Cimetidine and stress ulcer in aged rats

Physiology & Behavior, Vol. 33, pp. 305-308. Copyright©PergamonPress Ltd., 1984. Printed in the U.S.A.

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Cimetidine and Stress Ulcer in Aged Rats W I L L I A M P. PARI~ A N D G E O R G E P. V I N C E N T l Veterans Administration M e d i c a l Center (15R), Perry Point, M D 21902

R e c e i v e d 12 D e c e m b e r 1983 PARI~, W. P. AND G. P. VINCENT. Cimetidine and stress ulcer in aged rats. PHYSIOL BEHAV 33(2) 305-308, 1984.--Male Sprague-Dawley rats, 2, 6, 11, 18, and 26 months old, were subdivided into four drug treatment groups and received either 25, 50, 100 mg/kg of cimetidine or a placebo control before being exposed to restraint plus cold stress for 3 hr. Cimetidine, at all dose levels, significantly reduced ulcer severity in all age groups except the 18- and 26-month-old rats. Senescent rats were not more susceptible to restraint ulcer and cimetidine had the least anti-ulcer effect with the senescent 26-month-old rats. Cimetidine

Stomach lesions

Aged rats

Stress ulcer

CIMETIDINE, a histamine Hz-receptor antagonist, is one of the most widely used drugs for the treatment of gastrointestinal disorders. In clinical trials, cimetidine has proved to be a potent gastric acid inhibitor [8, 10, 23, 45, 47] and an effective drug for the treatment of gastrointestinal ulcers [4, 5, 13, 17, 18, 31, 44, 55]. The success enjoyed by cimetidine in clinical patient applications was also reflected in animal models of the disease. In many instances, cimetidine reduced the incidence of stress ulcer in swine [l], dogs [2], and rats [7, 24, 29, 30, 36, 37, 48, 51, 52]. Because of its success, both in the animal laboratory and with clinical cases, cimetidine has evolved as the nation's second most prescribed drug after diazepam [27,28]. Cimetidine is also prescribed to prevent stress ulcer in critically ill patients [34]. The incidence of stress ulcer increases dramatically in the aged patient [9,35] and cimetidine therapy with elderly patients has received favorable reports [27]. The widespread use of cimetidine is remarkable when viewed against the background of its initial authorization. When the FDA authorized the clinical use of cimetidine in 1977, it was approved for only two clinical conditions: short-term treatment of duodenal ulcer and the treatment of gastric acid hypersecretion. Recent surveys of cimetidine prescription practices revealed that physicians were prescribing cimetidine for a wide variety of nonspecific gastrointestinal complaints, even though data were missing to support the use of cimetidine for these conditions [ 11, 27, 49]. This seemingiy indiscriminate use of cimetidine has facilitated its use with geriatric patients, especially when it has been demonstrated that cimetidine prevents rebleeding in patients with gastric ulcers [25]. However, there are many reasons why caution should be exerted when the use of cimetidine is contemplated with elderly patients. The half-life of cimetidine increases in elderly patients due to the reduction in the glomerular filtration rate [38]. Consequently, the toxic levels of the drug can build up, resulting in mental confusion and disorientation [57]. Other problems include possible fatal synergistic effects when used with other drugs [57], undesirable CNS side effects in patients with Alzheimers disease

[27], agitated and delirious behavior [21, 26, 33, 50], and the impaired elimination of other drugs which are frequently prescribed with elderly patients [12,28]. Considering the widespread use of cimetidine and the strong tendency to use the drug in a patient population with a high incidence of stress ulcer, more information is necessary regarding cimetidine effects on stress ulcer in aged organisms. This question is especially important since the use of cimetidine in elderly patients is questionable. In order to study this problem, we subjected young and old rats to restraint stress, and recorded the incidence of gastric lesions in rats subjected to different dose levels of cimetidine. METHOD Animals

The study used 200 male Sprague-Dawley rats. There were 40 rats in each of five age groups. The age groups were 2, 6, 11, 18, and 26 months of age. The mean age group body weights were 364.7, 475.5, 491.7, 621.8 and 702.5 grams respectively. Animals were housed in group cages, with four animals per cage. Purina Rat Chow pellet food was always available in food hoppers which were mounted on the cage walls. Artificial daylight conditions were maintained between 6 a.m. and 6 p.m. Procedure

