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Effects of veratrine and paeoniflorin on isolated mouse vas deferens.

Y.F. Chen (1), Y.T. Lin (1), T.W. Tan (1) and H.Y. Tsai (1,2)

Summary

In this study, we attempted to identify the interactions and mechanisms between veratrine and paeoniflorin on isolated mouse vas deferens. Paeoniflorin had no effect on isolated mouse vas deferens. Veratrine (1 x [10.sup.-5] ~ 1 x [10.sup.-3] g/ml) could directly induce contraction of isolated rat and mouse vas deferens. The concentration induced by veratrine (1 x [10.sup.-5] g/ml) was completely inhibited by [Ca.sup.2+]-free solution and verapamil (1 x [10.sup.-5] M), in both the epididymal and the prostatic portions of isolated mouse vas deferens. Naloxone (1 x [10.sup.-5] M) did not alter the contraction induced by veratrine (1 x [10.sup.-5] g/ml) in either the epididymal or the prostatic portions of isolated mouse vas deferens. Paeoniflorin (4.8 x [10.sup.-5] g/ml) inhibited the contraction induced by veratrine (1 x [10.sup.-5] g/ml) in both the epididymal and the prostatic portions of isolated mouse vas deferens. Paeoniflorin (4.8 x [10.sup.-5] g/ml) potentiated norepinephrine (1 x [10.sup.-5] M)-induced phasic contraction in the epididymal portion, but decreased contractions in the prostatic portion. Paeoniflorin (4.8 x [10.sup.-5] g/ml) increased KCI (56 mM)-induced phasic contraction in the epididymal portion, but decreased the tonic contraction in either the epididymal or the prostatic portion. Veratrine (1 x [10.sup.-5] g/ml)-induced contractions could be decreased by pretreatment with ryanodine (1 x [10.sup.-5] M) in both the epididymal and the prostatic portions. Pretreatment with the combination of paeoniflorin (4.8 x [10.sup.-5] g/ml) and ryanodine (1 x [10.sup.-5] M) did not potentiate the inhibition of paeoniflorin in the veratrine-induced contraction in both the epididymal and the prostatic portions of isolated mouse vas deferens.

Key words: Paeoniflorin, veratrine, epididymal, prostatic, vas deferens

* Introduction

Peony roots (Paeonia lactiflora Pall., Ranunculaceae) exhibit anticoagulative activity (Ishida et al., 1987), mild sedative, potent analgesic, and antispasmodic actions (Chen et al., 1988). The analgesic, antispasmodic and antidiarrheal properties of peony roots are due to the anticholinergic action of its active derivatives of paeoniflorin (Kobayashi et al., 1990). The combination of paeoniflorin and glycyrrhizine blocked contractions of indirectly stimulated mouse diaphragm muscles, apparently by blocking intracellular calcium movement (Kimura et al., 1985a, 1985b). There have been few studies of the effects of peony root and paeoniflorin on isolated vas deferens.

Veratrine, the active component of Veratrum nigrum, is used widely as a pharmacological tool. It can affect excitable membranes, peripheral nerves, and skeletal and cardiac muscles (Brazil and Fontana, 1985). The effect of veratrine is related to increased intracellular [Na.sup.+], which in turn causes increased intracellular [Ca.sup.2+] via [Na.sup.+]-[Ca.sup.2+] exchange (Sperelakis and Pappano, 1969; Horackova and Vassort, 1973; Honerjager and Reiter, 1975; Arbel et al., 1975; Pang and Sperelakis, 1982; Brazil and Fontana, 1985; Brill and Wasserstorm, 1986; Erecinska et al., 1988; Patmore et al., 1989; Lang et al., 1993; Lin et al., 1996). Veratrine can also modify opiold and muscarinic binding sites in brain slices (Van Huizen et al., 1988).

In the present study, the interactions of paeoniflorin and veratrine, and the mechanisms through which they act, were investigated using isolated mouse vas deferens.

