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PubMed1975

Papaverine, cyclic AMP and the dependence of the rat aorta on extracellular calcium.

The spasmolytic effects of papaverine and dibutyryl cyclic AMP (db-cAMP) were compared on isometric contractile responses induced by addition of increasing amounts of external calcium to K+-depolarized or noradrenaline-stimulated rat aorta strips. Papaverine at a concentration active on depolarized strips (3 times 10(-5) moles/1) reduced the maximal contraction (Emax) elicited by Ca2+ in these preparations, while db-cAMP did not. Contrary to what was observed on depolarized aortae, the degree of inhibition of noradrenaline-stimulated strips did not decrease with increasing extracellular calcium concentration (Ca)e. Both db-cAMP and papaverine at a concentration which did not depress Emax (5 times 10(-6) moles/1) potentiated the relaxing effect of high (Ca)e on contractions elicited by noradrenaline. In conclusion, cyclic AMP is probably implicated in the mode of action of papaverine on the noradrenaline-stimulated rat aorta. At a concentration active on depolarized strips, papaverine is also able to impair contractility directly.

Animals↗
PubMed1980

Effects of perhexiline on contractile response of rabbit aorta to norepinephrine and potassium.

Perhexiline (3.2 X 10(-7)-6.4 X 10(-6) M) and verapamil (2 X 10(-8)-2 X 10(-7) M) inhibited the contraction of rabbit aorta induced with 40 mM K+ and with low concentrations (5.9 X 10(-9)-5.9 X 10(-8) M) of norepinephrine more effectively than the contraction induced by higher concentrations of norepinephrine. The tension induced by 1.2 X 10(-6) M norepinephrine was augmented with the above concentrations of perhexiline and verapamil. Higher concentrations (3.2 X 10(-5)-6.4 X 10(-5) M) of perhexiline significantly reduced the peak tension induced by norepinephrine. The results suggest that perhexiline is a Ca2+ antagonist and also has an unspecific spasmolytic action.

Animals↗
PubMed1983

The relaxing effect of caerulein on isolated human internal anal sphincter.

In the attempt to find a pharmacological treatment for the spasm of the internal anal sphincter, usually associated with anal fissures, the activity of caerulein on human internal and sphincter was investigated in vitro and in vivo. In the isolated distal part of the internal and sphincter, caerulein (0.61 microM) depressed resting muscle tone and caused marked relaxation of norepinephrine-contracted preparations. The effect of caerulein was reduced by atropine and increased by physostigmine, suggesting that it was largely due to the release of acetylcholine. In vivo, intravenous infusion of caerulein, both to healthy volunteers and to subjects affected by anal fissures and anal sphincter hypertone, did not modify the values of internal anal sphincter pressure. The lack of spasmolytic effect of caerulein in vivo may have been due to the relatively unimportant influence of cholinergic neurons on the control of internal anal sphincter tone. Alternatively, the presence of fibrosis caused by anal fissures could hinder sphincter relaxation.

Acetylcholine↗
PubMed1984

Differential inhibition of LTD4-mediated bronchopulmonary effects by salbutamol.

The effects of systemically administered salbutamol on LTD4-induced changes in pulmonary mechanics and tracheal microvascular permeability in the anesthetized guinea pig were compared. Salbutamol (50 micrograms/kg i.v.) virtually abolished the decreases in Cdyn and Gaw produced by i.v. LTD4, but did not alter the LTD4-induced increase in tracheal microvascular permeability. Thus, it appears that although the spasmolytic properties of salbutamol may profoundly inhibit LTD4-mediated bronchoconstriction, salbutamol might only be of limited value in reducing the airway inflammatory effects of LTD4.

Airway Resistance↗
PubMed1986

Actions and interactions of adenosine, theophylline and enprofylline on the guinea-pig spirally cut trachea.

