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Potentiating Effects on Contractions by Purified Baicalin and Baicalein in the Rat Mesenteric Artery

Tsang, S. Y.; Chen, Z. Y.*; Yao, X. Q.; Huang, Y.

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Journal of Cardiovascular Pharmacology: August 2000 - Volume 36 - Issue 2 - p 263-269
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Abstract

Baicalin and baicalein are two flavonoids contained in the dry roots of Scutellaria baicalensis Georgr (Huangqin). Huangqin has been used for centuries in traditional Chinese herbal medicine in the treatment of discomfort in the chest, nausea, acute dysentery, jaundice, carbuncles, and threatened miscarriage (1). The various pharmacologic effects of the dry roots include being antiviral (2), antiinflammatory (3), and sedative (4). The antithrombotic, antioxidant, and cholesterol-lowering effects of the roots also were reported (5-7). Baicalein was found to be a lipoxygenase inhibitor; it increased production of prostaglandin I2 in hypertensive rats (8). Treatment with baicalein also lowered the blood pressure in hypertensive but not in normotensive rats (8). Infusion of baicalein into the perfused feline pulmonary artery significantly reduced vasoconstrictor responses to angiotensin II but not the vasoconstrictor responses to Bay K 8644, serotonin (5-HT), norepinephrine (NE), or U-46619 (9). Baicalein was also found selectively to inhibit contractile responses to angiotensin II in isolated arteries (10), and this effect may be due its inhibitory effect on intracellular Ca2+ level in vascular smooth muscle cells (11). Other reported beneficial effects on the vascular system include suppression of smooth muscle cell proliferation (12) and inhibition of thrombin-induced formation of plasminogen activator inhibitor-1 in endothelium (13).

Baicalein possessed antiinflammatory activity, such as inhibition of carrageenan-induced paw edema (3); however, its reported vasodilating effect could be a disadvantageous factor. It is not clear whether baicalein may have other vascular actions that also contribute to its antiinflammatory effect. We have currently isolated and purified baicalein and baicalin from the dry root of Huangqin (7). This study was designed to examine whether both purified flavonoids exert any novel actions in isolated rat endothelium-intact mesenteric arteries.

METHODS AND MATERIALS

Isolation and purification of baicalein and baicalin

Baicalein and baicalin were isolated and identified as we previously described (7). In brief, the ground roots of Huangqin were extracted with acetone, followed by evaporation. The acetone extract (2.5 g) was dissolved in 150 ml methanol. Bacalein as a yellow crystal was isolated and redissolved in methanol followed by recrystallization at −20°C. To purify baicalin, the ground root powder was successively treated with hexane, acetone, and water. The water extract was adjusted to pH 1.2 and kept at 40°C for 1 h. After centrifugation, the yellow precipitate was then redissolved in water. After adjusting to pH 6.5 and addition of an equal volume of ethanol, the water extract was centrifuged, and the supernatant was collected. When the supernatant was adjusted to pH 8.0 followed by centrifugation, the gel-like substance was redissolved in water and adjusted to pH 1.5 and kept at 40°C for 1 h. After centrifugation, baicalin as a yellow crystal was separated and redissolved in methanol and recrystallized. The crystallization was performed 4 more times in methanol at −4°C. The chemical structures of baicalein and baicalin (Fig. 1) were verified on the basis of their spectra data of UV, LC-MS, 1H-NMR, and 13C-NMR.

FIG. 1
FIG. 1:
Chemical structure of baicalin and baicalein.

