Oropharyngeal granulomas and tracheal cartilage degeneration in Fischer-344 rats.

The development of tracheal cartilage degeneration and inflammation of the seromucinous glands of the oropharynx may be a factor causing early mortalities in long-term studies with Fischer-344 (F-344) rats. The presence of these lesions was investigated in groups of male and female F-344 rats killed at 6, 19, and 32 wk of age. Half of the rats killed at 19 and 32 wk of age were sham treated with water (pH 10) by daily oral gavage for a duration of 13 or 26 wk prior to autopsy in order to detect any influence on the laryngotracheal cavity due to dosing technique. A clear age-associated increase in severity and incidence of chondroid degeneration of the tracheal and laryngeal cartilage was revealed, with an onset as early as 6 wk of age. After 19 wk, a high frequency of oropharyngeal granuloma formation was found. No relationship of the lesions to the gavage technique was apparent. The F-344 rat strain may possess a predisposition for inflammatory and degenerative changes in the oropharyngeal and laryngotracheal cavity, changes that can lead to increased and unexpected mortality rates in nonclinical safety studies (7).

Comparison of the ECL-cell frequency in the stomachs of 3 different rat strains.

Three different rat strains, Sprague-Dawley, Wistar and Fischer 344, were treated for 3 months with 2 doses (0.8; 4 mg/kg) of the gastric acid suppressing ATPase inhibitor pantoprazole. The gastrin levels were determined, the height of the mucosa measured and the number of enterochromaffin-like (ECL) cells counted. Because these cells were stained according to the method of Grimelius they were designated as GPC (Grimelius positive cells). Under 4 mg/kg, the gastrin levels were increased 8 hours after administration, but fell again after 24 h. The Fischer rats showed the highest value. Also the height of the mucosa was increased under 4 mg/kg. A trend towards an increased mucosal height was noticeable even at 0.8 mg/kg. The number of GPC was determined in 2 ways: 1) without taking the mucosal height into account, 2) taking the height into account. An increase in GPC was observed at 4 mg/kg with both methods.

[Multiple myeloma/plasmacytoma in a young dog]. / Multiples Myelom/Plasmozytom bei einem jungen Hund.

A multiple myeloma in an unusually young Cairn terrier (13 months, female) is described. Radiographically, pelvic tumor masses and characteristic systemic osteolysis were found at the end of the 4 week disease course. Therapeutic attempts were hopeless at this stage of the disease, but a form of chemotherapy is recommended.

Effects of short-term treatment with an H+,K(+)-ATPase inhibitor (B8301-078) on enterochromaffin-like (ECL) cells in rat fundic mucosa.

In the present study, female Sprague-Dawley rats were treated orally over 2, 14, and 29 days with 50 mg/kg/day of the H+, K(+)-ATPase inhibitor B8301-078, a substituted benzimidazole. The endocrine cells in the fundic mucosa were quantified by light microscopy with the aid of Grimelius silver staining and examined by electron microscopy. After 2 days of treatment, the number of argyrophilic Grimelius-positive cells (GPC) was clearly reduced compared to the controls, whereas after 14 and 29 days, hyperplasia was observed. Electron microscopy showed that there was only an apparent decrease in GPC density after 2 treatments. This reduction was due to the massive degranulation of the enterochromaffin-like (ECL) cells and the resultant decrease in stainability with silver. After 14 and 29 days the granular depletion was less pronounced. The cells were, therefore, detectable again by light microscopy.

Influence of chronic drug-induced achlorhydria by substituted benzimidazoles on the endocrine stomach in rats.

The release of gastric somatostatinlike immunoreactivity and gastrin was studied in rats with chronic achlorhydria induced by the substituted benzimidazole BY 308. In vitro, stimulation of gastrin release by acetylcholine was slightly enhanced after 1 day of treatment but no further effects were observed compared to placebo controls. Four weeks of treatment evoked marked gastrin hypersecretion, which was atropine-resistant. Stimulation of gastrin release was inversely correlated to enhancement of basal gastrin levels. Chronic achlorhydria distinctly reduced somatostatin responses to isoproterenol, whereas potent stimulation was observed in controls. Treatment with BY 308 for 1 wk was associated with fully developed gastrin hypersecretion but isoproterenol-stimulated somatostatin release was still unaffected. Hypergastrinemia accompanied by increased antral gastrin and reduced antral and fundic somatostatin concentrations was also found in vivo after 4 wk of treatment with BY 308. It is concluded that chronic achlorhydria not only enhances storage and secretion of gastrin but also diminishes the secretion and tissue stores of somatostatin; adaptive changes of the somatostatin cell occur, however, with a much longer delay.