Adenosine, theophylline and enprofylline induced concentration-dependent relaxations of guinea-pig isolated tracheal spirals whether they had intrinsic tone or were precontracted with carbachol or histamine. The potency order was enprofylline greater than theophylline greater than adenosine and the maximum relaxation in absolute terms was generally less for adenosine. The maximum relaxation (measured in absolute terms of change in tension) induced by the three spasmolytics in preparations with intrinsic tone was generally less than in precontracted tissues. This was attributed to the higher resting tone of precontracted tissues than the intrinsic tone. The adenosine transport inhibitor dipyridamole potentiated adenosine but not theophylline or enprofylline so that the potency order became adenosine greater than enprofylline greater than theophylline. Without dipyridamole, theophylline in a concentration producing 10-30% relaxation of the trachea, failed to antagonize adenosine. However, in the presence of dipyridamole, adenosine was antagonized, indicating that the relaxation by adenosine was mediated via an extracellular P1 receptor. Enprofylline, in a concentration producing equivalent direct effects, failed to antagonize adenosine. It is concluded that the tracheal relaxation by xanthines is independent of adenosine antagonism.

Adenosine↗
PubMed1991

Comparison of isobutyl nitrate and isobutyl nitrite: tolerance and cross-tolerance to glyceryl trinitrate.

This study includes the first systematic comparison of an organic nitrate with the corresponding organic nitrite-isobutyl nitrate and isobutyl nitrite. The spasmolytic activity of the nitrite on isolated rabbit aortic strips was stronger, more rapid in onset, but less stable than the activity of the nitrate. In vitro tolerance to glyceryl trinitrate and isobutyl nitrite greatly weakened the activity of isobutyl nitrate, respectively, but had much less effect on isobutyl nitrite. Possible reasons for these differences are discussed.

Animals↗
PubMed1992

Epithelial modulation of the relaxant activity of atriopeptides in rat and guinea-pig tracheal smooth muscle.

Three peptide components of atrial natriuretic factor (ANF) caused relaxation of carbachol-contracted guinea-pig isolated tracheal smooth muscle. These were the 1-28, 5-28 and 5-27 peptide sequences (ANF(1-28), ANF-(5-28) and ANF-(5-27)). The peptides were 10-30 times more potent in epithelium-denuded than in epithelium-intact preparations. In the absence of airway epithelium, ANF-(1-28) was the most potent relaxant (mean pD2 = 7.40 +/- 0.08), with ANF-(5-27) and ANF-(5-28) 2-3 fold less potent. The neutral endopeptidase inhibitor phosphoramidon (1 microM) increased the potency of ANF-(5-27) in both epithelium-intact and epithelium-denuded guinea-pig tracheal rings. In contrast, removal of the epithelium from rat trachea, or pretreatment with phosphoramidon (1 microM) decreased relaxant responsiveness to ANF-(5-27). Thus, in rat trachea, epithelial endopeptidase may convert ANF-(5-27) to a more active relaxant peptide. Human bronchial preparations with or without epithelium, obtained from non-diseased lung samples and from a single sample of asthmatic lung, were virtually unresponsive to ANF-(5-27). Consistent with the spasmolytic effects of ANF in guinea-pig trachea, autoradiographic analysis revealed the presence of a sparse population of specific binding sites for [125I]ANF-(1-28) over both tracheal smooth muscle and epithelium. The present study shows that the relaxant effects of atriopeptins in rat and guinea-pig airway smooth muscle were modulated by the epithelium and the activity of neutral endopeptidase. However, marked species differences in airway smooth muscle responsiveness to ANF and in the modulatory role of the airway epithelium were evident.

Animals↗
PubMed1996

Blocking effects of otilonium on Ca2+ channels and secretion in rat chromaffin cells.