Experimental protocol

Male Sprague-Dawley rats (∼250-300 g) were killed by cervical dislocation and bled. The main branch of the superior mesenteric artery was dissected out, and the surrounding connective tissue was carefully trimmed off. The artery from each rat was cut into three ring segments, ∼3 mm in length; each ring was mounted between two stainless steel hooks in Krebs solution-filled organ baths (10 ml). The Krebs-Henseleit solution contained (in mM): NaCl, 119; KCl, 4.7; CaCl2, 2.5; MgCl2, 1; NaHCO3, 25; KH2PO4, 1.2; and D-glucose, 11.1. The bath solution was continuously bubbled with a mixture of 95% O2 and 5% CO2 and maintained at 37°C and pH 7.4. During an equilibrium period of ∼90 min, the basal tone of the vessel was kept at 5 mN. The isometric contraction was measured with a Grass FT03 force-displacement transducer (Grass Instruments, Quincy, MA, U.S.A.). In some experiments, the endothelial layer was disrupted mechanically by rubbing the lumen with fine plastic tubing. The functional removal of the endothelium was verified by the absence of relaxant response (>80%) to 1 μM acetylcholine at the beginning of each experiment. Denudation of the endothelium also was evaluated by light microscopy of the histologic section of the artery. A total of 58 rats was used in this study with an approval of animal use by the Animal Ethics Committee, Chinese University of Hong Kong. Each experiment was carried out on the arterial rings prepared from different rats.

Thirty minutes after setting up in organ baths, the contraction of each segment was initially induced by 1 μM phenylephrine to test their contractile response. The tissue was then rinsed 3 times in Krebs solution to restore tension to the preconstricted level. The arterial ring was then contracted with phenylephrine applied cumulatively (ranging from 1 nM to 30 μM) or with U46610 (1-30 nM) to obtain the first concentration-contraction curve. Once the maximal response to phenylephrine or to U46619 had been reached, the tissue was washed with Krebs solution every 20 min until the tension returned to the basal level, and then incubated for 30 min with vehicle [0.2% dimethylsulfoxide (DMSO)] or with different concentrations of baicalin and baicalein, and another concentration-contraction curve to phenylephrine or to U46619 was repeated. The effects of baicalin and baicalein also were examined in the endothelium-denuded arterial rings. In some experiments, the possible effect of 1 μM prazosin was tested on the contractile response to U46619 in the absence and presence of baicalein (10 μM) or baicalin (10 μM) and to phenylephrine in endothelium-intact rings. The effects of both flavonoids (30-min contact time) also were examined on 40 mM K+-induced contraction in endothelium-intact rings. The reversibility of both flavonoids was tested on arteries contracted by 3 μM phenylephrine 3 consecutive times (T1, T2, and T3) with an interval of ∼30 min in the absence and presence of either 10 μM baicalin or 10 μM baicalein (30-min contact time) before T2. Drug was then repetitively washed out within 30 min before addition of phenylephrine (T3). The ratio of T3/T1 was taken as an index of reversibility of the drug-induced effect.

In another set of experiments, after the first concentration-response curve for phenylephrine-induced contraction, the endothelium-intact rings were incubated for 30 min with 100 μM NG-nitro-L-arginine or with 100 μM NG-nitro-L-arginine plus 10 μM baicalin or 10 μM baicalein before repeating the second concentration-response curve to each agonist. The effect of 1 mM L-arginine also was tested on the potentiating effects of baicalin and baicalein in phenylephrine-contracted arteries.

In the final group of experiments, the effects of both baicalin and baicalein were examined on the endothelium-dependent relaxation induced by acetylcholine and ionomycin in endothelium-intact rings.

Chemicals

The following chemicals and drugs were used in this study: phenylephrine hydrochloride, acetylcholine hydrochloride, prazosin, U46619, NG-nitro-L-arginine, L-arginine, ionomycin (Sigma, St. Louis, MO, U.S.A.). Baicalin and baicalein were isolated and purified from the ground root of Huangqin that was purchased from a local store of traditional Chinese medicine in Hong Kong (7). Baicalin, baicalein, U46619, and ionomycin were dissolved in DMSO, and further dilution was made in fresh Krebs solution. DMSO at 0.2% in organ baths did not affect the basal tone or phenylephrine-induced contraction.

