Search

Summary The effect of ST91, a clonidine derivative crossing poorly the blood-brain barrier, was compared to that of clonidine on exocrine pancreatic secretion in rats. The experiments were performed in anaesthetized rats after stimulation by a maximal dose of 2-deoxy-D-glucose, and in conscious rats under basal interdigestive conditions. In anaesthetized rats, the 2-deoxy-D-glucose-induced stimulation of pancreatic secretion was suppressed by clonidine but not by ST91, both injected subcutaneously. This effect of clonidine was not antagonized by prazosin, but was decreased by 70–100% (according to the variables measured) by yohimbine. The alpha-2 antagonists rauwolscine and corynanthine were less efficient than yohimbine, while idazoxan suppressed totally the effect of clonidine. In conscious rats, the basal interdigestive secretion was inhibited by ST91 and by clonidine. After sc injections, the potency of ST91 was about ten times smaller than that of clonidine, whereas after injections in the cerebral ventricles, ST91 was as potent as clonidine to inhibit pancreatic secretion. Most (70–90%) of the inhibition induced by sc ST91 and clonidine in conscious rats was suppressed by yohimbine or by prazosin. It is concluded that both ST91 and clonidine inhibit pancreatic secretion in rats, and that this effect has probably both central and peripheral components. The central effect involves alpha-2 receptors, while the peripheral effect may involve alpha-1 and alpha-2 receptors.

The pharmacokinetics of adriamycin (ADR) and its 13-hydroxylated-metabolite adriamycinol (ADR-ol) was investigated during treatment with ADR in rats at a dose of 2 mg/kg i.v., once a week for 3 weeks. At various times, samples of blood and cardiac and pulmonary tissues were collected to measure the amount of ADR and ADR-ol by an HPLC procedure. Periodical ECG monitoring was performed during the study; the severity of cardiac lesions was histologically evaluated at the end of treatment. During the first 180 min after ADR administration, plasma levels of ADR and ADR-ol rapidly decreased; ADR levels in cardiac and in pulmonary tissues increased between the 15th and 30th min and than decreased between the 60th and 180th min; on the contrary, ADR-ol was undetectable in either cardiac or pulmonary tissues during the first 3 hours following ADR administration. Between the 1st and 3rd weeks of treatment, plasmatic levels of ADR and ADR-ol were unchanged; in a similar way, both cardiac and pulmonary tissue levels of ADR were constant during the period of treatment. By contrast, the cardiac tissue level of ADR-ol significantly increased between the 2nd and 3rd weeks. ECG tracings showed maximal enlargement of both QRS and S alpha T at the end of the 3rd week. The histological examination of cardiac tissue indicated the occurrence of degenerative changes in 20% of rats at the end of the experiment. Overall results seem to indicate that ADR-ol is produced and stored in cardiac tissue during repeated ADR administration; as a consequence the cytotoxic metabolite might contribute to the cardiotoxic effect of ADR.

The effects of tripotassium dicitrato bismuthate (TDB) on gastric acid, pepsin and mucoprotein secretion in rats and on hydrochloric-peptic secretion and plasma gastrin levels in dogs were investigated. In Shay rats, TDB did not affect acid secretion but significantly lowered pepsin concentration and increased the amount of bound mucoproteins. In addition, gastric mucosal lesions were significantly prevented by the drug. In dogs, chronically fitted with both gastric fistulae and Heidenhain pouches, acid secretion and plasma gastrin levels stimulated by a meat meal were unaffected by TDB, while pepsin concentration and pepsin output were significantly decreased. On the basis of these results, the antiulcer activity of TDB appears to be ascribed to the protection of the gastric mucosa through an increase in mucoprotein synthesis and a decrease of pepsin activity.