Review Article | Open Access
Natural Antispasmodics: Source, Stereochemical Configuration, and Biological Activity
Natural products with antispasmodic activity have been used in traditional medicine to alleviate different illnesses since the remote past. We searched the literature and compiled the antispasmodic activity of 248 natural compounds isolated from terrestrial plants. In this review, we summarized all the natural products reported with antispasmodic activity until the end of 2017. We also provided chemical information about their extraction as well as the model used to test their activities. Results showed that members of the Lamiaceae and Asteraceae families had the highest number of isolated compounds with antispasmodic activity. Moreover, monoterpenoids, flavonoids, triterpenes, and alkaloids were the chemical groups with the highest number of antispasmodic compounds. Lastly, a structural comparison of natural versus synthetic compounds was discussed.
Antispasmodic compounds are currently used to reduce anxiety, emotional and musculoskeletal tension, and irritability. Although most of the available antispasmodic compounds are synthetic or semisynthetic, traditional uses of this group of compounds are still popular.
We collected information about natural compounds with antispasmodic activity isolated from terrestrial plants. We searched the databases of Google Scholar, PubMed, and SciFinder and compiled the information about 248 compounds published until December 2017. This review focuses on the antispasmodic activity of isolated compounds and activities from extracts without further purification are not discussed.
2. The Neurons
Nerve cells or neurons are responsible for receiving, conducting, and transmitting signals. A neuron consists of a nucleated body, a long thin extension called an axon, and several dendrites or prolongations extended from the cell body. Axons conduct signals from the nucleated body towards distant targets, while dendrites provide an enlarged surface area to receive signals from the axons of other neurons.
Signal transmission through axons is driven by a change in the electrical potential across the plasma membrane of neurons. This plasma membrane contains voltage-gated cation channels, which are responsible for generation of action potentials. An action potential is triggered by a depolarization of the plasma membrane or a shift to a less negative value.
In nerve and skeletal muscle cells, a stimulus can cause sufficient depolarization to open voltage-gated Na+ channels allowing the entrance of Na+ into the cell. This influx of Na+ depolarizes the membrane further causing the opening of more Na+ channels. To avoid a permanent influx, Na+ channels are able to reclose rapidly even when the membrane is still depolarized. This function is based on the presence of voltage-gated K+ channels, which are responsible for K+ efflux equilibrating the membrane potential even before the total inactivation of Na+ channels. In some cases, the action potential in some muscles depends on voltage-gated Ca2+ channels.
2.1. Transmission of Signals
The transmission of signals occurs mainly between neurons or from neurons to skeletal muscles, which are the final acceptors of electrical signals, causing a muscular contraction.
2.1.1. Signal Transmission between Neurons
Neuronal signals are transmitted between neurons at specialized sites of contact known as synapses. Neurons are separated by a synaptic cleft where a release of a neurotransmitter occurs. This neurotransmitter is stored in vesicles and is released by exocytosis. Upon triggering, the neurotransmitter is released into the cleft provoking an electrical change in the postsynaptic cell by binding to the transmitter-gated ion channels. To avoid a continuous electrical change and to ensure both spatial and temporal precision of signal transmission, the neurotransmitter is rapidly removed from the cleft either by specific enzymes in the synaptic cleft or by reuptake mediated by neurotransmitter carrier proteins .
Neurotransmitters can also open cation channels causing an influx of Na+ and then called excitatory neurotransmitters (e.g., acetylcholine, glutamate, and serotonin) or produce an opening of Cl- channels and then inhibiting the signal transmission by maintaining the postsynaptic membrane polarization [e.g., γ-aminobutyric acid (GABA) and glycine].
2.1.2. Neuromuscular Signal Transmission
The transmission of electrical signals to muscles involves five sequential and orchestrated steps: (i) nerve electric signal reaches the nerve terminal, (ii) it depolarizes the plasma membrane of the terminal, (iii) voltage-gated Ca2+ channels opens causing an increase in Ca2+ concentration in the neuron cytosol, and (iv) release of acetylcholine into the synaptic cleft is triggered. Acetylcholine binds to acetylcholine receptors in the muscle plasma membrane opening Na+ channels and provoking a membrane depolarization. This depolarization enhances the opening of more Na+ channels causing a self-propagating depolarization. The generalized depolarization of the muscle plasma membrane activates Ca2+ channels in specialized regions on the membrane causing Ca2+ release from the sarcoplasmic reticulum (Ca2+ storage) into the cytosol.
As a consequence of an increase in the Ca2+ concentration, myofibrils in the muscle cell contract. The increase of Ca2+ in the cytosol is transient because Ca2+ is rapidly pumped back into the sarcoplasmic reticulum causing a relaxation of the myofibrils. This process is very fast and Ca2+ concentration at resting levels is restored within 30 milliseconds .
The autonomic nerve system controls and monitors the internal environment of the body. The input of its activity is provided by neurons that are associated with specific sensory receptors located in the blood vessels, muscles, and visceral organs (Table 1). According to the neurotransmitter secreted, these neurons are classified as adrenergic or cholinergic. The adrenergic neurons secrete the neurotransmitter noradrenalin termed also norepinephrine. Adrenergic receptors include the types α and β, which are further categorized as α1, α2, β1, β2, and β3. On the other hand, cholinergic neurons secrete acetylcholine, which induces a postsynaptic event. There are two types of cholinergic receptors, the nicotinic receptor (abundant at the neuromuscular junction) and the muscarinic receptor (abundant on smooth and cardiac muscles and glands).
There are several agonists (neurotransmitters, hormones, and others) able to bind to specific receptors and activate the contraction of smooth muscle. Upon binding the agonist to the receptor, the mechanism of contraction is based on an increase of phospholipase C. This enzyme hydrolyzes phosphatidylinositol 4,5-bisphosphate located on the membrane, producing two powerful secondary messengers termed diacylglycerol (DG) and inositol 1,4,5 triphosphate (IP3). IP3 binds to specific receptors in the sarcoplasmic reticulum, causing release of Ca2+ within the muscle. DG together with Ca2+ activates the protein kinase C (PKC), which phosphorylates specific proteins. In most smooth muscles, the contraction process commences when PKC phosphorylates Ca2+ channels or other proteins that regulate the cyclic process. For instance, Ca2+ binds to calmodulin (a multifunctional intermediate calcium-binding messenger protein), triggering the activation of the myosin light chain (MLC) kinase, which phosphorylates the light chain of myosin and together with actin carries out the process of initiating the shortening of the smooth muscle cell . However, the elevation of the intracellular concentration of Ca2+ is transient, and the contractile response is maintained by a mechanism sensitized by Ca2+ modulated by the inhibition of myosin phosphatase activity by Rho kinase. This mechanism sensitized to Ca2+ is initiated at the same time that phospholipase C is activated and involves the activation of the small RhoA protein bound to guanosine triphosphate (GTP). Above activation, RhoA increases the activity of Rho kinase, leading to the inhibition of myosin phosphatase. This promotes the contractile state, since the myosin light chain cannot be dephosphorylated .
Relaxation of smooth muscle occurs as a result of either removing the contractile stimuli or by the direct action of a substance that stimulates the inhibition of the contractile mechanism. In any circumstance, the relaxation process requires a decrease in the intracellular Ca2+ concentration and an increase in the activity of the MLC phosphatase. The sarcoplasmic reticulum and plasma membrane remove Ca2+ from the cytosol. Na+/Ca2+ channels are located on the plasma membrane and help to reduce the intracellular concentration of Ca2+. During relaxation, other contributors that restrict the Ca2+ entry into the cell are the voltage-operated channels and Ca2+ receptors in the plasma membrane, which remain closed .
4. Spasmodic Compounds
The historical antecedents date from the year 1504 when South American natives inhabiting the basins of the high Amazon and the Orinoco prepared a mixture of alkaloids termed curare. This substance was placed in the tips of arrows in order to hunt (prey paralyzing) and fight in wars. Curare produces muscle weakness, paralysis, respiratory failure, and death . In 1800, Alexander von Humboldt, identified that curare was made from the extracts of the species Chondrodendron tomentosum and Strychnos toxifera.
In 1935, the French physiologist Claude Bernard managed to isolate the alkaloid d-tubocurarine from the curare ; and one year later, it was elucidated that this compound had the ability to inhibit acetylcholine, blocking the transmission of nerve impulses to the muscles . Lastly, new benzylisoquinoline alkaloids were isolated from curare by Galeffi et al. in 1977 [151, 152].
In 1822, the pharmacist Rudolph Brandes obtained an impure alkaloid from Atropa belladonna (Solanaceae), which after purification was named atropine. Interestingly, atropine was not produced as a natural compound from the plant and it was a derivative generated from the alkaloid hyoscyamine during the process of purification . It is important to note that atropine has been naturally found in small quantities in other members of the Solanaceae family such as Datura stramonium, Duboisia myoporoides, and Scopolia japonica [154–156].
The use of the plant Papaver somniferum (opium poppy) (Papaveraceae) dates back to about 4000 BC. At present the plant is only used to extract a base material for the manufacture of other alkaloids, such as noscapine and codeine, both discovered by the French pharmacist Pierre-Jean Robiquet in 1831 and 1832, respectively . In 1848, papaverine was another substance extracted from the same plant by the German chemist Georg Merck , which is rarely used today because of the high doses needed (approximately 6 to 12 mg). However, it is still used as a control in experimental models with the purpose of studying antispasmodic activity of plant extracts.
