Prostaglandin stimulation of gastrointestinal transit in post-operative ileus rats

PROSTAGLANDINS

PROSTAGLANDIN

STIMULATION

OF GASTROINTESTINAL

IN POST-OPERATIVE M. J. Ruwart, Experimental

TRANSIT

ILEUS RATS

M. S. Klepper,

and B. D. Rush

Biology Research, The Upjohn Kalamazoo, Michigan 49001

Company

ABSTRACT The prostaglandins PGFpa, PGE2 and 16,16-dimethyl PGEz, when administered intravenously, orally, subcutaneously or intraduodenally to laparotomized rats, decreased gastric emptying, small intestinal transit and colonic transit as compared to unoperated controls. All three prostaglandins increased colonic transit above that found with unoperated controls. This activity was independent of small intestinal fluid accumulation (i.e., enteropooling) since ligating the ileal-cecal junction had no effect on colonic transit. Small 'intestinal transit was increased, but not normalized, by PGE2 and 16,16-dimethyl ,PGE2. 16,16Dimethyl PGE2 completely restored gastric emptying when given intravenously to laparotomized rats at doses greater than 5.0 ug/kg. This effect on gastric emptying lasted approximately 4 hrs. Thus, 16,16dimethyl PGE,, when given intravenously, normalized gastric emptying, significantly increased small intestinal transit, and made the colon hypermotile. Prostaglandins may be beneficial in the treatment of postoperative ileus and other conditions of sluggish gastrointestinal propulsion.

INTRODUCTION Propulsion through the gastrointestinal tract is transiently delayed after abdominal surgery even in patients exhibiting uncomplicated recovery (6,27,34,42,43). The etiology of the "post-operative ileus" is not well established but is believed to be due to stimulation of the sympathetic nervous system and/or suppression of cholinergic activity. If not spontaneously resolved, this condition can develop into a "para"Paralytic ileus" can also be lytic ileus" which can be fatal (6). caused by a number of other conditions (spinal injury, shock, gastrointestinal infection, mechanical obstruction, etc.). Prostaglandins have several attributes which might make them beneficial in the treatment of post-operative and paralytic ileus. Contraction of colonic and ileal tissue in vitro is a classical property of the prostaglandins (1,2,10,11,14,1%2~. Furthermore, PGE's have been shown to decrease noradrenalin release from the rabbit jejunum (16) and guinea pig ileum (21,29,38), possibly by restricting the availability of calcium (17). They also augment the effects of acetylcholine

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PROSTAGLANDINS

(4,41), perhaps by potentiating its release from post-ganglionic nerve terminals (21). Furthermore, in the isolated rat stomach fundus preparation, prostaglandins have been shown to initiate contractions which are antagonized by drugs which stimulate sympathetic receptors and potentiated by drugs which inhibit cholinergic fibers (3,7). Rat colon and human taenia coli strips reacted similarly to these agents (5,40). Thus, prostaglandins appear to antagonize sympathetic (inhibitory) activity thought to be responsible for post-operative ileus and augment parasympathetic (stimulatory) activity. In canine subcutaneous intestinal loops, PGFz, restored contractions which had been abolished by intraperitoneal potassium iodide (15). In a mechanical ileus model in rabbits, PGFz, was also effective in increasing intraluminal intestinal pressure and amplitude of peristalsis (12,13). Thus, prostaglandins can reverse loss of gut motility. In man, oral PGE2 has been reported to increase transit through the small intestine and colon (23) and oral 16,16-dimethyl PGE2 increased gastric emptying (28). Ileal flow has reportedly been increased by intravenous PGF2, and PGE (22), although another study (8) showed.no change in small intestinae transit time with intravenous PGFz,. Intrajejunal PGE,, however, prolonged the mean intestinal transit time in healthy volunteers (24). These studies suggest that under certain conditions, prostaglandins can increase propulsion in humans. Thus, prostaglandins have several properties which suggest that they may be useful in stimulating the gut following gastrointestinal surgery. This report details the experiments done to test this hypothesis, utilizing a rat model of post-operative ileus which measures gastric emptying (GE), small intestinal transit (SIT), and colonic transit (CT) simultaneously and quantitatively. METHODS Male Upjohn rats (210-2209) were restrained and fasted for 48 hrs prior to use. During this time they had free access to water. "Normal" rats received no surgical treatment prior to fasting. "Implant" rats had a cannula surgically inserted into the duodenum and proximal colon which exited at the back of the neck. Animals prepared in this manner were healthy and could be maintained for several months if desired. Solidified agar (1.5%) stained black with 0.4% India ink was injected into the duodenum and proximal colon of implant rats cannulated two weeks prior to use. The black dye (India ink) adhered to the agar in vivo as it had during -in vitro washing and provided a gelatinous, xsii?l-iy-detectablemarker. Intragastric sodium 51chromate was also administered, and the rats were sacrificed by CO;!asphyxiation 45 mins later. The pylorus was clamped, and the stomach and intestines were excised. Small intestinal transit was expressed as a percentage of the farthest length traversed by the duodenally administered marker divided