Statistical analysis

To study the effects of baicalin and baicalein on the agonist-induced contractile response, the values of pEC50 were the negative log of the agonist concentration that caused 50% of the maximal increase of muscle tension (Emax%). These values were compared in the absence and presence of baicalin or baicalein. Data were presented as mean ± SEM of n experiments. Statistical significance was analyzed by Student's t test or by one-way analysis of variance (ANOVA) followed by Student-Newman-Keuls test when more than two treatments were compared. A p value <0.05 was considered significant.

RESULTS

Phenylephrine contracted the rat isolated mesenteric artery rings with pEC50 of 6.07 ± 0.10 (n = 7) and 6.33 ± 0.16 (n = 7), respectively, for the first and second vehicle-control concentration-response curves (p > 0.05), and a maximal increase in tension of 7.23 ± 0.84 mN (n = 7) and 7.94 ± 0.79 mN (n = 7) for the first and second concentration-response curves, respectively. Pretreatment of an endothelium-intact ring with 10 μM baicalin (Fig. 2a) or 10 μM baicalein (Fig. 2b) significantly potentiated the concentration-dependent contractile response to phenylephrine. Figure 3 shows that both baicalin (1-100 μM;Fig. 3a and b) and baicalein (1-50 μM;Fig. 3c) caused a leftward shift of the phenylephrine concentration-response curve with significant increase in the maximal contraction. Baicalin at 300 μM enhanced the contraction induced by phenylephrine only at a concentration >10 μM(Fig. 3b), whereas baicalin at higher concentrations (100-300 μM) attenuated phenylephrine-induced contraction (Fig. 3d). The pEC50 and the maximal response to phenylephrine in the absence and presence of baicalin and baicalein are summarized in Table 1. In the endothelium-denuded arterial rings, phenylephrine caused a significantly greater contraction compared with that in the presence of endothelium (pEC50 with Emax, 7.19 ± 0.07; n = 6; p < 0.05 compared with the value obtained with endothelium-intact rings). In contrast, neither 10 μM baicalin nor 10 μM baicalein affected concentration-dependent response of phenylephrine in endothelium-denuded preparations (Fig. 4b; Table 1).

FIG. 2
FIG. 2:
Traces showing two consecutive concentration-response curves for phenylephrine-induced contraction in the absence and presence of 10 μM baicalin (a) or of 10 μM baicalein (b) before repeating the second concentration-response curve. This set of experiments was performed on endothelium-intact rat mesenteric artery rings.
FIG. 3
FIG. 3:
Concentration-response curves for phenylephrine-induced contraction in control (○, n = 7) and in the presence of baicalin (•, 1 μM, n = 8; ▪, 10 μM, n = 9; ▴, 50 μM, n = 5) (a), or of baicalin (▴, 50 μM, n = 5; (▾, 100 μM, n = 4; (♦, 300 μM, n = 4) in endothelium-intact rings (b). Concentration-response curves for phenylephrine in control (○, n = 7) and in the presence of baicalein (•, 1 μM, n = 7; ▪, 10 μM, n = 7; ▴, 50 μM, n = 5) (c) or of baicalein (▴, 50 μM, n = 5; (▾, 100 μM, n = 4; (♦, 300 μM, n = 4) in endothelium-intact rings (d). Drugs were applied 30 min before repeating the second concentration-response curve. Data are expressed as a percentage of the maximal response obtained in the first (control) concentration-response curve. Values expressed as mean ± SEM of n experiments.
TABLE 1
TABLE 1:
Effects of baicalin and baicalein on the contractile response to phenylephrine
FIG. 4
FIG. 4:
a: Concentration-response curves for phenylephrine-induced contraction in endothelium-intact rings in control (○, n = 6) and in the presence of 100 μM L-NNA (♦, n = 4), of 100 μM L-NNA plus 10 μM baicalin (•, n = 5) or of 100 μM L-NNA plus 10 μM baicalein (▪, n = 6). b: Concentration-response curves for phenylephrine in control (○, n = 6) and in the presence of 10 μM baicalin (•, n = 4) or 10 μM baicalein (▪, n = 7) in endothelium-denuded rings. Drugs were applied 30 min before repeating the second concentration-response curve. Data are expressed as a percentage of the maximal response obtained in the first (control) concentration-response curve. Values expressed as mean ± SEM of n experiments.

