Serotonin reuptake inhibitors fluoxetine and citalopram relax intestinal smooth muscle

2001 ◽  
Vol 79 (7) ◽  
pp. 580-584 ◽  
Author(s):  
Pal Pacher ◽  
Zoltan Ungvari ◽  
Valéria Kecskeméti ◽  
Tamás Friedmann ◽  
Susanna Furst
Keyword(s):  
Smooth Muscle ◽  
Serotonin Reuptake ◽  
Longitudinal Muscle ◽  
Contractile Activity ◽  
Electrical Field Stimulation ◽  
Intestinal Smooth Muscle ◽  
Dependent Manner ◽  
Guinea Pig Ileum ◽  
Electrical Field ◽  
Concentration Dependent Manner

Selective serotonin reuptake inhibitor antidepressants (SSRIs) exert depressant effects on cardiac myocytes and vascular smooth muscle cells by inhibiting Ca2+ channels. We hypothesized that the SSRIs fluoxetine and citalopram affect the contractile activity of intestinal smooth muscle by interfering with Ca2+ entry and (or) signaling pathways. The effects of fluoxetine and citalopram on contractions of guinea-pig ileum longitudinal muscle-myenteric plexus preparations (LMMP) were compared with the effects of the voltage-operated Ca2+ channel inhibitors nifedipine and diltiazem. In a concentration-dependent manner, nifedipine, diltiazem, fluoxetine, and citalopram elicited relaxation of LMMPs contracted by electrical field stimulation (EC50 values of 4 × 10–7 M, 1.4 × 10–6 M, 1.4 × 10–5, and 6.8 × 10–6 M, respectively). Nifedipine, diltiazem, fluoxetine, and citalopram also relaxed LMMPs contracted with a depolarizing concentration of KCl (48 mM; EC50 values of 1.8 × 10–8 M, 1.4 × 10–7 M, 3.7 × 10–6 M, and 6.3 × 10–6, respectively), a response that could be reversed by increasing the extracellular Ca2+ concentration (2.5–30 mM). These data suggest that fluoxetine and citalopram elicit relaxation of intestinal smooth muscle, likely by inhibiting Ca2+ channel(s). This effect may be of clinical importance.Key words: fluoxetine (Prozac(r)), citalopram (Seropram(r)), nifedipine, diltiazem, L-type Ca2+ channels, intestinal smooth muscle.

Control of neurotransmission by prostaglandins in canine trachealis smooth muscle

1984 ◽  
Vol 57 (1) ◽  
pp. 129-134 ◽  
Author(s):  
E. H. Walters ◽  
P. M. O'Byrne ◽  
L. M. Fabbri ◽  
P. D. Graf ◽  
M. J. Holtzman ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Prostaglandin E2 ◽  
Electrical Field Stimulation ◽  
Tracheal Smooth Muscle ◽  
Dependent Manner ◽  
Field Stimulation ◽  
Electrical Field ◽  
Similar Time ◽  
Concentration Dependent Manner ◽  
Contractile Responses

Contractile responses of canine tracheal smooth muscle to electrical field stimulation diminished over a 2-h period of incubation. However, addition of indomethacin (10(-5) M) for a similar time not only prevented this inhibition of contractile response, but actually markedly increased the response to electrical field stimulation, suggesting that prostaglandins were responsible for the time-dependent inhibition. Measured prostaglandin E2 increased in the tissue bath over 2 h in control tissues. Addition of prostaglandin E2 to the tissue produced similar inhibition of contractile responses to electrical field stimulation in a concentration-dependent manner. In contrast, incubation alone, treatment with indomethacin, or addition of prostaglandin E2 had little, if any, effect on contractions induced by acetylcholine. We conclude that the release of prostaglandins from canine tracheal smooth muscle that occurs with time has a predominantly inhibitory effect on cholinergic neurotransmission at a prejunctional site.

