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Inhibition of porcine detrusor contractility by the flavonoid fraction of Bryophyllum pinnatum--a potential phytotherapeutic drug for the treatment of the overactive bladder syndrome.


Aims: To determine if the phytotherapeutic agent, Bryophyllum pinnatum, could serve as an alternative drug for the overactive bladder syndrome, and to characterise the fraction responsible for the inhibition of detrusor contractility.

Methods: Fractions were prepared from the MeOH extract of B. pinnatum and further analysed by HPLCPDA-MS. Detrusor muscle strips were prepared from porcine bladders and the electrically induced muscle contractility measured by organ bath. The effect of B. pinnatum leaf press juice (2.5-10%), a flavonoid fraction (0.1-1 mg/ml), and a bufadienolide fraction (0.1-40 [micro]g/ml) on detrusor contractility was assessed and compared with controls (polar fraction (0.5-5 mg/ml) and oxybutynin ([10.sup.-8]-[10.sup.-6] M)).

Results: The press juice, at a concentration of 10% led to a reduction of detrusor contractility. Bladder strips treated with the flavonoid fraction showed a significant reduction of the contractility to 21.3 [+ or -] 5.2% (1 mg/ml) while the bufadienolide fraction had no inhibitory effect in the investigated concentrations. The polar fraction showed a reduction of the contractility in a pH-dependent fashion. At [10.sup.-6] M concentration oxybutynin reduced the detrusor contractility to 21.9 [+ or -] 4.7%.

Conclusions: The flavonoid fraction of Bryophyllum pinnatum reduces the porcine detrusor contractility in a dose- and time-dependent manner. Fractions from B. pinnatum may be a new pharmacological approach for the treatment of OAB.


Bryophyllum pinnatum


Overactive bladder

Detrusor muscle

Muscle relaxation

Muscle contractility


Overactive bladder (OAB) syndrome is a symptomatic diagnosis that was defined by the International Continence Society (ICS) as urgency, with or without urge incontinence, usually with frequency and nocturia, after exclusion of a bladder infection or other obvious pathology (Haylen et al. 2010).

In 2008, the worldwide prevalence was 10.7%, and is expected to rise to 20.1% in 2018 (Irwin et al. 2011). OAB often impacts negatively the quality of life especially in case of incontinence. However, many affected individuals do not seek help and therefore do not receive a treatment. Patients suffering from a neurological disease (e.g. multiple sclerosis, Parkinson's disease, stroke) have a higher incidence. Changes in lifestyle, bladder training, and pelvic floor muscle exercises are the first step of conservative treatments (Hashim and Abrams 2004).

Antimuscarinic drugs such as oxybutynin are used as first-line pharmacotherapy with a proven clinical benefit. However, many patients suffer from anticholinergic side effects, lack of efficacy, or unfulfilled treatment expectations. Up to 20% of the patients fail to respond adequately, or their expectations were too high (Veenboer and Bosch 2014).

As a new therapeutic approach [[beta].sub.3]-adrenoceptor agonists have been investigated. Mirabegron was recently introduced as a treatment of OAB. A multicentre randomised double-blind study showed good efficacy and tolerability compared to placebo (Khullar et al. 2012; Chappie et al. 2013).

If conservative treatment fails, surgical interventions like botulinum toxin injection, sacral nerve stimulation, or detrusor myectomy are recommended as further options (Toozs-Hobson 2010).

Given the drawbacks of the above-mentioned approaches, alternative pharmacological treatment options would be of value for patients suffering from OAB. Previous research indicated that Bryophyllum pinnatum could be such a new therapeutic approach.

Bryophyllum pinnatum (Lam.) Oken (syn. Kalanchoe pinnata Pers., Bryophyllum calycinum Salisb., Crassulaceae) is a succulent perennial plant native to Madagascar. The leaves have been used in traditional, native, and anthroposophical medicine (Kamboj and Saluja 2009; Daems et al. 1982). Since 1970, B. pinnatum is used as a tocolytic agent to prevent premature labour (Hassauer et al. 1985). Leaf press juice and a flavonoid fraction of B. pinnatum were shown to induce myometrial relaxation in vitro (Wachter et al. 2011).

