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冠動脈攣縮モデルにおける当帰芍薬散と木防已湯の影響とくに冠動脈攣縮発生について検討した。雄性ブタの左冠動脈前下行枝 (LAD) をカテーテルで擦過し内膜傷害を起こし, 胃瘻を設置した。実験群は当帰芍薬散群 (ツムラ製, n=6) と木防已湯群 (n=5) に分けて, 各エキス末を胃瘻より投与し4週間飼育した。その後, acetylcholine (ACh) を経カテーテル的に投与し攣縮発生を試みた。対照群 (n=5) は普通食のみで飼育し, 攣縮は冠動脈造影像上で確認した。ACh投与後, 擦過部を含むLADとその末梢枝の限局性ないしはびまん性過収縮像を認めた。ACh投与回数に対する当帰芍薬散群の攣縮発生は5/13, 木防已湯群5/12, 対照群7/13であり, 3群間に差異はなかった。しかし, 実験群全体の攣縮発生率は対照群よりも低下傾向にあった。その機序は明らかではないが, 被検方剤はブタ冠動脈攣縮発生に影響を及ぼす可能性が示唆された。

The effects of 1-hydroxyethylidene-1, 1-bisphosphonate (HEBP) and two Chinese traditional (Kampo) medicines, Dai-saiko-to and Saiko-ka-ryukotsu-borei-to on spontaneous soft tissue (heart and tongue) mineralization in DBA/2NCrj mice were studied. These agents were given orally for 4 weeks to DBA/2NCrj mice. After 2 weeks of administration in the heart, 0.006 and 0.03% (w/v) HEBP decreased calcium content by 90 and 30%, respectively, while 0.27 and 2.7 mg/ml Dai-saiko-to reduced calcium content by 30 and 45%, respectively. Saiko-ka-ryukotsu-borei-to (0.27 mg/ml) reduced both calcium and phosphorus content by 50 and 35%, respectively. However, their inhibitory effects on the heart were not observed after 4 weeks of administration. The compounds delayed the onset of increases of bulk calcium and phosphorus content. In the tongue, at 4 weeks, 0.006 and 0.03% (w/v) HEBP reduced calcium content by 30 and 45%, respectively, while two Kampo medicines (at both concentrations used) significantly reduced the content of calcium (by 27-79%) and phosphorus (by 24-32%). These results strongly suggest that two Kampo medicines as well as HEBP may be useful in preventing and curing soft tissue calcification.

It has been demonstrated that TJ-8007 (Tsumura-Zokumeito, A traditional Chinese medicine) has a protective effect against cerebral anoxia. This study was done to elucidate the protective mechanism of TJ-8007 against cerebral ischemia and anoxia. TJ-8007 (0.3 approximately 3.0 g/kg, p.o.) inhibited the rise in the cumulative mortality rate after ligation of the bilateral carotid artery (BCA) in mice. TJ-8007 also significantly prolonged the survival time at the dose of 3.0 g/kg, p.o. However, TJ-8007 (1.0 or 3.0 g/kg, p.o.) did not affect the mean survival time after ligation of BCA in Mongolian gerbils and the gasping movement in a decapitated mouse head that served as a complete ischemic model. Ifenprodil (30 mg/kg, p.o.) also showed the protective effect only against ischemic death after ligation of BCA in mice. TJ-8007 (1.0 or 3.0 g/kg, p.o.) increased the vertebral blood flow, but showed no effect on the internal carotid blood flow in anesthetized dogs. These results suggest that the mechanism for the cerebral protective effect of TJ-8007 may be due to its ameliorating action on the cerebral circulation.