Neural and myogenic effects of cyclooxygenase products on canine bronchial smooth muscle

1995 ◽  
Vol 268 (1) ◽  
pp. L47-L55 ◽  
Author(s):  
A. P. Abela ◽  
E. E. Daniel
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Electrical Field Stimulation ◽  
Resting Membrane Potential ◽  
Dependent Manner ◽  
Ach Release ◽  
Concentration Dependent Manner ◽  
Excitatory Junction Potentials ◽  
Pg E2 ◽  
Large Contraction

In canine bronchi bathed in 10(-6) M indomethacin (IDM), prostaglandin (PG) E2 inhibited electrical field stimulation (EFS)- and acetylcholine (ACh)-mediated contractions and excitatory junction potentials (EJP) in a concentration-dependent manner without altering the resting membrane potential. EFS-induced EJPs were abolished at 10(-7) M PGE2, which shifted responses to ACh 10-fold rightward. Thus PGE2 predominantly inhibited the release of ACh and secondarily decreased smooth muscle response to ACh. U-46619, an analogue of thromboxane A2 (TxA2), initiated tetrodotoxin- and atropine-insensitive contractions in a concentration-dependent manner. U-46619 (10(-9) M) did not alter significantly EFS- or ACh-stimulated contractions and potentiated EFS amplitude of EJPs without depolarizing muscle cells. Either prejunctional activation of ACh release by TxA2 or postjunctional potentiation of the response to ACh can explain these findings. U-46619 (<or = 10(-8) M) depolarized the membrane potential, initiating oscillations accompanied by a large contraction. Addition of 10(-8) M nitrendipine, but not tetraethylammonium (25 mM), blocked the oscillations selectively. Other prostanoids (PGD2, PGI2, and PGF2 alpha) had no significant effects on canine bronchi. In the absence of IDM, PGE2 accumulated, EFS contractions decreased with time, and EJPs disappeared. We conclude that in canine bronchi PGE2 predominantly inhibits ACh release and endogenous PGE2 acts similarly, whereas TxA2 excites, probably at postjunctional sites.

Darusentan is a potent inhibitor of endothelin signaling and function in both large and small arteriesThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.

2010 ◽  
Vol 88 (8) ◽  
pp. 840-849 ◽  
Author(s):  
Faquan Liang ◽  
Christopher B. Glascock ◽  
Denise L. Schafer ◽  
Jennifer Sandoval ◽  
LouAnn Cable ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Potent Inhibitor ◽  
Inositol Phosphate ◽  
Contractile Activity ◽  
Binding Activity ◽  
Dependent Manner ◽  
Endothelin Receptor ◽  
Resistance Arteries ◽  
Concentration Dependent Manner

Endothelin is a potent vasoconstrictor often up-regulated in hypertension. Endothelin vasoconstriction is mediated via the G-protein coupled endothelin A (ETA) receptor present on vascular smooth muscle. Endothelin receptor antagonists (ERAs) have been shown to antagonize ET-induced vasoconstriction. We describe the primary pharmacology of darusentan, a propanoic acid based ERA currently in phase 3 clinical trials for resistant hypertension. Darusentan was tested in membrane-, cell-, and tissue-based assays to determine its biochemical and functional potency. Rat aortic vascular smooth muscle cells (RAVSMs) were characterized using flow cytometry. RAVSM membrane fractions tested in saturation experiments exhibited moderate endothelin receptor density. Receptor counting revealed that >95% of the endothelin receptors in these fractions were the ETA subtype. (S)-Darusentan competed for radiolabeled endothelin binding in RAVSM membranes with single-site kinetics, exhibiting a Ki = 13 nmol/L. (R)-Darusentan exhibited no binding activity. In cultured RAVSMs, endothelin induced increases in inositol phosphate and Ca2+ signaling, both of which were attenuated by (S)-darusentan in a concentration-dependent manner. In isolated endothelium-denuded rat aortic rings, (S)-darusentan inhibited endothelin-induced vascular contractility with a pA2 = 8.1 ± 0.14 (n = 4 animals; mean ± SD). (R)-Darusentan had no effect. The vasorelaxant potency of (S)-darusentan did not change when determined in isolated denuded rat mesenteric arterioles, suggesting a similar mode of action in both conductance and resistance arteries. In vascular smooth muscle, (S)-darusentan is an ERA with high affinity for the ET receptor, which in this preparation is predominantly ETA receptors. (S)-Darusentan inhibits endothelin-induced signaling related to pro-contractile activity and is a potent inhibitor of vasoconstriction in large and small arteries.

scholarly journals Effects of enantiomers of β2-agonists on ACh release and smooth muscle contraction in the trachea

