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PubMed1975

Spasmolytic constituents of Cedrus deodara (Roxb.) Loud: pharmacological evaluation of himachalol.

Himachalol has been identified as the major antispasmodic constituent in the wood of Cedrus deodara. The pharmacological studies of himachalol on various isolated smooth muscles (guinea pig ileum, rabbit jejunum, rat uterus, and guinea pig seminal vesicle) and against different agonists (acetylcholine, histamine, serotonin, nicotine, and barium chloride) indicated spasmolytic activity similar to that of papaverine. It was a more potent antagonist of barium chloride-induced spasm of guinea pig ileum than papaverine but less effective in reverting a similar spasm of rabbit jejunum and had no relaxing effect alone. In the conscious immobilized cat, intragastric administration of himachalol or papaverine (100 mg/kg) produced equal inhibition of carbachol-induced spasm of the intestine, lasting about 2 hr, but himachalol had a faster onset of action. Himachalol was devoid of spasmolytic effect on the bronchial musculature of guinea pig but was 3.3 times more potent than papaverine in antagonizing epinephrine-induced contraction of the guinea pig seminal vesicle. Intravenous injection of himachalol (3-10 mg/kg) in the cat produced a dose-dependent fall in blood pressure and an increased femoral blood flow.

Animals↗

PubMed2002

Spasmolytic activity of Toddalia asiatica Var. floribunda.

The spasmolytic activity of the aerial parts of Toddalia asiatica var. floribunda (family Rutaceae) was evaluated. The ethanol extract exhibited significant spasmolytic activity and was then partitioned into five fractions. The activity was found to be concentrated only in the hexane and chloroform fractions. This activity was shown not to be due to the coumarins, toddalolactone and toddanone, as was previously thought.

Animals↗

PubMed1991

Comparison of various spasmolytic drugs on guinea-pig isolated common bile duct.

Guinea-pig common bile duct preparations were used to quantify the spasmolytic potency of N-butylscopolamine (NBS), papaverine, gallopamil and nifedipine. A method was developed which allowed the measurement of intraluminal pressure changes in vitro. Barium chloride, carbachol and a solution with elevated potassium concentrations were used to stimulate smooth muscles. Concentration-response relationships for the spasmogens as well as for the spasmolytic drugs were evaluated in a cumulative manner. Furthermore, non-cumulative concentration-response curves were constructed for carbachol in the absence and presence of NBS. The -log EC50-values of the spasmogens were found to be 3.28 +/- 0.08 (BaCl2), 6.46 +/- 0.07 (carbachol) and 1.31 +/- 0.08 (KCl), respectively. The Emax values of carbachol and potassium were comparable, and were twice as high as the Emax of BaCl2. Papaverine was less potent than the calcium antagonists gallopamil and nifedipine, but proved capable of completely suppressing elevated muscular tone of the common bile duct preparation, independent of the stimulus used. NBS showed a high potency in suppressing only a carbachol-induced pressure increase, while it was rather ineffective when BaCl2 or a high potassium solution was used as the spasmogen. The concentration-response-curve for carbachol was shifted to the right in a parallel manner by NBS. Only a slight depression of Emax was observed. From the results it is concluded that NBS acts mainly as a muscarinic receptor antagonist. The high potency found for the calcium antagonists, gallopamil and nifedipine, in this model may indicate a possible role for these compounds in the treatment of biliary colic.

Action Potentials↗

PubMed1992

Assignment of the gene for human spasmolytic protein (hSP/SML1) to chromosome 21.

A human cDNA corresponding to the porcine pancreatic spasmolytic protein (PSP) was isolated, and the recombinant clone was originally termed hSP for human spasmolytic protein. Later, the term SML1 for spasmolysin was suggested for the human gene. This protein shows a remarkable sequence homology to pS2, a protein coded by an estrogen-induced gene isolated from the breast carcinoma cell line MCF-7. Although, at the DNA level, the gene sequences pS2 and hSP/SML1 display insufficient homology for cross-hybridization, their expression in tumor cells occurs with remarkable coordination. The human pS2 gene sequence has been assigned to chromosome 21, and we have therefore attempted to map the hSP/SML1 gene by using cDNA and Southern blotting of genomic DNAs from a panel of human-rodent somatic cell hybrids carrying different complements of human chromosomes. Interestingly, the hSP/SML1 gene is also localized on chromosome 21.

Blotting, Southern↗

PubMed1995

Effect of spasmolytic drugs on esophageal foreign bodies.

