Comparative Effects of Four Prostaglandin Synthesis Inhibitors on the Obstructed Kidney in the Dog

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Vol.135,May

THE JOURNAL OF UROLOGY

Printed in U.S.A.

Copyright © 1986 by The Williams & Wilkins Co.

COMPARATIVE EFFECTS OF FOUR PROSTAGLANDIN SYNTHESIS INHIBITORS ON THE OBSTRUCTED KIDNEY IN THE DOG JAMES P. GASPARICH

AND

MICHAELE. MAYO*

From the Department of Urology, University of Washington, Seatt/,e, Washington

ABSTRACT

Comparative effects of four prostaglandin synthesis inhibitors (PGSI) on the acutely obstructed kidney were studied using an intact canine model. Trigonal vesicostomies were constructed and totally implanted nephrostomy tubes were placed to monitor renal pelvic pressures. After recovery, experiments were run at weekly intervals with one drug administered each week in a random fashion. Complete ureteral obstruction was obtained using a Fogarty balloon catheter passed retrogradely into the distal ureter and inflated. When renal pelvic pressure reached 80 cm./H20 the designated PGSI was given and a repeat dose was given 30 minutes later. Mean blood pressure was also monitored during several experiments. With the first dose significant decreases in renal pelvic pressure were obta,ined with all drugs tested. Only ibuprofen showed a significant f'Qrther decrease with the second dose. Ibuprofen showed the greatest decrease in pressure with the first dose, which was significantly greater than the other drugs tested. There was no association between mean blood pressure changes and the nadir of renal pelvic pressure. The pain associated with ureteral obstruction is caused by a rise in intraluminal pressure above the obstruction which in turn produces an increase in tension in the pelvic and ureteral walls. 1• 2 A reduction in pressure will result in decreased wall tension and relief of pain. In obstruction the increase in renal pelvic pressure stimulates the synthesis ofprostaglandin E 2 (PGE 2) in the renal medulla,3 which in turn causes an increase in renal blood flow and a sodium diuresis. 4 •5 Sjodin and Holmlund showed that there was a reduction in renal pelvic pressure in experimentally obstructed ureters using indomethacin, a prostaglandin synthesis inhibitor (PGSI). 6 Since then there have been several reports of the use of various PGSis for the treatment of pain in acute ureteral obstruction. MATERIALS AND METHODS

Six female mongrel dogs, weighing approximately 20 kg., were used in these studies and were prepared two to three weeks before the experiments were performed by inserting a totally implanted nephrostomy tube and constructing a vesicostomy. Under general anesthesia with endotracheal intubation and ventilation a subcostal retroperitoneal flank approach was made to the kidney. The nephrostomy tube used was a #8 French feeding tube shortened to approximately 15 cm. and fashioned with two subterminal side holes. The most convex edge of the kidney was identified and a 0.5 cm. incision was made into the renal capsule. The catheter, stiffened by a rigid metal stylet, was inserted to a depth of 3 cm. into the renal pelvis and the stylet was removed, leaving the tube in place. The resistance to insertion of the stylet and tube suddenly decreased as the tip of the papilla was punctured and the renal pelvis entered. The nephrostomy tube was secured to the renal capsule by use of a Dacron arterial graft fixed around the tube and to the capsule with 4.0 silk sutures. An intravenous catheter plug was placed on the other end of the #8 French feeding tube and irrigated with heparinized saline. The heparin lock was then secured in place subcutaneously. Subsequent access to the Accepted for publication November 27, 1985. * Requests for reprints: Dept. of Urology RL-10, University ofWaJ>hington School of Medicine, Seattle, WA 98195. Supported by grant 2 ROI AM 20671 from the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases.