Similar effects could be demonstrated on bladder detrusor muscle where B. pinnatum leaf press juice had an inhibitory effect on electrically or carbachol-induced porcine detrusor muscle contractility (Schuler et al. 2012). In a pilot study with 22 postmenopausal women suffering from OAB, a positive effect of leaf press juice on the frequency of micturition compared to placebo could be shown after 8 weeks of treatment (Betschart et al. 2013).

Based on these findings, we further investigated the effect of B. pinnatum on porcine detrusor contractility. Herbal extracts contain a multitude of different phytochemicals. B. pinnatum is known to contain various flavonoids, bufadienolides, alkaloids, triterpenes, phytosterols, fatty acids, minerals, and vitamins (Kamboj and Saluja 2009). For scientifically founded phytomedicines an identification of the pharmacologically active constituents is important, in that perspective a phytochemical profiling of B. pinnatum was performed. We isolated and identified two phenolic acid derivatives and nine flavonoid glycosides, and identified four bufadienolides with the aid of reference substances isolated from the taxonomically related B. daigremontianum (Fiirer et al. 2013). The latter species is known to contain higher amounts of bufadienolides, which have been shown to exert positive inotropic and CNS related activities (Wagner et al. 1986).

The aim of this study was to identify the active compounds/fractions of B. pinnatum responsible for the inhibitory effect on porcine detrusor muscle contractility. For that purpose a flavonoid, a bufadienolide fraction, and a control fraction containing highly polar compounds of B. pinnatum leaf extract were prepared and tested on porcine detrusor muscle strips.

Materials and methods

Plant material

B. pinnatum leaf press juice (BPJ)

Leaves were harvested in March 2010 from plants cultivated in Brazil by Weleda Brazil. The leaves were immediately frozen and sent by air mail to Weleda Arlesheim, Switzerland. The BPJ (03-23-2010) was produced within 3 days of arrival by mechanical pressing of leaves. BPJ was aliquoted into 1.5 ml samples and stored at -80[degrees]C. A voucher specimen (ZSS 29717) has been deposited at the Zurich Succulent Plant Collection.

B. pinnatum leaves

Leaves were harvested in August 2010 from plants cultivated in Schwabisch Gmund by Weleda Schwabisch Gmund, Germany. The leaves were kept frozen until processing. A voucher specimen (ZSS 29715) has been deposited at the Zurich Succulent Plant Collection.

Instruments and chemicals

For extraction and column chromatography (CC) technical grade solvents (Scharlau, Germany) were used after distillation. HPLC grade solvents were used for HPLC. HPLC grade water was obtained by an EASY-pure II (Barnstead) water purification system.

HPLC-PDA-MS analyses were performed using an Agilent 1100 Series HPLC system coupled to a Bruker Esquire 3000 plus mass spectrometer equipped with ESI or APCI source. MS data were recorded in positive ion mode. Separations were achieved on a SunFire[TM] [C.sub.18] column (3.5 [micro]m, 3 x 150 mm, Waters) equipped with a guard column (3 x 10 mm). The mobile phase consisted of 0.1% aqueous formic acid (A) and MeCN (B), and a linear gradient of 5-100% B in 30 min with a flow rate of 0.5 ml/min was applied.

Preparative fractionation of extract on Diaion HP-20 (250 [micro]m, Supelco) was achieved in a glass column (70 x 700 mm).

[sup.1]H NMR spectra were recorded at 23[degrees]C in DMSO-dg (Armar Chemicals, Switzerland) on a Bruker Avance III[TM] 500 MHz NMR spectrometer equipped with a 5-mm BBI probe. Data were processed with Topspin 3.0 software (Bruker). For quantification of L-malic acid, 1,3,5-trimethoxybenzene (>99, Sigma-Aldrich) was used as internal standard. Quantitative [sup.1]H NMR was carried out using the pulse program zg (Bruker) with a recycle delay of 20 s (>5xT1). The sample was prepared and measured in triplicate.