Muscle spasm has been proposed as the cause for esophageal food impaction. The aim was therefore to treat esophageal foreign bodies with spasmolytic drugs influencing both striated and smooth muscles of the esophagus. A multicenter, placebo-controlled, double-blind study of glucagon and diazepam was undertaken in 43 patients. The foreign body disimpacted in 9 of 24 patients given active substances and in 6 of 19 patients given placebo; there was no significant difference between these two groups. Almost all disimpactions occurred several hours after injection of the drugs. The hypothesis of muscle spasm as an important cause of esophageal obstruction was rejected. Medical therapies for food disimpaction other than spasmolytic drugs have to be investigated.

Adolescent↗

PubMed1991

Diclofenac sodium and spasmolytic drugs in the treatment of ureteral colic: a comparative study.

Forty-nine patients with ureteral colic were included in this prospective double-blind study investigating the analgesic efficacy and side effects of a prostaglandin synthetase inhibitor Diclofenac sodium (Voltaren) versus a spasmolytic drug Tropenzilium bromide (Palerol). The analgesic efficacy and side effects of the calcium antagonist Nifedipine (Nidilat) applied sublingually in ureteral colic were also investigated. It was concluded that diclofenac sodium was more efficient for relieving pain due to acute ureteral obstruction and had fewer side effects than spasmolytic drugs. Nifedipine proved to have an analgesic effect equivalent to that of Tropenzilium bromide.

Adult↗

PubMed2005

The potency of KUL-7211, a selective ureteral relaxant, in isolated canine ureter: comparison with various spasmolytics.

We compared the potency of a selective ureteral relaxant KUL-7211 (beta(2)/beta(3)-adrenoceptor agonist; (-)-2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)phenyloxy]acetic acid) with those of various spasmolytics on contractions in isolated canine ureteral preparations. Drug effects were evaluated on the tonic contraction induced by KCl (80 mM) and on spontaneous, 1x10(-5) M phenylephrine-, and 1x10(-6) M PGF(2alpha)-induced rhythmic contractions in isolated canine ureteral preparations using a functional experimental technique. The potencies (pD(2) value) of the following drugs were compared: KUL-7211, tamsulosin (an alpha(1A/1D)-adrenoceptor antagonist), prazosin (an alpha(1)-adrenoceptor antagonist), verapamil (a Ca(2+)-channel blocker), butylscopolamine (a nonselective muscarinic antagonist), and papaverine (a phosphodiesterase inhibitor). The rank order of relaxing potencies against KCl-induced tonic contraction was KUL-7211 (6.60)>tamsulosin(5.90)>verapamil(5.70)>papaverine(4.88)>prazosin (4.54). The rank order of potencies for reductions in spontaneous rhythmic contractions was KUL-7211 (6.80)>verapamil(6.12)>papaverine(5.05). Conversely, high concentrations of the two alpha-adrenoceptor antagonists (tamsulosin and prazosin) and of butylscopolamine enhanced the spontaneous contractions, although at low concentrations (up to 1x10(-6) M) they had no significant effects. For suppression of spasmogen-induced rhythmic contractions, the rank order of potencies was, against phenylephrine-induced contractions: KUL-7211 (6.95)>tamsulosin(6.26)>prazosin(5.68)>verapamil(5.64)>papaverine (5.03), and against PGF(2alpha)-induced contractions: KUL-7211 (7.05)>verapamil(6.70)>papaverine (5.27). Our results suggest that in dogs, the beta(2)/beta(3)-adrenoceptor agonist KUL-7211 is the most efficacious ureteral relaxant among the spasmolytics tested against various contractions. Possibly, KUL-7211 might be useful for promoting stone passage and relieving ureteral colic in urolithiasis patients.

Acetates↗

PubMed1991

Selective inhibition of a high affinity type IV cyclic AMP phosphodiesterase in bovine trachealis by AH 21-132. Relevance to the spasmolytic and anti-spasmogenic actions of AH 21-132 in the intact tissue.