We describe here the effects of otilonium bromide (an anticholinergic agent widely used as an intestinal spasmolytic) on whole-cell currents through Ca2+ channels (IBa) and catecholamine secretion in rat adrenal glands and isolated rat chromaffin cells. Otilonium blocked the peak IBa current in voltage-clamped chromaffin cells in a concentration-dependent manner; the IC50 to block IBa was 4.7 microM. Blockade was not accompanied by a significant shift in the I-V relationship for IBa, suggesting that such blockade was not affecting a specific subtype of Ca2+ channel. When given intracellularly through the patch pipette, otilonium (10 microM) did not block IBa. However, its external application to the same cell (10 microM) reversibly reduced IBa by 70%. Otilonium caused a concentration-dependent blockade of catecholamine release from perfused rat adrenal glands intermittently stimulated with methacholine, high K+ or histamine. The IC50 to block secretion after a 5 min incubation with otilonium was 0.02, 0.7 and 3 microM, respectively, for methacholine, K+ and histamine. The blocking effects of otilonium were fully reversible at concentrations below 10 microM. The Ca2+ channel agonist Bay K 8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyr idine-5- carboxylate) partially antagonized the effects of otilonium on K(+)-evoked secretion and accelerated the time course of recovery from inhibition. The results are compatible with the idea that otilonium blocks Ca2+ entry into chromaffin cells by blocking voltage-dependent Ca2+ channels. This would lead to a limitation in the rise in cytosolic Ca2+ at secretory sites and to inhibition of catecholamine release in response to stimulation of chromaffin cells.

Animals↗
PubMed1990

Expression of spasmolysin (FIM-A.1): an integumentary mucin from Xenopus laevis.

In the past, a unique type of precursor for a secretory protein was discovered. It contains a central repetitive domain rich in threonine residues and terminal cysteine-rich domains. Due to striking homologies of these terminal domains with pancreatic spasmolytic polypeptide, originally the name "prepro-spasmolysin" was proposed. Here we show that the mature protein has a MW of about 130 kDa, consisting of about 70% carbohydrate and 30% protein. Similar O-linked glycoproteins have been found in mucins from human intestine. For this and numerous other reasons we decided to rename this glycoprotein "frog integumentary mucin A.1" (FIM-A.1). Furthermore, analysis of the protein with specific antibodies against the predicted C-terminal end indicates that FIM-A.1 is probably not processed at pairs of basic residues. In situ hybridization as well as immunofluorescence studies revealed that FIM-A.1 is expressed and stored exclusively in mature mucous glands of Xenopus laevis skin. Only cone cells at the proximal part of these glands do not synthesize FIM-A.1. In contrast, all other physiologically active peptides from X. laevis skin investigated so far are synthesized in granular glands. A hypothetical function of FIMs for defense against microbial infections is discussed.

Amino Acid Sequence↗
PubMed1990

Dermal glands of Xenopus laevis contain a polypeptide with a highly repetitive amino acid sequence.

Mature dermal glands of Xenopus laevis contain storage granules with a characteristic ellipsoid shape. These granules contain, as a minor component, a heat-stable, acidic polypeptide with an apparent molecular mass of 75 kDa. Using antibodies against this protein, positive clones were isolated from a cDNA expression library prepared from skin of X. laevis. One of the cloned cDNAs encodes a pre-protein with a typical signal sequence and a mature part of 396 amino acids. The protein contains 33 copies of the sequence Gly-Gly/Glu-(Ala-Pro)2-4-Ala-Glu. Using the single-letter code for the four predominant amino acids, we have termed this polypeptide the APEG protein. Near its carboxy-terminus, one segment has been found with an amino acid sequence similar to that of spasmolytic polypeptide from porcine pancreas and to the human protein pS2.

Amino Acid Sequence↗
PubMed1993

Trefoil peptide gene expression in gastrointestinal epithelial cells in inflammatory bowel disease.

BACKGROUND: This work expands on recent observations that the trefoil peptides pS2 and human spasmolytic polypeptide (hSP) are expressed in the ulceration-associated cell lineage (UACL) glands developing in chronic ulcerative conditions. METHODS: Trefoil peptide expression in small intestinal Crohn's disease was examined by in situ hybridization to reveal sites of expression of the messenger RNAs encoding pS2 and hSP and by immunohistochemistry and immunoelectron microscopy to localize the peptides in the UACL and adjacent goblet and neuroendocrine cells. RESULTS: Goblet cells near the UACL expressed pS2 messenger RNA and peptide; ultrastructural immunolocalization revealed pS2 copackaged within mucous cell granules. Neuroendocrine cell hyperplasia was marked in crypts near the UACL; pS2 was copackaged with the neuroendocrine granules. CONCLUSIONS: Copackaging of a secretory protein, pS2, in both mucous and neuroendocrine granules, which have different functions, is unusual and indicates an important role for pS2 in the secretory process itself or as a ligand delivered to its receptors via different routes. It is concluded that trefoil peptides are of considerable potential functional importance in inflammatory bowel disease.