416

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PROSTAGLANDINS

divided by the total length of the small intestine. Colonic transit (CT) was defined as the percentage of large intestinal length traveled by the agar bolus which had been injected into the proximal colon. Gastric emptying (GE) was defined as the percent of isotope in the small intestine at the time of sacrifice. These values of GE, SIT, and CT were considered to be those of "unoperated controls". Previous studies had shown that GE could only be measured with a fluid marker postsurgery, since a semi-solid one would not empty at all; CT measurements required agar, since fluids exhibited a retrograde motion. SIT was unchanged in untreated, laparotomized rats with either intraduodenal fluid or semi-solid markers. Agar was chosen to study SIT, since a liquid marker such as ink might be expected to migrate due to mixing with enteropooling fluids induced by prostaglandin administration (33). Post-operative ileus was induced via laparotomy in normal rats under methoxyfluorane anesthesia. Agar was injected into the duodenum and proximal colon with a 23 gauge needle and the abdominal incision was repaired with wound clips. The rats were then administered intragastric slchromium oxide in saline. Forty-five minutes later the animals were sacrificed by CO2 asphyxiation. GE, SIT and CT were measured as above. Previous studies had indicated that these measurements were not different from those found with laparotomized "implant" rats (35). Experiments were performed on 4 groups of five animals. One group was always a vehicle group and the others received varying doses of a single prostaglandin. For the data presented in the Tables, two repetitions of each experiment were averaged. The data was subjected to Wilcoxon's test (18), since it does not require equality of variances within treatment groups for validity as does the Student T test. To obtain a more complete dose response curve for intravenous 16,16-dimethyl PGE,, two separate experiments in duplicate were performed to cover the indicated range. Thus, the 0 ug/kg value is a composite of 20 values rather than 10. Each ileus rat received one of three prostaglandins (E2, Fza, and 16,16-dimethyl PGE ) administered at a dose and route indicated in the Tables. Since the f D 5ds for these compounds are lowest when given by the intravenous route, smaller doses were used. Intravenous and subcutaneous doses were given as a single bolus injection; intraduodenal compounds were administered as a bolus at the time of surgery; oral doses were given with an intragastric dosing tube. The amount of PGF2, and lower doses of PGE, administered were 0, 100, 1000, or 10,000 ug/kg. 16,16-Dimethyl PGE, was used (0, 250, 500 or 1000 Pg/kg) since this compound was shown to be more potent than the natural prostaglandins in other gastrointestinal assays such as enteropooling (33). If GE, SIT or CT differed from control values, other doses were tested to determine the approximate dose at which the effects began. Doses where no significant effects were seen such as i.d. doses between 0 and 15,000 pg/kg in Table 1 were omitted from the Tables for the sake of brevity. Prostaglandins were diluted from an ethanol stock into saline. Matched GE, SIT and CT were determined in order vehicles were used as controls. to establish whether prostaglandins influenced these parameters. PGF2,

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PROSTAGLANDINS

Table

1.

Effect

of PGF2,

in Ileus Rats.

Dose Route

ug/kg 0 100

S.C.