The ability of a papaverine-derived bronchodilator, AH 21-132, to inhibit cyclic nucleotide hydrolysis and to increase the cAMP content and the activity of cAMP-dependent protein kinase (A-kinase) was evaluated in bovine tracheal smooth muscle (BTSM) and related to the mechanical effects elicited by this compound in vitro. AH 21-132 (100 nM-1 mM) produced a concentration-related relaxation of BTSM pre-contracted with methacholine (MCh) that was subject to marked functional antagonism. AH 21-132 (100 microM) also displayed anti-spasmogenic activity preventing the generation of tone induced by low, but not high, concentrations of MCh. Neither the spasmolytic nor anti-spasmogenic effects of AH 21-132 were antagonized by the beta 2-adrenoceptor blocking drug ICI 118551 (50 nM). Three Ca(2+)- and calmodulin-independent cyclic nucleotide phosphodiesterases (PDE) were resolved from the soluble fraction of BTSM homogenates by Q-Sepharose anion exchange chromatography. These PDEs were identified by kinetic and inhibitor sensitivity criteria as the Type II (cGMP-stimulated), Type IV (Ro 20-1724-inhibited) and Type V (cGMP-specific) isoenzymes. A small amount (approximately 5%) of a Type III PDE seemed to be present but this was not identified with certainty. AH 21-132 selectively inhibited Type IV PDE in a competitive manner with an IC50 and KI of 3.7 and 2.7 microM, respectively. AH 21-132 similarly increased the cAMP content (from 5.3 to 23.1 pmol/mg protein after 1 mM AH 21-132) and activated A-kinase (from 29.6% to 53.5% after 1 mM AH 21-132) in intact BTSM over the same concentration range at which this compound influenced tone. In addition, AH 21-132 in high concentrations (greater than 100 microM), while exerting no direct effect on A-kinase itself, markedly potentiated (ca. four-fold at 3 mM AH 21-132) the ability of cAMP to activate A-kinase without affecting the affinity of cAMP for this enzyme. It is concluded that the spasmolytic and anti-spasmogenic effects of AH 21-132 in BTSM may be related, in part, to its ability to inhibit Type IV PDE, increase the intracellular cAMP content and so activate A-kinase. A cyclic nucleotide-dependent mechanism is therefore proposed. In addition, the ability of AH 21-132 to augment cAMP-dependent phosphorylation in a cell-free system, when Type IV PDE is inhibited fully, provides the possibility that the observed relaxation elicited by high concentrations of AH 21-132, while cAMP-dependent, does not require any further increase in the intracellular cAMP concentration.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1983

Dissociation of the spasmolytic and metabolic effects of glucagon.

Glucagon and glucagon-(1-21)-peptide were equipotent with regard to inhibitory effect on the amplitude of electrically evoked contractions of the isolated guinea-pig ileum. The effect was not potentiated by isobutylmethylxanthine (IBMX) nor inhibited by phentolamine or propranolol. Both peptides inhibited intestinal motility in rabbits in vivo. Glucagon and equimolar doses of glucagon-(1-21)-peptide exerted a relaxing effect on the rabbit gall bladder in vitro and in vivo and increased bile flow in rats. Both peptides inhibited pentagastrin stimulated gastric acid secretion in cats. However, contrary to glucagon, glucagon-(1-21)-peptide did not increase blood glucose and plasma IRI levels after intravenous administration to rats in vivo. Whereas the entire glucagon molecule was required for the metabolic effects, the amino acid sequence (1-21) of glucagon exerted a full spasmolytic action on the enteric muscles and the biliary tree. The spasmolytic effects on these organs are therefore likely to be mediated via a mechanism that does not involve the activation of adenyl cyclase.

Animals↗

PubMed1995

Effects of spasmolytic and/or non-steroidal antiinflammatory drugs on muscle hyperalgesia of ureteral origin in rats.

Rats with artificial calculosis of one ureter develop hyperalgesia in the ipsilateral oblique musculature as evidenced by decreased vocalization threshold to electrical muscle stimulation lasting over a week. The aim of the study was to evaluate the effect on this hyperalgesia of spasmolytic anticholinergic and/or non-steroidal antiinflammatory drugs, common therapies for colic pain in humans. Rats implanted with a unilateral ureteral stone were treated for 10 days with: (1) saline; (2) hyoscine-N-butylbromide (15 mg/kg/day i.p.); (3) ketoprofen (15 mg/kg/day); or (4) hyoscine-N-butylbromide + ketoprofen (15 + 15 mg/kg/day). Oblique muscle vocalization thresholds were measured daily for 3 days before and 10 days after operation. Ipsilateral thresholds decreased significantly after stone implantation on: (1) seven days (max. 32%) for saline; (2) one day (max. 20%) for hyoscine-N-butylbromide; (3) one day (max. 18%) for ketoprofen, but did not change significantly for hyoscine-N-butylbromide + ketoprofen. These results indicate a protective effect against muscle hyperalgesia of ureteral origin by spasmolytic and antiinflammatory drugs, maximal when the two treatments are combined.

