Plasma histamine and coagulation time of the blood in dogs after administration of different histamine releasers

Compound 48/80, sinomenine, tween 20 and polyvinylpyrrolidone (PVP) were injected intravenously to dogs, in doses producing similar degree of profound hypotension, and changes in the plasma histamine content and coagulation time were followed on the blood from the femoral artery. After the injection of 48/80 or sinomenine plasma histamine rose rapidly and markedly, attaining its maximum within 2 minutes, but the increase was rather of a short duration. In contrast, after the injection of tween 20 or PVP a less marked increase in plasma histamine developed more slowly, but lasted longer. The blood coagulation time was prolonged in all the cases injected with 48/80, and occasionally with sinomenine. Both beginning and recovery of the prolongation of blood coagulation time were sluggish as compared with the changes of plasma histamine. Tween 20 and PVP did not induce any detectable change of the blood coagulation time. These data were discussed with reference to the sites of action of different histamine releasers.</p

DNA rearrangement activity during retinoic acid-induced neural differentiation of P19 mouse embryonal carcinoma cells.

Because of the many superficial similarities between the immune system and the central nervous system, it has long been speculated that somatic DNA recombination is, like the immune system, involved in brain development and function. To examine whether or not the V(D)J recombination signals of the immune system work in an in vitro neural differentiation model, the P19 mouse embryonal carcinoma cell line was transfected with a reporter gene that is designed, when rearranged, to express bacterial beta-galactosidase, which was previously reported to exhibit somatic DNA recombination in the transgenic mouse brain. The cloned cells were then induced into neural cells by retinoic acid treatment. This neural induction treatment resulted in the cloning of a P19 cell line that showed a high incidence of beta-galactosidase-positive cells. Most of these beta-galactosidase-positive cells were immunocytochemically identified as either neurons, neuroepithelial cells, or astrocytes. The 5'-end sequences of the beta-galactosidase transcripts expressed in the induced cells were analyzed, and sequences were found that seemed to reflect DNA rearrangement through re-integration of the reporter gene into the host genome. However, the V(D)J recombination signals did not work in the in vitro model. These results suggested that DNA rearrangement activity though integration increased during neural differentiation of P19 cells.</p

Histamine release inhibition in anti-inflammatory mechanism

Rats were depleted of skin histamine by more than 80 % by intraperitoneal injections of sinomenine with daily increasing doses for 6 days. In these rats, egg-white edema induced in the hind paws was inhibited by 68 % of control. The weight of the wall of granuloma pouch made by croton oil was also evidently smaller in the rat treated similarly with sinomenine than that of control. This suggests an important role of histamine participating in the inflammation. It has been observed that a variety of non-steroidal anti-inflammatory drugs inhibited both degranulation and histamine release induced by compound 48/80 of mast cells isolated from rat peritoneal fluid. The degranulation inhibiting actions of anti-inflammatory drugs were markedly decreased in the presence of glucose as in cases of dinitrophenol, dicumarol and warfarin which are known uncouplers of oxidative phosphorylation. Also, prevention of edema provoked by anti-rat serum is roughly correlated to a potency of degranulation inhibiting effect of anti-inflammatory agents. These observations suggest that there is a common mechanism between these two phenomena, and the prevention of mast cell degranulation by the anti-inflammatory agents is, at least, partially due to their uncoupling effects. A working hypothesis explaining the process of edema formation at the inflammatory site has. been made based on the data of the present experiment and other ob3ervations: a leakage of plasma into the tissue space from the gap between two adjacent endothelial cells which are contracted by released histamine may activate a kinin-forming system in the plasma, and kinin(s) may further aggravate a leakage. The mechanism of action of anti-inflammatory agents, which interfere with the histamine effect in inflammation, should be understood in twofold: one is prevention of histamine release from the tissue, mainly by inhibiting mast-cell degranulation, and the other is prevention of the contraction of endothial cells by their uncoupling activities.</p

Inhibition by drugs of passive cutaneous anaphylaxis-induced skin histamine decrease.

Passive cutaneous anaphylaxis (PCA) was produced in the rat with mouse IgE-rich antiserum. The effect of drugs on the PCA-induced skin histamine decrease and leakage of protein-bound dye was studied. Salbutamol (0.5 mg/kg i.v. or 1.0 mg/kg s.c.) and cromoglycate (10 mg/kg i.v.) significantly inhibited the skin histamine decrease. A combination of salbutamol (0.5 mg/kg i.v. or 1.0 mg/kg s.c.) and aminophylline (25 mg/kg i.v. or 75 mg/kg s.c.) had an additive or greater than additive effect on the histamine decrease. Salbutamol (1.0 mg/kg s.c.) inhibited the dye leakage markedly, and aminophylline (75 mg/kg s.c.) slightly. These results indicate that the decrease in the skin histamine content is useful as an index of the in vivo inhibitory effect of antiallergic drugs on the antigen-induced histamine release.</p

The inhibition of substance P-induced histamine release from mast cells by 6, 7-dihydro-6, 8, 8, 10-tetramethyl-8H-pyrano-[3, 2-g] chromone-2-carboxylic acid (EAA).

In the presence of extracellular Ca2+, 6,7-dihydro-6,8,8, 10-tetramethyl-8H-pyrano [3, 2-g] chromone-2-carboxylic acid (EAA) had an inhibitory effect on the substance P-induced histamine release from rat peritoneal mast cells. Not only Ca2+ but also Mg2+, Sr2+ and Ba2+ were effective in enhancing the activity of EAA. Marked tachyphylaxis to EAA developed irrespective of the presence or absence of extracellular Ca2+. Cross-tachyphylaxis was observed between EAA and disodium cromoglycate (DSCG). These results indicate that the mode of action of EAA is similar, but not identical, with that of DSCG.</p

In Vivo and In Vitro Release of Indomethacin from Water-Soluble and Fatty Base Suppositories

The plasma concentration of indomethacin was measured after the rectal administration of water-soluble and fatty base suppositories in rats. The results were compared with the in vitro indomethacin release from suppositories determined by Paddle method using three different types of membranes: cellulose membrane, artificial sausage membrane and natural sausage membrane. The plasma concentrations of indomethacin during the first 4h after the rectal administration were higher in rats that received water-soluble base suppositories than in those that received fatty base types. When either a cellulose membrane or an artificial sausage membrane of cow protein was used in the Paddle method, the amount of indomethacin released from fatty base suppositories was significantly higher than that from water-soluble base ones. However, the results were reversed when a natural sausage membrane of pig colon was used. The discrepancy in the in vitro experiments using water-soluble base suppositories seemed to be due to the difference of pore size of membrane used. Careful consideration should be given to the membrane used in the Paddle method especially when this method is employed to examine the release of poorly soluble drugs like indomethacin in both water-soluble and fatty base suppositories.</p

Effect of acute and chronic immobilization stress on plasma levels of nicorandil administered orally to rats.

Effects of acute (15h) and chronic (15h x 7 days) immobilization (IM) stress on plasma levels of nicorandil [N-(2-hydroxyethyl) nicotinamide nitrate (ester)] administered orally were examined in rats. The maximum plasma level was reached 30 min after administration. Acute IM stress significantly reduced plasma nicorandil levels both in the absorption and elimination phases (15 min and 2-6h after administration, respectively). Chronic IM stress further intensified the reduction of nicorandil levels in the absorption phase, but attenuated the influence of acute stress in the elimination phase. No significant difference was observed one day after removal of chronic IM stress. These results suggest that chronic IM stress markedly inhibits the absorption of nicorandil, but the distribution, metabolism and excretion were influenced more by acute IM stress.</p