In the century, extracts and powders derived from A. belladonna were widely used as antispasmodics, but from the 1950s these preparations were displaced by synthetic and semisynthetic anticholinergic compounds in order to obtain a better response , such as the case of methocarbamol and guaifenesin. On the other hand, a series of compounds such as dantrolene, glutethimide, methaqualone, chlormezanone, metiprilone, and ethchlorvynol were introduced to replace the meprobamate, which had to be withdrawn from the market in 1960 due to problems resulting from use such as abstinence, addictions, and overdoses.
In 1962, the Swiss chemist Heinrich Keberle synthesized baclofen, which can be obtained by reacting glutarimide with an alkaline solution . Glutarimide can also be found in plants such as Croton cuneatus and C. membranaceus (Euphorbiaceae) [161, 162].
The arrival of the quaternary compounds of nitrogen reinforce their peripheral anticholinergic activity offering also the advantages of being poorly absorbed in the gastrointestinal tract, producing a more powerful and longer lasting sedative effect unlike atropine . For example, ipratropium bromide was developed by the German company Boehringer Ingelheim in 1976 and used to treat asthma. This compound was obtained by reacting atropine with isopropyl bromide . Another quaternary compound was the n-butylhyoscine bromide, which is possible to obtain by the organic synthesis of scopolamine and the cimetropium bromide found in the A. belladonna . Although at present the preparations of plant mixtures are no longer used for therapeutic purposes, these compounds formed a part of and served as the basis for modern pharmacology for their applicability as antispasmodics and anesthetics.
Spasms are involuntary contractions of the muscles, which are normally accompanied by pain and interfere with the free and effective muscular voluntary activity. Muscle spasm can originate from multiple medical conditions and is often associated with spinal injury, multiple sclerosis, and stroke.
Spasticity and rigidity are caused by a disinhibition of spinal motor mechanisms. There are several scenarios where a muscle can produce a spasm: (i) unstable depolarization of motor axons; (ii) muscular contractions persist even if the innervation of muscle is normal and despite attempts of relaxation (myotonia); (iii) after one or a series of contractions, the muscle can decontract slowly, as occurring in hypothyroidism; and (iv) muscles lack the energy to relax.
4.1. Distribution of Spasmodic Compound in Nature
Spasmodic compounds are widely distributed in nature (Table 2). Frequently, these compounds are found in animals that paralyze their preys or used for defense. Some examples include the venom of the black widow and tarantula spiders [11, 165] and the venom of snakes . Plants also produce spasmodic metabolites, such as strychnine, an alkaloid obtained from the tree Strychnos nux-vomica (Loganiaceae). Furthermore, microorganisms synthesize spasmodic compounds such as the neurotoxins tetanospasmin and botulinum toxin from the Gram-positive bacteria Clostridium tetani and C. botulinum, respectively. These toxins produce a toxic disorder, which is characterized by persistent spasms of skeletal muscles on spinal neurons similar to strychnine.
4.2. Mechanisms of Antispasmodic Activity of Natural Products
Antispasmodic compounds exert their activity in different ways, such as antispasmodic activity through inhibition of the response to the neurotransmitters 5-hydroxytryptamine (5-HT) or serotonin and acetylcholine. However, other authors attribute the antispasmodic effect to (i) capsaicin-sensitive neurons, (ii) the participation of vanilloid receptors , (iii) the activation of K+ ATP channels, (iv) the blockade of Na+ channels and muscarinic receptors, (v) the reduction of extracellular Ca2+, or (vi) the blockade of Ca2+ channels [22, 168, 169]. The above is merely a reflection of the ambiguity of the studies showing the mechanisms of action of the antispasmodic compounds . For example, the hydroalcoholic extract of Marrubium vulgare showed antispasmodic effect, having the ability to inhibit the neurotransmitters acetylcholine, bradykinin, prostaglandin E2, histamine, and oxytocin , whereas a dual effect of antidiarrheal and laxative activities was reported in Fumaria parviflora .
5. Methods Used to Evaluate Antispasmodic Compounds
5.1. Gastrointestinal Model
The small intestine is characterized by its large surface area as a result of its circular folds, villi, and microvilli. It is the longest part of the GI system (approximately 5 meters) and comprises about 5% of its initial length, which corresponds to the duodenum (characterized by the absence of the mesentery) and then the jejunum (around 40% of the intestinal length), ending with the ileum. It is the organ of absorption of nutrients and digestion in organisms. These functions are carried out mainly in the duodenum and jejunum.
The main types of bowel movement are the segmentation and peristaltism. The segmentation is most frequent in the small intestine and consists of contractions of the circular muscle layer in very close areas. Contractions last for 11-12 and 8-9 contractions per min in the duodenum and ileum, respectively. When this segmentation is rhythmic, the contractions are alternated with relaxation. This type of movement results in a mixed effect of the chyme (acidic fluid that passes from the stomach to the small intestine) with the digestive secretions, allowing an optimal contact with the intestinal mucosa. In the case of peristalsis, contractions of successive sections of the circular smooth muscle cause the movement of the intestinal contents in anterograde form. The short peristaltic movement also takes place in the small intestine, but less frequently than the segmentation movements. Peristaltic waves rarely cross more than 10 cm of intestine and, due to the low frequency of propulsion of the chyme, it is in this zone where digestion and absorption are preferably carried out. Peristalsis is regulated mainly by the nervous action of the myenteric plexus (major nerve supply to the gastrointestinal tract that controls GI tract motility) in the intestinal wall.
The diversity of experimental models used for the testing of antispasmodic compounds is large. These models mainly use isolated organs or live animals. Once the organ is extracted from the animal, the intestinal motility is assessed with the administration of a substance. The use of extracted organs can be sustained for hours when placed in a physiological solution, such as Ringer, Jalon, Tyrode, and Krebs .
The most used organs to perform the studies are guinea pig ileum, duodenum, heart, trachea, and jejunum. The same organs can be also extracted from rabbit, mouse, rat, and hamster (Table 3). The preparation of ileum is preferred because it evaluates the spasmolytic activity. However, although the jejunum contracts spontaneously, it allows evaluating the spasmolytic activity directly and without the use of an agonist .
IC = isolated compound, E = extract, EO = essential oil, ACh = acetylcholine, O = oxytocin, PMA = β-Phenylethyl amsine, PGF = Prostaglandin F2α, H = histamine, S = serotonin.
Some advantages of performing ex vivo experiments are as follows: (i) different substances can be evaluated in fresh tissues without absorption factors, metabolic excretion or interference due to nerve reflexes; (ii) it is possible to quantify the effect produced by a precisely determined drug; and (iii) it is easier to obtain dose-effect curves, such as the smooth muscle where the contraction obtained under the influence of a spasm or in tissue homogenates is measured by determination of the enzyme activities [172, 174].
5.2. Guinea Pig Ileum and Rat Stomach
The ileum is removed and cut in strips of approximately 2 cm long and then placed in a bath filled with an isotonic solution as mentioned earlier. Electrophysiological studies are performed by graphically recording the contractions with the aid of a transducer, which is calibrated 30 min before the treatment begins. A range of 0.01 to 0.03 μM is generally used to determine dose response curves of the antispasmodic substance .
In rats, the stomach is removed and the corpus and fundus are cut in strips of approximately 5 mm x 15 mm and placed on a prewarmed warm solution as mentioned before.
5.3. Compounds Used to Elicit a Spasmodic Activity
The main compounds used are acetylcholine, atropine, BaCl2, carbachol, histamine, KCl, and serotonin.
Acetylcholine is a postganglionic neurotransmitter in the parasympathetic neurons that innervate the intestine. The response to acetylcholine is regulated by activation of the two types of muscarinic receptors: M2 and M3 . The activation of these receptors causes contractions by increasing the intracellular concentration of Ca2+ via IP3 . Atropine is a competitive reversible antagonist of muscarinic acetylcholine receptors M1, M2, M3, M4, and M5.
Different substances are used to produce contractions. For example, BaCl2 induces contractions by mobilizing membrane-bound Ca2+ , carbachol is a cholinomimetic drug (cholinergic agonist) that binds and activates acetylcholine receptors , histamine acts by either accelerating the release of acetylcholine or interacting supra-additively with the acetylcholine at the smooth muscle , whereas KCl increases the voltage-operated Ca2+ channel activity by increasing intracellular free Ca2+ in smooth muscle . Serotonin is also an important neurotransmitter mainly stored in the digestive tract, affecting the secretory and motor activities. At high concentrations, it acts as a vasoconstrictor by contracting endothelial smooth muscle directly or by potentiating the effects of other vasoconstrictors [181, 182].
6. Antispasmodic Activity of Natural Compounds
Compounds isolated from terrestrial plants have shown the ability to function as antispasmodic compounds. The chemical group with the highest number of members of antispasmodic compounds is the monoterpenoid group (41 compounds) followed by flavonoids (35 compounds), alkaloids (with 33 compounds), and triterpenes with 31 (Figure 1). Although we summarize in Table 3 248 compounds, in most of the cases the mechanism behind their activity has not been elucidated.