Animals↗

PubMed1995

Human spasmolytic polypeptide is a cytoprotective agent that stimulates cell migration.

BACKGROUND/AIMS: Gastric epithelium is attacked by acid, pepsin, and ingested agents. When a mucosal lesion occurs, the defect is rapidly closed by cell migration. Because spasmolytic polypeptide is rapidly produced at sites of injury, we postulated that human spasmolytic polypeptide (hSP) was important in mucosal repair. Recombinant hSP was used to test this hypothesis. METHODS: The ulcer healing effect of various doses of hSP administered orally and subcutaneously was examined using an indomethacin (20 mg/kg) restraint rat model of gastric damage. Stability of hSP in gastrointestinal juice was determined using size-exclusion chromatography. The effect of hSP on migration of human colonic carcinoma cell lines HT29 and SW480 was determined using collagen gel invasion and wounded monolayer assays. Proliferation was assessed using [3H]thymidine incorporation and toluidine blue staining. RESULTS: Infusions of hSP at 25 and 50 micrograms.kg-1.h-1 subcutaneously decreased gastric damage by about 50% (P < 0.01) without changing acid secretion. Oral hSP was ineffective. hSP was stable in gastrointestinal juice. hSP stimulated migration of HT29 cells but did not affect proliferation and had no effect on SW480 cells. CONCLUSIONS: hSP may play a key role in the early stages of mucosal repair by stimulating the initial re-epithelialization by cell migration.

Animals↗

PubMed1983

In vivo rat bladder: a new model to screen spasmolytic compounds.

A model for in vivo screening of spasmolytic compounds of the rat urinary bladder has been developed. It is physiological, specific, and adaptable. A filling volume of the bladder of 0.6-1 ml proved to be optimal. Agonists such as acetylcholine, KCl and BaCl2 exerted almost identical spasmogenic effects on both the in vivo and the in vitro model (isolated rat bladder strip). Moreover, the antagonistic effects of atropine, N-butylscopolammonium bromide, or flavoxate hydrochloride were directly comparable between the two models. Intravenously administered atropine was shown to be effective immediately; after intragastric application the maximum effect can not be observed until after 9 min. The in vivo rat bladder model presented is proposed to be a suitable method for advanced screening of spasmolytic compounds to include their absorption, biotransformation, and excretion.

Acetylcholine↗

PubMed1982

Evaluation of spasmolytic activity of clausmarin-A. a novel coumarin from Clausena pentaphylla (Roxb.) DC.

Crude ethanolic (50%) extracts of five species of Clausena exhibited varying degrees of spasmolytic activity on the isolated guinea-pig ileum preparation. The aerial parts of Clausena pentaphylla had maximum activity. Its active principle clausmarin-A, a novel coumarin terpenoid, was evaluated in detail for spasmolytic activity in various in vivo and in vitro test models. The activity of clausmarin A compared favourably with that of papaverine.

Anesthetics, Local↗

PubMed1992

The gene encoding the human spasmolytic protein (SML1/hSP) is in 21q 22.3, physically linked to the homologous breast cancer marker gene BCEI/pS2.

The human spasmolytic protein, SML1/hSP, an inhibitor of spasmolytic activity and gastric acid secretion in the pig, has been shown to exhibit homology to the pS2 protein, an estrogen-dependent breast cancer marker. Moreover, SML1/hSP and pS2 are expressed at the same localization in the normal stomach and during healing of the gastrointestinal tract. Here we report the chromosomal localization, obtained by in situ hybridization, of the hSP gene (SML1) to chromosome 21 at 21q22.3. Using pulsed-field gel electrophoresis, we found SML1 to be within 230 kb of the BCEI/pS2 gene.

Biomarkers, Tumor↗

PubMed1982

Spasmolytic agents. 2. 1,2,3,4-Tetrahydro-2-naphthylamine derivatives.

N-[(Benzoyloxy)alkyl]-1,2,3,4-tetrahydro-2-naphthylamine derivatives were synthesized from 1,2,3,4-tetrahydro-2-naphthylamines and evaluated for their spasmolytic. Some of these compounds showed a nerve-selective effect on colon rather than stomach in anesthetized dogs and were found to be equal to or more active than the reference drug (mebeverine). The biological data have indicated some structure-activity relationships. Among these compounds, N-ethyl-N-[6-(3,4-dimethoxybenzoyl)oxy]hexyl]-1,2,3,4-tetrahydro-6-methoxy-2- napththylamine hydrochloride (63) was found to be the most active spasmolytic agent.