nephrostomy was easily accomplished by a percutaneous puncture with a 25 gauge needle for injection of contrast material or measurement of pressure. The dog was then repositioned and draped and a low midline laparotomy incision was made into the peritoneal cavity to expose the bladder. A subtotal cystectomy was performed and a trigonal vesicostomy was created in the lower half of the incision. This allowed visual exposure of the ureteral orifices and retrograde access to the distal ureter. After two weeks of recuperation and adjustment to urinary incontinence, the animals underwent a nephrostogram to assess the degree of ureteral dilation, if any, which followed the creation of the trigonal vesicostomy. If satisfactory, the dog was now ready to serve as a chronic model for the studies. Intravenous formulations of the four prostaglandin synthesis inhibitors used in this study (indomethacin, ibuprofen, naproxen and RS 37619) were obtained from their respective manufacturers. Experiments were run in each animal at weekly intervals with the drugs and placebo given randomly. Food and water were withheld from the animals overnight and after sedation with surital (25 mg./kg.) an intravenous infusion of 0.9 per cent saline was maintained at 40 cc an hour via a Harvard pump. A 25 gauge needle was inserted percutaneously into the nephrostomy and this was connected to a quartz pressure transducer (Hewlett Packard model #740A). Arterial pressure was measured via trancutaneous puncture and cannulation of the femoral artery. A five-minute period of base-line renal pelvic pressure was recorded. Free flow of urine down the ureter was verified by injecting a bolus of indigo carmine into the nephrostomy. A #4 French Fogarty catheter was inserted in a retrograde fashion into the distal ureter via the trigonal vesicostomy and a balloon inflated with 0.2 to 0.4 ml. of saline to obstruct the ureter. The obstruction was confirmed when a second bolus of indigo carmine given via the nephrostomy tube did not appear at the ureteral orifice. When renal pelvic pressure reached 80 cm. of water, the selected drugs were given intravenously in the pre-determined doses (table 1). All doses were given over 30 seconds in four ml. of fluid. The effect of the drugs on renal pelvic and arterial pressures was recorded for 30 minutes and then a second dose was given. Observations were continued for a minimum of 30 minutes after the second dose was given. Obstruction was relieved by

1088

1089

EFFECT OF PROSTAGLANDIN SYNTHESIS INHIBITORS ON OBSTRUCTED KIDNEY

deflating the Fogarty balloon and observations continued until base-line pressures were reached. Statistical analyses were performed using the paired t test. RESULTS

After the first dose of all agents tested, statistically significant decreases in renal pelvic pressure were obtained when compared to the control injection of normal saline (fig. 1 and table 2). Ibuprofen was significantly more efficacious in reducing renal pressure than the other three drugs tested, and also produced a significantly more rapid fall in pressure than indomethacin or RS 37619. Ibuprofen was the only agent that produced a significant response to the second dose (table 3). There was no association between blood pressure changes and the nadir of renal pelvis pressure (table 4). DISCUSSION

The comparative effects of the various parenteral prostaglandin synthesis inhibitors on acutely obstructed kidneys has not TABLE

1. Drug dosages

Saline (0.9%) lndomethacin Ibuprofen Naproxen RS 37619

0.25 ml./kg. 2.5 mg./kg. 10 mg./kg. 5 mg.fkg. 0.2 mg./kg.

NAPROXEN 100mgln5ml

~

100

l

Min,mum

/:Jl'.

RS376f9 4 mginSml

l

Ii,'

