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PubMed2001

Spasmolytic effects of three harmala alkaloids on guinea-pig isolated trachea.

The present study examined and compared the spasmolytic effects of 3 harmala alkaloids, harmine, harman, and harmaline, on carbachol-, histamine-, and KCl-induced contractions of guinea-pig isolated tracheal preparations. All 3 compounds relaxed the tracheal preparations contracted by these spasmogens with similar or different EC50 values, harmine being the most potent one. The cumulative concentration-response curves of all 3 compounds for carbachol-induced contraction were shifted to the right by propranolol (1 microM) pretreatment, indicating the involvement of the activation on the beta-adrenoceptors. All 3 compounds shifted the concentration-response curves of carbachol to the right in a parallel manner with the pA2 values comparable with their relaxation EC50 values, indicating a competitive antagonism at the muscarinic receptors. Receptor binding assays indicated that all 3 compounds interacted with lung muscarinic receptors (Ki = 11-13 microM), histamine H1 receptors (Ki = 27-107 microM), and beta2-adrenoceptors (Ki = 20-51 microM). Therefore, in addition to their actions on receptor-linked and voltage-dependent Ca2+ channels as reported in other types of smooth muscle, the present study suggests that the actions on muscarinic receptors, histamine H1 receptors, and beta2-adrenoceptors are also involved in their spasmolytic effects on airway smooth muscles.

Adrenergic beta-Antagonists↗

PubMed2005

Norsecofriedelanes as spasmolytics, advances of structure-activity relationships.

Galphimia glauca has been used in Mexican traditional medicine as a remedy for the treatment of nervous excitement and other central nervous system disorders. Previous work has demonstrated the sedative, spasmolytic and anticonvulsant activities of an extract obtained from the aerial parts of this plant. A norsecotriterpene named galphimine B was found to be responsible for the sedative and spasmolytic activities. Activity-guided fractionation making use of the guinea pig ileum as an experimental system was used for the isolation of five compounds. They were identified as a new norsecotriterpene, galphimine J (2) and four known norsecotriterpenes (1, 3 - 5). Nine derivatives of 3 (5, 6 and 8 - 14) were obtained by chemical modification of the alpha,beta-unsaturated lactone, the olefinic bonds on the A and E rings, the hydroxy groups on ring B, or a combination thereof, and a structure-activity correlation study was carried out. The results indicate the existence of a clear structure-activity relationship. They suggest the involvement of the double bond in the E ring as well as the hydroxy groups at C-4, C-6 and C-7 in biological activity and emphasize the relevance of a free OH group at C-6 and C-4.

Animals↗

PubMed2005

Mechanism involved in the spasmolytic effect of a mixture of two triterpenes, cycloartenol and cycloeucalenol, isolated from Herissanthia tiubae in the guinea-pig ileum.

The smooth muscle relaxant properties of a mixture of the two triterpenoids cycloeuclalenol and cycloartenol (CC) isolated from Herissanthia tiubae (Malvaceae) were studied in several smooth muscle preparations. CC inhibited contractions induced by carbachol, histamine and KCl in the guinea-pig ileum, but no spasmolytic activity was found in guinea-pig trachea or rat aorta. In guinea-pig ileum, concentration-response curves to carbachol and CaCl (2) in high K(+) were shifted to the right by CC in a concentration-dependent manner with slopes of the Schild plot differing from the unity. IC(50) values were 3.4 +/- 0.8 x 10 (-5) M and 8.44 +/- 1.87 x 10 (-5) M for carbachol and CaCl(2), respectively. The phorbol ester TPA, which activates protein kinase C (PKC), potentiated contractions induced by submaximal concentrations of carbachol. This potentiation was inhibited by CC. Desensitization of PKC by TPA completely abolished the inhibition produced by CC on carbachol-induced contractions. Together, our results indicate that inhibition of PKC is involved in the spasmolytic effect of CC in the guinea-pig ileum.