1,000

S.C.

10,000

S.C.

S.C.

10: 1,000 10,000

0 350 1,000

3.3 2.3 3.7 5.7

f + f +

SIT 1.4 1.6 0.9 1.9

7.0 6.4 10.7 7.1

A + c +

CT 2.8 5.0 1.9 0.7

11.8 +

2.1

23.1 i 4.7 89.3 f 10.7*

p.0.

19.0 9.7 t f 3.8 7.9

11.3 + 0.8 10.1 2.2

13.9 If 1.9

;::: p.0.

18.3 + 5.5 8.3 + 1.0

13.5 * 4.3 10.8 + 2.0

31.2 + 14.1 21.5 + 3.5

. i.V.

6.9 f 3.7 12.6 c 6.3 6.7 f 2.4

10.5 _+ 2.8 9.6 f 0.8 11.3 f 1.3

19.8 f 3.8 20.9 + 2.4 47.4 + 26.5

i.d. i.d.

18.8 + 2.4 24.2 it 6.0

10.6 + 0.6 15.0 f. 1.3

15.3 f 25.4 r

K:

0 15,000

GE

1.4 4.9

*Value differs significantly from corresponding value at 0 pg/kg (pcO.05). Fasted rats were laparotomized and administered PGF2, at various doses by the route indicated (p.0. = oral, i.v. = intravenous, Subcutaneous prosi.d. = intraduodenal, S.C. = subcutaneous). taglandin was administered 15 min prior to surgery; prostaglandin Rats was given post-operatively when other routes were used. were sacrificed 45 min after laparotomy for measurement of GE, SIT, and CT. RESULTS

&SIT,

and CT in Unoperated

Implant

Rats

Values and standard deviations for GE, SIT and CT in ten unoperated implant rats were 63.1 + 2.7, 64.8 -+ 3.0 and 34.0 ?r 3.5, respectively. Previous studies have shown that GE and SIT measured in implant rats are statistically the same as GE and SIT measured in normal rats with oral 5lCr and ink (35). The above values of GE, SIT and CT were used as the yardstick to determine whether or not the prostaglandins could "normalize" bowel function after laparotomy. The Effect of Prostaglandins Transit and Colonic Transit. PGF2,

418

did not change

on Gastric

Emptying,

GE and SIT compared

Small

Intestinal

to vehicle-treated

ileus

MARCH 1980VOL.19N0.3

PROSTAGLANDINS

rats over the dose range and by the routes tested (Table 1). PGFz, administered at high S.C. doses increased colonic propulsion above that of unoperated implant rats. PGE, (s.c. or i.v.) increased CT to values above those of unoperated implant rats also (Table 2). In addition, small but significant increases in SIT could be produced by oral or intraduodenal administration. Gastric emptying was never altered by PGE2 in the experiments reported herein.

Table

2.

Effect

of PGE, in Ileus

Dose uglkg

Route

GE

SIT

CT

1,oo:

S.C. S.C.

12.0 16.9 f 5.4 3.1

8.0 f 2.1

64.1 11.8 k c 16.4* 2.1

10,000

S.C.

13.8 + 2.3

10.2 + 2.2

89.3 c 10.7*

10:

20.3 14.8 t ? 4.2 6.7

10.6 r 11.1 ? 0.8 0.2

13.9 +

1,000 10,000

p.0. p.0. p.0. p.0.

15.5 + 3.4 17.1 f 5.2

15.3 * 0.6" 19.7 f 3.5*

18.9 f 2.0 16.8 j: 3.1

0 500 2,500

i.v. i.v. i.v.

17.8 + 7.3 8.1 + 2.1 8.1 + 3.0

10.6 + 1.7 15.6 * 4.7 7.9 + 0.9

20.7 f 5.2 73.8 c 15.2 64.7 i. 16.9*

0 10,000

i.d. i.d.

