaluate the mechanism by which digitalis altered pressure-volume relations. We hypothesized that the drug-induced changes were probably related to an alteration of the autonomic motor influence to the bladder. As a test of the hypothesis, we evaluated the effect of digitalis on pressurevolume relations following impairment of the parasympathetic innervation by administration of atropine sulfate. Figure 1C shows a representative experiment indicating that digitalis was without significant effect on pressure-volume relations in the presence of atropinization. Composite results comparing the effects of atropine pretreatment on MBC and MP with and without digitalis may be seen in Figures 2A and B, respectively. These data show that experimental points representing MBC and MP before and after digitalis, cluster around the line of identity when experiments were performed in atropine-treated animals. Statistical evaluation confirmed that digitalis had no significant effect (p > 0.05) on MBC and MP under these conditions. These effects of digitalis on pressure-volume relations in the bladder are,

Recordings of intravesical pressure-volume relations were made for the purpose of assessing the effects of a digitalis preparation, ouabain, on the bladder in monkeys. Slow, intravenous administration of a single dose of ouabain decreased bladder capacity and increased isovolemic inThese effects could be travesical pressure. blocked by prior administration of atropine sulfate. No change was observed in resting pressure or in maximum pressure at the point of voiding following administration of drug. Two basic interpretations are offered to explain our findings. First, the increase in isovolemic pressure and decrease in bladder capacity are due to an action of ouabain which increases tension in the bladder wall. Support for this interpretation is based on the relationship between pressure, wall tension, and volume in a hollow viscus. The law of Laplace states that the pressure (P) in a distensible sphere-like structure, such as the bladder at equilibrium, is equal to the wall tension (T) divided by one-half the radius (R) or P = (T/R)2.’ Under control conditions in our experiments, a given filling volume (and therefore R value) was associated with certain pressure and wall tension values designated P and T according to the Laplace equation. After digitalis, pressure was recorded at the same volume (and R value), and was found to be 1.77. Therefore, the wall tension must also have increased to 1.77T to satisfy the equation. We conclude that digitalis is, therefore, capable of increasing wall tension in the bladder. Second, the drug-induced increase in wall tension and associated effects are dependent on the parasympathetic innervation to the bladder.

/ / //I

600

/ . = &

FIGURE 2. Effects of digitalis on (A) maximum bladder capacity and (B) maximum intravesical pressure in group of animals given atropine.

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With pharmacologic blockade of atropine sensitive sites, digitalis had no effect on maximum bladder capacity or isovolemic intravesical pressure. Gillis et al. 7 have previously demonstrated that ouabain can produce significant activation of parasympathetic nerves as well as other neural outflow from the CNS (central nervous system). These authors suggested that the neurotropic effects of digitalis which they observed were largely due to a direct action on the CNS. The importance of brain stem sites is supported by their observations that spinal cord transection at the first cervical nerve and bilateral cervical vagotomy prevented ouabain from increasing the electrical discharge of parasympathetic, sympathetic, and phrenic nerves. Also the druginduced activity in each nerve occurred with similar doses of ouabain and during similar periods of time. These findings do not rule out peripheral effects of digitalis such as parasympathetic enhancement or effects on peripheral afferent nerves. However, excitation of afferent reflex structures does not lead to simultaneous enhancement of all three nerves.7 Finally, one may speculate that the effect of digitalis is mediated by increasing the influence of facilitatory neural pathways which modulate the spinal reflex related to bladder emptying. Since the final common motor pathway to the bladder is parasympathetic, this would account for the lack of effect following atropine pretreatment. This, of course, assumes that atropine is at least capable of partial impairment of the parasympathetic nerves to the bladder. This apparently deserves special mention since other authors have often observed only partial blockade of parasympathetic

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influence to the bladder with atropine in response to electrical stimulation of the nerves in other species. * In conclusion clinical studies are required to determine the prospective value of digitalis in rehabilitation of the bladder in some patients with flaccid, hypotonic bladder or persistent vesical decompensation following correction of obstructive uropathy. Additional studies are also required to define further the detailed mechanism of the vesicotropic action of digitalis. Division of Urology Little Rock, Arkansas 72201 (DR. BISSADA) References 1. SADOUGHI, N., et al. : Effects of digitalis on urinary bladder, Urology 2: 582 (1973). 2. SOLINGER, R. C., et al.: Effect of ouabain on ion transport mechanisms in the isolated turtle bladder, Am. J. Physiol. 215: 249 (1968). potassium-potassium 3. FINN, A. L. : Ouabain-dependent exchange in the toad bladder, J. Membr. Biol. 12: 301 (1973). 4. LEFEVRE, M. E. : Effects ofouabain and high potassium on respiration of turtle brain and urinary bladder in vitro, Comp. Biochem. Physiol. 45: 283 (1973). 5. COPLAN, N. S., and MAFLY, R. H.: The effect of ouabain on sodium transport and metabolism of the toad bladder, Biochim. Biophys. Acta 282: 250 (1972). 6. GANONG, W. F.: Review of Medical Physiology, Los Altos, Lange Medical Publications, 1971, p. 420. effects of digitalis 7. GILLIS, R. A., et al. : Neuroexcitatory and their role in the development ofcardiac arrhythmas, J. Pharmacol. Exp. Ther. 183: 154 (1972). 8. TAIRA, N.: Cited in Elliott, H. W., et al.: The autonomic pharmacology of the bladder, Annu. Rev. Pharmacol. 12: 197 (1972).

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VOLUME V, NUMBER3

Vesicotropic action of digitalis.

VESICOTROPIC LARRY T. WELCH, NABIL JOHN ACTION OF DIGITALIS* PH.D. K. BISSADA, F. REDMAN, M.D. M.D. From the Department University of Arkansas of...
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