Studies related to the mutagenicity of antispasmodics are very scarce. This topic has been underestimated when testing the bioactivities of ethnomedicinal plants. Probably the most useful method to determine the mutagenicity of natural products or plant extracts is the Ames method . This test is based on the rate of mutations detected in genetically modified strains of Salmonella typhimurium. Moreover, this test has also been developed to detect mutagenicity of metabolized compounds in the liver. In this situation, a mixture of liver enzymes (S9 microsomal fraction) is used to mimic the metabolites that will be produced in the liver .
Few studies have been performed to determine the mutagenicity of natural products with antispasmodic activity. For example, the flavonoids quercetin and luteolin were tested using the Ames method and the appearance of point mutations in four of the tested bacterial strains was shown . In another study, the extracts of the plants Brickellia veronicaefolia, Gnaphalium sp., Poliomintha longiflora, and Valeriana procera were studied. Compounds isolated from these plants are listed as antispasmodic compounds (Table 3). Results of the mutagenicity test indicated that Gnaphalium sp., Poliomintha longiflora (used in the Mexican cuisine and as a traditional medicine), and Valeriana procera induced mutagenesis in the tested bacterial strain .
8. Chemical Similarities between Natural and Synthetic Antispasmodic Compounds
To determine whether or not there is an analogy between synthetic (Table 4) and natural antispasmodic compounds, the structures of both groups were compared. Results showed that no similarities were found except for alkaloids, amines, and amino acids.
One of the main differences is that commercial alkaloids are methylated in their nitrogen to make them positive, increasing their solubilities because of salt formation. In contrast, natural products have no positive nitrogen, rendering the molecule neutral and pH dependent. Thus, the compound may or may not be protonated, resulting in a change in its solubility and consequently a change on the targeting tissues.
The comparison can perhaps be focused on the distribution of charges rather than by functional groups or families of compounds, emphasizing the electron distribution. For example, a physical characterization such as the heat of formation, the surface electrostatic potential, the molecular weight, the surface tension, the refractive index, the lipophilicity, and others has been used to characterize the structure-activity relationship of alkaloids extracted from the Amaryllidaceae family . These alkaloids were selected because of their ability to inhibit the effect of the acetylcholinesterase enzyme.
Of special interest is the natural compound salvinorin A isolated from the Mexican hallucinogenic Salvia divinorum (Lamiaceae) used in the traditional medicine as an antidiarrheal. It has been reported that this compound inhibited the intestinal motility through the activation of other receptors such as κ-opioid receptors (KORs). Upon inflammation of the gut, the cannabinoid C, B1, and KOR receptors are upregulated. It appears that salvinorin A interacts in the cross-talk between these receptors with a reduction of the inflammation as demonstrated in murine and guinea pig models [188, 189].
Analysis of the similarities between synthetic and natural antispasmodic structures is depicted in Table 5.
A large number of natural products with antispasmodic activities have been reported. Although the use of plants in traditional medicine is still relevant, it is necessary to perform new studies to elucidate the mechanism of action of antispasmodics. Moreover, more information about cytotoxicity and mutagenesis should be explored to ensure that these compounds are safe for consumption. The findings of this study corroborated the need for safety studies on plants extensively used for primary health care in countries such as Mexico. Such studies must be carried out before continuing with the widespread use of some species, which may provoke long-term and irreversible damage.
Conflicts of Interest
The authors declare no conflicts of interest.
The authors thank Marilyn Robertson for helpful discussion.
This file contains the structures of the compounds described in the main text. (Supplementary Materials)
- D. M. Warburton, “Behavioral effects of central and peripheral changes in acetylcholine systems,” Journal of Comparative and Physiological Psychology, vol. 68, no. 1, pp. 56–64, 1969.
- F. Anthony Lai, H. P. Erickson, E. Rousseau, Q.-Y. Liu, and G. Meissner, “Purification and reconstitution of the calcium release channel from skeletal muscle,” Nature, vol. 331, no. 6154, pp. 315–319, 1988.
- A. Apostolidis, A. Haferkamp, and K. R. Aoki, “Understanding the Role of Botulinum Toxin A in the Treatment of the Overactive Bladder-More than Just Muscle Relaxation,” European Urology, Supplements, vol. 5, no. 11, pp. 670–678, 2006.
- O. Rossetto, M. Scorzeto, A. Megighian, and C. Montecucco, “Tetanus neurotoxin,” Toxicon, vol. 66, pp. 59–63, 2013.
- A. Marino, V. Valveri, C. Muià et al., “Cytotoxicity of the nematocyst venom from the sea anemone Aiptasia mutabilis,” Comparative Biochemistry and Physiology - C Toxicology and Pharmacology, vol. 139, no. 4, pp. 295–301, 2004.
- R. J. A. Hughes, J. A. Angus, K. D. Winkel, and C. E. Wright, “A pharmacological investigation of the venom extract of the Australian box jellyfish, Chironex fleckeri, in cardiac and vascular tissues,” Toxicology Letters, vol. 209, no. 1, pp. 11–20, 2012.
- T. D. Nguyen-Huu, C. Mattei, P. J. Wen et al., “Ciguatoxin-induced catecholamine secretion in bovine chromaffin cells: Mechanism of action and reversible inhibition by brevenal,” Toxicon, vol. 56, no. 5, pp. 792–796, 2010.
- M. E. P. Junqueira, L. Z. Grund, N. M. Orii et al., “Analysis of the inflammatory reaction induced by the catfish (Cathorops spixii) venoms,” Toxicon, vol. 49, no. 7, pp. 909–919, 2007.
- J. Sawynok, “GABAergic mechanisms of analgesia: an update,” Pharmacology Biochemistry & Behavior, vol. 26, no. 2, pp. 463–474, 1987.
- D. Quan and A.-M. Ruha, “Priapism associated with Latrodectus mactans envenomation,” The American Journal of Emergency Medicine, vol. 27, no. 6, pp. 759–e2, 2009.
- N. Ahmed, M. Pinkham, and D. A. Warrell, “Symptom in search of a toxin: Muscle spasms following bites by Old World tarantula spiders (Lampropelma nigerrimum, Pterinochilus murinus, Poecilotheria regalis) with review,” QJM: An International Journal of Medicine, vol. 102, no. 12, pp. 851–857, 2009.
- S. Liang, “An overview of peptide toxins from the venom of the Chinese bird spider Selenocosmia huwena Wang [=Ornithoctonus huwena (Wang)],” Toxicon, vol. 43, no. 5, pp. 575–585, 2004.
- K. J. Swartz, “Tarantula toxins interacting with voltage sensors in potassium channels,” Toxicon, vol. 49, no. 2, pp. 213–230, 2007.
- B. A. Cromer and P. McIntyre, “Painful toxins acting at TRPV1,” Toxicon, vol. 51, no. 2, pp. 163–173, 2008.
- Z.-F. Chai, M.-M. Zhu, Z.-T. Bai et al., “Chinese-scorpion (Buthus martensi Karsch) toxin BmK αIV, a novel modulator of sodium channels: From genomic organization to functional analysis,” Biochemical Journal, vol. 399, no. 3, pp. 445–453, 2006.
- C. Bon, “Synergism of the two subunits of crotoxin,” Toxicon, vol. 20, no. 1, pp. 105–109, 1982.
- C. C. Câmara, N. R. F. Nascimento, C. L. Macêdo-Filho, F. B. S. Almeida, and M. C. Fonteles, “Antispasmodic Effect of the Essential Oil of Plectranthus barbatus and some Major Constituents on the Guinea-Pig Ileum,” Planta Medica, vol. 69, no. 12, pp. 1080–1085, 2003.
- H. Ponce-Monter, E. Fernández-Martínez, M. I. Ortiz et al., “Spasmolytic and anti-inflammatory effects of Aloysia triphylla and citral, in vitro and in vivo studies,” Journal of Smooth Muscle Research, vol. 46, no. 6, pp. 309–319, 2010.
- R. C. Devi, S. M. Sim, and R. Ismail, “Spasmolytic effect of citral and extracts of Cymbopogon citratus on isolated rabbit ileum,” Journal of Smooth Muscle Research, vol. 47, no. 5, pp. 143–156, 2011.
- H. Sadraei, A. Ghannadi, and K. Malekshahi, “Relaxant effect of essential oil of Melissa officinalis and citral on rat ileum contractions,” Fitoterapia, vol. 74, no. 5, pp. 445–452, 2003.
- A. Karim, M. Berrabah, H. Mekhfi et al., “Effect of essential oil of Anthemis mauritiana Maire & Sennen flowers on intestinal smooth muscle contractility,” Journal of Smooth Muscle Research, vol. 46, no. 1, pp. 65–75, 2010.
- A. H. Gilani, A. J. Shah, A. Zubair et al., “Chemical composition and mechanisms underlying the spasmolytic and bronchodilatory properties of the essential oil of Nepeta cataria L.,” Journal of Ethnopharmacology, vol. 121, no. 3, pp. 405–411, 2009.
- H. Sadraei, G. Asghari, and S. Emami, “Inhibitory effect of Rosa damascena Mill flower essential oil, geraniol and citronellol on rat ileum contraction,” Research in Pharmaceutical Sciences, vol. 8, no. 1, pp. 17–23, 2013.
- A. Riyazi, A. Hensel, K. Bauer, N. Geißler, S. Schaaf, and E. J. Verspohl, “The effect of the volatile oil from ginger rhizomes (Zingiber officinale), its fractions and isolated compounds on the 5-HT3 receptor complex and the serotoninergic system of the rat ileum,” Planta Medica, vol. 73, no. 4, pp. 355–362, 2007.
