Effects of route of administration on the production of gastric hemorrhage in the rat by aspirin and sodium salicylate

Dose response curves were obtained in food-deprived rats for aspirin-induced incidence of gastric hemorrhage by four routes of administration: oral (ED₅₀=18 mg/kg); intravenous (ED₅₀=36 mg/kg); small intestinal (ED₅₀=34 mg/kg); and colonic (ED₅₀=12 mg/kg). A similar study with sodium salicylate gave a dose response curve after oral administration (ED₅₀=33 mg/kg), but no incidence of gastric hemorrhage was produced when sodium salicylate was given by the other three routes, even at toxic dose levels. The data indicate that aspirin can produce gastric hemorrhage in the rat by parenteral as well as by oral route, but that sodium salicylate causes gastric hemorrhage in the rat only on direct contact with the gastric mucosa.     

Investigations of the influence of sodium salicylate on the gastric mucosa of the rat (author's transl)

1. The investigation of the influence of sodium salicylate in therapeutic doses (100 mg/body weight/day) on the gastric mucosa of 60 rats revealed at the acute phase of the experiment morphological lesions of the superficial epithelium in term of an acute gastritis. At this stage neutral and acid mucopolysaccharides of gastric mucus were reduced. 2. Contrary to this, in long-term experiments epithelial changes and reduction of the mucous content of the cells were no longer detectable.     

Adaptation of the gastric mucosa to repeated administration of aspirin in the rat

The effects of single and repeated doses of aspirin on the gastric mucosa of the rat were compared to determine whether the mucosal response alters after repeated aspirin. Aspirin (120 mg/kg) was administered by esophageal intubation either as a single dose or daily for 3, 14, 28 and 56 days. Mucosal damage was present in all treated rats but, on histologic quantitation, there was a highly significant reduction in the numbers of acute erosions in the groups receiving repeated daily aspirin. This apparent adaptation did not persist when aspirin administration was interrupted for 3 days. Repeated aspirin administration was not associated with any reduction in aspirin absorption or excretion, nor was there any significant change in hydrochloric acid or pepsin secretion. The investigation has shown an adaptation to repeated aspirin in the rat which appears to result from an alteration in the gastric mucosa. The precise mechanism of the adaptation remains uncertain.Supported by the National Health and Medical Research Council and the Alfred Hospital.Presented, in part, to the Gastroenterological Society of Australia, May 1971.     

Effect of simulated systemic administration of aspirin, salicylate, and indomethacin on amphibian gastric mucosa

The effects of 20 mM aspirin (ASA), 20 mM sodium salicylate (SA), or 10(-4) M indomethacin placed in the nutrient solution (N) to stimulate systemic administration were investigated at pHN 7.3 in Ussing-chambered amphibian gastric mucosae. In histamine-stimulated tissues, the initial rise and subsequent rapid fall in potential difference, rise in resistance, and inhibition of hydrogen ion (H+) secretion induced by SAN did not occur with ASAN unless hydrolysis of ASAN produced a SAN of greater than 3 mM. In metiamide-treated tissues, 20 mM SAN caused an immediate fall in potential difference and an increase in resistance; 2 mM SAN and 20 mM ASA produced similar qualitative electrical changes, but only those induced by ASA were reversible. IndomethacinN caused no significant changes in potential difference, resistance, or H+ secretion in histamine- or metiamide-treated tissues. Despite producing highly significant reductions in generation of prostaglandin E2, and prostaglanndin F2 alpha and 6-keto prostaglandin F1 alpha, ASAN and indomethacin caused no surface ulceration. Sodium salicylate placed in the nutrient solution caused only a small reduction in prostaglandin F2 alpha, without change in the other prostaglandins, and produced extensive edema in the lamina propria, histologically. We conclude the following: (a) The inhibition of H+ secretion and electrical changes caused by SAN in histamine-treated gastric fundus are not observed with ASAN unless there is hydrolysis to [SAN] greater than 3 mM. (b) Our data strongly implicate the SAN in ASAN-containing solutions as being responsible for the electrical effects and inhibition of H+ secretion. (c) There is no correlation in vitro between inhibition of prostaglandin synthesis and the electrical or morphologic changes produced by nutrient exposure to ASA, SA, or indomethacin.     

Effect of carbenoxolone sodium on aspirin-induced injury of the rat gastric mucosa

Investigations were performed in the rat to examine the effect of carbenoxolone sodium on aspirin-induced gastric mucosal injury. Mucosal damage was quantitated histologically in the body of the stomach (corpus) after a single dose of aspirin and after 2 weeks of daily aspirin. Over dosage ranges of 2–30 mg/kg/day of carbenoxolone and 10–120 mg/kg of aspirin, carbenoxolone treatment conferred no protection, despite evidence of a significant carbenoxolone effect on gastric mucus. This contrasts with the known protective action of carbenoxolone against injury by restraint stress and by corticosteroids. Much current evidence suggests that the mechanisms of erosion production by aspirin differ from those by restraint stress and corticosteroids, and it is likely that the present findings reflect such differences in pathogenesis.     