* Materials and Methods

Preparation of isolated vas deferens

Male ICR strain mice weighing 18-25 g each were struck on the back of the head and the abdomen was opened surgically to isolate the vasa deferentia. Each vas deferens was dissected free from surrounding tissue, divided into prostatic and epididymal segments and placed into Krebs' solution of the following composition (mM): NaCl, 118; KCl, 4.7; Mg[SO.sub.4], 1.2; Ca[Cl.sub.2], 2.5; NaH[CO.sub.3], 25.0; glucose, 11.0; [KH.sub.2][PO.sub.4], 1.2; bubbling with 95% [O.sub.2] and 5% [CO.sub.2]. The ends of each segment were tied with thread and mounted in a 5-ml Magnus organ bath containing Krebs' solution bubbling with 95% [O.sub.2] and 5% [CO.sub.2], and maintained at 37 [+ or -] 0.5 [degrees]C. One end of the segment was attached to the bottom of the organ bath, the other end was attached to a Grass Isometric Displacement Transducer FT03, which was connected to a Gould Transducer Amplifier, and the contraction of vas deferens was recorded using Gould 2600s recorders. An initial preload of 1.0 g was applied, and the tissue allowed to stabilize for 1 h. During this period, the Krebs' solution was exchanged every 10 min.

Effects of paeoniflorin and veratrine on isolated mouse vas deferens

Paeoniflorin (1 X [10.sup.-4]-1 X [10.sup.-2] M) or veratrine (1 X [10.sup.-5]-1 X [10.sup.-3] g/ml) were administered alone, to the epididymal and prostatic portions of isolated mouse vas deferens in the organ bath.

Paeoniflorin (1 X [10.sup.-4] M) and naloxone (1 X [10.sup.-6] M) were administered 10 min before veratrine (1 X [10.sup.-5] g/ml).

The preparations were preincubated with [Ca.sup.2+]-free Krebs' Ringer solution containing 0.1 mM EGTA or verapamil (1 X [10.sup.-5] M), a [Ca.sup.2+] channel blocker, before administration of 1 X [10.sup.-5] g/ml veratrine.

Paeoniflorin (1 x [10.sup.-4]M) was administered 10 min before norepinephrine (1 x [10.sup.-5] M) or a high concentration of KCI (56 mM) which induced contraction to the epididymal and pro static portions of isolated mouse vas deferens.

Ryanodine (1 x [10.sup.-5] M), an intracellular [Ca.sup.2+] blocker, and paeoniflorin (1 x [10.sup.-4] M) were added 20 min and 10 min, respectively, before administering veratrine (1 x [10.sup.-5] g/ml), or simultaneously.

Chemicals

Paeoniflorin (Nacalai Tesque Japan), veratrine hydrochloride (Sigma, USA), verapamil hydrochloride (Sigma USA), ethylene glycol-bis([beta]-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA)(Sigma USA), naloxone (Sigma USA), ryanodine (RBI USA), norepinephrine (RBI USA) and potassium chloride (Merck USA) were dissolved in Krebs' Ringer solution.

Statistical analysis

The results were expressed as mean [+ or -] S.E. The differences between mean values were compared using one-way ANOVA or the Student t-test and were considered statistically significant when P < 0.05.

* Results

Paeoniflorin (1 x [10.sup.-4] x [10.sup.-2] M) had no effect on isolated rat and mouse vas deferens (data are not shown), but veratrine (1 x [10.sup.-5]-1 x [10.sup.-3] g/ml) induced contraction of both the epididymal and the prostatic portions of isolated mouse vas deferens (Fig. 1).

As Tables 1 and 2 show, the phasic contractions induced by veratrine were concentration-dependent. Paeoniflorin (1 x [10.sup.-4]M) decreased the contraction induced by veratrine (1 x [10.sup.-5] g/ml) in both the epididymal and the prostatic portions of isolated mouse vas deferens at 0-12 min. Pretreatment with [Ca.sup.2+]-free Krebs Ringer solution completely inhibited the contraction induced by veratrine (1 x [10.sup.-5] g/ml) in both the epididymal and the prostatic portions of isolated mouse vas deferens. The L-type calcium channel blocker, verapamil (1 x [10.sup.-5] M) also completely inhibited the veratrine (1 x [10.sup.-5] g/ml)-induced contraction in both the epididymal and the prostatic portions. Naloxone (1 x [10.sup.-5] M) had no effect on the contraction induced by veratrine (1 x [10.sup.-5] M) in either the epididymal or the prostatic portions of isolated mouse vas deferens.