18.5 2 6.0 12.4 ? 7.3

10.7 i 0.8 24.7 -f:3.9*

18.3 f 24.0 f

-

1.9

4.5 2.5 --

*Value differs significantly from corresponding value at 0 ug/kg (pco.05). Fasted rats were laparotomized and administered PGE2 at various doses by the route indicated (p.o. = oral, i.v. = intravenous, i.d. = intraduodenal, S.C. = subcutaneous). Subcutaneous prostaglandin was administered 15 min prior to surgery; prostaglandin was given post-operatively when other routes were used. Rats were sacrificed 45 min after laparotomy for measurement of GE, SIT, and CT.

16,16-Dimethyl PGE, increased SIT and CT by the same routes as PGE, (Table 3). In addition, CT was increased by intraduodenal administration and SIT by subcutaneous and intravenous dosing. The outstanding difference between 16,16-dimethyl PGE, and the other prostaglandins was its ability to accelerate gastric emptying when given intravenously. Thus, 16,16-dimethyl PGE, was able to stimulate GE, SIT and CT simultaneously when given by the i.v. route.

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1980 VOL. 19 NO. 3

419

PROSTAGLANDINS Table 3.

Dose pg/kg 0

250 500 2,500 25:

Route S.C. S.C.

S.C. S.C.

Effect of 16,16-dimethyl PGE, in Ileus.

GE 15.1 11.9 2.1 1.1

* f + +

SIT 5.1 6.8 6.5 0.3*

500 1,000

p.0. p.0. p.0. p.0.

0.: 1.5 3.0 5.0 25 50 250

i.v. i.V. i.v. i.v. i.v. i.v. i.v. i.v.

17.4 4.4 12.5 28.2 36.7 36.2 33.2 24.6

25: 500

i.d. i.d. i.d.

10.0 + 2.1 19.8 + 6.1 3.5 + 0.8*

7.0 15.7 28.8 9.8

* f r ?

CT

l

1.9 1.9* 3.1* 2.2

22.1 84.2 100.0 62.4

?r 1.4 + 11.2* + 0.0" + 17.8*

5.9 f 6.0 5 4.3 3.1

18.1 8.2 f 0.8 1.5*

23.0 12.9 k f

5.9 L 3.6 8.4 + 5.3

14.6 c 1.6* 16.4 ?r 1.5*

31.5 ?: 7.0 21.1 f 4.3

8.2 8.3 9.3 10.1 13.1 16.3 15.2 22.5

22.8 17.6 20.3 26.2 35.0 68.8 54.7 63.5

+ 6.9* 1.1 1 5.9* + 3.7* + 4.4* f 5.4* ?:6.9* ? 5.1*

+ f 0.4 0.8 + 1.3 + 0.9 + 1.1 + 2.2" _+3.1* ?r2.8*

10.0 + 1.0 18.4 + 0.8 13.6 + 2.1

6.5 1.9

+ 1.4 1.5 f 4.8 ?: 8.2 r 7.1* + 12.5* f 8.7* + 8.6*

18.8 ?I 1.6 23.9 * 3.9 53.4 * 10.8*

*Value differs significantly from 0 ug/kg (~~0.05). Fasted rats were laparotomized and administered 16,16-dimethyl PGE2 at various doses by the route indicated (p.o. = oral, i.v. - intravenous, i.d. = intraduodenal, S.C. = subcutaneous). Subcutaneous prostaglandin was administered 15 min prior to surgery; prostaglandin was given post-operatively when other routes were used. Rats were sacrificed 45 min after laparotomy for measurement of GE, SIT, and CT. Duration of Pharmacological Activity The duration of a single intravenous bolus dose of 16,16-dimethyl PGE, on gastric emptying was tested. Rats were administered i.v. vehicle or 16,16-dimethyl PGEZ (50 pg/kg) immediately after laparotomy. Intragastric 51Cr was administered at various times post-surgery to animals which were sacrificed 45 mins later for measurement of GE. GE was increased to values greater than those found in unoperated implant rats approximately 2-3 hrs after drug administration. Activity was still apparent 3 3/4 hrs after laparotomy (Figure l), after which time GE returned to the values of vehicle-treated controls.

