Pharmacological activities of khellactones, compounds isolated from Peucedanum japonicum THUNB. and Peucedanum praeruptorium DUNN.

The spasmolytic and antiallergic effects of AA and BB, compounds isolated from Peucedanum japonicum THUNB. (P. japonicum THUNB.) and Peucedanum praeruptorium DUNN. (P. praeruptorium DUNN.), were investigated in isolated smooth muscle and rat PCA. AA and BB showed noncompetitive antagonistic effects on Ach- and histamine-induced contraction in the isolated guinea pig ileum. Both AA and BB at 10(-6) g/ml caused a slight shift to the right of the dose-response curve for Ca2+ in isolated guinea pig ileum, and a concentration up to 3 x 10(-6) g/ml displayed noncompetitive antagonistic effects. The Ba2+ (3 x 10(-4) g/ml)-induced contraction in ileum and the histamine (10(-3) g/ml)-induced contraction in trachea were obtained to relaxation by AA and BB in a concentration-dependent fashion. AA and BB showed noncompetitive antagonist action on serotonin-induced contraction of the rat uterus excised 24-48 h after subcutaneous injection of female rats with estradiol. But, AA and BB were found to have hardly any inhibitory effect on rabbit thoracic aorta contractions induced by epinephrine (3 x 10(-6) g/ml). When the effect of oral administration of 40 mg/kg dose of BB was tested on the rat homologous PCA using anti-egg albumin mouse serum dilutions (1:100, 1:250, 1:500 and 1:750), it inhibited the 1:750 serum reaction 42.6%, but the inhibition rates for the other dilutions were 12-20%. Thus, based on the results of testing AA and BB, compounds isolated from P. japonicum THUNB. and P. praeruptorium DUNN. were confirmed to possess a spasmolytic effect on different types of smooth muscle and a mild antiallergic effect. These findings are of interest in regard to the medical uses of P. japonicum THUNB. and P. praeruptorium DUNN. as a herbal drug for bronchial asthma, spasmolytic effect, etc.

The antagonistic effects of khellactones on platelet-activating factor, histamine, and leukotriene D4.

Khellactones of Peucedanum praeruptorum DUUN., including praeruptorins A (= Pd-Ia, 2) and B (= Pd-II,11), had an antagonistic effect specifically on platelet aggregation induced by platelet activating factor (PAF) among various aggregating agents examined, and represent a new class of PAF antagonists. We examined the effects of twenty compounds on PAF-induced platelet aggregation and on histamine- and leukotriene D4 (LTD4)-induced contractions in isolated guinea pig ileum. Compounds 2, (+/-)-cis-3',4'-diacetylkhellactone (3), (+/-)-cis-4'-acetyl-3'-crotonoylkhellactone (5), (+/-)-cis-4'-acetyl-3'-tetrolylkhellactone (6), (+/-)-cis-4'-acetyl-3'-tigloylkhellactone (7), (+/-)-cis-4'-acetyl-3'-(2"-methylbutyryl)khellactone (8), (+/-)-cis-3',4'-ditigloylkhellactone (10), and 11 all strongly inhibited PAF-induced platelet aggregation. (+/-)-cis-4'-Acetyl-3'-(2"-methyl-2"-dodecenoyl)khellactone (9), (+/-)-cis-4'-ethyl-3'-tigloylkhellactone (13), (+/-)-cis-4'-ethyl-3'-[N-(2"-triethylammonio)ethylcarbamoyl] khellactone iodide (16), (+/-)-trans-3',4'-diacetylkhellactone (18), (+/-)-trans-4'-acetyl-3'-crotonoylkhellactone (19), (+/-)-trans-4'-acetyl-3'-valerylkhellactone (20), (+/-)-trans-4'-acetyl-3'-isovalerylkhellactone (21), and (+/-)-trans-4'-acetyl-3'-tigloylkhellactone (22) were weakly inhibitory. Most of the compounds exhibited noncompetitive antagonist actions on histamine- and LTD4-induced contractions.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological activities of the prenylcoumarins, developed from folk usage as a medicine of Peucedanum japonicum THUNB.

In connection with the chemical structure of coumarin 1 (a mixture of acetylangeloylkhellactone and acetyltigloylkhellactone), a compound isolated from Peucedanum japonicum THUNB., we synthesized eight coumarin compounds (3-10) and performed pharmacological studies on these nine compounds, as well as on another coumarin, praeruptorin A (= Pd-Ia) (2), a compound isolated from Peucedanum praeruptorum DUNN. We studied the effects of compounds 1-5 on isolated smooth muscle and of compounds 1-10 on the cardiovascular system. These compounds showed dose-related antagonistic effects on histamine- and Ca(2+)-induced contractions in smooth muscle and the potencies were in the order 2 greater than 1 greater than seselin (3) greater than xanthyletin (4) = 2.2.10-trimethyl-2H,8H-benzo[1,2-b: 3,4-b']dipyran-8-one (5). All the compounds except 7-geranyloxy-4-methylcoumarin (10) produced a dose-related increase in vertebral, carotid and femoral blood flow. Compounds 1, 5, and 4-methyl-7-(3-methyl-2-butenyloxy)coumarin (8) caused an increase in blood pressure, but 3 and 4 caused a slight decrease. Compounds 2, 3, 4, 5, and 8 increased heart rate. Jatamansinone (6) and jatamansinol (7) caused only slight changes in blood pressure. All the compounds except 10 increased heart rate. Compound 1 also increased blood flow in the cerebral cortex. Thus, compound 1 was confirmed to have an inhibitory effect on contraction in isolated smooth muscle and an action increasing arterial blood flow. Among the compounds tested in this study, 3, as well as 6 and 7 synthesized on the basis of 3, showed actions similar to those of Ca2+ blockers and some compounds had papaverine-like activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) on interleukin 1 production by macrophages.

The effects of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) on the in vitro functions of guinea pig macrophages were studied. A high dose (1 mg/ml) of EHDP inhibited interleukin 1 (IL 1) production by oil-induced peritoneal macrophages stimulated with muramyl dipeptide (MDP), lipopolysaccharide (LPS), phorbol myristic acetate (PMA), heat-aggregated IgG2 or calcium ionophore A23187. On the other hand, low doses (less than 0.125 mg/ml) of EHDP augmented the MDP induced IL 1 production by macrophages. This biphasic effect was also observed when macrophages were exposed to EHDP at 37 C for 24 hr and then stimulated with IL 1 inducers. Superoxide anion generation induced by formyl peptide or PMA was not affected by preincubation of the macrophages with doses of EHDP up to 1 mg/ml. Adherence and spreading of macrophages was inhibited by EHDP in a dose dependent manner without affecting cell viability. These results demonstrated that EHDP acted on macrophages directly and modulated IL 1 production in vitro.