All animals were placed in individual cages five days prior to the testing period. Food and water were always available. Rats within each age group were randomly assigned to one of four drug dose conditions. These drug dose conditions, selected on the basis of previous research [41], consisted of cimetidine at either 25, 50, or 100 mg/kg, or a saline placebo condition. Each subgroup consisted of 10 rats. Rats were food deprived 12 hr before restraint, and injected intraperitoneally 1 hr before restraint, with the appropriate drug dose or saline injection. Rats were restrained according to a procedure outlined by Vincent, Glavin, Par6 and Rutkowski

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305

306

PARI~ AND VINCENT TABLE 1 MEAN (-+SE) PERCENT BODY WEIGHT LOSS FOR RATS IN ALL TREATMENT GROUPS

Cimetidine Dose Level (mg/kg) Age (Months)

Saline

2 6 11 18 26

4.6 3.1 4.0 3.8 3.2

25

_+ 0.32 -+ 0.26 _+ 0.23 _+ 0.39 _+ 0.26

4.7 3.9 3.4 2.7 3.0

50

_+ 0.17 _+ 0.44 _+ 0.27 +_ 0.19 _+_0.34

4.9 3.1 3.4 2.6 3.4

_+ 0.32 _+ 0.30 _+ 0.18 -+ 0.23 _+ 0.16

I 2 Months

TABLE 2

100 5.6 3.3 3.6 2.7 3.2

6 Menflm

_+ 0.23 _+ 0.32 _+ 0.37 _+ 0.20 _+ 0.32

I I Meeths

18 Months

] ~.~Meefhs

NUMBER OF RATS IN EACH TREATMENT GROUP REVEALING ULCERS

Cimetidine Dose Level(mg/kg) Age (Months) 2 6 11 18 26

Saline

25

50

100

I0" 10 10 10 10

I0 9 9 9 10

8 7 8 8 10

10 6 6 7 10

tL

| ==

*n= 10 for each age-drug dose group.

[56]. This immobilization procedure required that rats be restrained in a supine position on a plastic form with all four limbs secured with umbilical tape. The restrained rat was subsequently placed in a ventilated refrigerator which was maintained at 5°C. Rats were restrained between 10 a.m. and 1 p.m. After 3 hr of cold-restraint stress, the rat was removed from the refrigerator and sacrificed. Body weights were recorded before and after restraint. The stomach was removed, after the animal was sacrificed, and inspected for the presence of lesions by a naive observer. Each discrete ulcer was counted. The length of each ulcer was determined (mm) and the sum of all these measurements provided the cumulative ulcer length score for each rat. The dependent variables of percent body weight loss, number of ulcers and cumulative length of ulcers were analyzed using a two-factor analysis of variance design with five levels for the main factor of age, and four levels for the main factor of drug dose. Group differences were evaluated using a Tukey (a) test procedure. RESULTS

An analysis of the percent body weight loss data revealed that the 2-month-old rats lost a significantly greater percentage of their body weight during the restraint procedure, F(4,180)=20.60, p<0.01, Tukey (a) test, p = < 0 . 0 5 . The different drug dose levels, for all age groups, did not significantly affect the percentage of body weight loss, F(3,180)=0.35. The mean percent body weight loss for all treatment conditions are contained in Table 1. Body weight

PLACEBO & DRUG DOSES

FIG. 1. Mean ( - SEM) for number of ulcers and cumulative length of ulcers for the four drug conditions within each age group. Notations on the ordinate as follows: P=placebo control; 25, 50, and 100 mg/kg. The asterisks indicate significant differences as compared to the placebo control mean [Tukey (a) test, p<0.05].

loss may, in some instances, represent a subjective response index to an environmental stressor [6, 18, 19, 20, 39, 40, 46. 58]. In this particular study, percent weight loss is not significantly correlated with the measures of ulceration, which could also be considered indices of stress. For all animals, percent body weight loss correlated +.009 with number of lesions, and - . 0 0 7 with the size of lesions. Two-month-old rats at 100 mg/kg lost a greater percentage of body weight, as compared to the other 2-month-old rats, yet the 100 mg/kg rats had very few ulcers. These seemingly paradoxical results exemplify the near-zero correlation. A comparison of all the saline control groups for all age categories revealed no significant differences in terms of the number and size of stomach ulcers. Thus, older rats were not, in this study,