- L. Pinho-Da-Silva, P. V. Mendes-Maia, T. M. Do Nascimento Garcia et al., “Croton sonderianus essential oil samples distinctly affect rat airway smooth muscle,” Phytomedicine, vol. 17, no. 10, pp. 721–725, 2010.
- O. Prakash, V. K. Kasana, A. K. Pant, A. Zafar, S. K. Hore, and C. S. Mathela, “Phytochemical composition of essential oil from seeds of Zingiber Roseum Rosc. and its antispasmodic activity in rat duodenum,” Journal of Ethnopharmacology, vol. 106, no. 3, pp. 344–347, 2006.
- D. P. De Sousa, G. A. S. Júnior, L. N. Andrade et al., “Structure and spasmolytic activity relationships of monoterpene analogues found in many aromatic plants,” Section C Journal of Biosciences, vol. 63, no. 11-12, pp. 808–812, 2008.
- H. Sadraei, G. Asghari, and F. Kasiri, “Comparison of antispasmodic effects of Dracocephalum kotschyi essential oil, limonene and α-terpineol,” Research in Pharmaceutical Sciences, vol. 10, no. 2, pp. 109–116, 2015.
- A. Astudillo, E. Hong, R. Bye, and A. Navarrete, “Antispasmodic activity of extracts and compounds of Acalypha phleoides Cav.,” Phytotherapy Research, vol. 18, no. 2, pp. 102–106, 2004.
- N. Wienkötter, D. Höpner, U. Schütte et al., “The effect of nigellone and thymoquinone on inhibiting trachea contraction and mucociliary clearance,” Planta Medica, vol. 74, no. 2, pp. 105–108, 2008.
- S. V. Brankovic, D. V. Kitic, M. M. Radenkovic, S. M. Veljkovic, and T. D. Golubovic, “Calcium blocking activity as a mechanism of the spasmolytic effect of the essential oil of Calamintha glandulosa Silic on the isolated rat ileum,” General Physiology and Biophysics, vol. 28, pp. 174–178, 2009.
- K. Heimes, F. Hauk, and E. J. Verspohl, “Mode of action of peppermint oil and (-)-menthol with respect to 5-HT3 receptor subtypes: Binding studies, cation uptake by receptor channels and contraction of isolated rat ileum,” Phytotherapy Research, vol. 25, no. 5, pp. 702–708, 2011.
- H. Ponce-Monter, M. G. Campos, S. Pérez et al., “Chemical composition and antispasmodic effect of Casimiroa pringlei essential oil on rat uterus,” Fitoterapia, vol. 79, no. 6, pp. 446–450, 2008.
- S. V. F. Madeira, M. Rabelo, P. M. G. Soares et al., “Temporal variation of chemical composition and relaxant action of the essential oil of Ocimum gratissimum L. (Labiatae) on guinea-pig ileum,” Phytomedicine, vol. 12, no. 6-7, pp. 506–509, 2005.
- I. Rivero-Cruz, G. Duarte, A. Navarrete, R. Bye, E. Linares, and R. Mata, “Chemical composition and antimicrobial and spasmolytic properties of poliomintha longiflora and lippia graveolens essential oils,” Journal of Food Science, vol. 76, no. 2, pp. C309–C317, 2011.
- S. I. H. Taqvi, A. J. Shah, and A. H. Gilani, “Insight into the possible mechanism of antidiarrheal and antispasmodic activities of piperine,” Pharmaceutical Biology, vol. 47, no. 8, pp. 660–664, 2009.
- F. Begrow, J. Engelbertz, B. Feistel, R. Lehnfeld, K. Bauer, and E. J. Verspohl, “Impact of Thymol in thyme extracts on their antispasmodic action and ciliary clearance,” Planta Medica, vol. 76, no. 4, pp. 311–318, 2010.
- T. Görnemann, R. Nayal, H. H. Pertz, and M. F. Melzig, “Antispasmodic activity of essential oil from Lippia dulcis Trev.,” Journal of Ethnopharmacology, vol. 117, no. 1, pp. 166–169, 2008.
- T. A. Abere, P. E. Okoto, and F. O. Agoreyo, “Antidiarrhoea and toxicological evaluation of the leaf extract of Dissotis rotundifolia triana (Melastomataceae),” BMC Complementary and Alternative Medicine, vol. 10, article 71, 2010.
- F. J. B. Lima, T. S. Brito, W. B. S. Freire et al., “The essential oil of Eucalyptus tereticornis, and its constituents α- And β-pinene, potentiate acetylcholine-induced contractions in isolated rat trachea,” Fitoterapia, vol. 81, no. 6, pp. 649–655, 2010.
- H. Sadraei, G. R. Asghari, V. Hajhashemi, A. Kolagar, and M. Ebrahimi, “Spasmolytic activity of essential oil and various extracts of Ferula gummosa Boiss. on ileum contractions,” Phytomedicine, vol. 8, no. 5, pp. 370–376, 2001.
- T. M. S. Da Silva, B. A. Da Silva, and R. Mukherjee, “The monoterpene alkaloid cantleyine from Strychnos trinervis root and its spasmolytic properties,” Phytomedicine, vol. 6, no. 3, pp. 169–176, 1999.
- A. V. Ortiz De Urbina, M. L. Martin, B. Fernandez, L. San Roman, and L. Cubillo, “In vitro antispasmodic activity of peracetylated penstemonoside, aucubin and catalpol,” Planta Medica, vol. 60, no. 6, pp. 512–515, 1994.
- M. F. Cometa, L. Parisi, M. Palmery, A. Meneguz, and L. Tomassini, “In vitro relaxant and spasmolytic effects of constituents from Viburnum prunifolium and HPLC quantification of the bioactive isolated iridoids,” Journal of Ethnopharmacology, vol. 123, no. 2, pp. 201–207, 2009.
- B. Hazelhoff, T. M. Malingre, and D. K. F. Meijer, “Antispasmodic effects of valeriana compounds: An in-vivo and in-vitro study on the guinea-pig ileum,” Archives Internationales de Pharmacodynamie et de Thérapie, vol. 257, no. 2, pp. 274–287, 1982.
- R. K. Cimanga, P. N. K. Mukenyi, O. K. Kambu et al., “The spasmolytic activity of extracts and some isolated compounds from the leaves of Morinda morindoides (Baker) Milne-Redh. (Rubiaceae),” Journal of Ethnopharmacology, vol. 127, no. 2, pp. 215–220, 2010.
- R. Mata, A. Rojas, L. Acevedo et al., “Smooth muscle relaxing flavonoids and terpenoids from Conyza filaginoides,” Planta Medica, vol. 63, no. 1, pp. 31–35, 1997.
- V. Leonhardt, J. H. Leal-Cardoso, S. Lahlou et al., “Antispasmodic effects of essential oil of Pterodon polygalaeflorus and its main constituent β-caryophyllene on rat isolated ileum,” Fundamental & Clinical Pharmacology, vol. 24, no. 6, pp. 749–758, 2010.
- A. Nasiri, A. Holth, and L. Bjork, “Effects of the sesquiterpene capsidiol on isolated guinea-pig ileum and trachea, and on prostaglandin synthesis in vitro,” Planta Medica, vol. 59, no. 3, pp. 203–206, 1993.
- W.-C. Ko, C.-B. Lei, Y.-L. Lin, and C.-F. Chen, “Mechanisms of relaxant action of S-petasin and S-isopetasin, sesquiterpenes of Petasites formosanus, in isolated guinea pig trachea,” Planta Medica, vol. 67, no. 3, pp. 224–229, 2001.
- O. Maschi, E. Dal Cero, G. V. Galli, D. Caruso, E. Bosisio, and M. Dell'Agli, “Inhibition of human cAMP-phosphodiesterase as a mechanism of the spasmolytic effect of Matricaria recutita L.,” Journal of Agricultural and Food Chemistry, vol. 56, no. 13, pp. 5015–5020, 2008.
- N. Perez-Hernandez, H. Ponce-Monter, J. A. Medina, and P. Joseph-Nathan, “Spasmolytic effect of constituents from Lepechinia caulescens on rat uterus,” Journal of Ethnopharmacology, vol. 115, no. 1, pp. 30–35, 2008.
- F. Emendörfer, F. Bellato, V. F. Noldin et al., “Antispasmodic activity of fractions and cynaropicrin from Cynara scolymus on guinea-pig ileum,” Biological & Pharmaceutical Bulletin, vol. 28, no. 5, pp. 902–904, 2005.
- S. Ammar, H. Edziri, M. A. Mahjoub, R. Chatter, A. Bouraoui, and Z. Mighri, “Spasmolytic and anti-inflammatory effects of constituents from Hertia cheirifolia,” Phytomedicine, vol. 16, no. 12, pp. 1156–1161, 2009.
- K. Kar, V. N. Puri, G. K. Patnaik et al., “Spasmolytic constituents of Cedrus deodara (Roxb.) Loud: Pharmacological evaluation of himachalol,” Journal of Pharmaceutical Sciences, vol. 64, no. 2, pp. 258–262, 1975.
- U. Pongprayoon, P. Baeckstrom, U. Jacobsson, M. Lindstrom, and L. Bohlin, “Antispasmodic activity of β-damascenone and E-phytol isolated from Ipomoea pes-caprae,” Planta Medica, vol. 58, no. 1, pp. 19–21, 1992.