Reference substances used for compound identification were previously isolated from the MeOH extract of B. pinnatum and from the C[H.sub.2][Cl.sub.2]-soluble fraction of the MeOH extract of B. daigremontianum (Furer et al. 2013).


Frozen leaves of B. pinnatum were lyophilised, and pulverised in a mortar. The powdered leaves (1064.7 g) were extracted with MeOH (101). The suspension was stirred 2 h at RT and subsequently sonicated for additional 20 min. The extract was filtered, and evaporated under reduced pressure to yield the MeOH extract (262.4 g).

Preparation of fractions from the MeOH extract

We obtained three fractions from the MeOH extract. A portion (111.9 g) of the MeOH extract was partitioned between C[H.sub.2][Cl.sub.2] and [H.sub.2]O, and each phase was washed twice. The C[H.sub.2][Cl.sub.2]-soluble phase was evaporated to yield the bufadienolide-containing fraction (10.8 g). The aqueous phase was fractionated by CC with Diaion HP-20 resin. Elution with [H.sub.2]O gave 56.5 g of a highly polar fraction, and elution with MeOH afforded 12.0 g of a flavonoid fraction.

Identification of the constituents of the fractions

The flavonoid, bufadienolide, and polar fractions were analysed by HPLC-PDA-MS. ESI and APCI were used as ionization modes (detailed results are provided as supporting information). The samples were dissolved in DMSO at a concentration of 1 mg/ml, and aliquots of 20 [micro]l were injected. Peak identification was achieved by chromatographic comparison with reference compounds, and by analysis of PDA and MS data (Fiirer et al. 2013).

The ESIMS analysis of the flavonoid fraction is shown in Fig. 1. Ten peaks could be identified. The formulas with their names, one phenolic acid glucoside (1) and nine flavonoid glycosides (2-10), are shown in Fig. 2. The APCIMS analysis revealed four bufadienolides. The formulas of the bufadienolides (11-14) with their names are seen in Fig. 3. Constituents of the polar fraction could not be identified by ESIMS and APCIMS.

Porcine bladder muscle strips

For in vitro contractility experiments the Krebs solution (pH 7.4) containing (in mmol/l) 119.0 NaCl (AppliChem, Darmstadt, Germany), 15.0 NaHC03 (Sigma-Aldrich, Steinheim, Germany), 11.0 glucose (Sigma-Aldrich, Steinheim, Germany), 4.6 KCl (Zurich canton pharmacy, Zurich, Switzerland), 1.5 Ca[Cl.sub.2] (Dr. Bender and Dr. Hobein AG, Zurich, Switzerland), 1.2 Mg[Cl.sub.2] x 6[H.sub.2]O (AppliChem, Darmstadt, Germany), 1.2 Na[H.sub.2]P[O.sub.4] x [H.sub.2]O (Merck, Darmstadt, Germany) was used (Badawi et al. 2006).

Oxybutynin (see formula in Fig. 4), L-malic acid, D-malic acid and succinic acid were purchased from Sigma-Aldrich.

Porcine urinary bladders were obtained from the slaughterhouse in Zurich. They were from 5 months old female pigs weighing around 100 kg. Immediately after slaughtering, bladders were kept in Krebs solution. All experiments were done within 9 h after removal of bladders.

Bladders were emptied before cutting off the dome and trigone. The urothelium was carefully removed from the detrusor. After, the serosa was removed and longitudinal muscle strips (5x2x1 [mm.sup.3], 25-40 mg) were prepared. Eight muscle strips were deposited in Krebs solution (on ice) until use.

Organ bath measurements

The experiments were performed with a DMT 610M Multi Chamber Myograph connected to an ADlnstruments PowerLab 4/30 signal transducer and to a Grass S48 Electrical field stimulator. In the organ bath chamber (Krebs solution aired with 5% C02 and 95% [O.sub.2], 6 ml, 37[degrees]C) the strips were fixed between two jaws, which were connected either to a force transducer or a micropositioner.

The electrical field stimulation (EFS) was performed with squared twin pulses with duration of 2 ms and an interval of 3 min. The muscle strips were stimulated for 5 s with a constant voltage and frequency (40 V, 32 Hz) and the contraction force recorded.

