Rql

54 ± 8** (0.4)

Note: (L): longitudinal; (C): circular; C: contraction; R: relaxation.

The contraction to PGF2o[ (0.3 mM) without gingerol was used as the control = 100 percent. The values are expressed as mean percentage ± S.E.M. (n = 4).

Significant difference from the control value without gingerol were determined by paired ¿-test at *P < .05 and **P < .01.

Source: Kimura et al. (1989a).

Note: (L): longitudinal; (C): circular; C: contraction; R: relaxation.

The contraction to PGF2o[ (0.3 mM) without gingerol was used as the control = 100 percent. The values are expressed as mean percentage ± S.E.M. (n = 4).

Significant difference from the control value without gingerol were determined by paired ¿-test at *P < .05 and **P < .01.

Source: Kimura et al. (1989a).

Effects of (±)-(6)-Gingerol on Eicosanoid-Induced Contractions in Mice Mesenteric Veins

Cumulative additions of prostaglandins (F2a, E2, and D2), prostacyclin stable derivatives (PGI2 -Na and TRK-100), a stable TXA2 (U-46619), and leukotrienes (C4 and D4) induced concentration-dependent contractions of mice mesenteric veins. The maximal contraction for PGF2a was obtained at a 0.28 mM concentration. PGE2 and PGD2 (0.28 mM) caused 48 percent and 12 percent of the maximal response to PGF2a, respectively. PGI2-Na (0.27 mM) produced the same maximal contraction as PGF2a. The other prostacyclin derivative, TRK-100 (0.24 mM), induced a contraction that was 27 percent of the maximal response for PGF2a. The muscle segments were more sensitive to U-46619, LTC4, and LTD4. Higher amplitudes of contractions were obtained at low concentrations; that is, 152 percent for U-46619 (29 ^M), 179 percent for LTC4 (1^M), and 163 percent for LTD4 (1^M). Arachidonic acid and PGD1 failed to cause contractions even at high concentrations (0.3 mM).

Figure 13.7 shows typical recordings of the mesenteric vein contraction response to maximum concentrations of PGF2a, PGE2, and TRK-100 in the absence and presence of (±)-(6)-gingerol. The gingerol alone caused a transient relaxation of the smooth muscle that immediately recovered to baseline tension, then after 5 minutes, it significantly potentiated the prostanoid-induced contraction. The response to TRK-100 was the most markedly potentiated.

The contractions induced by prostanoids except PGD2 were significantly enhanced by gingerols. In contrast, the contractions induced by PGD2, U-46619, LTC4, and LTD4 were significantly inhibited by gingerols (Table 13.5). The effects of the gingerols disappeared completely after a washout of 30 minutes to 1 hour.

The prostaglandins, thromboxane, and leukotrienes induce concentration-dependent contractions of various blood vessels. In rabbit and rat aorta (Borda et al., 1983), human coronary artery (Davis et al., 1980), and canine basilar artery (Chapleau et al., 1979),

Figure 13.7 Typical recordings of the contractile responses to maximum concentrations of PGF2a (A), PGE2 (B), and TRK-100 (C) with or without (±)-(6)-gingerol (0.3 mM). Each response was observed at 30-minute intervals in separate experiments for each prostanoid. (From Kimura et al., 1989a.)

Table 13.5 Effects of (±)-(6)-gingerol on eicosaoid-induced contractions in mice mesenteric veins

(±)-(6)-Gingerol % Contraction Action pattern Compounds (mM) 0.03 0.1 0.3

Potentiation PGF2„ (0.28)

Inhibition PGD2 (0.28)

128 ± 3** 135 ± 5** 117 ± 0.3** 162 ± 9** 69 ± 8* 91 ± 1** 86 ± 2* 95 ± 3

Note: The contraction induced by the above compounds without gingerol was taken as the control = 100 percent. The values are expressed as mean percentages ± SEM (n = 3—5). Significant differences from the control value without gingerol were determined by ¿-test at *P < .05 and **P < .01. Source: Kimura et al. (1989a).

low doses of PGI2 relax the vascular smooth muscle, but higher doses elicit concentration-dependent contractile responses. In this study, the prostanoids and leukotrienes induced concentration-dependent contractions in mice mesenteric veins. The longitudinal segments of mice mesenteric artery, rat mesenteric vein, and rat vena cava and the circular segments of the rat aorta also contracted in response to PGF2a. On the other hand, PGF2a relaxed the longitudinal segments of rat aorta and mesenteric artery.

(±)-(6)-Gingerol exhibited different actions on veins (longitudinal) and arteries (longitudinal and circular). It augmented the PGF2a-induced contractions in veins and decreased the PGF2a-induced relaxation or inhibition of PGF2a-induced contraction in arteries. The stimulation of the cyclooxygenase pathway induced opposite responses in rat isolated blood vessels; that is, relaxation in arteries and contraction in veins (Van-houtte et al., 1986). The potentiation of PGF2a-induced contraction in veins and inhibition of the PGF2a contractile response in arteries by (±)-(6)-gingerol suggest that the effects of (±)-(6)-gingerol involve the cyclooxygenase system.

Both the leukotrienes and thromboxane A2 (TXA2) derivative produced a response of higher sensitivity and greater maximal response than the other prostaglandins in mice mesenteric veins. The order of potency of the prostanoids and leukotrienes was estimated to be LTs > TXA2 > PGF2a > PGI2-Na > PGE2 > TRK-100 > PGD2 for mice mesenteric vein. The responses were similar to those obtained for guinea pig lung (Coleman and Kennedy, 1985) and isolated bronchus (Black et al., 1986). The results suggest that the mice mesenteric veins contain more than one type of eicosanoid receptor mediating the contraction. The receptors for prostanoids (Coleman and Humphrey, 1993) with lower potency may not be so abundant in the mesenteric veins or these agents may be partial agonists.

(±)-(6)-Gingerol alone induced transient relaxation of the mice mesenteric veins which then recovered to baseline force, but did not induce direct contractile effect. However, (±)-(6)-gingerol potentiated the contraction induced by PGF2a, PGI2, and PGE2, but inhibited the contractions induced by LT, TXA2 and PGD2. The inhibition of TXA2 synthesis (Uotila and Matintalo, 1984) and the LT receptors (Mong et al., 1986) has been reported to convert arachidonic acid to PGF2a, PGI2, and PGE2 via the cycloxyge-nase system. The results of this study further suggest that gingerol-induced potentiation of prostanoid contractions (except PGD2) involves the cyclooxygenase.

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