Parenteral aspirin produces and enhances gastric mucosal lesions and bleeding in rats

The effect of parenteral sodium acetylsalicylate (Na ASA) on the development of gastric mucosal lesions and bleeding was studied in control rats and in rats subjected to cold-restraint stress. Although both doses of Na SAS studied, 15 and 60 mg/kg intraperitoneally, alone resulted in lesion formation, only with the larger dose did this reach the level of statistical significance. However both doses of Na ASA alone significantly increased blood loss as measured by a decrease in hematocrit value. The administration of Na ASA 15 mg/kg intraperitoneally to animals subjected to cold-restraint significantly increased blood loss, but not lesion formation, while the larger dose of Na ASA significantly increased both parameters. Thus parenteral aspirin not only can cause gastric mucosal damage and bleeding, but it can enhance lesion for mation and blood loss produced by cold-restraint. Two mechanisms may be involved: a smaller dose of Na ASA significantly affecting hemostasis but a larger dose being required for gastric mucosal damage.     

Changes in potential difference across the human buccal mucosa with buffered or unbuffered aspirin and salicylate.

The potential difference (PD) across the gastric mucosa is an index of mucosal integrity, and is lowered by topical application of irritants such as aspirin. There are basic similarities in the PD across the buccal and gastric mucosae, and we have therefore investigated the actions of various salicylates in buffered or un-buffered solution on buccal PD in human subjects. Aspirin (at pH 2) and soluble aspirin (pH 4.4) applied topically reduced buccal PD, but this fall was abolished by buffering to pH 7. Sodium salicylate likewise reduced buccal PD at pH 4 and pH 6, but not when buffered to pH 7. Two other soluble aspirin mixtures also reduced buccal PD, indicating insufficient buffering capacity to prevent topical irritancy. Ingestion of aspirin (600 mg), avoiding topical contact with the buccal mucosa, did not alter buccal PD. Paracetamol applied topically likewise failed to reduce buccal PD. Measurement of buccal PD may be useful in the preliminary assessment of the gastrointestinal irritation provoked by anti-inflammatory and other compounds.     

Interaction of a selective cyclooxygenase-2 inhibitor with aspirin and NO-releasing aspirin in the human gastric mucosa

In addition to inhibiting cyclooxygenase (COX)-1-derived prostanoid biosynthesis, aspirin acetylates COX-2, enabling the conversion of arachidonic acid to 15(R)-epi lipoxin A4, or aspirin-triggered lipoxin (ATL). Selective COX-2 inhibitors block ATL formation and exacerbate mucosal injury in rats treated with aspirin. In the present study, we have examined whether inhibition of COX-2 activity in healthy volunteers taking aspirin exacerbates gastric mucosal injury and if such an effect would be prevented by NCX-4016, a NO-releasing derivative of aspirin. Thirty-two volunteers were randomized to receive 2 wk of treatment with NCX-4016 (800 mg twice a day) or aspirin (100 mg once a day) alone or in combination with 200 mg of celecoxib twice a day. Mucosal damage was assessed by endoscopy. The mean mucosal injury score was 5.8 +/- 1.8 in subjects treated with aspirin and 2.4 +/- 0.7 (P < 0.01 vs. aspirin) in subjects treated with NCX-4016. Administration of celecoxib increased the injury score in volunteers treated with aspirin (9.9 +/- 1.9) but not in subjects taking NCX-4016 (1.5 +/- 0.8). Aspirin and NCX-4016 caused a comparable suppression of serum thromboxane B2 levels and increased urinary excretion of ATL. Celecoxib inhibited endotoxin-induced prostaglandin E2 generation in whole blood by approximately 80% and abolished ATL formation. These findings suggests that (i) aspirin and NCX-4016 trigger ATL formation in humans, (ii) celecoxib inhibits ATL formation and exacerbates the mucosal injury caused by low doses of aspirin, and (iii) the NO-donating moiety of NCX-4016 protects the gastric mucosa even in the presence of suppression of COX-1 and COX-2.     