Baicalin (10 μM) and baicalein (10 μM) enhanced phenylephrine-induced contraction in endothelium-intact rings (T2/T1, 1.07 ± 0.02 in control, 1.33 ± 0.05 in baicalin, and 1.34 ± 0.05 in baicalein; n = 4 in each case; p < 0.01 compared with control), and these potentiating effects were almost fully reversible after a 30-min washing period (T3/T1, 1.09 ± 0.01 in control, 1.12 ± 0.01 in baicalin, and 1.08 ± 0.04 in baicalein; p > 0.05 compared with control; n = 4 in each case). Pretreatment with both flavonoids also enhanced contractile response to 40 mM extracellular K+ (T2/T1, 1.02 ± 0.05, n = 6 in control; 1.42 ± 0.10, n = 5 in 10 μM baicalin; and 1.36 ± 0.05, n = 4 in 10 μM baicalein; p < 0.01 compared with control).

Inhibition of nitric oxide synthase with 100 μM NG-nitro-L-arginine (L-NNA) significantly potentiated the contractile response to phenylephrine with 69.9 ± 11.8% increase of maximal contraction compared with the control (n = 5 in each case, p < 0.05; Fig. 4a). Combined treatment with 100 μM L-NNA and 10 μM baicalin or 10 μM baicalein did not further increase the contractile sensitivity to phenylephrine (Fig. 4a; Table 1).

Pretreatment with 1 mM L-arginine, the precursor of nitric oxide synthesis, slightly but insignificantly reduced the phenylephrine-induced contraction in endothelium-intact rings (Fig. 5, Table 2). In the presence of 1 mM L-arginine, baicalin-induced potentiation of phenylephrine-induced contraction was reversed (Fig. 5a). In contrast, the baicalein-induced potentiation was unaffected by L-arginine (Fig. 5b; Table 1).

FIG. 5
FIG. 5:
a: Concentration-response curves for phenylephrine-induced contraction in endothelium-intact rings in control (○, n = 6) and in the presence of 1 mM L-arginine (□, n = 4), of 10 μM baicalin (•, n = 9), or of 1 mM L-arginine plus 10 μM baicalin (▪, n = 5). b: Concentration-response curves for phenylephrine in endothelium-intact rings in control (○, n = 6) and in the presence of 1 mM L-arginine (□, n = 4), of 10 μM baicalein (•, n = 7), or of 1 mM L-arginine plus 10 μM baicalein (▪, n = 5). Drugs were applied 30 min before repeating the second concentration-response curve. Data are expressed as a percentage of the maximal response obtained in the first (control) concentration-response curve. Values expressed as mean ± SEM of n experiments.
TABLE 2
TABLE 2:
Effect of L-arginine on the vascular response to baicalin and baicalein

Pretreatment of endothelium-intact rings with 10 μM baicalin, 10 μM baicalein, or 30 μM L-NAME significantly attenuated the relaxant response to acetylcholine (pIC50, 8.10 ± 0.07; n = 6 in control; 7.43 ± 0.07, n = 4 in baicalin; 7.67 ± 0.04, n = 4 in baicalein; and 7.03 ± 0.07, n = 5 in L-NAME; Fig. 6a). Both flavonoids also inhibited ionomycin-induced relaxation (pIC50: 8.27 ± 0.06, n = 5 in control; 7.99 ± 0.05, n = 4 in 10 μM baicalin; 7.64±0.05, n = 5 in 10 μM baicalein; Fig. 6b). Besides, L-NAME at 30 μM inhibited relaxation induced by ionomycin (pIC50: 7.55 ± 0.11, n = 4; Fig. 6b).