Norepinephrine (1 x [10.sup.-7] M~1 x [10.sup.-4] M) evoked phasic contractions in a concentration-dependent manner in both the epididymal portion (0.04 [+ or -] 0.01, 0.15 [+ or -] 0.01, 0.39 [+ or -] 0.04 and 0.53 [+ or -] 0.04 g) and the prostatic portion (0.01 [+ or -] 0.01, 0.08 [+ or -] 0.01, 0.35 [+ or -] 0.05 and 0.53 [+ or -] 0.04 g) of isolated mouse vas deferens. Paeoniflorin (1 x [10.sup.-4] M) increased the phasic contraction of the epididymal portion, but decreased contraction in the prostatic portion induced by norepinephrine (1 x [10.sup.-5] M) (Fig. 2).

The phasic contraction induced by KC1 (56 mM) was increased by paeoniflorin (1 x [10.sup.-4] M) in the epididymal portion, but had no effect in the prostatic portion of isolated mouse vas deferens (Fig. 3). The tonic contraction induced by KC1 (56 mM) was decreased by paeoniflorin (1 x [10.sup.-4] M) in both the epididymal and the prostatic portions (Fig. 4).

Ryanodine (1 x [10.sup.-5] M) decreased the contraction induced by veratrine (1 x [10.sup.-5] g/ml) in both the epididymal and the prostatic portions of isolated mouse vas deferens (Fig. 5). The inhibition of combined paeoniflorin (1 x [10.sup.-4] M) and ryanodine (1 x [10.sup.-5] M) was not more potent than paeoniflorin or ryanodine alone in either the epididymal or the prostatic portions of isolated mouse vas deferens (Fig. 5).

* Discussion

Various concentrations of veratrine (1 x [10.sup.-5] g/ml~1 x [10.sup.-3] g/ml) evoked contraction of both the epididymal and the prostatic portions of isolated mouse vas deferens in a dose-dependent manner. The L-type calcium channel blocker, verapamil (1 x [10.sup.-5] M), and [Ca.sup.2+]-free medium completely inhibited the contractions induced by veratrine (1 x [10.sup.-5] g/ml). Thus, extracellular [Ca.sup.2+] is important for the action of veratrine. Veratrine can affect excitable membranes and peripheral nerves, as well as skeletal and cardiac muscles (Brazil and Fontana, 1985). The effect of veratrine is to activate sodium channels, which increases intracellular [Na.sup.+], in turn causing increased intracellular [Ca.sup.2+] via [Na.sup.+]-[Ca.sup.2+] exchange (Brazil and Fontana, 1985; Brill and Wasserstorm, 1986; Erecinska et al., 1988; Patmore et al., 1989; Lin et al., 1996). The mechanism of veratrine-induced contraction might also be mediated by directly activating calcium channels to increase int racellular [Ca.sup.2+]. The [micro]- (Miller et al., 1986), [[delta].sub.2]- (Wild et al., 1992) and [kappa]- (Leslie, 1987) opioid receptors were found in isolated mouse vas deferens. In our study, the non-selective opioid antagonist naloxone did not affect the contraction induced by veratrine in isolated mouse vas deferens. Thus, the contraction induced by veratrine was not related to the opioid receptors.

In the prostatic portion of vas deferens, the phasic contraction induced by norepinephrine results from the release of intracellular [Ca.sup.2+] stores, and the tonic contraction results from extracellular [Ca.sup.2+] influx (Burt et al., 1998; Vesperinas et al., 1989). In the epididymal portion of vas deferens, the phasic contraction induced by norepinephrine results from the influx of extracellular [Ca.sup.2+] (Burt et al., 1995, 1998). Membrane depolarization with KC1 involved directly activating voltage-dependent calcium channels (Kageyama et al., 1997), According to our results, paeoniflorin (1 x [10.sup.-4] M) increased the phasic contraction of the epididymal portion induced by norepinephrine and KC1, but decreased the phasic contraction of the prostatic portion induced by norepinephrine. The tonic contraction induced by KC1 was decreased by paeoniflorin (1 x [10.sup.-4] M) in both the epididymal and the prostatic portions of isolated mouse vas deferens. These results indicate the effect of paeoniflor in on isolated vas deferens might be to the altered calcium movement.

