Mechanism of the antinociceptive action of mesaconitine: participation of brain stem and lumbar enlargement.

The antinociceptive action of mesaconitine (MA) microinjected into the nucleus reticularis gigantocellularis (NRGC), the nucleus reticularis paragigantocellularis (NRPG), the periaqueductal gray (PAG) or the lumbar enlargement was investigated in rats by use of the tail immersion test. In addition, the effects of beta-adrenoceptor antagonists and an alpha-adrenoceptor antagonist administered intrathecally (i.t.) on the antinociceptive action of MA given into the NRPG were also examined by the tail immersion test. MA (50, 100 ng per rat) microinjected into the NRGC, the NRPG, and PAG and the lumbar enlargement increased the response latency in rats in a dose-dependent fashion. MA (50 ng per rat) microinjected into neighbouring sites, the nucleus reticularis parvocellularis, the nucleus originis nervi abducentis and the fasciculus longitudinalis medialis, elicited no significant effect. Intrathecally administered propranolol (1 and 5 micrograms per rat), atenolol (1 and 5 micrograms per rat) and IPS-339 (1 and 5 micrograms per rat) remarkably inhibited the increase of the response latency induced by MA (50 ng per rat) given into the NRPG. Intrathecally administered phenoxybenzamine (1 and 5 micrograms per rat) inhibited the increase of the response latency induced by MA (50 ng per rat) injected into the NRPG but to a lesser extent than the beta-adrenoceptor antagonists. It is concluded that the NRGC, the NRPG, the PAG and the lumbar enlargement are involved in the sites of the antinociceptive action of MA and that the antinociceptive effect of MA administered into NRPG is elicited by activation of the inhibitory noradrenergic neurones from the NRPG in particularly via beta-receptor-mediated effects of noradrenaline.

Effect of cyclic AMP on mesaconitine-induced analgesia in mice.

The effects of cyclic AMP, dibutyryl cyclic AMP, theophylline, isoproterenol and propranolol on mesaconitine (MA)-induced antinociception in mice were investigated employing the tail flick and acetic acid-induced writhing methods for the evaluation of antinociceptive activity. MA-induced antinociception was significantly potentiated by cyclic AMP and dibutyryl cyclic AMP. The phosphodiesterase inhibitor theophylline also significantly potentiated the MA-induced antinociception. Further, MA-induced antinociception was markedly increased by a beta-adrenoceptor agonist, isoproterenol, and reduced by a beta-adrenoceptor antagonist, propranolol. These results suggest that the antinociceptive action of MA is potentiated through cyclic AMP and stimulation of the central beta-adrenergic system.

Mechanism of mesaconitine-induced contractile response in guinea pig vas deferens.

Mesaconitine (MA) caused contraction of the isolate guinea pig vas deferens in a dose-dependent manner (3 x 10(-6) - 10-(-4) g/ml) and nonspecifically potentiated the contractile response to norepinephrine (NE), acetylcholine, histamine and tyramine. Tachyphylaxis developed during the repeated application of MA. The contraction produced by MA was prevented by treatment with phentolamine, phenoxybenzamine, procaine, bretylium or tetrodotoxin, pretreatment with reserpine or 6-hyroxydopamine, or denervation. Atropine or hexamethonium did not abolish the effect of MA, excluding the possibility that the muscarinic and nicotinic receptors are the site of action of MA. MA elicited a dose-dependent release of NE from the isolated vas deferens which had been blocked by treatment with tetrodotoxin, pretreatment with reserpine, or the exclusion of calcium ion from the bath medium. Consequently, it is concluded that MA-induced contraction was brought about by the release of NE from pre-synaptic neuronal sites and by excitation of the post-synaptic membrane.

Mechanism of analgesic action of mesaconitine. I. Relationship between analgesic effect and central monoamines or opiate receptors.

The contribution of the central monoamines and the opiate receptor to mesaconitine (MA)-induced analgesia was investigated by means of pharmacological and neurochemical methods in which morphine (Mor) was used for comparison. The analgesic action of MA (i.c.) determined by the acetic acid-induced writhing method and the tail flick method was dose-dependent, indicating that its activity is elicited through the central nervous system. MA-induced analgesia was decreased by alpha-methyl-p-tyrosine (alpha-MT), 6-hydroxydopamine, diethyldithiocarbamate, disulfiram and reserpine, and increased by methamphetamine and norepinephrine (NE). The mode of action of MA was similar to that of Mor except for the results obtained upon combined administration with 1-dopa, dopamine, alpha-MT or chemicals related to 5-hydroxytryptamine. In addition, MA promoted the alpha-MT-induced decrease in NE levels in hippocampus, medulla oblongata plus pons and spinal cord. Levallorphan did not affect the analgesic activity of MA, showing that its activity is not mediated via the opiate receptors. Consequently, it is concluded that the analgesic activity mediated by MA is closely related to responses involving the central catecholaminergic system, in particular, the noradrenergic system.

Mechanism of inhibitory action of mesaconitine in acute inflammations.