Pharmacological actions of (6)-shogaol and capsaicin were studied. Both (6)-shogaol (0.5 mg/kg, i.v.) and capsaicin (0.1 mg/kg, i.v.) caused a triad such as a rapid fall in blood pressure, bradycardia and aponea in rats. Both drugs-induced marked pressor responses in blood pressure, which occurred after the rapid fall, were markedly reduced by a spinal destruction. In pithed rats, both drugs-induced peripheral pressor responses were markedly reduced with the combined treatment of [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-substance P (0.5 mg/kg, i.v.), phentolamine (10 mg/kg, i.v.) and the section of sciatic nerves. In isolated guinea-pig trachea, (6)-shogaol (100 microM) and capsaicin (10 microM) induced contractile responses which were slightly inhibited by substance P antagonist (10 microM), but exhibited also a tachyphylaxis. Furthermore, although (6)-shogaol (3.6 microM) showed positive inotropic and chronotropic actions on isolated atria in rats, this effect of (6)-shogaol disappeared by repeated injections or pretreatment (100 mg/kg, s.c.) of (6)-shogaol. These results suggest that (6)-shogaol and capsaicin have similar actions, and that both drugs may cause a peripheral action by releasing an unknown active substance from nerve ends.

General pharmacological studies were performed on (6)-gingerol and (6)-shogaol which are the pungent constituents of ginger (Zingiber officinale Roscoe). Intravenous (i.v.) administration of (6)-gingerol (at 1.75-3.5 mg/kg) or (6)-shogaol (at 1.75-3.5 mg/kg) and oral administration of them (at 70-140 mg/kg) produced an inhibition of spontaneous motor activity, an antipyretic and analgesic effects, prolonged hexobarbital-induced sleeping time, and these effects of (6)-shogaol were mostly more intensive than that of (6)-gingerol. (6)-Shogaol showed an intense antitussive effect in comparison with dihydrocodeine phosphate. In the electro-encephalogram of cortex, the low amplitude fast wave pattern was observed for 5 min after i.v. administration of (6)-shogaol, and then changed to the drowsy pattern, which was restored after 60 min. In the gastro-intestinal system, (6)-shogaol intensively inhibited the traverse of charcoal meal through the intestine in contrast with (6)-gingerol after i.v. administration of 3.5 mg/kg, but (6)-shogaol facilitated such an intestinal function after oral administration of 35 mg/kg. Both (6)-shogaol and (6)-gingerol suppressed gastric contraction in situ, and the suppression by the former was more intensive than that by the latter. In the cardiovascular system, both (6)-shogaol and (6)-gingerol produced depressor response at lower doses on the blood pressure. At high doses, both drugs produced three phase pattern.

The protective effects of TJ-8007 (Tsumura-Zokumeito, Traditional chinese medicine) against cerebral anoxia were investigated with various experimental models in mice and rats. 1) In histotoxic anoxia, TJ-8007 (0.3-3.0 g/kg, p.o.) dose-dependently demonstrated a protective effect on coma induced by a sublethal dose of KCN (1.8 mg/kg, i.v.) in mice. Ifenprodil (30 mg/kg, p.o.) tended to reduce the coma time, but papaverine (100 mg/kg, p.o.) showed a negative effect. 2) TJ-8007 (0.3-3.0 g/kg, p.o.) dose-dependently tended to prolong the survival time of mice subjected to a lethal dose of KCN (3.0 mg/kg, i.v.), TJ-8007 also improved the survival rate at the dose of 3.0 g/kg. Ifenprodil (30 mg/kg, p.o.) or papaverine (100 mg/kg, p.o.) exerted a similar effect on the survival time, but did not affect the mortality. 3) In the normobaric hypoxia with a gas mixture of 96% N2 and 4% O2, TJ-8007 (0.3-3.0 g/kg, p.o.) did not affect the survival time of mice. On the other hand, papaverine (100 mg/kg, p.o.) prolonged the survival time, and phenytoin (100 mg/kg, p.o.) showed a marked protective effect, but ifenprodil (30 mg/kg, p.o.) produced an adverse effect. 4) In the asphyxic anoxia induced by stopping artificial respiration of immovable rats, TJ-8007 (1.0, 3.0 g/kg, p.o.) showed a protective effect on the fall of systemic blood pressure and on the decline of heart rate; furthermore, it dose-dependently prolonged the disappearance time of cortical activity. Also, phenytoin (100 mg/kg, p.o.) tended to protect against the fall of blood pressure and prolonged the cortical resistance time.(ABSTRACT TRUNCATED AT 250 WORDS)