Animals↗

PubMed1996

Spasmolytic activity of a lipidic extract from Sabal serrulata fruits: further study of the mechanisms underlying this activity.

The mechanisms involved in the spasmolytic effect of a lipidic extract from Sabal serrulata fruits were investigated. The extract relaxed vanadate-induced contractions on rat uterus incubated in a calcium free solution (EC50 = 11.41 +/- 1.38 micrograms/ml). The modification of the effect by a cyclooxygenase inhibitor (indomethacin), a protein kinase A inhibitor (TPCK), calcium modifying drugs, and drugs interfering with transcription and protein synthesis has been assayed. The effect was unmodified by a 3 microM concentration of indomethacin, (EC50 = 8.77 +/- 1.28 vs 11.41 +/- 1.38 micrograms/ml) and a 5 micrograms/ml concentration of the transcription inhibitor, actinomycin D, (EC50 = 8.23 +/- 2.19 vs 11.41 +/- 1.38 micrograms/ml). The inhibitor of intracellular calcium mobilization TMB-8 (0.1 mM), the Na+/Ca+2 exchanger inhibitor amiloride (0.1 mM), the calcium chelator BAPTA-AM (50 microM), the PKA inhibitor TPCK (10 microM), and the protein synthesis inhibitor cycloheximide (10 micrograms/ml) significantly shifted to the right the dose-response curve of the extract (EC50 = 17.83 +/- 1.87 micrograms/ml, 18.61 +/- 2.50 micrograms/ml, 35.28 +/- 9.13 micrograms/ml, 33.99 +/- 3.07 micrograms/ml, and 27.31 +/- 4.93 micrograms/ml, respectively, vs 11.41 +/- 1.38 micrograms/ml). These results suggest that the effect of the lipidic extract from S. serrulata fruits could be partially due to Na+/Ca+2 exchanger activation and interference with intracellular calcium mobilization, and point to cAMP as a possible mediator. Moreover, protein synthesis seems to be involved in the spasmolytic activity.

Animals↗

PubMed2000

A comparison of the spasmolytic effects of olprinone and aminophylline on serotonin-induced pulmonary hypertension and bronchoconstriction with or without beta-blockade in dogs.

In the present study in dogs, we compared with aminophylline the spasmolytic effects of olprinone, a novel phosphodiesterase 3 inhibitor, on serotonin-induced pulmonary hypertension (PH) and bronchoconstriction. Mongrel dogs were anesthetized with pentobarbital. PH and bronchoconstriction were induced with serotonin: 10 microg/kg + 1 mg x kg(-1) x h(-1), and assessed as % changes in pulmonary vascular resistance and bronchial cross-sectional area (basal = 100%). Initially, the relaxant effects of olprinone (n = 8: 0-1000 microg/kg) and aminophylline (n = 8: 0-100 mg/kg) were compared. Pulmonary vascular resistance and bronchial cross-sectional area were assessed before and 30 min after serotonin infusion began and 5 min after each dose of olprinone or aminophylline. We then determined whether propranolol (0.4 mg/kg) reversed the relaxation induced by olprinone (1000 microg/kg, n = 6) or aminophylline (100 mg/kg, n = 6) compared with saline (n = 6 each). Olprinone and aminophylline dose-dependently attenuated both PH and bronchoconstriction (olprinone > aminophylline: -logED(50)[mean] for PH and bronchoconstriction 5.37+/- 0.35[4.24 microg/kg] vs. 1.60+/-0.23[25.4 mg/kg] and 4.06+/-0.12[87.8 microg/kg] vs. 1.51+/-0.21[30.6 mg/kg], respectively). In addition, olprinone produced more potent pulmonary vasodilation than bronchodilation while aminophylline was equipotent. In addition, there was a significant increase in plasma catecholamines after olprinone (> or =100 microg/kg) and aminophylline (> or =10 mg/kg). With the exception of aminophylline-induced bronchodilation, propranolol did not reverse any of the other effects measured. Therefore, the spasmolytic effects of olprinone are independent of plasma catecholamines, while the bronchodilating effect of aminophylline may partially involve increased levels of circulating catecholamines.