- G. M. Natividad, K. J. Broadley, B. Kariuki, E. J. Kidd, W. R. Ford, and C. Simons, “Actions of Artemisia vulgaris extracts and isolated sesquiterpene lactones against receptors mediating contraction of guinea pig ileum and trachea,” Journal of Ethnopharmacology, vol. 137, no. 1, pp. 808–816, 2011.
- H. Guo, J. Zhang, W. Gao, Z. Qu, and C. Liu, “Gastrointestinal effect of methanol extract of Radix Aucklandiae and selected active substances on the transit activity of rat isolated intestinal strips,” Pharmaceutical Biology, vol. 52, no. 9, pp. 1141–1149, 2014.
- H. Ponce-Monter, S. Perez, M. A. Zavala et al., “Relaxant effect of xanthomicrol and 3α-angeloyloxy-2α-hydroxy- 13,14Z-dehydrocativic acid from Brickellia paniculata on rat uterus,” Biological & Pharmaceutical Bulletin, vol. 29, no. 7, pp. 1501–1503, 2006.
- D. Rigano, G. Aviello, M. Bruno et al., “Antispasmodic effects and structure-activity relationships of labdane diterpenoids from Marrubium globosum ssp. libanoticum,” Journal of Natural Products, vol. 72, no. 8, pp. 1477–1481, 2009.
- S. El Bardai, N. Morel, M. Wibo et al., “The vasorelaxant activity of marrubenol and marrubiin from Marrubium vulgare,” Planta Medica, vol. 69, no. 1, pp. 75–77, 2003.
- L. A. Aguiar, R. S. Porto, S. Lahlou et al., “Antispasmodic effects of a new kaurene diterpene isolated from Croton argyrophylloides on rat airway smooth muscle,” Journal of Pharmacy and Pharmacology, vol. 64, no. 8, pp. 1155–1164, 2012.
- S. R. Ambrosio, C. R. Tirapelli, D. Bonaventura, A. M. De Oliveira, and F. B. Da Costa, “Pimarane diterpene from Viguiera arenaria (Asteraceae) inhibit rat carotid contraction,” Fitoterapia, vol. 73, no. 6, pp. 484–489, 2002.
- L. van Puyvelde, R. Lefebvre, P. Mugabo, N. De Kimpe, and N. Schamp, “Active principles of Tetradenia riparia; II. Antispasmodic activity of 8 (14),15-sandaracopimaradiene-7α,18-diol,” Planta Medica, vol. 53, no. 2, pp. 156–158, 1987.
- G. Romussi, G. Ciarallo, A. Bisio et al., “A new diterpenoid with antispasmodic activity from Salvia cinnabarina,” Planta Medica, vol. 67, no. 2, pp. 153–155, 2001.
- A. Zamilpa, J. Tortoriello, V. Navarro, G. Delgado, and L. Alvarez, “Antispasmodic and antimicrobial diterpenic acids from Viguiera hypargyrea roots,” Planta Medica, vol. 68, no. 3, pp. 281–283, 2002.
- R. F. Santos, I. R. R. Martins, R. A. Travassos et al., “Ent-7α-acetoxytrachyloban-18-oic acid and ent-7α- hydroxytrachyloban-18-oic acid from Xylopia langsdorfiana A. St-Hil. & Tul. modulate K + and Ca 2+ channels to reduce cytosolic calcium concentration on guinea pig ileum,” European Journal of Pharmacology, vol. 678, no. 1-3, pp. 39–47, 2012.
- J. Hu, W.-Y. Gao, L. Ma, S.-L. Man, L.-Q. Huang, and C.-X. Liu, “Activation of M3 muscarinic receptor and Ca2+ influx by crude fraction from Crotonis Fructus in isolated rabbit jejunum,” Journal of Ethnopharmacology, vol. 139, no. 1, pp. 136–141, 2012.
- M. Ghanadian, H. Sadraei, S. Yousuf, G. Asghari, M. I. Choudhary, and M. Jahed, “New diterpene polyester and phenolic compounds from Pycnocycla spinosa Decne. Ex Boiss with relaxant effects on KCl-induced contraction in rat ileum,” Phytochemistry Letters, vol. 7, no. 1, pp. 57–61, 2014.
- E. Barile, R. Capasso, A. A. Izzo, V. Lanzotti, S. E. Sajjadi, and B. Zolfaghari, “Structure-activity relationships for saponins from Allium hirtifolium and Allium elburzense and their antispasmodic activity,” Planta Medica, vol. 71, no. 11, pp. 1010–1018, 2005.
- S. Begum, I. Sultana, B. S. Siddiqui, F. Shaheen, and A. H. Gilani, “Structure and spasmolytic activity of eucalyptanoic acid from Eucalyptus camaldulensis var. obtusa and synthesis of its active derivative from oleanolic acid,” Journal of Natural Products, vol. 65, no. 12, pp. 1939–1941, 2002.
- G. Corea, E. Fattorusso, V. Lanzotti, R. Capasso, and A. A. Izzo, “Antispasmodic saponins from bulbs of red onion, Allium cepa L. var. Tropea,” Journal of Agricultural and Food Chemistry, vol. 53, no. 4, pp. 935–940, 2005.
- M. González-Cortazar, J. Tortoriello, and L. Alvarez, “Norsecofriedelanes as spasmolytics, advances of structure-activity relationships,” Planta Medica, vol. 71, no. 8, pp. 711–716, 2005.
- A. Y. S. Gomes, M. D. F. V. Souza, S. F. Cortes, and V. S. Lemos, “Mechanism involved in the spasmolytic effect of a mixture of two triterpenes, cycloartenol and cycloeucalenol, isolated from Herissanthia tiubae in the guinea-pig ileum,” Planta Medica, vol. 71, no. 11, pp. 1025–1029, 2005.
- F. Palacios-Espinosa, M. Déciga-Campos, and R. Mata, “Antinociceptive, hypoglycemic and spasmolytic effects of Brickellia veronicifolia,” Journal of Ethnopharmacology, vol. 118, no. 3, pp. 448–454, 2008.
- O. Estrada, J. M. González-Guzmán, M. Salazar-Bookaman, A. Z. Fernández, A. Cardozo, and C. Alvarado-Castillo, “Pomolic acid of Licania pittieri elicits endothelium-dependent relaxation in rat aortic rings,” Phytomedicine, vol. 18, no. 6, pp. 464–469, 2011.
- M. E. González-Trujano, R. Ventura-Martínez, M. Chávez, I. Díaz-Reval, and F. Pellicer, “Spasmolytic and antinociceptive activities of ursolic acid and acacetin identified in Agastache mexicana,” Planta Medica, vol. 78, no. 8, pp. 793–799, 2012.
- S. Begum, Farhat, I. Sultana, B. S. Siddiqui, F. Shaheen, and A. H. Gilani, “Spasmolytic constituents from Eucalyptus camaldulensis var. obtusa leaves,” Journal of Natural Products, vol. 63, no. 9, pp. 1265–1268, 2000.
- R. Aquino, S. Tortora, S. Fkih-Tetouani, and A. Capasso, “Saponins from the roots of Zygophyllum gaetulum and their effects on electrically-stimulated guinea-pig ileum,” Phytochemistry, vol. 56, no. 4, pp. 393–398, 2001.
- A. Trute, J. Gross, E. Mutschler, and A. Nahrstedt, “In vitro antispasmodic compounds of the dry extract obtained from Hedera helix,” Planta Medica, vol. 63, no. 2, pp. 125–129, 1997.
- N. Ali, “Brine shrimp cytotoxicity of crude methanol extract and antispasmodic activity of α-amyrin acetate from Tylophora hirsuta Wall,” BMC Complementary and Alternative Medicine, vol. 13, article 135, 2013.
- A.-U. Khan, A.-H. Gilani, and Najeeb-Ur-Rehman, “Pharmacological studies on Hypericum perforatum fractions and constituents,” Pharmaceutical Biology, vol. 49, no. 1, pp. 46–56, 2011.
- E. J. Oliveira, M. A. Romero, M. S. Silva, B. A. Silva, and I. A. Medeiros, “Intracellular calcium mobilization as a target for the spasmolytic action of scopoletin,” Planta Medica, vol. 67, no. 7, pp. 605–608, 2001.
- V. Lakshmi, S. Kapoor, K. Pandey, and G. K. Patnaik, “Spasmolytic activity of Toddalia asiatica var. floribunda,” Phytotherapy Research, vol. 16, no. 3, pp. 281-282, 2002.
- I. Pavlović, A. Krunić, D. Nikolić et al., “Chloroform extract of underground parts of ferula heuffelii: Secondary metabolites and spasmolytic activity,” Chemistry & Biodiversity, vol. 11, no. 9, pp. 1417–1427, 2014.
- H. Sadraei, Y. Shokoohinia, S. E. Sajjadi, and M. Mozafari, “Antispasmodic effects of Prangos ferulacea acetone extract and its main component osthole on ileum contraction,” Research in Pharmaceutical Sciences, vol. 8, no. 2, pp. 137–144, 2013.
- G. K. Patnaik, K. K. Banaudha, K. A. Khan, A. Shoeb, and B. N. Dhawan, “Spasmolytic activity of angelicin: A coumarin from Heracleum thomsoni,” Planta Medica, vol. 53, no. 6, pp. 517–520, 1987.