Ryanodine (1 x [10.sup.-5] M), an intracellular [Ca.sup.2+] blocker, decreased the contraction induced by veratrine in both the epididymal and the prostatic portions of isolated mouse vas deferens. These results indicated that intracellular calcium was related to the contraction of veratrine in isolated mouse vas deferens. The inhibition of combined paeoniflorin (1 x [10.sup.-4] M) and ryanodine (1 x [10.sup.-5] M) was not more potent than paeoniflorin or ryanodine alone in either the epididymal or the prostatic portions of isolated mouse vas deferens. The inhibition of paeoniflorin on veratrine-induced contractions of isolated mouse vas deferens was not via the blocking of intracellular calcium. These results indicate that intracellular calcium is not directly involved in the inhibition of veratrine-induced contraction by paeoniflorin in isolated mouse vas deferens. In previous studies, paeoniflorin antagonized the contraction and arrhythmia induced by veratrine in isolated rat atria, and the mechanism was related to the blocking of calcium channels (Tsai et al., 1997). Therefore, interactions occurred between paeoniflorin and veratrine, and the mechanisms might be mediated via the blocking of calcium channels by paeoniflorin.

In conclusion, veratrine could induce contraction in a concentration-dependent manner, and paeoniflorin could decrease veratrine-induced contraction in isolated mouse vas deferens.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

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[FIGURE 5 OMITTED]
Table 1

Effects of various drugs on veratrine (VR 1 x [10.sup.-5] g/ml)-induced
contraction in the epididymal portion of isolated mouse vas deferens.

Drugs Tension of contraction (g)
 2 min 4 min

Control (VR) 0.13 0.18
 [+ or -] 0.01 [+ or -] 0.01
PF 0.06 *** 0.08 ***
(1 x [10.sup.-4] M) [+ or -] 0.01 [+ or -] 0.01
[Ca.sup.2+]-free 0 *** 0 ***
VP 0 * 0 ***
(1 x [10.sup.-5] M)
NX 0.07 0.14
(1 x [10.sup.-5] M) [+ or -] 0.01 [+ or -] 0.02

Drugs Tension of contraction (g)
 6 min 8 min 10 min

Control (VR) 0.28 0.31 0.38
 [+ or -] 0.02 [+ or -] 0.03 [+ or -] 0.03
PF 0.11 *** 0.24 0.20 ***
(1 x [10.sup.-4] M) [+ or -] 0.01 [+ or -] 0.01 [+ or -] 0.04
[Ca.sup.2+]-free 0 ** 0 ** 0 **
VP 0 ** 0 ** 0 **
(1 x [10.sup.-5] M)
NX 0.23 0.35 0.41
(1 x [10.sup.-5] M) [+ or -] 0.07 [+ or -] 0.13 [+ or -] 0.09

Drugs Tension of contraction (g)
 12 min 14 min 16 min

Control (VR) 0.43 0.45 0.46
 [+ or -] 0.04 [+ or -] 0.04 [+ or -] 0.05
PF 0.35 0.50 0.41
(1 x [10.sup.-4] M) [+ or -] 0.05 [+ or -] 0.04 [+ or -] 0.04
[Ca.sup.2+]-free 0 ** 0 ** 0 **
VP 0 ** 0 * 0 **
(1 x [10.sup.-5] M)
NX 0.5 0.52 0.60
(1 x [10.sup.-5] M) [+ or -] 0.11 [+ or -] 0.10 [+ or -] 0.11

Drugs Tension of contraction (g)
 18 min 20 min

Control (VR) 0.50 0.41
 [+ or -] 0.04 [+ or -] 0.03
PF 0.57 0.43
(1 x [10.sup.-4] M) [+ or -] 0.02 [+ or -] 0.06
[Ca.sup.2+]-free 0 ** 0 **
VP 0 ** 0 **
(1 x [10.sup.-5] M)
NX 0.57 0.56
(1 x [10.sup.-5] M) [+ or -] 0.09 [+ or -] 0.09

PF: paeoniflorin

VP: verapamil

NX: naloxone.

