Vascular pharmacology of mokuboito (mu-fang-yi-tang) and its constituents on the smooth muscle and the endothelium in rat aorta.

Pharmacological actions of Mokuboito and its constituents (Sinomenium acutum and sinomenine) on rat aorta were examined. Mokuboito and S. acutum at lower concentrations (0.03-1 mg ml(-1)) contracted the non-loaded aorta, but at higher concentrations (1-3 mg ml(-1)), reversed to dilate it. The vasoconstriction was blocked by phentolamine (10 muM). Sinomenine failed to exhibit the vasoconstriction. On the other hand, Mokuboito and S. acutum dilated the NE (5 muM)-induced vasoconstriction: at 3 mg ml(-1), by 98.9 +/- 2.5% (n = 6, P < 0.01) and 97.0 +/- 4.8% (n = 6, P < 0.01). Vasorelaxation induced by Mokuboito and S. acutum was attenuated by indomethacin, L-NMMA and nicardipine. Propranolol decreased the vasorelaxation induced by Mokuboito, but not by S. acutum. Sinomenine also relaxed the constriction and at 100 muM, by 68.8 +/- 5.1% (n = 7, P < 0.01). This vasorelaxation was attenuated by indomethacin, L-NMMA and nicardipine, and also by propranolol. Therefore, these results indicate that Mokuboito and its constituents exert both vasodilating actions mediated by endothelium-dependent mechanisms (PGI(2) and NO from endothelium) and by endothelium-independent mechanisms (Ca(2+) influx control on smooth muscle cells). Simultaneously, Mokuboito and S. acutum cause the vasoconstrictions mediated through alpha-adrenoceptor stimulation, but not sinomenine. Also, Mokuboito and sinomenine possess beta-adrenoreceptor stimulating action, but not S. acutum.

Age-related changes in the vasodilating actions of Ginkgo biloba extract and its main constituent, bilobalide, in rat aorta.

BACKGROUND: Age-related modulation in vasodilating actions induced by Ginkgo biloba extract (GBE) and bilobalide, a main constituent of GBE, were examined using rat aorta ring strips. METHODS: Wistar rats from 5 to 25 weeks old were used, and the isolated aorta ring strips were fixed in Krebs-Henseleit solution. RESULTS: GBE and bilobalide concentration-dependently dilated norepinephrine (NE)-induced vasoconstriction in all aged rats. The vasodilating actions generally decreased in accordance with aging. GBE at 1 mg/ml decreased from 28.4+/-3.8% (n=5) in 5-week-old rats to 23.7+/-7.1 (n=7) in 25-week-old rats, but not significantly. GBE (3 mg/ml)-induced vasodilation was maximum by 73.7+/-2.1% (n=4, P<0.001) in 10-week-old rats. GBE had the marked vasodilation at younger ages and further decreased it with developing ages. In the rats older than 20 weeks, however, GBE tended to rather increase the strength of vasodilating action. On the other hand, the vasorelaxation induced by 30 micromol/l bilobalide significantly decreased from 11.8+/-1.4% (n=4) in 5-week-old rats to 2.3+/-1.5% (n=5, P<0.01) in 25-week-old rats, and by 100 micromol/l from 20.2+/-3.4% (n=4) to 5.6+/-2.5% (n=5, P<0.01), respectively. Bilobalide had the similar age-related actions. The age-dependent attenuation was produced milder by bilobalide than by GBE. At lower concentrations, however, bilobalide caused the weak vasocontriction in 20- and 25-week-old rats. CONCLUSION: GBE and bilobalide possess a similar characteristic for age-related modification, clinically suggesting the more effective actions of GBE for elder persons.

Electropharmacological actions of Ginkgo biloba extract on vascular smooth and heart muscles.