- Y. Sato, T. Akao, J.-X. He et al., “Glycycoumarin from Glycyrrhizae Radix acts as a potent antispasmodic through inhibition of phosphodiesterase 3,” Journal of Ethnopharmacology, vol. 105, no. 3, pp. 409–414, 2006.
- H. Nagai, Y. Yamamoto, Y. Sato, T. Akao, and T. Tani, “Pharmaceutical evaluation of cultivated Glycyrrhiza uralensis roots in comparison of their antispasmodic activity and glycycoumarin contents with those of licorice,” Biological & Pharmaceutical Bulletin, vol. 29, no. 12, pp. 2442–2445, 2006.
- O. Desire, C. Rivière, R. Razafindrazaka et al., “Antispasmodic and antioxidant activities of fractions and bioactive constituent davidigenin isolated from Mascarenhasia arborescens,” Journal of Ethnopharmacology, vol. 130, no. 2, pp. 320–328, 2010.
- Y. Shi, D. Wu, Z. Sun et al., “Analgesic and uterine relaxant effects of isoliquiritigenin, a flavone from Glycyrrhiza glabra,” Phytotherapy Research, vol. 26, no. 9, pp. 1410–1417, 2012.
- Y. Sato, J.-X. He, H. Nagai, T. Tani, and T. Akao, “Isoliquiritigenin, one of the antispasmodic principles of Glycyrrhiza ularensis roots, acts in the lower part of intestine,” Biological & Pharmaceutical Bulletin, vol. 30, no. 1, pp. 145–149, 2007.
- H. Nagai, J.-X. He, T. Tani, and T. Akao, “Antispasmodic activity of licochalcone A, a species-specific ingredient of Glycyrrhiza inflata roots,” Journal of Pharmacy and Pharmacology, vol. 59, no. 10, pp. 1421–1426, 2007.
- A. Rojas, S. Cruz, H. Ponce-Monter, and R. Mata, “Smooth muscle relaxing compounds from Dodonaea viscosa,” Planta Medica, vol. 62, no. 2, pp. 154–159, 1996.
- L. Abu-Niaaj, M. Abu-Zarga, S. Sabri, and S. Abdalla, “Isolation and biological effects of 7-O-methyleriodictyol, a flavanone isolated from Artemisia monosperma, on rat isolated smooth muscles,” Planta Medica, vol. 59, no. 1, pp. 42–45, 1993.
- M. B. Da Rocha, F. V. M. Souza, C. D. S. Estevam, C. Pizza, A. E. G. Sant'Ana, and R. M. Marçal, “Antispasmodic effect of 4′-methylepigallocatechin on guinea pig ileum,” Fitoterapia, vol. 83, no. 7, pp. 1286–1290, 2012.
- R. Lemmens-Gruber, E. Marchart, P. Rawnduzi, N. Engel, B. Benedek, and B. Kopp, “Investigation of the spasmolytic activity of the flavonoid fraction of Achillea millefolium s.l. on isolated guinea-pig ilea,” Arzneimittel-Forschung/Drug Research, vol. 56, no. 8, pp. 582–586, 2006.
- S. Gorzalczany, V. Moscatelli, and G. Ferraro, “Artemisia copa aqueous extract as vasorelaxant and hypotensive agent,” Journal of Ethnopharmacology, vol. 148, no. 1, pp. 56–61, 2013.
- H. Fleer and E. J. Verspohl, “Antispasmodic activity of an extract from Plantago lanceolata L. and some isolated compounds,” Phytomedicine, vol. 14, no. 6, pp. 409–415, 2007.
- J. Engelbertz, M. Lechtenberg, L. Studt, A. Hensel, and E. J. Verspohl, “Bioassay-guided fractionation of a thymol-deprived hydrophilic thyme extract and its antispasmodic effect,” Journal of Ethnopharmacology, vol. 141, no. 3, pp. 848–853, 2012.
- M. I. Ragone, M. Sella, P. Conforti, M. G. Volonté, and A. E. Consolini, “The spasmolytic effect of Aloysia citriodora, Palau (South American cedrón) is partially due to its vitexin but not isovitexin on rat duodenums,” Journal of Ethnopharmacology, vol. 113, no. 2, pp. 258–266, 2007.
- A. H. Gilani, A.-U. Khan, M. N. Ghayur, S. F. Ali, and J. W. Herzig, “Antispasmodic effects of Rooibos tea (Aspalathus linearis) is mediated predominantly through K+-channel activation,” Basic & Clinical Pharmacology & Toxicology, vol. 99, no. 5, pp. 365–373, 2006.
- C. L. Macêdo, L. H. C. Vasconcelos, A. C. D. C. Correia et al., “Spasmolytic effect of galetin 3,6-dimethyl ether, a flavonoid obtained from Piptadenia stipulacea (Benth) Ducke,” Journal of Smooth Muscle Research, vol. 47, no. 5, pp. 123–134, 2011.
- F. Rodríguez-Ramos and A. Navarrete, “Solving the confusion of gnaphaliin structure: Gnaphaliin A and gnaphaliin B identified as active principles of Gnaphalium liebmannii with tracheal smooth muscle relaxant properties,” Journal of Natural Products, vol. 72, no. 6, pp. 1061–1064, 2009.
- X. Lozoya, M. Meckes, M. Abou-Zaid, J. Tortoriello, C. Nozzolillo, and J. T. Arnason, “Quercetin glycosides in Psidium guajava L. leaves and determination of a spasmolytic principle,” Archives of Medical Research, vol. 25, no. 1, pp. 11–15, 1994.
- M. F. Melzig, H. H. Pertz, and L. Krenn, “Anti-inflammatory and spasmolytic activity of extracts from Droserae Herba,” Phytomedicine, vol. 8, no. 3, pp. 225–229, 2001.
- L. Krenn, G. Beyer, H. H. Pertz et al., “In vitro antispasmodic and anti-inflammatory effects of Drosera rotundifolia,” Arzneimittel-Forschung/Drug Research, vol. 54, no. 7, pp. 402–405, 2004.
- W. C. Ko, H. L. Wang, C. B. Lei, C. H. Shih, M. I. Chung, and C. N. Lin, “Mechanisms of relaxant action of 3-O-methylquercetin in isolated guinea pig trachea,” Planta Medica, vol. 68, no. 1, pp. 30–35, 2002.
- O. Bergendorff and O. Sterner, “Spasmolytic flavonols from Artemisia abrotanum,” Planta Medica, vol. 61, no. 4, pp. 370-371, 1995.
- M. D. Herrera, E. Marhuenda, and A. Gibson, “Effects of genistein, an isoflavone isolated from Genista tridentata, on isolated guinea-pig ileum and guinea-pig ileal myenteric plexus,” Planta Medica, vol. 58, no. 4, pp. 314–316, 1992.
- F. Borrelli, N. Milic, V. Ascione et al., “Isolation of new rotenoids from Boerhaavia diffusa and evaluation of their effect on intestinal motility,” Planta Medica, vol. 71, no. 10, pp. 928–932, 2005.
- O. B. Balemba, T. D. Stark, S. Lösch et al., “(2R,3S,2''R,3''R)-manniflavanone, a new gastrointestinal smooth muscle L-type calcium channel inhibitor, which underlies the spasmolytic properties of Garcinia buchananii stem bark extract,” Journal of Smooth Muscle Research, vol. 50, no. 1, pp. 48–65, 2014.
- E. J. Verspohl, H. Fujii, K. Homma, and S. Buchwald-Werner, “Testing of Perilla frutescens extract and Vicenin 2 for their antispasmodic effect,” Phytomedicine, vol. 20, no. 5, pp. 427–431, 2013.
- N. F. De Moura, A. F. Morel, E. C. Dessoy et al., “Alkaloids, amides and antispasmodic activity of Zanthoxylum hyemale,” Planta Medica, vol. 68, no. 6, pp. 534–538, 2002.
- W.-J. He, T.-H. Fang, X. Ma, K. Zhang., Z.-Z. Ma, and P.-F. Tu, “Echinacoside elicits endothelium-dependent relaxation in rat aortic rings via an NO-cGMP pathway,” Planta Medica, vol. 75, no. 13, pp. 1400–1404, 2009.
- J. Yang, P. S. P. Ip, J. H. K. Yeung, and C.-T. Che, “Inhibitory effect of schisandrin on spontaneous contraction of isolated rat colon,” Phytomedicine, vol. 18, no. 11, pp. 998–1005, 2011.
- J.-M. Yang, P. S. P. Ip, C.-T. Che, and J. H. K. Yeung, “Relaxant effects of Schisandra chinensis and its major lignans on agonists-induced contraction in guinea pig ileum,” Phytomedicine, vol. 18, no. 13, pp. 1153–1160, 2011.
- Y. Hernández-Romero, J.-I. Rojas, R. Castillo, A. Rojas, and R. Mata, “Spasmolytic Effects, Mode of Action, and Structure-Activity Relationships of Stilbenoids from Nidema boothii,” Journal of Natural Products, vol. 67, no. 2, pp. 160–167, 2004.
- S. Estrada, A. Rojas, Y. Mathison, A. Israel, and R. Mata, “Nitric oxide/cGMP mediates the spasmolytic action of 3,4'-dihydroxy- 5,5'-dimethoxybibenzyl from Scaphyglottis livida,” Planta Medica, vol. 65, no. 2, pp. 109–114, 1999.