been previously reported. Our study confirms the effectiveness of PGSls in reducing the pelvic pressure during acute obstruction. This effect was not attributable to arterial pressure changes. Parenteral ibuprofen showed a significantly greater decrease in renal pressure than the other three agents, including indomethacin, the "Gold Standard" of PGSls. The decision to give the drugs at a pressure of 80 cm. of water was based on our previous study. In this it was found that ureteral peristalsis in dogs had disappeared and spontaneous movement of calculi had not usually occurred at this pressure level. 7 The doses of PGSls chosen were similar to those used in man for their effects as anti-il).flammatory agents. Because the ureter was completely occluded in this model, the effects of these agents on urinary prostaglandin excretion could not be measured, and the differential effect of the PGSls could have been due to unequal inhibition of PGE 2 • It has been known for some time that there is a transitory rise in renal blood flow and urine output after ureteral obstruction.4·8· 9 In 1976 Olsen et al. 3 showed that renal compression or ureteral occlusion caused an increase in renal blood flow in anesthetized dogs. This was associated with an increase in urinary PGE2 excretion and was abolished by indomethacin. This effect of PGE2 on renal resistance in obstructed kidneys was confirmed by Nishikawa et al. 10 who suggested that the later reduction in renal pressure at 72 hours was due to the vasoconstrictor substance thromboxane A2. 11 Allen et al. 12 studied the response of the normal and obstructed kidney to indomethacin and found that the normal blood flow decreased by 35 to 40 per cent. In the presence of indomethacin, obstruction did not produce the characteristic renal vasodilation and the ureteral pressure was significantly lower than in the control animals. Sjodin and Holmlund13 found that the reduction in urine output due to the effect of PGSls could be overridden by a diuresis induced by saline infusion or hypertonic contrast medium. It is possible that prostaglandin synthesis inhibitors are affecting ureteral tension by direct action on the ureteral smooth muscle. However, Sjodin and Holmlund13 could show no difference in the effect of indomethacin on pelvic pressure whether the upper tract was obstructed near the ureteropelvic TABLE

IOmin

IBUPROFEN

Number

200mqin5ml

t I : f

'i'"""""" : I! I

Naproxen 6

RS 37619 6

H20)

/!:ti/ I I/ I Ii I I Ii~;u:~I·~··~··~~-

Before After % Change

Rise/fall time (min.) *p < 0.05.

50mgin5ml

JWR IUllllll:ll~flfl-

TABLE 4.

JOmin

FIG. 1. Effect of first dose of PGSis on renal pelvic pressure. At "S" 1 ml. i.v. anesthetic agent thiamylal sodium (surital) was given.

TABLE 2.

Renal pressure (cm-H2 0) Before After % Change Rise/fall time (min.)

Ibuprofen 6

Renal pressure (cm.

I' I':

INDOMETHACIN

Number

3. 2nd dose response

Indomethacin 6

66.3 (±5.43) 49.7 (±4.81) 40.8 (±2.36) 65.8 (±4.87) -18.9* -0.7 10.8 (±2.29) 2.1 (±0.79)

64.3 (±2.86) 64.0 (±3.60) 65.7 (±4.36) 64.5 (±4.40) +2.1 +0.8 10.5 (±2.13) 9.1 (±1.37)

Comparison of arterial and renal pressure after PGSI

Indomethacin Ibuprofen Naproxen RS 37619

Mean Arterial Pressure (% Change)

Mean Renal Pressure (% Change)

-2.0 +7.1 -5.0 -6.0

-28.0 -51.1 -36.0 -29.5

1st dose response

Control 6

Indomethacin 6

Ibuprofen 6

Naproxen 6

RS 37619 6

77.5 (±2.17) 87.8 (±3.28) +12.7** 15.0

79.3 (±2.39) 60.0 (±3.02) -24.5*** 17.2 (±2.25)

82.3 (±3.62) 34.5 (±3.06) -58.0*** 5.3 (±1.63)

82.0 (±2.37) 58.2 (±1.78) -28.8*** 11.7 (±1.59)

79. 7 (±2.16) 57.3 (±2.21l) -28.0*** 14.7 (±2.03)

(Raw data in means± Standard error). * p = 0.05 - 0.01. ** p = 0.01 - 0.001. *** p < 0.001.

1090

GASPARICH AND MAYO

or ureterovesical junctions. However the mechanism of the reduction of renal pressure is at present unclear. Since 1978 a number of clinical reports have been published from European centers in which pain relief has been obtained by the administration of PGSis. The commonest agent used was indomethacin given either intravenously6 or intramuscularly, 14 and in one study indomethacin suppositories were selfadministered.15 The other agent used clinically was diclofenac sodium. 16 However, none of these agents are available in the United States for parenteral use at the present time. The effect of intravenous indomethacin was found to be greatest when ADH levels were high, indicating that the volume status of the patient and/or the level of ADH itself may be important for pain relief following indomethacin administration in acute ureteral obstruction.17 Although pain relief can be obtained by using these agents parenterally instead of opiate analgesics, it is not clear how the use of these drugs will affect stone progression in the early and/or late phases of the disease. In the late phase when ureteral impaction has occurred with the formation of an edematous bar distal to the stone, anti-inflammatory agents may help by reducing the edema and inflammatory response. 18 However, there are reports of reduced renal function due to these agents19• 20 and although tnost of these are in patients with underlying renal disease, increased vascular tone or prerenal azotemia, it has not been established experimentally or clinically whether there is any long-term decrease in renal function when PGSis are administered in the presence of unilateral or bilateral ureteral obstruction. Acknowledgments. The authors acknowledge the generQus support of Merck, Sharp and Dohme Research Labs for indomethacin, Upjohn Co. for ibuprofen and Syntex Research for naproxen and R.S. 39619.