C I M E T I D I N E IN A G E D RATS

307

more susceptible to the ulcerogenic effects of restraint stress. Age differences, however, were observed with the cimetidine data. Young rats and old rats seem to be the least affected, in terms of ulcer incidence, by the anti-ulcer effects of cimetidine. While cimetidine may have reduced the number and size of ulcers, it failed, at all dose levels, to prevent the occurrence of ulcers in 26-month-old rats and, as Table 2 reveals, only two 2-month-old rats (in the 50 mg/kg group) were found to be ulcer free. The reduced effectiveness of cimetidine is also observed with the other measure of ulcer severity but resistance is revealed primarily with the 26-month-old rats. An analysis of the number o f ulcers for the various treatment groups revealed a significant group difference for the main effect of drug dose, F(4,108)=5.03, p<0.001. Cimetidine, at all dose levels, significantly reduced the number of ulcers as compared to the saline condition, Tukey (a) test, p<0.05. These data are illustrated in Fig. 1. Comparisons within age groups revealed further that the effectiveness of cimetidine diminished with the age of the rat. With the exception o f the 25 mg/kg dose in the 6-month group, cimetidine, at all dose levels, significantly reduced the number of ulcers, as compared to saline, for 2-, 6-, and 11-month-old rats. However, for 18-month-old rats, only the highest dose of cimetidine produced a significant reduction, and none of the dose levels significantly reduced ulceration for the 26-month-old rats. Essentially, the same results were found for the ulcer length data. The 26-month-old rats had larger ulcers as compared to the other age groups, F(4,180)=8.06, p<0.001, Tukey (a) test, p <0.05; and cimetidine, at all dose levels, reduced ulcer size, F(3,180)=15.22, p<0.001, Tukey (a) test, p<0.05. Again, 2-, 6-, and I l-month-old rats revealed significantly smaller ulcers for all dose levels of cimetidine, but only the highest 100 mg/kg dose was effective in significantly reducing ulcer size for the 18- and 26-month-old rats, Tukey (a) test, p<0.05. Figure 1 suggests that 100 mg/kg of cimetidine is required for 26-month-old rats to produce a therapeutic effect which is comparable to that obtained with only 25 mg/kg in the other younger age groups. DISCUSSION The aged rat is not necessarily more susceptible to restraint-induced stress ulcer. Some reports have suggested

that resistance to stress is inversely related with age [14, 32, 53, 54], but contradictory results have been reported [15,59]. The present data with the saline-treated groups are in agreement with a previous study [42] which reported that older rats were not more susceptible to stress-ulcer. While restraint stress may not necessarily produce more pathology in older rats, the ulcerogenic process, in the older rat, seems more resistant to the anti-ulcer effects of cimetidine. The reduced effectiveness of cimetidine, in the aged rats, may be due to the inferior physiological responsiveness o f the senescent organism. Some reviewers have noted delay o f gastric emptying and diminished absorption as a function of age [3]. Cimetidine is metabolized more slowly and its half-life, in elderly patients, is twice as long as compared to its action in middle age patients. The reduced clearance of cimetidine would argue for a more dramatic anti-ulcer effect in older subjects since the stomach is exposed to the drug for a longer time period. Reduced physiological responsiveness would argue for a greater therapeutic effect for cimetidine, but the present results are contradictory to that explanatory notion. It may be that stress ulcer is produced by different mechanisms in young and old rats. To support this conjecture, we note that in young rats, immobilization-induced stress ulcer may be related to hypersecretion of gastric acid; in senescent rats, stress ulcer may be related to other sympathetic mechanisms. There are several reports [22,42] which suggest that gastric hyposecretion characterizes the aging gut. The therapeutic effects of cimetidine are achieved through its acid-inhibiting function. Thus, it is effective in young, mature rats, where stress-ulcer is acid related, but it has less effect in senescent rats where the ulcer mechanism may be dependent on other physiological processes. These results would argue for differential mechanisms of stress ulcer, depending on the age of the organisms. In the present study, significantly higher doses were required in the senescent rats to produce a therapeutic effect comparable to that obtained with the low 25 mg/kg dose in the younger rats. While the relatively high 100 mg/kg dose does reduce ulcer size in the older rats, this high dose would also potentiate the adverse side effects which have been reported in elderly subjects treated with cimetidine. The present study reiterates the therapeutic efficacy of cimetidine with respect to stressulcer. This effect is most dramatic with young and mature groups. However, this study also suggests that cimetidine had dubious value in aged organisms due to its reduced effectiveness in protecting the organism from stress ulcer.

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