Cell Line↗
PubMed1980

A micro-computerised system to measure the colonic contractile activity: application to pharmacological tests in dogs.

This paper describes a rapid and reproducible technique for measuring the contractile activity of the colon, from strain-gauge signals, using a microcomputer data-processing PDS M 6800. This system can be used on-line, or after a 32 times compression, with only slight modifications of the data collection program. The motility index of the colon, calculated from the surface of the contractile waves, was automatically given at 5-min intervals. A series of comparative measurements of colonic motility and its changes after administration of drugs, such as morphinomimetics and spasmolytics, have been reported.

Animals↗
PubMed1984

Mechanisms of methacholine-induced coronary vasospasm in an experimental model of variant angina in the anesthetized rat.

Methacholine (Mch), when injected near the ostia of the coronary arteries, induces an intense coronary vasospasm which can be measured by the degree of S wave elevation monitored from an electrocardiogram (ECG). The observed ECG changes resemble those occurring in patients with variant angina. The effects of Mch were blocked by atropine, but not by d-tubocurarine, hexamethonium, adrenergic receptor blockade, or prior reserpinization, indicating that Mch is acting directly on muscarinic receptors to produce a vasoconstriction of the coronary arteries. This model of Mch-induced coronary vasospasm appears to be useful for testing spasmolytic agents which might be of benefit in variant angina.

Angina Pectoris, Variant↗
PubMed1992

Caroverine depresses the activity of cochlear glutamate receptors in guinea pigs: in vivo model for drug-induced neuroprotection?

With the aid of microiontophoretic techniques the action of caroverine, a quinoxaline-derivative, was tested on the receptor-linked depolarisation of the subsynaptic membrane of cochlear afferents. This membrane can be depolarised by the afferent transmitter agonist glutamate, mediated by NMDA and non-NMDA receptors and by acetylcholine, one of the different transmitter substances, released physiologically on axodendritic efferent synapses. Caroverine antagonized the membrane response to glutamate in an enduring but reversible manner. In contrast, the drug exhibited no effect on the depolarising action of acetylcholine. Therefore, the pharmacological profile of caroverine corresponded to the action of selective glutamate receptor antagonists. Since glutamate is likely to be the major mediator of neurotoxicity in the central nervous system, the selective glutamate-antagonism of caroverine is of particular interest, due to its putative neuroprotective competence. Caroverine is currently available clinically in some countries as a spasmolytic drug. Following these results it is proposed to test the drug for clinical efficacy in putatively glutamate-induced, excitotoxic disorders of the brain.

Animals↗
PubMed1986

The use of a compact protable microcomputer system (EPSON HX 20) to measure on-line the contractile activity of the digestive tract from eight channels. Application to pharmacological tests.

The chronically prepared gut with strain-gauge transducers is a useful model to evaluate the effects of drugs affecting the digestive motility in fed and fasted animals. This paper describes a rapid and reproducible on-line microcomputerized technique to evaluate continuously, 23 hr per day, the level of gut motility using a portable compact microcomputer (EPSON HX 20). The gastric, intestinal, and colonic motility indexes were automatically determined from the surface of the contractile waves from eight different sites over periods of time varying from 1 to 120 min. This system has been successfully used to investigate the motor effects of spasmolytic or antidiarrheal drugs inravenously (N-butyl-hyoscine, trospium, secoverine, and prifinium) or orally (trimebutine, loperamide) administered in conscious, fed dogs.

Animals↗
PubMed1995

Immunoprecipitation and characterization of a binding protein specific for the peptide, intestinal trefoil factor.