When (6)-shogaol (0.5 mg/kg, i.v.) was administered to rats, blood pressure showed a tri-phasic response which was comprised of a rapid fall, followed by a rise and a delayed fall. The rapid fall, which followed immediately after injection of (6)-shogaol, disappeared with the use of atropine and vagotomy. The marked rise, which occurred after the rapid fall, was not affected by alpha-adrenoceptor blockades, Ca antagonists and ganglion blockade. However, a combination of alpha-adrenoceptor blockade and Ca antagonist inhibited this pressor response. In hindquarters perfused with a nutrient solution, (6)-shogaol (10(-5) g)-induced peripheral pressor response was also not affected by alpha-adrenoceptor blockades and Ca antagonists, but was inhibited by the combination of an alpha-adrenoceptor blockade and a Ca antagonist. Furthermore, this peripheral pressor response was eliminated by the removal of Ca ion from the perfusate. (6)-Shogaol did not exhibit a pressor response in an artery and a vein of the tail or an artery of the femur perfused with a nutrient solution. (6)-Shogaol-induced peripheral pressor response in hindquarters was markedly potentiated during the perfusion of norepinephrine (5 X 10(-6) g/ml), but this potentiation was prevented by pretreatment with reserpine (5 mg/kg, i.p.). Moreover, repeated injections of (6)-shogaol caused a tachyphylaxis in mesenteric and tail vascular beds and a slight tachyphylaxis in hindquarters.

(6)-Shogaol-induced pressor responses in blood pressure of rats were studied. Intraventricular injection of (6)-shogaol (0.1 to 0.5 microgram) caused a pressor response in a dose-dependent manner. (6)-Shogaol (0.5 mg/kg, i.v.)-induced pressor response was markedly reduced by a spinal destruction to the sacral cord level. However, norepinephrine (10 micrograms/kg, i.v.)-induced pressor response was not affected by the spinal destruction. In rats in which the spinal cord was destroyed to the thoracic cord level, (6)-shogaol-induced pressor response was reduced by hexamethonium (10 mg/kg, i.v.) and phentolamine (10 mg/kg, i.v.), etc. When the spinal cord was destroyed to the sacral cord level, the pressor response was not affected by these blockades. In the hindquarters of rats which were perfused with rats' blood, (6)-shogaol caused two pressor responses on the perfusion pressure. The first pressor response, which was accompanied by a rise in systemic blood pressure, was reduced by hexamethonium but was not entirely eliminated by phentolamine. However, the pressor response disappeared with spinal destruction to the sacral cord level. The second pressor response, which occurred about when the systemic blood pressure regained its original pressure, was not affected by hexamethonium, phentolamine or spinal destruction. Pressor response induced by the injection of (6)-shogaol (10 micrograms) into the perfusion circuit was not affected by phentolamine and spinal destruction. Furthermore, (6)-shogaol-induced peripheral pressor response disappeared with the combined treatment of [D-Arg1, D-Pro2, D-Trp7.9, Leu11]-substance P (0.5 mg/kg, i.v.), phentolamine and the section of the sciatic nerves.

(6)-Shogaol, a pungent component of ginger, which is contained in semi-dried ginger but is rarely found in fresh ginger inhibited carrageenin-induced swelling of hind paw in rats and arachidonic acid (AA)-induced platelet aggregation in rabbits. Moreover, (6)-shogaol prevented prostaglandin I2 (PGI2) release from the aorta of rats when tested as an inhibitor of platelet aggregation. These results suggest that (6)-shogaol may have an inhibitory action on the cyclo-oxygenases in both platelets and aorta. Examination of the effects of (6)-shogaol on cyclo-oxygenases in rabbit platelets and microsome fractions of rat aorta indicated that (6)-shogaol inhibited cyclo-oxygenase activities of both tissues in a concentration-dependent manner. Furthermore, when we examined the effect of (6)-shogaol on 5-lipoxygenase from RBL-1 cells, (6)-shogaol exhibited an inhibitory action on 5-lipoxygenase activity. Therefore, it seems that the inhibitory effects of (6)-shogaol on the carrageenin-induced paw edema, AA-induced platelet aggregation and PGI2 production of aorta may be caused by the inhibition of cyclo-oxygenase activity.