Acute effect of systemic aspirin on gastric mucosa in man

Aspirin was administered intravenously to study its effect upon gastric mucosa at high blood levels in the therapeutic range for rheumatic diseases. Five healthy volunteers were studied twice each with intravenous aspirin (3 g over 2 hr) and isotonic salline infusion as control. In one study, gastric potential difference was measured; in the other, coded gastric biopsies were taken sequentially prior to infusion, and at the end of infusion. Duplicate biopsies were taken for light and scanning electron microscopy. Mean potential difference at the end of the intravenous aspirin infusions was ?47.7±1.4 mV, compared with saline, ?51.1±2.5 mV (P>0.05). The percentage of cells damaged after 2 hr intravenous infusion of aspirin (3.2±0.4%) was not significantly different from that after intravenous saline (2.6±0.3%). In contrast to oral aspirin, acute administration of aspirin parenterally does not produce detectable histological damage in man, nor does it significantly alter gastric mucosal potential difference. We conclude that high blood levels of circulating salicylate do not acutely damage gastric mucosa. Thus, histologic gastric mucosal damage produced acutely after single oral doses of aspirin are due to its topical, rather than systemic, action.     

Effects of aspirin on tight junction structure of the canine gastric mucosa

The effects of aspirin on the canine gastric mucosal barrier were examined using the freeze-fracture and extracellular tracer techniques. Aspirin treatment (3, 20, or 40 min) resulted in alterations in tight junction complex morphology and permeability. Discontinuities in the apical occluding complex, hyperplastic tight junctions (extensions of the apical tight junction strands radiating over the lateral plasma membrane), and a variability in the number of strands (1-20) comprising the complex were observed. A concurrent increase in lanthanum permeability between nonnecrotic surface mucous epithelial cells was also demonstrated. The results of these experiments may suggest that aspirin-induced impairment of the tight junction complexes between viable gastric mucosal epithelial cells may be a major contributing factor in the etiology of stomach disorders.     

Modulation of leukocyte adhesion in rat mesenteric venules by aspirin and salicylate.

Erythrocyte velocity, vessel diameter, leukocyte rolling velocity, and number of adherent and emigrated leukocytes were measured in postcapillary venules both before and during superfusion of rat mesentery with either aspirin or sodium salicylate. In some experiments, animals were treated with either a leukotriene (LT)-synthesis inhibitor (L-663,536), an LTD4 antagonist (MK-571), an LTB4 antagonist (SC-41930), misoprostol, or prostaglandin (PG) I2, then the aspirin protocol was repeated. Superfusion of aspirin but not sodium salicylate resulted in increased leukocyte adherence and a reduced leukocyte rolling velocity but did not affect leukocyte emigration. Aspirin-induced leukocyte adhesion was effectively prevented by the LT-synthesis inhibitor and LTB4 antagonist but not by the LTD4 antagonist. Misoprostol and PGI2 also prevented the aspirin-induced adhesion responses. Superfusion of the mesentery with either platelet-activating factor (PAF) or LTB4 enhanced leukocyte adherence and emigration while reducing leukocyte rolling velocity. Sodium salicylate prevented all of the adhesion responses elicited by LTB4. Although salicylate did not affect the PAF-induced leukocyte adherence and rolling responses, it completely prevented the increased leukocyte emigration. These results indicate that aspirin promotes, whereas sodium salicylate inhibits, leukocyte-endothelial cell adhesive interactions at therapeutically relevant concentrations.     

Effects of aspirin,acetaminophen, and salicylamide on gastric mucosa of dogs

Summary The effects of aspirin, acetaminophen, and salicylamide on the gastric mucosa of dogs were studied in a blind controlled experiment. Oral dosage ranged from a single 5-gr. dose up to 30 gr. per day for 10 days. Seven different dosage levels were tested. Aspirin, when given for more than one day, proved highly irritating in doses of 5–15 gr. b.i.d. With the higher dosage, widespread hemorrhage and ulceration of the gastric mucosa occurred after 3 and 6 days' administration. Irritation occurred but was less evident after 10 days' administration. In contrast, acetaminophen and salicylamide were essentially nonirritating. These drugs would seem to merit consideration in patients with gastrointestinal lesions or in those requiring more than occasional analgetic-antipyretic therapy.This study was supported by Smith Kline & French Laboratories, Philadelphia, Pa.     

Titration of sodium channels in canine gastric mucosa.

Net Na+ flux from mucosa to lumen, potential difference, and volume and plasma protein outputs were measured in vagally denervated, separated pouches of the dog's oxyntic or pyloric glandular mucosa when the pouches were irrigated with Na+-free solutions whose pH ranged from 1.5 to 12.2. The apparent permeability to Na+(P'Na) was calculated. P'Na is lowest when the mucosa is bathed with acid and increases 2- to 3-fold when the pH is raised to 10. In the range of pH 10.0--11.2 P'Na is greater by an order of magnitude, but volume output is small, and no plasma proteins are shed. When the pH is above 11.2 there is an abrupt increase in P'Na, and the mucosa sheds a large volume of fluid containing plasma proteins. The change effected by raising the pH to the range of 10.0--11.2 occurs within 10 sec, and it is reversible. The change effected by raising the pH above 11.2 also occurs within 10 sec, and it is partly reversible.