Adrenergic beta-Antagonists↗

PubMed2002

Association of spasmolytic polypeptide-expressing metaplasia with carcinogen administration and oxyntic atrophy in rats.

Spasmolytic polypeptide (TFF2)-expressing metaplasia (SPEM) is a gastric metaplastic lineage associated with the development of intestinal-type gastric adenocarcinoma. To study the etiology of this potential neoplastic precursor metaplasia, we used surgical rat models of remnant gastric adenocarcinoma studied with and without exposure to nitroso carcinogen. Animals with truncal vagotomy without duodenogastric reflux procedures demonstrated normal mucous neck cell spasmolytic polypeptide (SP) immunostaining. In these animals, anti-proliferating cell nuclear antigen (PCNA)-labeled nuclei were found in the normal midgland progenitor zone. Rats that received anatomic alterations that augmented the degree of duodenogastric reflux, however, revealed expansion of basally placed SP immunoreactive cells with early phenotypic changes of SPEM. Seventy percent of animals with antrectomy and carcinogen (with or without vagotomy) developed SPEM at the base of the gastric mucosa. In association with the appearance of this metaplastic lineage, a distinct second zone of PCNA-labeled nuclei developed in the deepest portion of the mucosa. Of interest, three animals demonstrating these changes developed intestinal-type gastric adenocarcinoma. Finally, we studied the immunostaining pattern of intrinsic factor, normally a chief cell marker in rat fundic mucosa. In animals with SPEM, we observed coexpression of SP and intrinsic factor in SPEM cells at the base of the mucosa. These findings support our hypothesis that SPEM develops from a second progenitor cell population, reflecting either the unmasking of a cryptic zone or transdifferentiation of chief cells.

Animals↗

PubMed1998

Oral human spasmolytic polypeptide protects against aspirin-induced gastric injury in rats.

Spasmolytic polypeptide (SP) is a member of the trefoil peptide family; gut peptides that participate in the protection and repair of the gastric mucosa. Previous studies have failed to agree on the mode of action of human SP (hSP). We investigated the effect of orally administered human SP on the protection and repair of rat gastric mucosa in an established in vivo model of damage induced by the non-steroidal anti-inflammatory drug aspirin (ASA). The integrity of the gastric mucosa was quantified in four ways: the temporal change in transmucosal potential difference (PD), area of macroscopic damage by planimetry, relative area of microscopic damage by histological morphometry, and the number of deep erosions per centimetre of mucosa sectioned. Human SP (200 micromol/L) administered orally before, or in combination with ASA significantly reduced the fall in PD, the area of microscopic damage, and the number of deep erosions (P < 0.05). The area of macroscopic damage was significantly reduced only in rats where hSP (200 micromol/L) was given in conjunction with ASA (P < 0.05). Human spasmolytic polypeptide (70 or 200 micromol/L) administered after ASA failed to hasten the re-establishment of PD or stimulate the repair of the gastric mucosa in the 90 min following injury (P > 0.05, compared with ASA alone). We conclude that hSP prevents gastric mucosal damage by its topical actions, probably by a rapid interaction with luminal mucins or epithelial cells, but fails to stimulate early restitution in the injured gastric mucosa.

Administration, Oral↗

PubMed1983

Coronary vasodilatory, spasmolytic and cAMP-phosphodiesterase inhibitory properties of dihydropyranocoumarins and dihydrofuranocoumarins.