Animals↗

PubMed2004

Spasmolytic effects, mode of action, and structure-activity relationships of stilbenoids from Nidema boothii.

A CH(2)Cl(2)-MeOH (1:1) extract prepared from the whole plant of Nidema boothii inhibited spontaneous contractions (IC(50) = 6.26 +/- 2.5 microg/mL) of the guinea-pig ileum. Bioassay-guided fractionation of the active extract led to the isolation of the novel spiro compound 1, which was given the trivial name nidemone, and the new dihydrophenanthrene 3, characterized as 1,5,7-trimethoxy-9,10-dihydrophenanthrene-2,6-diol. In addition, the known stilbenoids aloifol II (2), 1,5,7-trimethoxyphenanthrene-2,6-diol (4), ephemeranthoquinone (5), gigantol (6), ephemeranthol B (7), 2,4-dimethoxyphenanthrene-3,7-diol (8), lusianthridin (9), and batatasin III (10) were obtained. The isolates were characterized structurally by spectroscopic data interpretation. Compounds 2-6, 9, and 10 induced notable concentration-dependent inhibition of the spontaneous contractions of the guinea-pig ileum with IC(50) values that ranged between 0.14 and 2.36 microM. Bibenzyl analogues 23-35 were synthesized and tested pharmacologically. The results indicated that for maximum spasmolytic activity the bibenzyls should have oxygenated substituents on both aromatic rings; on the other hand, methylation of free hydroxyl groups as well as the increment of oxygenated groups in relation to compounds 6 and 10 decreased the smooth muscle relaxant activity. It was also demonstrated that bibenzyls 6 and 10 might exert their spasmolytic action not only by a nitrergic mechanism but also by inhibiting CaM-mediated processes.

Animals↗

PubMed2006

Spasmolytic effects of nonprenylated rotenoid constituents of Boerhaavia diffusa roots.

Boerhaavia diffusa is an Ayurvedic remedy used traditionally for the treatment of a number of diseases, including those affecting the gastrointestinal tract. In the current investigation, a methanol extract obtained from roots of B. diffusa exhibited a significant spasmolytic activity in the guinea pig ileum, probably through a direct effect on the smooth muscle. A detailed phytochemical analysis of this methanol extract led to the isolation of one new (12) and six known (6-11) rotenoid derivatives. The structure of the new compound was determined through interpretation of its MS and NMR data. All the isolated rotenoids were evaluated for their effect on intestinal motility in vitro, and the results obtained showed unambiguously that they are active spasmolytic constituents. Preliminary structure-activity relationships for this class of compounds are suggested.

Medicine, Ayurvedic↗

PubMed2003

Spasmolytic polypeptide-expressing metaplasia (SPEM) associated with gastric cancer in Iceland.

Recent studies have described a spasmolytic polypeptide-expressing metaplastic cell lineage (SPEM) in the gastric fundic mucosa associated with both chronic H. pylori infection and gastric adenocarcinoma. We investigated the association of SPEM both with early gastric adenocarcinoma and in biopsies taken from patients prior to diagnosis of cancer. Two cohorts were examined. First, gastric resections from 29 patients with early gastric cancer were examined. Second, biopsies taken from 18 patients prior to the diagnosis of gastric cancer were compared with their respective resection specimens as well as with control biopsies from a cohort of 19 patients diagnosed with gastritis without subsequent development of cancer. The presence of SPEM and intestinal metaplasia (IM) adjacent to and distant from the cancer was compared and spasmolytic polypeptide (SP) immunostaining within dysplastic/cancerous cells was identified. SPEM was present adjacent to cancer in all early cancer cases where the tumor was located in the body or at the body/antrum junction, and was present in the body mucosa distant from the cancer in 76% of cases. Intestinal metaplasia was found adjacent to the tumor in 76% of cases and in body sections in 52% of resections. SP immunostaining was noted within cancer cells in 62% of tumors, and within dysplastic cells in 76% of resections where dysplasia was present. SPEM was present in 82% of the biopsies obtained prior to the diagnosis of cancer, compared with only 37% in the gastritis cohort. IM was present in only 57% of biopsies. In conclusion, SPEM is strongly associated with early gastric cancers and is observed in gastric biopsies prior to the development of cancer. In addition, early gastric cancers demonstrated a high incidence of SP expression. These results suggest that SPEM merits consideration as an important pre-neoplastic gastric lesion.

Adenocarcinoma↗