Recombinant rat intestinal trefoil factor (rITF) and human spasmolytic polypeptide (hSP) were irreversibly cross-linked to specific binding sites in solubilized rat intestinal epithelial membranes and human adenocarcinoma cells. Analysis of the immunoprecipitates by immunoblotting identified a cross-linked protein complex of approximately 45 kDa, which under reducing conditions appeared as a approximately 28-kDa band and the latter displayed ligand-stimulated phosphorylation of a tyrosine, but not a threonine or serine, residue in the binding complex. [125I]rITF was used to localize binding sites by autoradiography of frozen sections from rat gastrointestinal tissues. A high density of specific [125I]rITF binding sites was present within gastric, colonic, and jejunal mucosal glands. Unlabeled hSP partially inhibited [125I]rITF binding at a concentration of 1 microM when compared with the same concentration of unlabeled rITF. These studies support earlier observations for the existence of trefoil binding sites in the gastrointestinal tract and further suggest that hSP has affinity for the mucosal rITF binding site.

Animals↗
PubMed1995

Short-term electrical stimulation enhances the effectiveness of Botulinum toxin in the treatment of lower limb spasticity in hemiparetic patients.

The study tested the spasmolytic effect of Botulinum toxin A in two groups of hemiparetic patients with lower limb spasticity: in the first group (n = 5) 2000 U Dysport were injected into the soleus, tibialis posterior and both heads of gastrocnemius muscles alone; the second (n = 5) received additional repetitive alternating electrical stimulation of M. tibialis anterior and plantar flexors for 30 min six times per day during the 3 days following the injection. Muscle tone, rated by the Ashworth spasticity score, and gait analysis including recording of vertical ground reaction forces, were assessed before and 4 weeks after injection. The combined treatment proved to be more effective with respect to the clinically assessed reduction of muscle tone, gait velocity, stride length, stance- and swing-symmetry (P < 0.05). The result is discussed with reference to animal experiments demonstrating enhanced toxin uptake and accelerated onset of its paralytic effect by electrical stimulation.

Adult↗
PubMed1986

Activation of inhibition from the periaqueductal grey matter mediates central analgesic effect of metamizol (dipyrone).

The pyrazolone derivative, metamizol (dipyrone), possesses analgesic, antipyretic, anti-inflammatory and spasmolytic properties. It is often classified as peripherally acting. To test the possibility that a central action of the drug contributes to its antinociceptive and analgesic effects, experiments were carried out in which the tail-flick response to radiant heat, flexor reflex activity in the tibialis anterior muscle and activity in ascending spinal axons evoked by stimulation of afferent C fibres in the sural nerve, and activity of neurones in the periaqueductal grey matter and the substantia nigra were assessed in rats. Metamizol administered by intraperitoneal (i.p.; 10, 20 and 40 mg/kg) or intrathecal (i.t.; 50 to 400 micrograms) injection to intact rats dose-dependently prolonged the tail-flick latency. Administration by i.t. injection to spinal rats was without effect. Intravenous (i.v.) injection of metamizol (140 mg/kg) reduced flexor reflex activity in intact animals, while an i.t. injection to spinal rats was ineffective at a low dose (100 micrograms) or enhanced the reflex activity at a higher dose (400 micrograms). Activity in ascending axons responding to afferent C fibre stimulation was mostly depressed by i.t. injection of metamizol (40, 80 and 140 mg/kg) in rats with an intact spinal cord. Ascending activity was increased by i.t. injection of the drug (100 and 200 micrograms) to spinal rats. Metamizol (140 mg/kg) i.v. increased the activity of neurones in the PAG and reduced that of neurones in the substantia nigra. Metamizol administered by microinjection into the PAG prolonged the tail-flick latency (15-100 micrograms) and depressed C fibre-evoked activity in ascending axons (100 micrograms). The results suggest that a central action is involved in the analgesic effect of metamizol and that this central action manifests itself by an activation of inhibition originating in the PAG.

Action Potentials↗