Twenty-three dihydropyrano- and dihydrofuranocoumarins, most of plant origin, were examined for their effects on the coronary flow of isolated perfused guinea-pig heart, on the Ba2+-induced spasms in isolated guinea-pig ileum, on the cAMP level in guinea-pig heart homogenate and on the cAMP metabolising activity of purified beef heart cAMP-phosphodiesterase. For certain esters of dihydropyranocoumarin- and dihydrofuranocoumarin alcohols coronary vasodilatory and spasmolytic activities comparable to those of papaverine were observed. A very close correlation between the coronary vasodilatory and the spasmolytic activity was found. The most potent structures maximally increased the cAMP level from 19 pmol/mg protein to about 60 pmol/mg protein and inhibited the cAMP-phosphodiesterase activity with about 90%. The potencies were comparable to those of papaverine. A significant correlation was obtained between the coronary vasodilatory and the cAMP-phosphodiesterase inhibitory activity. The results indicate involvement of cAMP-phosphodiesterase inhibition in coronary vasodilatory effects of acyloxydihydropyrano- and acyloxydihydrofurano-coumarins.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1997

Pancreatic spasmolytic polypeptide protects the gastric mucosa but does not inhibit acid secretion or motility.

The objectives of these studies were to examine whether the trefoil peptide porcine pancreatic spasmolytic polypeptide (PSP) had gastric mucosal protectant properties similar to its human equivalent human spasmolytic polypeptide (hSP) and to confirm the antisecretory and antimotility action of the peptide. PSP and recombinant hSP reduced gastric mucosal damage caused by a combination of subcutaneous indomethacin and restraint stress in the conscious rat. At a dose of 500 micrograms/kg bolus plus 500 micrograms.kg-1.h-1 sc, PSP significantly reduced the total area of damage by 58%. PSP at a dose of 150 micrograms/kg iv had no inhibitory effect on pentagastrin-stimulated gastric acid secretion in the perfused stomachs of anesthetized rats. This lack of antisecretory activity was confirmed in vitro using an isolated stomach preparation from the immature rat. PSP and hSP at concentrations up to 800 nM did not inhibit electrically or chemically evoked contractions of the guinea pig ileum and duodenum in vitro. Thus antisecretory and antimotility actions do not underlie the mucosal protectant properties of PSP. PSP did, however, stimulate cell migration, and this may, at least in part, account for its protectant properties.

Animals↗

PubMed1991

S-adenosylhomocysteine levels are not involved in the spasmolytic activity of 3-deazaadenosine in guinea-pig lung parenchyma.

The effects of two S-adenosylhomocysteine (SAH) hydrolase inhibitors, MDL 28,842 and 3-deazaadenosine (3-DAA), on the tissue levels of SAH, cAMP and cGMP and on the contractile responses to leukotriene D4 and histamine were compared in guinea-pig lung parenchyma. MDL 28,842 and 3-DAA (both in the presence of L-homocysteine) increased tissue levels of SAH to the same degree, indicating that both compounds had inhibited SAH hydrolase. However, only 3-DAA inhibited the contractile response of the lung parenchyma. The spasmolytic activity of 3-DAA was inhibited by co-incubation with MDL 28,842, suggesting that 3-DAA must be metabolized by SAH hydrolase, probably to 3-deazaadenosylhomocysteine, in order to exert its effect. 3-DAA did not elevate tissue levels of cAMP or cGMP. Although the mechanism by which 3-DAA exerts its spasmolytic effects is unknown, direct inhibition of methyltransferase is a plausible explanation. These data indicate that SHA levels do not regulate the contractile response of guinea-pig lung parenchyma.

Adenosine↗

PubMedDate not supplied

Otilonium bromide: a selective spasmolytic for the gastrointestinal tract.