After attaching the muscle strips, an equilibrium phase with 10 mN was applied. The stretching of the muscle strips was repeated after 5 and 10 min. Krebs solution was exchanged every 10 min. After 30 min of equilibration, the baseline contraction force of each strip was set to zero. Before application of test solutions, the muscle strips were stimulated 7 times each 3 min by EFS to determine the maximum contraction of each strip.

BPJ, fractions, oxybutynin, or control solution (Krebs solution or DMSO (0.5%)) were added in the corresponding concentration to the organ bath chamber. The following concentrations were tested: BPJ (2.5,5,10% (v/v)), flavonoid fraction (0.1, 0.33, 0.4, 0.5, 0.64, 0.8, 1 mg/ml in DMSO), bufadienolide fraction (0.1, 0.5, 2, 5,15, 30, 40 [micro]g/ml in DMSO), polar fraction (0.5, 1, 2, 3, 4, 5 mg/ml in Krebs solution), and oxybutynin ([10.sup.-8], [10.sup.-7], [10.sup.-6] M in Krebs solution). After an incubation time of 5 min, the muscle strips were electrically stimulated 24 or 28 times, in intervals of 3 min. This was followed by a washout phase, whereby, for 30 min the Krebs solution was renewed every 6 min. After that, the muscle strips were stimulated 9 times to check the muscle vitality.

A total of 35 porcine bladders were used to treat n = 7 muscle strips per concentration for all test samples.

Data analysis and statistics

The contractility (amplitude of the peak) of the muscle strips was recorded by LabChart 7 Pro (ADinstruments) and analysed with the peak analysis module. The mean of 6-7 muscle contractions before treatment was set as the maximum contraction (100%). The contractility after treatment was expressed as a percentage of the maximum contraction of the muscle strips. The data are presented either as mean or as mean [+ or -] standard error of the mean (SEM). For the statistical evaluation a two-way ANOVA was performed by GraphPad Prism 5 comparing the results of the test solution to the control. A significance level p < 0.05 was considered statistically significant.


To investigate the contribution of the different constituents of B. pinnatum on porcine detrusor contractility, three district fractions were prepared from the MeOH extract. A fraction rich in bufadienolides was obtained by liquid/liquid partition with dichloromethane, while the remaining aqueous phase was subjected to CC with HP-20 to afford a polyphenol-rich fraction consisting mainly of flavonoid glycosides, and a highly polar fraction containing sugars and L-malic acid.

HPLC-ESI-MS analysis of the flavonoid fraction revealed the presence of a phenolic acid derivative and nine flavonoid glycosides. No further compounds and, in particular, no bufadienolides were detected by HPLC-APCI-MS analysis.

Five bufadienolides were identified in the bufadienolide fraction by APC1-MS. In addition, a flavonoid glycoside, and lysophosphatidylcholine derivatives were detected by ESI-MS analysis of the bufadienolide fraction.

The compounds contained in the polar fraction could not be identified by HPLC-PDA-MS analysis. [sup.1]H NMR analysis of the polar fraction revealed the presence of large amounts of L-malic acid, and a mixture of different sugars. With the aid of quantitative NMR, the content of L-malic acid in this fraction was determined as 17.83 [+ or -] 0.17% (detailed results are provided as supporting information).

In this study, the effect of BPJ and the three fractions of B. pinnatum on the contractility of porcine detrusor strips in a tissue organ bath system were compared with oxybutynin.