FIG. 6
FIG. 6:
Concentration-response curves for the relaxant effects of acetylcholine(a) and of ionomycin in control (○, n = 5-6) and in the presence of (•, n = 4) 10 μM baicalin (▪, n = 4) 10 μM baicalein, or (♦, n = 4) 30 μM L-NAME in endothelium-intact rings (b). Each ring was exposed to the drug for 30 min before application of U46619. Values expressed as mean ± SEM of n experiments.

In another set of experiments, both baicalin (10 μM) and baicalein (10 μM) enhanced U46619 (30 nM)-induced contraction in the endothelium-intact rings (Fig. 7a), whereas both flavonoids had no effect on the U46619-contracted endothelium-denuded rings (Fig. 7c). However, the potentiating effects of baicalin and baicalein were absent in the presence of 100 μM L-NNA (Fig. 7b; Table 3). To test the possibility that both flavonoids may stimulate sympathetic input, the effect of α1-adrenoceptor antagonist prazosin was used. Prazosin at 1 μM did not affect the U46619 (10 nM)-induced contraction in control and in the presence of 10 μM baicalin or 10 μM baicalein, whereas this concentration of prazosin abolished the contraction induced by 30 μM phenylephrine (n = 4 in each case; data not shown).

FIG. 7
FIG. 7:
a: Concentration-response curves for the contractile response to U46619 in control (○, n = 5) and in the presence of 10 μM baicalin (•, n = 6) or 10 μM baicalein (▪, n = 7) in endothelium-intact rings. b: Concentration-response curve for U46619 under various conditions (○, n = 5 for control; (♦, n = 4 for L-NNA; (•, n = 4 for 10 μM baicalin plus L-NNA; (▪, n = 5 for 10 μM baicalein plus L-NNA). c: Concentration-response curves for U46619 in control (○, n = 5) and in the presence of 10 μM baicalin (•, n = 4) or 10 μM baicalein (▪, n = 6) in endothelium-denuded rings. Drugs were applied 30 min before repeating the second concentration-response curve. Data are expressed as a percentage of the maximal response obtained in the first (control) concentration-response curve. Values expressed as mean ± SEM of n experiments.
TABLE 3
TABLE 3:
Effects of baicalin and baicalein on U46619-induced contraction

DISCUSSION

We have recently isolated and purified two flavonoids, baicalin and baicalein from the dry roots of Scutellaria baicalensis Georgr (Huangqin) and found that these two compounds possessed antioxidant effects (7). The results of our investigation demonstrated a novel vascular response to these two flavonoids. In the rat isolated mesenteric arteries, both baicalin and baicalein reversibly potentiated the contractile response in a concentration-related manner, and this effect depended on the presence of the functional endothelium. Removal of endothelium eliminated the potentiating effects of baicalin and baicalein on vasoconstriction. Pretreatment of endothelium-intact arterial rings with L-NNA, the nitric oxide synthase inhibitor markedly increased the phenylephrine-induced contraction, whereas baicalin and baicalein failed to induce further potentiation in the presence of L-NNA. In some instances, the vasoconstriction induced by membrane depolarization of arterial smooth muscle is caused by a decrease in K+ permeability. In this study, when contractions of similar size were induced by 40 mM K+ or by phenylephrine, both were enhanced to similar extent by baicalin and baicalein, indicating that inhibition of K+ channels (inhibition of endothelium-derived hyperpolarizing factor) may not be involved in their potentiating effects on arterial tone. These findings clearly indicate that baicalin and baicalein may inhibit production of endothelial nitric oxide but not of other endothelium-derived relaxing factors. We also showed that pretreatment with baicalin or baicalein significantly attenuated the relaxation induced by either acetylcholine or ionomycin, with little effect on the maximal relaxation. L-NAME, the nitric oxide synthase inhibitor, reduced the maximal relaxation induced by both endothelium/nitric oxide-dependent dilators.