1998 ◽  
Vol 274 (1) ◽  
pp. L32-L38 ◽  
Author(s):  
Xiang-Yang Zhang ◽  
Feng-Xia Zhu ◽  
Michal A. Olszewski ◽  
N. Edward Robinson
Keyword(s):  
Smooth Muscle ◽  
High Performance ◽  
Muscle Tension ◽  
Electrical Field Stimulation ◽  
Smooth Muscle Contraction ◽  
Acute Administration ◽  
Dependent Manner ◽  
Ach Release ◽  
Concentration Dependent Manner ◽  
Parasympathetic Nerves

The β2-agonists currently used as bronchodilators are racemic mixtures of R- and S-enantiomers. In the present study, we examined the effects of enantiomers of the β2-agonists albuterol and formoterol on acetylcholine (ACh) release from equine trachealis parasympathetic nerves. ACh release was evoked by electrical field stimulation (20 V, 0.5 ms, 0.5 Hz) and measured by high-performance liquid chromatography coupled with electrochemical detection. We also tested the effects of enantiomers of albuterol and formoterol on equine tracheal smooth muscle (TSM) contraction in response to exogenous ACh. R- and RS-albuterol (10−8 to 10−5 M) and RR- and RR/SS-formoterol (10−8 to 10−5 M) augmented ACh release in a concentration-dependent manner. Beginning at 10−6 M, SS-formoterol significantly increased ACh release, and at 10−5 M, release increased by 71.9 ± 8.7% over baseline. This effect was only observed, however, when the prejunctional muscarinic autoinhibitory effect of ACh was prevented with atropine. Both the RR- and SS-formoterol-induced increases in ACh release were abolished by the β2-antagonist ICI-118551 (3 × 10−7 M). The effect of S-albuterol on ACh release was variable, and the mean increase induced by 10−5 M was 30.8 ± 16.1% in the presence of atropine. In the muscle tension study, R- and RS-albuterol and RR- and RR/SS-formoterol (10−8 to 10−5 M) but not the S-enantiomers inhibited TSM contraction. Even though R-enantiomers augment ACh release, they potently inhibit TSM contraction. Because racemic β2-agonists are bronchodilators on acute administration, the postjunctional spasmolytic effects of R-enantiomers predominate over the spasmogenic effect evoked via increased ACh release. The S-enantiomers, in contrast, do not inhibit TSM contraction and therefore would not contribute to the observed bronchodilation of the racemate. The S-enantiomers do prejunctionally facilitate ACh release when prejunctional muscarinic autoreceptors are dysfunctional, suggesting a potentially deleterious effect.

scholarly journals Effects of Ursolic Acid on Contractile Activity of Gastric Smooth Muscles

2015 ◽  
Vol 10 (4) ◽  
pp. 1934578X1501000 ◽  
Author(s):  
Natalia Prissadova ◽  
Petko Bozov ◽  
Kiril Marinkov ◽  
Hristo Badakov ◽  
Atanas Kristev
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Ursolic Acid ◽  
Slow Wave ◽  
Contractile Activity ◽  
Smooth Muscles ◽  
Dependent Manner ◽  
Krebs Solution ◽  
Concentration Dependent Manner ◽  
Gastric Smooth Muscle

Ursolic acid (UA) in concentrations of 1×10−7 mol/L - 5×10−5 mol/L induced relaxation in gastric smooth muscle (SM) tissues, in a concentration-dependent manner. The relaxation did not change membrane potential and slow wave contraction patterns. A significant decrease in amplitude and frequency of spike-potentials was observed. UA-induced reactivity was removed when SM preparations were treated with nifedipine (1×10−6 mol/L). Ca2+- induced contractions of the depolarized SM preparations (42 mmol/L K+; Ca2+- free Krebs solution) were substantially reduced in the presence of UA. It was determined that, in certain concentrations, UA influenced L – type Ca2+ channels, and reduced the Ca2+ influx.

scholarly journals Phytochemical Evaluation of Lythrum Salicaria Extracts and Their Effects on Guinea-Pig Ileum

