Mechanism Involved in Potentiation of PGF2aInduced Contractions by 6Gingerol in Mice Mesenteric Veins

The vascular endothelium releases various chemical mediators (including PGs, TX and LTs) that control the contraction of the underlying smooth muscles (Rang et al., 1999). The influence of the endothelial cells and the involvement of the cyclooxygenases in the potentiation of PGF2a-induced contraction by (±)-(6)-gingerol in mice mesenteric veins were investigated by Hata et al. (1998) and Kimura et al. (1989b).

Influence of Endothelial Cells on (±)-(6)-Gingerol Potentiation of PGF2a-Induced Contractions in Mice Mesenteric Veins

To determine whether the endothelial cells are involved in the potentiation mechanism, the effects of (±)-(6)-gingerol on PGF2a-induced contractions were compared in isolated

Table 13.6 Influence of endothelial cells on (±)-(6)-gingerol potentiation of PGF2a-induced contraction in mice mesenteric veins mg tension (% contraction) by PGF2a ( ±)-(6)-Gingerol With endothelium Without endothelium

Note: The values are the means ± SEM (n = 3—12). Significant differences at *P < .05 by paired t-test. NS, not significant.

mice mesenteric veins with or without endothelium (Table 13.6). Removal of the endothelium was confirmed by the lack of relaxation response to acetylcholine (60 ^M). The maximum contraction elicited by PGF2a (0.28 mM) was significantly potentiated up to 28 percent by (±)-(6)-gingerol in intact mesenteric veins (with endothelium). In mesenteric veins without endothelium, the contractile responses to PGF2a tended to increase slightly, but did not significantly change from those in intact veins. The potentiating effect of (±)-(6)-gingerol on the PGF2a contractile response disappeared completely in veins without endothelium.

Effects of Cyclooxygenase and Lipoxygenase Inhibitors on the Potentiation of PGF2a-lnduced Contractions by (±)-(6)-Gingerol in Mice Mesenteric Veins

The cyclooxygenase inhibitors aspirin (0.2 mM) and indomethacin (0.2 mM) markedly reduced the potentiation of PGF2a-induced contractions by (±)-(6)-gingerol, whereas a lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA, 0.03 mM), and a TXA2 antagonist, 0N0-3708 (3 nM, data not shown), had no effect (Table 13.7).

Table 13.7 Effects of cyclooxygenase and lipoxygenase inhibitors on the potentiation of PGF2a-induced contractions by (±)-(6)-gingerol in mice mesenteric veins

Compounds Concentration mM Potentiation %

Note: The maximal contraction elicited by PGF2o[ alone (0.28 mM) was taken as 100 percent response. The inhibitors were applied for 1 hour. The values are the means ± SEM (n = 4—5). Significant differences from the response with (±)-(6)-gingerol alone were determined by unpaired t-test at *P < .05. Source: Hata et al. (1998).

Effects of (±)-(6)-Gingerol on PGF2a-\nduced Contractions in Normal and Streptozotocin-Diabetic Mice Mesenteric Veins

The PGF2a-induced contractions were two times greater in the veins of streptozotocin (STZ)-diabetic mice than in normal mice (Table 13.8). Removal of the endothelial cells significantly reduced the responses to PGF2a in the diabetic mesenteric veins. The diabetic enhancement of PGF2a contractile responses was not suppressed by cyclooxyge-nase inhibitors, aspirin (0.2 mM) and indomethacin (0.2 mM) and a TXA2 antagonist, ONO-3708 (0.003 ^M), but were significantly suppressed by lipoxygenase inhibitors, NDGA (0.03 mM), and phenidone (0.05 mM) (data not shown).

The potentiating effects of (±)-(6)-gingerol (0.3 mM) on PGF2a (0.28 mM)-induced contractions were compared in the mesenteric veins of STZ-induced diabetic (10 weeks old) and of normal age-matched mice. (±)-(6)-Gingerol significantly potentiated the contractile responses to PGF2a in both normal and diabetic mice mesenteric veins. However, the potentiation percentages by (±)-(6)-gingerol were not significantly different between STZ-diabetic (26 ± 6 percent) and normal (30 ± 3 percent) veins (see Table 13.8).

It is known that the endothelial cells release potent chemical mediators (Rang et al., 1999) and modulate the contraction of vascular smooth muscles (Hickey et al., 1985; Vanhoutte et al., 1986). The potentiation of PGF2a-induced contractions by (±)-(6)-gingerol disappeared completely in mesenteric veins without endothelium. The results suggest that gingerol stimulates the release of a vasoconstrictor substance from the endothelial cells inducing potentiation of PGF2a-induced contractions in mice mesenteric veins.

The endothelium-dependent potentiation of PGF2a-induced contractions by (±)-(6)-gingerol were inhibited by cyclooxygenase inhibitors but not affected by the thrombox-ane antagonist and the lipoxygenase inhibitors. This indicates that the vasoconstrictors released by cyclooxygenase from the endothelial cells, except thromboxane, contribute to the potentiation of PGF2a-induced contractions by gingerol in mice mesenteric veins.

(±)-(6)-Gingerol significantly potentiated the PGF2a-induced contraction in mesenteric veins of both normal and diabetic mice to a similar extent. These results suggest that the mechanism involved in the potentiation of the PGF2a contractile response by (±)-(6)-gingerol is the same in normal and diabetic mesenteric veins; that is, via the cyclooxy-genase pathway.

Table 13.8 Effect of (±)-(6)-Gingerol on PGF2a-induced contractions in normal and STZ-diabetic mice mesenteric veins

(±)-(6)-Gingerol

ms tension (% contraction) by PGF2a

Normal

STZ-diabetic

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