Effect of acid inhibition on gastric endocrine cells.

There is increasing evidence that the numbers of antral G cells and of fundic argyrophil (ECL) cells are influenced by agents that inhibit gastric acid secretion. Antral G cells increase in states of achlorhydria in man and animals provided atrophic antral gastritis is absent. In rats, treatment with substituted benzimidazoles like omeprazole and BY 308 increase G-cell densities dose-dependently. Even high doses of histamine H-2 antagonists and antacids increase antral G-cell densities. In contrast to G cells, antral D cells decrease in these instances. Fundic ECL cells increase in all experimental conditions of complete achlorhydria provided intact antral mucosa is present, i.e. there is elevated serum gastrin. Antacid treatment is not followed by an increase of fundic ECL cells, which could be explained by the less sustained increase of serum gastrin.

A fluorescent histochemical investigation of the rat submandibular gland after ligation of the excretory duct and isoproterenol treatment.

Fluorescent histochemical investigations were carried out on the adrenergic terminal plexus in the salivary gland of the rat 24 hours, 72 hours, and 14 days after ligation of the main excretory duct and the concomitant administration of isoproterenol (IPR, 60 mg/kg body weight subcutaneously). The atrophy of the salivary gland occurring after ligation was also present after the concomitant administration of IPR which induces amylase secretion and DNA synthesis in intact salivary glands. The adrenergic fibres in the atrophic gland exhibited an intensive fluorescence of the adrenergic terminal plexus after IPR treatment. Thus the presynaptic elements remain intact, although the acini are atrophic, and the reason for the absence of the stimulus response probably lies in the effector cells.

Light-microscopic and fluorescent histochemical investigations on the salivary glands of rats after isoproterenol treatment.

The effect of isoproterenol (IPR) on the salivary glands of the rat were investigated after single and repeated administration of 80 mg/kg body weight subcutaneously. Adrenergic nerve fibres were demonstrated with the aid of formalin-induced fluorescence, and cholinergic fibres by means of the acetylcholinesterase reaction. After a single dose of IPR the acini of the submandibular and parotid glands were depleted and then hypertrophic and hyperplastic. Large scattered cells with retained secretory granules transiently occurred after three days' treatment. They were identified as cells which degenerated mainly during mitosis. The distribution pattern of the autonomic nerve fibres in both glands adjusted to the changes preformed by the acini in the course of treatment. After long-term treatment there was a distinct loss of fibre structures and intensity of fluorescence. Thus it can be concluded that the autonomic fibres degenerate. The effect of IPR on the proliferation kinetics of the salivary glands is discussed. The fluorescent histochemical results are compared with the electron-microscopic findings in autonomic nerves reported in the literature.

Morphological findings in spontaneously hypertensive rats in comparison with findings after experimental renal hypertension.

The morphological findings in spontaneously hypertensive rats (SHR) were compared with the findings after experimental renal hypertension. In addition the effect of an arteriosclerogenic diet was investigated. Cardiac hypertrophy occurred in all types of hypertension. During the course of renal hypertension there was also hypertrophy of the tunica media of the arterial vessels of the heart, kidneys, mesenterium, and orta. Degenerative changes in the vascular walls occurred when nephrectomized rats were given a diet containing 2% cholesterol and 1% cholic acid. This produced intima lipoidosis after seven to eleven weeks. The intensity seemed to be dependent on the degree of hypertension and the duration of the experiment.

Wasting syndrome in neonatal mice after administration of salivary gland homogenate.

A wasting syndrome, similar to that occurring after cortisol treatment, was induced in neonatal mice by means of the daily i.p. administration of salivary gland homogenate: 24 h after a single injection of the homogenate, profuse cell necrosis was observed in the thymic cortex, 48 h later the cortex was devoid by lymphocytes. It is hypothesized that the submandibular glands of mice contain substances which are capable of inducing a cortisol-like effect.