Further supporting evidence comes from experiments with L-arginine, the precursor of nitric oxide biosynthesis. Pretreatment with L-arginine slightly reduced the sensitivity of the arteries to phenylephrine, but it reversed the potentiating effect of baicalin but not the effect of baicalein. Neither baicalin nor baicalein at concentrations that enhanced vasoconstriction affected the basal tone, suggesting that both compounds did not the basal release of nitric oxide. These novel data suggest that L-arginine can antagonize the effect of baicalin but not baicalein, although both flavonoids are structurally similar. These results indicate that, like the nitric oxide synthase inhibitors, both flavonoids may inhibit nitric oxide production and/or secretion in rat mesenteric arteries. It is possible that baicalin may act as a competitive antagonist of nitric oxide synthase, while baicalein acts as a noncompetitive antagonist. Nevertheless, the exact mechanism responsible for this discrepancy remains to be elucidated.

Diffusion of endothelial nitric oxide into the underlying vascular smooth muscle cells normally activates guanylate cyclase, the first step leading to vasorelaxation. It is possible that both baicalin and baicalein might also act as inhibitors of guanylate cyclase, and thus potentiate the contractile response. However, baicalein did not affect the vasorelaxation of the same preparations induced by sodium nitroprusside, the exogenous donor of nitric oxide in our previous study, suggesting that baicalein may not suppress the activity of guanylate cyclase as does methylene blue in arterial smooth muscle cells (14). Therefore, both baicalin and baicalein very likely exert their effects on endothelium in isolated rat mesenteric arteries. Baicalein was shown to inhibit intracellular Ca2+ concentration in human umbilical vein endothelial cells (13). Therefore, further experiments with Ca2+ fluorescence measurement are needed to examine whether baicalin and baicalein would affect endothelium-dependent vasodilator-induced increase of endothelial Ca2+ levels and thus impair the activity of Ca2+-dependent nitric oxide synthase.

These results did not suggest that the potentiating effects were confined to their possible modulatory action on α-adrenoceptors because both baicalin and baicalein enhanced the contractile response to U46619 or to 40 mM extracellular K+. It also can be ruled out that baicalin and baicalein may stimulate noradrenaline release from sympathetic nerve terminals that supply the rat mesenteric arteries because 1 μM prazosin, a potent antagonist of α1-adrenoceptors, did not affect the potentiating effects of both flavonoids on contraction induced by submaximal concentrations of U46619. In contrast, this concentration of prazosin abolished the contractile response to 30 μM phenylephrine.

The dry roots of Huangqin and baicalein were previously shown to lower blood pressure in rats and cats (8,9). The exact mechanisms underlying the hypotensive action are basically unclear. Baicalein also possesses a sedative effect (4), which may contribute at least in part to the hypotensive effects in vivo. Our results show that higher concentrations (100-300 μM) of baicalein markedly reduced the phenylephrine-induced contractile response. It is apparent that baicalein exerts opposing vasoconstrictive and vasodilator effects, depending on differences in drug concentrations. It is therefore possible that the observed hypotensive action of baicalein may be caused by its high plasma concentration together with its reported sedative effect.

In summary, this study has provided novel information on the arterial action of purified Huangqin baicalin and baicalein. In isolated rat mesenteric arteries, both compounds (1-10 μM) enhanced the contraction induced by phenylephrine, U46619, or 40 mM extracellular K+, and they attenuated acetylcholine- or ionomycin-induced endothelium-dependent relaxation primarily through their inhibition of nitric oxide release and/or production in endothelium. It has yet to be demonstrated whether baicalin or baicalein would interfere with endothelium/nitric oxide-dependent vasodilators in vivo. At higher concentrations, baicalein reduced the phenylephrine-induced contractile response that may contribute to its in vivo hypotensive action.

Acknowledgment: This work was supported by a grant from Hong Kong Research Grants Committee. S.Y.T. was supported by a CUHK Postgraduate Studentship.

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Keywords:

Baicalin; Baicalein; Contraction; Nitric oxide; Endothelium; Mesenteric artery; Rat

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