Values are expressed as mean [+ or -] S.E., n = 8.

* P < 0.05

** P < 0.01

*** P < 0.001 compared with control.

Table 2

Effects of various drugs on veratrine (VR 1 x [10.sup.-5] g/ml)-induced
contraction in the prostatic portion of isolated mouse vas deferens.

Drugs Tension of contraction (g)
 2 min 4 min

Control (VR) 0.23 0.29
 [+ or -] 0.01 [+ or -] 0.03
PF 0.10 *** 0.12 **
(1 x [10.sup.-4] M) [+ or -] 0.01 [+ or -] 0.01
[Ca.sup.2+]-free 0 *** 0 **
VP 0 *** 0 ***
(1 x [10.sup.-5] M)
NX 0.10 0.12
(1 x [10.sup.-5] M) [+ or -] 0.02 [+ or -] 0.02

Drugs Tension of contraction (g)
 6 min 8 min

Control (VR) 0.50 0.68
 [+ or -] 0.03 [+ or -] 0.05
PF 0.20 *** 0.28 ***
(1 x [10.sup.-4] M) [+ or -]0.01 [+ or -] 0.03
[Ca.sup.2+]-free 0 *** 0 ***
VP 0 ** 0 **
(1 x [10.sup.-5] M)
NX 0.27 0.33
(1 x [10.sup.-5] M) [+ or -] 0.09 [+ or -] 0.13

Drugs Tension of contraction (g)
 10 min 12 min 14 min

Control (VR) 0.78 0.89 0.96
 [+ or -] 0.04 [+ or -] 0.05 [+ or -] 0.03
PF 0.53 0.92 0.82
(1 x [10.sup.-4] M) [+ or -] 0.12 [+ or -] 0.03 [+ or -] 0.05
[Ca.sup.2+]-free 0 *** 0 *** 0 ***
VP 0 ** 0 *** 0 ***
(1 x [10.sup.-5] M)
NX 0.64 0.87 0.73
(1 x [10.sup.-5] M) [+ or -] 0.18 [+ or -] 0.19 [+ or -] 0.19

Drugs Tension of contraction (g)
 16 min 18 min 20 min

Control (VR) 0.96 0.90 0.89
 [+ or -] 0.05 [+ or -] 0.06 [+ or -] 0.07
PF 0.96 0.947 0.67
(1 x [10.sup.-4] M) [+ or -] 0.09 [+ or -] 0.05 [+ or -] 0.11
[Ca.sup.2+]-free 0 *** 0 ** 0 ***
VP 0 ** 0 *** 0 ***
(1 x [10.sup.-5] M)
NX 0.77 0.79 1.02
(1 x [10.sup.-5] M) [+ or -] 0.19 [+ or -] 0.18 [+ or -] 0.12

PF: paeoniflorin

VP: verapamil

NX: naloxone.

Values are expressed as mean [+ or -] S.E., n = 8.

** P < 0.01

*** P < 0.001 compared with control.


Acknowledgment

This study was supported by a grant from the National Science Council, Republic of China (NSC 88-2314-B-039-007).

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Y. F. Chen (1), Y. T. Lin (1), T. W. Tan (1) and H. Y. Tsai (1,2)

(1.) Department of Pharmacology and Institute of Pharmaceutical Sciences, China Medical College, Taichung, Taiwan, ROC

(2.) Department of Pharmacy, China Medical College Hospital, Taichung, Taiwan, ROC

Address

Huei-Yann Tsai, Ph.D., China Medical College, Taichung, 404 Taiwan, Republic of China. Tel./Fax: 886-4-22064601; e-mail: hytsai@mail.cmc.edu.tw
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Author:Chen, Y.F.; Lin, Y.T.; Tan, T.W.; Tsai, H.Y.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Date:May 1, 2002
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