At a test concentration of 10%, BPJ reduced the contractility of the detrusor to 58.6 [+ or -] 13.3% after 74 min, after a dose-independent initial increase in contractility during the first 40 min (Fig. 5). The flavonoid fraction, at 1 mg/ml, led to a maximum reduction of the contractility to 21.3 [+ or -] 5.2% after 77 min. The significant inhibitory effect was dose- and time-dependent, when compared to control strips (p < 0.0001). As in the case of BPJ, the muscle strips showed an increased contractility in the first 35 min of the stimulation period (Fig. 6a). The bufadienolide fraction showed no inhibitory effect on the contractility at concentrations of 0.1-40 [micro]g/ml. The muscle contractility became more intense with increasing bufadienolide concentration (Fig. 6b). The polar fraction reduced the contractility of the detrusor muscle strip in a reversible manner. A maximum reduction of the detrusor contractility to f 5.5 [+ or -] 5.5% was achieved after 23 min (p < 0.0001) (Fig. 7a). In experiments with L-malic acid (1.5 mg/ml) a similar time-effect curve as for the polar fraction (3 mg/ml) was obtained. It therefore seemed that L-malic acid significantly contributed to the inhibitory effect of the polar fraction (Fig. 7b). For a clarification of the mechanism involved, we performed pFl measurements over a period of 74 min. The results suggested that the inhibitory effect of the polar fraction was due to a pH decrease from 7.4 to 4.5. The effect was reversed when the pH was increased to 7.4 (with NaOH) during the experiment. Also, we found that D-malic acid (1.5 mg/ml) and succinic acid (1.3 mg/ml, pH 5.4 in the chamber) both inhibited the contractility of muscle strips. Based on these experiments, we concluded that the inhibitory effect of the polar fraction was caused by a lowering of the pH.

The reference compound oxybutynin reduced at a [10.sup.-6] M concentration the detrusor muscle contractility to 21.9 [+ or -] 4.7% after 50 min (p < 0.0001). A rapid inhibition of the detrusor contractility was observed as a consequence of the muscarinic receptor antagonism (Fig. 8).

Muscle vitality of the strips treated with the highest test concentrations was checked by further 9 stimulations after a washout period of 30 min. The muscle contractility at 20 min and 68 min, and at the end of the second stimulation period (recovery) is shown in Fig. 9. Muscle strips treated with BPJ recovered to 82.4% of contractility before treatment. The flavonoid fraction altered the muscle vitality irreversibly, as muscle strips only recovered to 32% of contractility. The muscle contractility after treatment with the bufadienolide fraction was still increased (121.3%) compared to the contractility before application. After treatment with the polar fraction, muscle strips recovered to 77.1% of initial contractility. In contrast, muscle strips treated with oxybutynin did not recover and showed a contractility of 19.5% at the end of the second stimulation period. The contractility of control strips treated with Krebs solution was only slightly reduced to 90.8% over the study period.

Discussion and conclusion

Many individuals are affected by OAB, a heterogeneous disease, and different, though not always satisfying treatment options are available. Treatment alternatives with phytopharmaceuticals such as Bryophyllum pinnatum are increasingly popular for patients with lower urinary tract disorders (Slavin et al. 2010). We here investigated the effect of BPJ, of flavonoid, bufadienolide, and polar fractions on the porcine detrusor contractility induced by EFS.

We observed an inhibitory effect of total BPJ on porcine detrusor contractility of 41.4%, and a significant dose- and time-dependent inhibition of the contractility by the flavonoid fraction of 78.7%. Hence, this fraction seems to play a major role in the inhibition of detrusor contractility by BPJ.

Normal bladder function includes the storage phase and the voiding/micturition phase. It is regulated through a complex efferent and afferent activity of parasympathetic, sympathetic, and somatic peripheral nervous systems (Abrams and Andersson 2007). Recent studies have indicated locations where BPJ and flavonoids might alter bladder contractility. A previous study with BPJ (2%) showed an inhibition of the oxytocin-induced increase of [[[Ca.sup.2+].sub.i] in human myometrial cells, which could be explained through a blockage of [Ca.sup.2+] release from intracellular stores (Simoes-Wust et al. 2010). This study further showed that BPJ could delay voltage-dependent [Ca.sup.2+]-influx through L-type [Ca.sup.2+] channels. An inhibitory effect on porcine detrusor contractility through an inhibition of [Ca.sup.2+] release from intracellular stores, and the involvement of L-type [Ca.sup.2+] channels was described for the flavonoid galangin. Involvement of adrenergic and vanilloid receptors were ruled out (Dambros et al. 2005). Likewise, flavoxate (a synthetic flavone derivative) inhibits L-type [Ca.sup.2+] channels in human detrusor (Tomoda et al. 2005).