- S. Estrada, J. J. López-Guerrero, R. Villalobos-Molina, and R. Mata, “Spasmolytic stilbenoids from Maxillaria densa,” Fitoterapia, vol. 75, no. 7-8, pp. 690–695, 2004.
- C. Itthipanichpong, W. Kemsri, N. Ruangrungsi, and A. Sawasdipanich, “Antispasmodic effects of curcuminoids on isolated guinea-pig ileum and rat uterus,” Journal of the Medical Association of Thailand, vol. 86, no. 2, pp. S299–S309, 2003.
- K. Seya, K.-I. Furukawa, S. Taniguchi et al., “Endothelium-dependent vasodilatory effect of vitisin C, a novel plant oligostilbene from Vitis plants (Vitaceae), in rabbit aorta,” Clinical Science, vol. 105, no. 1, pp. 73–79, 2003.
- M.-J. Liang, L.-C. He, and G.-D. Yang, “Screening, analysis and in vitro vasodilatation of effective components from Ligusticum Chuanxiong,” Life Sciences, vol. 78, no. 2, pp. 128–133, 2005.
- D. Rigano, C. Formisano, F. Senatore et al., “Intestinal antispasmodic effects of Helichrysum italicum (Roth) Don ssp. italicum and chemical identification of the active ingredients,” Journal of Ethnopharmacology, vol. 150, no. 3, pp. 901–906, 2013.
- S. Baldassano, L. Tesoriere, A. Rotundo, R. Serio, M. A. Livrea, and F. Mulè, “Inhibition of the mechanical activity of mouse ileum by cactus pear (Opuntia ficus Indica, L, Mill.) fruit extract and its pigment indicaxanthin,” Journal of Agricultural and Food Chemistry, vol. 58, no. 13, pp. 7565–7571, 2010.
- S. S. Gambhir, S. P. Sen, A. K. Sanyal, and P. K. Das, “Antispasmodic activity of the tertiary base of Daucus carota, Linn. seeds,” Indian Journal of Physiology and Pharmacology, vol. 23, no. 3, pp. 225–228, 1979.
- M. Tsukiyama, T. Ueki, Y. Yasuda et al., “β2-adrenoceptor-mediated tracheal relaxation induced by higenamine from nandina domestica thunberg,” Planta Medica, vol. 75, no. 13, pp. 1393–1399, 2009.
- C.-H. Lin, F.-N. Ko, Y.-C. Wu, S.-T. Lu, and C.-M. Teng, “The relaxant actions on guinea-pig trachealis of atherosperminine isolated from Fissistigma glaucescens,” European Journal of Pharmacology, vol. 237, no. 1, pp. 109–116, 1993.
- F. Orallo, “Pharmacological effects of (+)-nantenine, an alkaloid isolated from Platycapnos spicata, in several rat isolated tissues,” Planta Medica, vol. 69, no. 2, pp. 135–142, 2003.
- A. M. El-Shafae and A. S. Soliman, “A pyranocoumarin and two alkaloids (one with antispasmodic effect) from Citrus deliciosa,” Die Pharmazie, vol. 53, no. 9, pp. 640–643, 1998.
- C. Lin, C. Yang, F. Ko, Y. Wu, and C. Teng, “Antimuscarinic action of liriodenine, isolated from Fissistigma glaucescens, in canine tracheal smooth muscle,” British Journal of Pharmacology, vol. 113, no. 4, pp. 1464–1470, 1994.
- J. Yuan, J. Zhou, Z. Hu, G. Ji, J. Xie, and D. Wu, “The effects of jatrorrhizine on contractile responses of rat ileum,” European Journal of Pharmacology, vol. 663, no. 1-3, pp. 74–79, 2011.
- M. Zhao, Y. Xian, S. Ip, H. H. S. Fong, and C. Che, “A new and weakly antispasmodic protoberberine alkaloid from rhizoma coptidis,” Phytotherapy Research, vol. 24, no. 9, pp. 1414–1416, 2010.
- R. Sotníková, V. Kettmann, D. Kostálová, and E. Táborská, “Relaxant properties of some aporphine alkaloids from Mahonia aquifolium,” Methods and Findings in Experimental and Clinical Pharmacology, vol. 19, no. 9, pp. 589–597, 1997.
- K.-O. Hiller, M. Ghorbani, and H. Schlicher, “Antispasmodic and relaxant activity of chelidonine, protopine, coptisine, and Chelidonium majus extracts on isolated guinea-pig ileum,” Planta Medica, vol. 64, no. 8, pp. 758–760, 1998.
- L. Rastrelli, A. Capasso, C. Pizza, N. De Tommasi, and L. Sorrentino, “New protopine and benzyltetrahydroprotoberberine alkaloids from Aristolochia constricta and their activity on isolated guinea-pig ileum,” Journal of Natural Products, vol. 60, no. 11, pp. 1065–1069, 1997.
- R. C. Oliveira, J. T. Lima, L. A. A. Ribeiro et al., “Spasmolytic action of the methanol extract and isojuripidine from Solanum asterophorum Mart. (Solanaceae) leaves in guinea-pig ileum,” Zeitschrift fur Naturforschung - Section C Journal of Biosciences, vol. 61, no. 11-12, pp. 799–805, 2006.
- A.-U. H. Gilani, A. Khalid, Zaheer-ul-Haq, M. I. Choudhary, and Atta-ur-Rahman, “Presence of antispasmodic, antidiarrheal, antisecretory, calcium antagonist and acetylcholinesterase inhibitory steroidal alkaloids in Sarcococca saligna,” Planta Medica, vol. 71, no. 2, pp. 120–125, 2005.
- A. Khalid, Zaheer-Ul-Haq, M. N. Ghayur et al., “Cholinesterase inhibitory and spasmolytic potential of steroidal alkaloids,” The Journal of Steroid Biochemistry and Molecular Biology, vol. 92, no. 5, pp. 477–484, 2004.
- Y. Zhang, Z. Long, Z. Guo et al., “Hydroxycinnamic acid amides from Scopolia tangutica inhibit the activity of M1 muscarinic acetylcholine receptor in vitro,” Fitoterapia, vol. 108, pp. 9–12, 2016.
- P. Pongkorpsakol, P. Wongkrasant, S. Kumpun, V. Chatsudthipong, and C. Muanprasat, “Inhibition of intestinal chloride secretion by piperine as a cellular basis for the anti-secretory effect of black peppers,” Pharmacological Research, vol. 100, pp. 271–280, 2015.
- R. Capasso, G. Aviello, B. Romano et al., “Modulation of mouse gastrointestinal motility by allyl isothiocyanate, a constituent of cruciferous vegetables (Brassicaceae): Evidence for TRPA1-independent effects,” British Journal of Pharmacology, vol. 165, no. 6, pp. 1966–1977, 2012.
- D. Kanjanapothi, P. Soparat, A. Panthong, P. Tuntiwachwuttikul, and V. Reutrakul, “A uterine relaxant compound from Zingiber cassumunar,” Planta Medica, vol. 53, no. 4, pp. 329–332, 1987.
- A. A. Moazedi, N. Dabir, M. K. Gharib Naseri, and M. R. Zadkarami, “The role of NO and cGMP in antispasmodic activity of Ruta chalepensis leaf extract on rat ileum,” Pakistan Journal of Biological Sciences, vol. 13, no. 2, pp. 83–87, 2010.
- H. Sadraei, M. Ghanadian, G. Asghari, E. Madadi, and N. Azali, “Antispasmodic and antidiarrhoeal activities of 6-(4-hydroxy-3- methoxyphenyl)-hexanonic acid from Pycnocycla spinosa Decne. exBoiss,” Research in Pharmaceutical Sciences, vol. 9, no. 4, pp. 279–286, 2014.
- H. Sadraei, M. Ghanadian, G. Asghari, and N. Azali, “Antidiarrheal activities of isovanillin, iso-acetovanillon and Pycnocycla spinosa Decne ex.Boiss extract in mice,” Research in Pharmaceutical Sciences, vol. 9, no. 2, pp. 83–89, 2014.
- R. C. Webb, “SMOOTH MUSCLE CONTRACTION AND RELAXATION,” Advances in Physiology Education, vol. 27, no. 4, pp. 201–206, 2003.
- “Copyright page,” Clinical Pharmacology & Therapeutics, vol. 73, no. 6, p. 578, 2003.
- O. Wintersteiner and J. D. Dutcher, “Curare alkaloids from Chondodendron tomentosum,” Science, vol. 97, no. 2525, pp. 467–470, 1943.
- H. H. Dale, W. Feldberg, and M. Vogt, “Release of acetylcholine at voluntary motor nerve endings,” The Journal of Physiology, vol. 86, no. 4, pp. 353–380, 1936.
- C. Galeffi, P. Scarpetti, and G. B. Marini-Bettolo, “Peinamine, a new bisbenzylisoquinoline alkaloid from arrow tips (pei-namô) of the Upper Orinoco.,” Il Farmaco; edizione scientifica, vol. 32, no. 9, pp. 665–671, 1977.
- C. Galeffi, P. Scarpetti, and G. B. Marini Bettolo, “New curare alkaloids. II. New bisbenzylisoquinoline alkaloids from Abuta grisebachii (Menispermaceae),” Farmaco, Edizione Scientifica, vol. 32, no. 12, pp. 853–865, 1977.