420

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1980 VOL. 19 NO. 3

PROSTAGLANDINS

100

*

80

p

* --_ --_ P\\ \

80

\

\

\

\

ii5

\

\ *

z 40

20

0 0

I

I

I

I

I

I

1

2

3

4

5

8

HOURS

AFTER

DRUG

Figure 1. Duration of 16,16-dimethyl PGE2 effects on gastric emptying. GE is expressed as defined in text. "Hours after drug" indicate time of sacrifice post-laparotomy and administration of drug open circles) or vehicle (solid circles). "*" in(50 Pg/kg, t.v., dicates a value significantly (~~0.05) different from corresponding vehicle-treated value. Each point is the mean of 8 rats. Influence of Small Intestinal Fluid Secretion ih Colonic Transit The contribution of prostaglandin-induced enteropooling (33) on colonic transit was tested by tying the ileal-cecal junction in ten

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421

PROSTAGLANDINS

laparotomized rats administered a black agar bolus in the proximal colon. Ten other animals undergoing laparotomy only were used as controls. The wound was closed and rats were administered subcutaneous PGE: (1000 ug/kg) and sacrificed 45 min later for measurement of CT. This procedure prevented movement of small intestinal fluid into the cecum and colon where it might stimulate propulsion. Post-surgical administration of the prostaglandin eliminated fluid accumulation in the colon prior to the surgical intervention. CT in PGE2-treated rats with tied ileal-cecal junctions did not differ significantly from rats receiving laparotomy and subcutaneous PGE2 (1 mg/kg) only (cf. 60.1 * 9.9 vs. 55.4 f 12.2, respectively).

DISCUSSION Laparotomy has previously been shown to cause post-operative ileus in the rat (25). Delays in gastrointestinal propulsion have been measured 15-24 hrs after surgery (25), but are most pronounced in the immediate post-operative period (35). The parameters measured, especially GE, showed a greater day-to-day variation than that seen within each experiment. Since isotopic measurement of GE has been successively used in the past (9,30,39), these fluctuations are probably indicative of biological, rather than methodological variability. Even though GE values range from 3.3 to 20.3, this is well below that seen for normal rats (63.1 r 2.7). This variation, however, makes daily vehicle controls mandatory as outlined in the Methods section. These studies show that prostaglandins are able to stimulate GE and CT in the ileus rat, and to a lesser extent, increase SIT. The type of prostaglandin and the route of administration were critical in determining which organ was affected and to what extent. This differential activity of the prostaglandins indicates that the organs of the gastrointestinal tract do not respond to propulsive stimuli in the same manner. Metabolism of the prostaglandins may account for the variation in results when different routes of administration are used. The gastric emptying properties of 16,16-dimethyl PGE? might be predicted from the increase seen after oral administration of this compound to human volunteers (28). However, only intravenous administration of 16,16-dimethyl PGE2 showed efficacy in the rat. In normal rats, this compound inhibited emptying if given by the subcutaneous but not oral route (32). Subcutaneous PGF2, caused duodenal gastric reflux (26). Thus, the route as well as the type of prostaglandin is critical in producing effects on gastric emptying. The minimal increase in SIT contrasts with the normalization of GE and CT by 16,16-dimethyl PGE,. However, recent evidence indicates that rat small intestinal propulsion, unlike that of the stomach and colon, is not primarily mediated by cholinergic transmission (36). This indi-

422

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1980 VOL. 19 NO. 3

PROSTAGLANDINS

cates that in rat SIT is controlled by nonclassical mechanisms, and could account for the minimal effect of the prostaglandins on SIT, which effectively normalize CT and GE. The effect of a single bolus injection of 16,16-dimethyl PGE2 lasted for approximately four hours, after which time GE returned to the value of untreated controls. Thus, the prostaglandin's effect on GE is a temporary alleviation of ileus, not a curative one. More studies are needed to determine if prostaglandins could be useful for clinical application in post-operative ileus. Comparison of 16,16-dimethyl PGE2 with carbachol (35), bethanechol (37), guanethidine 137) . , and neostiomine (37j irjdicate that this orostaqlandin is equally CT. effective in increasing GE, and possibl:/ superior in accelerating 4

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