5. 6. 7. 8. 9. 10.

11. 12.

13.

14. 15. 16. 17.

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18. 19. 20.

anism of acute hemodynamic response to ureteral occlusion. Invest. Urol., 9: 109, 1971. Horton, E.W.: Hypotheses on physiological roles ofprostaglandins. Physiol. Rev., 49: 122, 1969. Holmlund, D. and Sjodin, J. G.: Treatment of ureteral colic with intravenous indomethacin. J. Urol., 120: 676, 1978. Algood, C. B., Sood, N., Fairchild, T. and Mayo, M. E.: Experimental study of ureteral calculus disease: effects of calculus size, obstruction and hydration. J. Urol., 130: 999, 1983. Gilmore, J. P.: Renal vascular resistance during elevated ureteral pressure. Circ. Res., 15: 148, 1964. Abe, Y., Kishimoto, T., Yamamota, K. and Ueda, J.: Intrarenal distribution of blood flow during ureteral and venous pressure elevation. Am. J. Physiol., 224: 746, 1973. Nishikawa, K., Morrison, A. and Needleman, P.: Exaggerated prostaglandin biosynthesis and its influence on renal resistance in the isolated hydronephrotic rabbit kidney. J. Clin. Invest., 59: 1143, 1977. Morrison, A. R., Nishikawa, K. and Needleman, P.: Unmasking of thromboxane A2 synthesis by ureteral obstruction in the rabbit kidney. Nature, 267: 259, 1977. Allen, J. T., Vaughan, E. D. and Gillenwater, J. Y.: The effect of indomethacin on renal blood flow and ureteral pressure in unilateral ureteral obstruction in awake dogs. Invest. Urol., 15: 324, 1978. Sjodin, J. G. and Holmlund, D. E. W.: Effects of saline load, roentgen contrast medium and indomethacin on diuresis and pelvic pressure in the acute obstructed kidney. Br. J. Urol., 54: 446, 1982. Marsala, F.: Treatment of ureteral and biliary pain with an injectable salt of indomethacin. Pharmathera., 2: 357, 1980. Flannigan, G. M., Clifford, R. P. C., Carver, R. A., Yule, A. G., Madden, N. P. and Towler, J.M.: lndomethacin-an alternative to pethidine in uteric colic. Br. J. Urol., 55: 6, 1983. Lundstam, S., W ahlander, L. and Kral, J. G .: Treatment of ureteral colic by prostaglandin synthetase inhibition with diclofenac sodium. Curr. Ther. Res., 28: 355, 1980. Grenabo, L., Aurell, M., Delin, K., Holmlund, D. and Sjodin, J. G.: Antidiuretic hormone levels and the effect of indomethacin on ureteral colic. J. Urol., 129: 941, 1983. Nygard, A. and Bjorneby, S.: Oxyphenbutazone in the treatment of acute ureteral stone disease. Scand. J. Urol. Nephrol., 9: 36, 1975. Kleinknecht, C., Broyer, M., Gubler, M. C. and Palcoux, J. B.: Irreversible renal failure after indomethacin in steroid-resistant nephrosis. N. Engl. J. Med., 302: 691, 1980. Kimberly, R. P., Bowden, R. E., Keiser, H. R. and Plotz, P. H.: Reduction of renal function by newer nonsteroidal anti-inflammatory drugs. Am. J. Med., 64: 804, 1978.