Ginkgo biloba extract (GBE) is composed mostly of two constituents: One is terpenoids (such as bilobalide, ginkgolides A, B and C), and the other is flavonoids (such as quercetin and rutin). After oral administration of GBE (160 mg) to healthy volunteers, the plasma concentrations of ginkgolides A and B and bilobalide are 41.8, 5.6 and 37.6 ng/ml, respectively. GBE and bilobalide cause a potent concentration-dependent relaxation. NG-Monomethyl-l-arginine acetate (l-NMMA), an NO synthesis inhibitor, reduces the vasodilation induced by GBE. Furthermore, the vasorelaxation of GBE is attenuated in Ca2+-free medium. Bilobalide possesses similar mechanisms. The other constituents also produce vasorelaxation. On the other hand, all the compounds markedly modify the action potential configuration in guinea pig ventricular cardiomyocytes. GBE prolongs the action potential duration (APD), whereas bilobalide shortens the APD. In patch-clamp experiments, GBE markedly inhibits the Ca2+ current (ICa), the delayed rectifier K+ current (IK) and the inwardly rectifying K+ current (IK1). On the contrary bilobalide enhances the ICa and IK currents concentration-dependently. The other constituents do not cause their actions in a uniform direction. In the rat sino-atrial (SA) node, GBE causes a negative chronotropic effect. These results indicate that GBE and the constituents produce effective electropharmacological actions in the cardiomyocytes and cause vasodilation, mainly due to the inhibitions of Ca2+ influx through the Ca2+ channel and the activation of NO release in the endothelium and aortic vascular muscles.

Comparative vasodilating actions among terpenoids and flavonoids contained in Ginkgo biloba extract.

BACKGROUND: Comparative vasodilating actions of the constituents of Ginkgo biloba extract (GBE), terpenoids (bilobalide, ginkgolides A, B and C) and flavonoids (quercetin and rutin), were examined using rat aorta ring strips. METHODS: Cumulative administrations of GBE and its constituents were followed with the pretreatment of 5 micromol/l NE. RESULTS: GBE at 0.03 to 3 mg/ml had a potent concentration-dependent relaxation; by 70 +/- 4.5% (n = 6, P < 0.001) at 3 mg/ml. Terpenoids and flavonoids at 0.1 to 100 micromol/l had potent concentration-dependent relaxation. At 100 micromol/l, bilobalide dilated by 17.6 +/- 3.9% (n = 7, P < 0.05), and ginkgolides A, B and C also caused it to the almost same extent. Quercetin (100 micromol/l) caused a potent vasorelaxation by 49.9 +/- 4.8% (n = 10, P < 0.001). Rutin at 100 micromol/l had weaker vasorelaxation; by 13.7 +/- 3.2% (n = 6, P < 0.01). CONCLUSIONS: All constituents of GBE have the concentration-dependent vasorelaxtant effect. The potency of GBE's action was not made simply by addition of those of the constituents. Each constituent itself would contribute to the GBE-induced vasodilation, although the constituents have the complicated interactions with each other.

Mechanisms for the vasodilations induced by Ginkgo biloba extract and its main constituent, bilobalide, in rat aorta.

Vasodilating actions of Ginkgo biloba extract (GBE) and bilobalide, a main constituent, were examined using rat aorta ring strips. GBE at the concentration ranges from 0.03 to 3 mg/ml had a potent concentration-dependent relaxation, reaching 70 +/- 4.5% (n = 6, P < 0.001) at 3 mg/ml. Bilobalide at 0.1 to 100 microM also caused the relaxation in a concentration-dependent manner. At 100 microM, bilobalide caused dilation by 17.6 +/- 3.9% (n = 7, P < 0.05). NG-monomethyl-L-arginine acetate (L-NMMA)(100 microM), an NO synthesis inhibitor, reduced the vasodilation of GBE (3 mg/ml) to 57.6 +/- 2.5% (n = 6, P < 0.05), and was accompanied with a decrease in the rate of relaxation. Tetraethylammonium (TEA)(100 microM), a Ca(2+)-activated K(+) channel inhibitor, also decreased the GBE (3 mg/ml)-induced relaxation to 63.1 +/- 4.6% (n = 6), but not significantly. Indomethacin tended to reduce the GBE (3 mg/ml)-induced vasorelaxation to 67.3 +/- 4.1% (n = 6). In contrast, the vasorelaxation of GBE (3 mg/ml) was strongly attenuated to 53 +/- 6.1% (n = 7, P < 0.05) in Ca(2+)-free medium. Similarly, the vasorelaxation induced by bilobalide significantly decreased both by pretreatment with NO inhibitor (L-NMMA) and in Ca(2+)-free solution. These results indicate that the relaxation induced by GBE would be due to the inhibition of Ca(2+) influx through the Ca(2+) channel and the activation of NO release, and might be in part due to the inhibitions of Ca(2+)-activated K(+) current and PGI(2) release, in the endothelium and aortic vascular muscles. Bilobalide possesses the similar mechanisms for the vasodilation.