- Geiger and Hesse, “Darstellung des Atropins,” Annalen der Pharmacie, vol. 5, no. 1, pp. 43–81, 1833.
- J. F. Coulson and W. J. Griffin, “The alkaloids of Duboisia myoporoides. I. Aerial parts.,” Planta Medica, vol. 15, no. 4, pp. 459–466, 1967.
- J. F. Coulsen and W. J. Griffin, “The alkaloids of Duboisia myoporoides. II. Roots.,” Planta Medica, vol. 16, no. 2, pp. 174–181, 1968.
- E. Miraldi, A. Masti, S. Ferri, and I. Barni Comparini, “Distribution of hyoscyamine and scopolamine in Datura stramonium,” Fitoterapia, vol. 72, no. 6, pp. 644–648, 2001.
- J. Wisniak, “Pierre-Jean Robiquet,” Educación Química, vol. 24, pp. 139–149, 2013.
- A. N. Hayes and S. G. Gilbert, “Historical milestones and discoveries that shaped the toxicology sciences.,” EXS, vol. 99, pp. 1–35, 2009.
- G. Grynkiewicz and M. Gadzikowska, “Tropane alkaloids as medicinally useful natural products and their synthetic derivatives as new drugs,” Pharmacological Reports, vol. 60, no. 4, pp. 439–463, 2008.
- H. Keberle, J. W. Faigle, and M. Wilhelm, Beta-(para-halo-phenyl)-glutaric acid imides, https://patents.google.com/patent/US3634428A/en, 1972.
- F. A. Aboagye, G. H. Sam, G. Massiot, and C. Lavaud, “Julocrotine, a glutarimide alkaloid from Croton membranaceus,” Fitoterapia, vol. 71, no. 4, pp. 461-462, 2000.
- A. I. Suárez, Z. Blanco, F. Delle Monache, R. S. Compagnone, and F. Arvelo, “Three new glutarimide alkaloids from Croton cuneatus,” Natural Product Research (Formerly Natural Product Letters), vol. 18, no. 5, pp. 421–426, 2004.
- J. A. Oates, A. J. J. Wood, and N. J. Gross, “Ipratropium Bromide,” The New England Journal of Medicine, vol. 319, no. 8, pp. 486–494, 1988.
- R. Litta Modignani, M. Mazzolari, E. Barantani, D. Bertoli, and C. Vibelli, “Relative potency of the atropine-like effects of a new parasympatholytic drug, scopolamine-n-(Cyclopropy 1 methyl) bromide and those of hyoscine-n-butyl bromide,” Current Medical Research and Opinion, vol. 5, no. 4, pp. 333–340, 1977.
- P. K. Timms and R. B. Gibbons, “Latrodectism - Effects of the black widow spider bite,” Western Journal of Medicine, vol. 144, no. 3, pp. 315–317, 1986.
- D. O. Toyama, A. C. Boschero, M. A. Martins, M. C. Fonteles, H. S. Monteiro, and M. H. Toyama, “Structure-function relationship of new crotamine isoform from the Crotalus durissus cascavella,” The Protein Journal, vol. 24, no. 1, pp. 9–19, 2005.
- F. N. McNamara, A. Randall, and M. J. Gunthorpe, “Effects of piperine, the pungent component of black pepper, at the human vanilloid receptor (TRPV1),” British Journal of Pharmacology, vol. 144, no. 6, pp. 781–790, 2005.
- J. Gálvez, F. Sánchez De Medina, J. Jiménez, and A. Zarzuelo, “Effects of flavonoids on gastrointestinal disorders,” in Bioactive Natural Products (Part F), vol. 25 of Studies in Natural Products Chemistry, pp. 607–649, Elsevier, 2001.
- M. H. Mehmood, H. S. Siddiqi, and A. H. Gilani, “The antidiarrheal and spasmolytic activities of Phyllanthus emblica are mediated through dual blockade of muscarinic receptors and Ca2+ channels,” Journal of Ethnopharmacology, vol. 133, no. 2, pp. 856–865, 2011.
- V. Schlemper, A. Ribas, M. Nicolau, and V. Cechinel Filho, “Antispasmodic effects of hydroalcoholic extract of Marrubium vulgare on isolated tissues,” Phytomedicine, vol. 3, no. 2, pp. 211–216, 1996.
- Najeeb-ur-Rehman, S. Bashir, A. J. Al-Rehaily, and A.-H. Gilani, “Mechanisms underlying the antidiarrheal, antispasmodic and bronchodilator activities of Fumaria parviflora and involvement of tissue and species specificity,” Journal of Ethnopharmacology, vol. 144, no. 1, pp. 128–137, 2012.
- M. K. R. Peddireddy, “In vitro evaluation techniques for gastrointestinal motility,” Indian Journal of Pharmaceutical Education and Research (IJPER), vol. 45, no. 2, pp. 184–191, 2011.
- A. Astudillo-Vázquez, R. Mata, and A. Navarrete, “El reino vegetal, fuente de agentes antiespasmódicos gastrointestinales y antidiarreicos,” Revista Latinoamericana de Química, vol. 37, pp. 7–44, 2009.
- E. J. Ariens, P. A. Lehmann, and A. M. Simonis, Introduccion a la toxicologia general, MΘxico D.F, Diana, 1978.
- M. Khan, A.-U. Khan, Najeeb-Ur-Rehman, and A.-H. Gilani, “Gut and airways relaxant effects of Carum roxburghianum,” Journal of Ethnopharmacology, vol. 141, no. 3, pp. 938–946, 2012.
- F. J. Ehlert, “Contractile role of M2 and M3 muscarinic receptors in gastrointestinal, airway and urinary bladder smooth muscle,” Life Sciences, vol. 74, no. 2-3, pp. 355–366, 2003.
- J. G. Clement, “BaCl2-induced contractions in the guinea pig ileum longitudinal muscle: Role of presynaptic release of neurotransmitters and Ca2+ translocation in the postsynaptic membrane,” Canadian Journal of Physiology and Pharmacology, vol. 59, no. 6, pp. 541–547, 1981.
- A. M. Blackwood and T. B. Bolton, “Mechanism of carbachol‐evoked contractions of guinea‐pig ileal smooth muscle close to freezing point,” British Journal of Pharmacology, vol. 109, no. 4, pp. 1029–1037, 1993.
- S. Shore, C. G. Irvin, T. Shenkier, and J. G. Martin, “Mechanisms of histamine-induced contraction of canine airway smooth muscle,” Journal of Applied Physiology, vol. 55, no. 1, pp. 22–26, 1983.
- P. H. Ratz, K. M. Berg, N. H. Urban, and A. S. Miner, “Regulation of smooth muscle calcium sensitivity: KCl as a calcium-sensitizing stimulus,” American Journal of Physiology-Cell Physiology, vol. 288, no. 4, pp. C769–C783, 2005.
- P. H. Ratz and S. F. Flaim, “Mechanism of 5-HT contraction in isolated bovine ventricular coronary arteries. Evidence for transient receptor-operated calcium influx channels,” Circulation Research, vol. 54, no. 2, pp. 135–143, 1984.
- M. J. Sumner, W. Feniuk, J. D. McCormick, and P. P. A. Humphrey, “Studies on the mechanism of 5‐HT1 receptor‐induced smooth muscle contraction in dog saphenous vein,” British Journal of Pharmacology, vol. 105, no. 3, pp. 603–608, 1992.
- B. N. Ames, W. E. Durston, E. Yamasaki, and F. D. Lee, “Carcinogens are mutagens: a simple test combining liver homogenates for activation and bacteria for detection,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 70, no. 8, pp. 2281–2285, 1973.
- D. M. Maron and B. N. Ames, “Revised methods for the Salmonella mutagenicity test,” Mutation Research, vol. 113, no. 3-4, pp. 173–215, 1983.
- H. Czeczot, B. Tudek, J. Kusztelak et al., “Isolation and studies of the mutagenic activity in the Ames test of flavonoids naturally occurring in medical herbs,” Mutation Research - Genetic Toxicology and Environmental Mutagenesis, vol. 240, no. 3, pp. 209–216, 1990.
- M. Déciga-Campos, I. Rivero-Cruz, M. Arriaga-Alba et al., “Acute toxicity and mutagenic activity of Mexican plants used in traditional medicine,” Journal of Ethnopharmacology, vol. 110, no. 2, pp. 334–342, 2007.
- E. E. Elgorashi, S. F. Malan, G. I. Stafford, and J. van Staden, “Quantitative structure-activity relationship studies on acetylcholinesterase enzyme inhibitory effects of Amaryllidaceae alkaloids,” South African Journal of Botany, vol. 72, no. 2, pp. 224–231, 2006.
- R. Capasso, F. Borrelli, F. Capasso et al., “The hallucinogenic herb Salvia divinorum and its active ingredient salvinorin A inhibit enteric cholinergic transmission in the guinea-pig ileum,” Neurogastroenterology & Motility, vol. 18, no. 1, pp. 69–75, 2006.
- R. Capasso, F. Borrelli, M. G. Cascio et al., “Inhibitory effect of salvinorin A, from Salvia divinorum, on ileitis-induced hypermotility: cross-talk between kappa-opioid and cannabinoid CB1 receptors,” British Journal of Pharmacology, vol. 155, no. 5, pp. 681–689, 2008.
Copyright © 2018 Edith Fabiola Martínez-Pérez et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.