Hence, modulation of intracellular calcium concentration seems to be a mechanism by which the flavonoid fraction exerts its activity on the detrusor muscle. An [[alpha].sub.1]-adrenoceptor antagonistic effect, as described for some flavonoids, could be an alternative mechanisms which would need further investigations with B. pinnatum (Li et al. 2011).

All muscle strips treated with BPJ and flavonoid fraction showed an initial increase of contraction for about 35 min prior to relaxation phase. This can be explained by a bimodal effect, which has been reported for some flavonoids. For example, myricetin showed a potentiation of muscle contraction in vascular tissue when administered at low concentrations, and a stimulatory activity on L-type [Ca.sup.2+] channels. With higher concentrations, however, myricetin had a relaxant effect on the smooth muscle (Fusi et al. 2003).

As expected, the bufadienolide fraction showed no inhibitory effect on porcine detrusor contractility. While bufadienolides inhibit the [Na.sup.+]-[K.sup.+] -ATPase in the kidney they are not known to affect the bladder wall directly (Puschett et al., 2010).

The polar fraction showed a reversible inhibitory effect on porcine detrusor contractility through a non-physiologic pH-drop in the organ bath, without any pharmacological influence on the muscle strips.

Our research indicates that the flavonoid fraction of B. pinnatum appears to be the pharmacologically relevant portion causing bladder muscle relaxation. While oxybutynin demonstrated a fast onset of relaxation to 21.9% after 50 min, the flavonoid fraction demonstrated an initial increase followed by a decrease in contractility to 21.3% after 77 min. At a concentration of 1 mg/ml the flavonoid fraction showed a reduction in contractility comparable to oxybutynin at a concentration of 10 5 M. Further investigations are needed for a better understanding of the underlying molecular pathways.


Financial support by the Swiss National Science Foundation (Project 31600-113109) (to M.H.), the University Hospital Zurich, Switzerland (to U.v.M.), and Weleda AG, Arlesheim, Switzerland, is gratefully acknowledged.

Conflict of interest

M.M. and M.S. are employees of Weleda AG.


APCI                  atmospheric-pressure chemical ionization
BPJ                   Bryophyllum pinnatum leaf press juice
[[Ca.sup.2+].sub.i]   intracellular free calcium concentration
CC                    column chromatography
EFS                   electrical field stimulation
ESI                   electrospray ionization
HPLC                  high-performance liquid chromatography
OAB                   overactive bladder
PDA                   photodiode array


Article history:

Received 28 May 2014

Revised 12 September 2014

Accepted 15 November 2014


Thanks are due to Weleda AG for providing the plant material, and to the slaughterhouse of Zurich for providing the porcine bladders.

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi: 10.1016/j.phymed.2014.11.009.


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K. Furer (a,b), (1), D. Eberli (c), (1), C. Betschart (d), R. Brenneisen (e), M. De Mieri (b), M. Hamburger (b), M. Mennet-von Eiff (f), O. Potterat (b), M. Schnelle (f), A.P. Simoes-Wust (g), U. von Mandach (a), *

(a) Department of Obstetrics, University Hospital Zurich, CH-8091 Zurich, Switzerland

(b) Division of Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, CH-4056 Basel, Switzerland

(c) Urology Clinic, University Hospital Zurich, CH-8091 Zurich, Switzerland

(d) Department of Gynaecology, University Hospital Zurich, CH-8091 Zurich, Switzerland

(e) Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland

(f) Weleda AG, CH-4144 Arlesheim, Switzerland

(g) Research Department, Paracelsus Hospital Richterswil, CH-8805 Richterswil, Switzerland

* Corresponding author at: Department of Obstetrics, University Hospital Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland. Tel.? +41 44 255 51 36; fax: +41 44 255 44 30.

E-mail address: (U. von Mandach).

(1) Both authors contributed equally to this work.
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Author:Furer, K.; Eberli, D.; Betschart, C.; Brenneisen, R.; De Mieri, M.; Hamburger, M.; Eiff, M. Mennet-v
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Geographic Code:4EUGE
Date:Jan 15, 2015
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