Experimental studies have shown that otilonium bromide (OB) inhibits both baseline and chemically or physically stimulated gastrointestinal motility. The spasmolytic activity of OB in the gastrointestinal tract occurs at doses that do not affect gastric secretion or produce typical atropine-like side-effects. The mechanism of action is composite: interference with calcium ion movement from intra- and extracellular sites; blockade of calcium channels; and binding to muscarinic receptors and tachykinin neurokinin-2 receptors. Pharmacokinetic studies have shown that OB accumulates in the lower intestine and has poor systemic absorption. Clinical studies have confirmed OB as a potent spasmolytic drug with a good tolerability profile. Studies in patients with irritable bowel syndrome demonstrated OB to be superior to placebo and reference drugs in parameters such as pain, abdominal distension and motility. The composite and local mechanism of OB action reduces hypermotility and modulates visceral sensation: factors thought to be responsible for pain improvement recorded in clinical trials. The compound is marketed worldwide and no serious adverse events have been reported as yet, confirming its excellent tolerability.

Animals↗

PubMed1986

Mechanisms of spasmolytic action of bile salts in depolarized guinea-pig taenia coli.

The effects of bile salts on the calcium movements and the electrical activity of the guinea-pig taenia coli were investigated and compared with those of papaverine in order to explore the mechanisms of their spasmolytic action. Four bile salts, deoxycholate, chenodeoxycholate, ursodeoxycholate and cholate, as well as papaverine, dose-dependently relaxed the depolarized taenia coli. The bile salts and papaverine caused the acceleration of 45Ca-efflux with the synchronous muscle relaxation and inhibited the cellular 45Ca-uptake by the depolarized muscle preparation. The bile salts also inhibited the increased spike frequency and the developed tension in the depolarized taenia coli. Furthermore, the dose-relaxation curves for bile salts were shifted to the right as the external calcium ion was increased. These findings suggest that the bile salts, like papaverine, may exert their spasmolytic action through accelerating the Ca-efflux and inhibiting the Ca-influx of the smooth muscle cells.

Animals↗

PubMed1990

Possible mechanisms of spasmolytic action of bile salts on the isolated guinea-pig gallbladder.

The spasmolytic action of bile salts on gallbladder smooth muscle could explain the alleged relief of biliary colic seen during bile acid therapy. The mechanisms of spasmolytic action of bile salts, ursodeoxycholate and deoxycholate were studied in the isolated gallbladder of guinea-pigs. The bile salts accelerated the 45Ca-efflux from the gallbladder with synchronous relaxation and inhibited the cellular 45Ca-uptake by the depolarized muscle preparation. Further, they sensitively inhibited CaCl2-induced contraction of the depolarized muscle. The tissue cyclic AMP content of the gallbladder was significantly elevated by the bile salts. Dibutyryl cyclic AMP mimicked the effects of bile salts on the Ca-efflux and the muscle relaxation, but showed no effect on the cellular Ca-uptake. From these results, it is suggested that the bile salts produce the relaxant action through accelerating Ca-efflux, which is probably coupled with the elevation of the cellular cyclic AMP level, and through suppressing the Ca-influx across the cell membrane.

Animals↗

PubMed1979

Standard treatment of dysmenorrhea with special reference to treatment with spasmolytics and hormones.

A survey of the methods of treatment used in dysmenorrhea is given. Special importance is focused on most frequently used methods of treatment in recent years, e.g. treatment with spasmolytics and hormones. The spasmolytics are by no heans effective in all cases in treatment of dysmenorrhea and undesirable side-effects are of frequent occurrence. When oral contraceptives became available it was found that they represented an effective remedy for dysmenorrhea. Whether the Pill should be used for treatment of dysmenorrhea must depend on whether there is also a desire of contraception or not. It is not unusual that women with severe dysmenorrhea have to abandon oral contraceptives because of side-effects or possible risks of this treatment. There is a need for alternative treatment, and the new effective prostaglandin synthetase inhibitors may meet this need.

Analgesics↗

PubMed2001

Bronchodilator, spasmolytic and calcium antagonist activities of Nigella sativa seeds (Kalonji): a traditional herbal product with multiple medicinal uses.