Mesaconitine (MA) inhibited carrageenin-induced hind-paw edema in sham-operated mice as well as adrenalectomized mice. Hind-paw edema produced by subplantar injection of histamine, serotonin and prostaglandin E1 was suppressed by MA, indicating that it elicits the antiinflammatory activity at the early exudative stage of inflammations. However, MA did not affect the biosynthesis of the prostaglandins. Trazoline and propranolol had no effect on the inhibitory activity of MA on carrageenin-induced hind-paw edema. MA when administered i.c. at the doses where it shows marked analgesic activity produced dose-dependent antiinflammatory responses on paw edema produced by carrageenin and on vascular permeability accelerated by acetic acid and agar. The inhibitory activity of morphine on carrageenin-induced paw edema failed to be potentiated by the concurrent administration of MA, demonstrating that the mechanism of the antiinflammatory activity of MA involves the central nervous system.

Phytoecdysones from Diplazium donianum.

From Diplazium donianum, makisterone A, makisterone D, and an unidentified stereoisomer of makisterone B have been isolated. The presence of two other unidentified phytoecdysones has been noted.

Mechanism of mesaconitine-induced contractile response in guinea-pig ileum.

Mesaconitine (MA) caused contractions of the guinea-pig isolated ileum in a dose-dependent manner (10-8-10-5 g ml-1), slightly potentiated the contractile response to acetylcholine (ACh) and histamine and enhanced responses to electrical stimulation. Repeated application of MA (10-5 g ml-1) produced tachyphylaxis. Atropine blocked contractions to MA (3 X 10-M g ml-1), but only partially those to MA (10-5 G ML-1). Morphine, strychnine and hemicholinium-3, but not hexamethonium, also inhibited MA-induced contractions. Contractions produced by both doses of MA were abolished by cocaine, tetrodotoxin, or noradrenaline, or by previous cooling of the ileum. The atropine-resistant contractions produced by MA (10-5 g ml-1) were blocked by indomethacin. MA (3 X 10-7-10-5 g ml-1) elicited a dose-dependent release of ACh from the isolated ileum which was blocked by treatment with tetrodotoxin or cocaine, or exclusion of calcium ions from the bath. It is concluded that the contractions induced by lower doses of MA are brought about by the release of ACh from the postganglionic cholinergic nerve and that the contractions by higher doses could also be mediated by release of prostaglandins from the ileum.

Stimulating actions on ribonucleic acid biosynthesis of aconitines, diterpenic alkaloids of Aconitum roots.

Mesaconitine (MA) significantly stimulated the incorporation of 5-[3H]-orotic acid into liver nuclear RNA 16 h after its administration. MA exhibited the strongest activity among the aconitine alkaloids. This stimulatory effect of MA was inhibited by actinomycin D, but the incorporation ratio of 5-[3H]orotic acid in the combined treatment group with MA and actinomycin D was significantly higher than that in the single treatment group with actinomycin D. MA also increased the incorporation of 5-[3H]orotic acid into polysomal RNA in mouse liver. When MA was added to the RNA polymerase (EC 2.7.7.6) preparation obtained from rat liver, the increase of the enzyme activity was weak. While RNA polymerase preparation from the liver of rats, which were previously treated with MA, elicited increased incorporation of [3H]cytidine monophosphate into RNA as compared with that from the livers of normal rats. Accumulated data indicate that aconitine alkaloids, in particular MA, accelerate liver RNA synthesis mainly by the increase of RNA polymerase.

Anabolic principles of Aconitum roots.

The methanol extracts of raw and processed roots of Aconitum carmichaeli were shown to stimulate amino acid incorporation into mouse liver protein after approx. 10 h of ingestion. The extract of the raw roots was fractionated by monitoring the anabolic activity to furnish the aconitine alkaloids as active principles, among which mesaconitine exhibited the strongest activity. Amino acid incorporation into liver protein in the mesaconitine treated mice was inhibited by actinomycin D to the level of normal mice. Long-term administration of mesaconitine induced no reinforcement of the anabolic activity in mouse liver. Examination of the anabolic activity in liver, spleen, kidney, testis and serum revealed that mesaconitine potentiated protein synthesis only in liver and rather reduced it in kidney.

Isolation and hypoglycemic activity of panaxans I, J, K and L, glycans of Panax ginseng roots.

From an aqueous extract of the Oriental crude drug "ninjin" (ginseng), Panax ginseng roots from Korea, four glycans, panaxans I, J, K and L, have been isolated. These components remarkably reduced blood sugar levels in normal and alloxan-induced hyperglycemic mice.

Antihepatotoxic actions of papyriogenins and papyriosides, triterpenoids of Tetrapanax papyriferum leaves.

Antihepatotoxic actions of the papyriogenins and papyriosides from Tetrapanax papyriferum leaves were examined utilizing carbon tetrachloride (CCl4)- and galactosamine (GalN)-induced cytotoxicity in primary cultured rat hepatocytes. Remarkable antihepatotoxic effects were observed with papyriogenin B, papyriogenin A, propapyriogenin A2, papyriogenin C, 11-dehydropropapyriogenin A2, 16-epi-saikogenin C and propapyriogenin A1 in the CCl4-induced cytotoxicity assay, and papyriogenin A, propapyriogenin A1 and propapyriogenin A2 were active in preventing GalN-induced cytotoxicity although these triterpenoids were rather cytotoxic at a higher dose in the latter assay. Structure-activity relationship is discussed.