OBJECTIVE: The seeds of Nigella sativa locally known as "Kalonji" has been used in traditional medicine for the treatment of a variety of diseases including diarrhoea and asthma. The crude extract of N. sativa seeds (Ns.Cr) was studied in vitro for its possible spasmolytic and bronchodilator activities to rationalize the folkloric uses. METHODS: Isolated rabbit jejunum and guinea-pig tracheal preparations were set up in Tyrode's and Kreb's solutions respectively and aerated with 5% CO2 in oxygen. Isotonic and isometric responses were measured on Bioscience oscillograph and Grass polygraph respectively. RESULTS: The Ns.Cr caused a dose-dependent (0.1-3.0 mg/ml) relaxation of spontaneous contractions in rabbit jejunum. Ns.Cr also inhibited K(+)-induced contractions in a similar dose range, suggestive of calcium channel blockade (CCB). This effect was confirmed when pretreatment of the tissue with Ns.Cr, produced a dose-dependent shift in the Ca++ dose-response curves to the right similar to that of verapamil, a standard calcium channel blocker. In guinea-pig trachea, it caused relaxation of carbachol-, histamine- or K(+)-induced contractions indicating CCB. Activity-directed fractionation revealed that the CCB activity is concentrated in the petroleum ether fraction, which was found to be approximately 10 times more potent than the crude extract both in jejunum and tracheal preparations. CONCLUSION: These data indicate that the crude extract of Nigella sativa seeds exhibits spasmolytic and bronchodilator activities mediated possibly through calcium channel blockade and this activity is concentrated in the organic fraction. Its usefulness for diarrhoea and asthma in traditional medicine, appears thus to be based on a sound mechanistic background.

Animals↗

PubMed1975

[Spasmolytic activity of a piperazine derivative under the code number of 4P-79].

The author examined the pharmacologic spasmolytic action of a pyperasine derivative under the code 4P-79. She examined the effect of the compound on four types of spasms, induced by acethylcholine, nicotine, histamine and serotonine on an isolated rabbit intestine. The mean effective concentrations were determined and they were compared with the mean effective concentrations of papaverine and benzylharmine, estimated in parallel experiments. It was found that 4P-79 had high spasmolytic activity, surpassing several times that of the preparations used for comparison. There was a marked antiserotonine effect on the first place. The compound was examined also on an intestine "in situ" by the method of Nikolaev Comparative experiments with papaverine and deseryl were conducted.

Acetylcholine↗

PubMed1979

[Action mechanism of vascular spasmolytics. 5. Drug-related relaxation and adenosine-3',5'-monophosphate content of isolated coronary arteries under conditions of fluoride-induced contracture].

Tetracaine and SKF 525-A as well as stimulators of adenylate cyclase and inhibitors of the nucleoside-3',5'-monophosphate phosphodiesterase have spasmolytic effects. At the fluoride-iuduced contracture -- a form of contracture independent of extracellular calcium -- tetracaine and SKF 525-A effect an additional increase in muscular tension. Their relaxing effect evidently presupposes a functioning calcium exchange. Drugs acting on the cAMP system have invariably spasmolytic effects at this contracture model, although they produced no change of the cAMP content under these conditions. An increase in total cAMP content is not obviously a necessary condition for the occurrence of drug-induced relaxation.

Adenosine↗

PubMed1987

[The spasmolytic activity of propiverine and some of its structural analogs].

The spasmolytic activity of propiverine and its corresponding methyl ether analogue was investigated in the isolated ileum and urinary bladder of the rat. It could be demonstrated that the antispasmodic properties of propiverine were, in contrast to its methyl ether analogue, not only based on a blockade of muscarinic receptors but were also a consequence of nonspecific papaverine-like effects. Investigations with three putative metabolites showed that the alcohol derivative O-desalkylpropiverine was about two orders of magnitude more potent than propiverine itself in blocking spasmogenic effects of the agonist arecaidine propargyl ester. In contrast no spasmolytic effect could be observed after application of the corresponding carboxylic acids (benzilic acid propyl ether; benzilic acid 2-hydroxypropyl-ether.

Adrenergic alpha-Antagonists↗