Antihepatotoxic actions of Cochlospermum tinctorium rhizomes.

The antihepatotoxic activity of the rhizomes of Cochlospermum tinctorium was investigated using carbon tetrachloride- and galactosamine-induced cytotoxicity in primary cultured rat hepatocytes. Because the methanol and ethanol extracts of C. tinctorium rhizomes exhibited antihepatotoxic effects, the former was fractionated in order to elucidate the active constituents. Polyphenol compounds (gallic and ellagic acids) were detected in the active fractions and may account for much of the antihepatotoxic activity. Carotenoids could also be implicated in the activity of the total extracts.

Mechanisms of hypoglycemic activity of aconitan A, a glycan from Aconitum carmichaeli roots.

Aconitan A did not affect plasma insulin levels in normal, glucose-loaded and alloxan-induced hyperglycemic mice and gave no influence on insulin binding to isolated adipocytes. Aconitan A exerted no effect on the activities of hepatic hexokinase, glucokinase, glucose-6-phosphatase and glucose-6-phosphate dehydrogenase, whereas it significantly increased hepatic phosphofructokinase activity. Although the activity of hepatic glycogen synthetase showed a tendency to increase, the activity of liver phosphorylase and glycogen content were unchanged by aconitan A. Aconitan A did not change the total cholesterol and triglyceride contents of plasma and liver.

Pharmacology of ephedroxanes.

On the central nervous system, ephedrine showed intense stimulatory activities but pseudoephedrine mediated weaker influences, while ephedroxane and pseudoephedroxane exerted inhibitory actions. The effects of ephedroxane were generally intense as compared with those of pseudoephedroxane. On the autonomic nervous system, the ephedrines contracted vas deferens and potentiated the effect of norepinephrine, while the ephedroxanes elicited no contraction of vas deferens but potentiation of the action of norepinephrine in the catecholaminergic nervous system. In antihistamine and antibarium activity, the ephedrines elicited remarkable actions but the effects of the ephedroxanes were weak.

Isolation and hypoglycemic activity of panaxans Q, R, S, T and U, glycans of Panax ginseng roots.

From a water extract of the Oriental crude drug "ninjin" (ginseng), Panax ginseng roots from Nagano, Japan, five glycans, panaxans Q, R, S, T and U, have been obtained. These constituents displayed marked hypoglycemic action in normal and alloxan-induced hyperglycemic mice.

Anticomplementary activity of the constituents of Eucommia ulmoides bark.

A study was made on the anticomplementary activity of the lignoid and iridoid derivatives isolated from the bark of Eucommia ulmoides as well as the enzymatic hydrolysis products of the isolated iridoid glucosides.

Antihepatotoxic actions of tannins.

The antihepatotoxic effects of tannin analogues were examined utilizing carbon tetrachloride- and galactosamine-induced cytotoxicity in primary cultured rat hepatocytes. Most tannins showed significant antihepatotoxic effects in these two assay systems. Hydrolyzable tannins generally exhibited an intense enzyme inhibitory action on glutamic-pyruvic transaminase while condensed tannins exerted a much less inhibitory action, although variations were observed depending on structure. Structure-activity relationships are discussed.

Antihepatotoxic actions of Formosan plant drugs.

One hundred twenty-nine samples of Formosan plants were screened for antihepatotoxic activity in primary cultured hepatocytes to reveal that 19 and 26 plants exhibited more than 50% inhibition against cytotoxicity produced by carbon tetrachloride and D-galactosamine, respectively. Plants which disclosed significant antihepatotoxic activity in both assay methods are: Wedelia chinense, Mallotus repandus, Phyllantus urinaria, Loranthus parasiticus, Ludwigia octovalvis, Onychium japonicum, Tamarix chinensis and Ampelopsis brevipedunculata.

Antihepatotoxic principles of Phyllanthus niruri herbs.

Among phyllanthin, hypophyllanthin, triacontanal and tricontanol isolated from a hexane extract of Phyllanthus niruri, phyllanthin and hypophyllanthin protected against carbon tetrachloride- and galactosamine-induced cytotoxicity in primary cultured rat hepatocytes, while triacontanal was protective only against galactosamine-induced toxicity.

Effect of glycans of Saccharum officinarum on carbohydrate and lipid metabolism of rats.

A polysaccharide fraction of Saccharum officinarum was tested for its effects on carbohydrate and lipid metabolism in normal rats and those fed a high sugar diet. Feeding with the high sugar diet induced an elevation of serum glucose and significant accumulation of lipid peroxides in the serum and liver. The accumulation of lipid peroxides was inhibited by combined feeding with the polysaccharide fraction. Pathological examination showed that endothelial cell swelling in ascending aorta was found in one third of rats receiving the high sugar diet control but no pathological change was observed in all of the rats concurrently treated with the polysaccharide fraction.