2013 ◽  
Vol 8 (9) ◽  
pp. 1934578X1300800 ◽  
Author(s):  
Tímea Bencsik ◽  
Loránd Barthó ◽  
Viktor Sándor ◽  
Nóra Papp ◽  
Rita Benkó ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Ethyl Acetate ◽  
Water Extract ◽  
Lythrum Salicaria ◽  
Dependent Manner ◽  
Guinea Pig Ileum ◽  
Concentration Dependent Manner ◽  
Ethanol In Water

n-Hexane, chloroform, ethyl acetate and 50% ethanol in water extracts prepared from the air-dried flowering parts of Lythrum salicaria L. were tested for in vitro pharmacological properties on Guinea-pig ileum, which is suitable for detecting a whole range of neuronal and smooth muscle effects. UHPLC-MS was used to evaluate polyphenol components of the extracts. In the ileum, the most prominent response (46.4% related to 0.5 μM histamine) of the extracts causing smooth muscle contractions were triggered by the 50% ethanol in water extract in a concentration-dependent manner. Atropine, indomethacin and PPADS plus suramin significantly reduced the contractile response caused by this extract. The strongest inhibition was due to atropine. The results suggest that L. salicaria extracts have a moderate muscarinic receptor agonist effect in Guinea-pig ileum and that prostanoids and purinoceptor mechanisms are involved to some extent. Therefore diluted extracts of L. salicaria p.o. could be used as a mild stimulant of gastrointestinal motility. The 50% ethanol in water extract was rich in polyphenols. n-Hexane, chloroform and ethyl acetate extracts failed to contain catechin, caffeic acid, quercetin-3-D-galactoside and rutin, but they all showed spasmogenic effects, and, therefore we do not think that these compounds could be involved in the spasmogenic activity.

Neural and myogenic effects of leukotrienes C4, D4, and E4 on canine bronchial smooth muscle

1994 ◽  
Vol 266 (4) ◽  
pp. L414-L425 ◽  
Author(s):  
A. Abela ◽  
E. E. Daniel
Keyword(s):  
Smooth Muscle ◽  
Receptor Antagonist ◽  
Contractile Activity ◽  
Neuromuscular Control ◽  
Dependent Manner ◽  
Gamma Glutamyl Transpeptidase ◽  
Response Curves ◽  
Bronchial Smooth Muscle ◽  
Concentration Dependent Manner

The leukotrienes (LTs), referred to as the slow-reacting substance of anaphylaxis (SRS-A), are reported to have little or no activity in the canine airway. The objective of this study was to determine whether LTC4, LTD4, and LTE4 (10(-10)-10(-7) M) play a role in neuromuscular control of third- to fifth-order canine bronchi. In the presence of 1 microM indomethacin (Indo), canine bronchial smooth muscle contracted and was depolarized in a concentration-dependent manner by LTC4 or LTD4 but not by LTE4. LTC4 and LTD4 concentration-response curves were not significantly affected when conducted in the presence of any of the following: 10(-7) M propranolol (beta-adrenoceptor antagonist), 10(-6) M chlorpheniramine (H1-receptor antagonist), 10(-6) M ketanserin (nonselective 5-hydroxytryptamine receptor antagonist), 10(-7) M atropine (muscarinic receptor antagonist), and 10(-6) M tetrodotoxin (sodium channel blocker). LTC4 and LTD4 also potentiated electrical field-stimulated (EFS) excitatory junction potentials (EJPs), suggesting a possible prejunctional enhancement of acetylcholine release. In the absence of Indo, no postjunctional responses to LTC4 and LTD4 occurred. Endogenous prostaglandin E2 (PGE2) and 6-keto-PGF1 alpha (a stable metabolite of PGI2) levels from canine bronchi were significantly reduced by Indo. In the presence of Indo, addition of > or = 10(-8) M of PGE2 suppressed contractions to LTC4 and LTD4. These data suggest that the decrease in PGE2 and PGI2 production by Indo is sufficient to unmask the excitatory postjunctional actions of LTC4 and LTD4 on bronchial smooth muscle. Serine borate (45 mM; an inhibitor of gamma-glutamyl transpeptidase, which prevents the conversion of LTC4 to LTD4) increased selectively the contractile activity of LTC4. L-Cysteine (3 mM; an inhibitor of an aminopeptidase, which prevents the conversion of LTD4 to LTE4) enhanced the contractile responses to LTD4. Serine borate increased the amplitude and duration of EFS contractions and potentiated the amplitude of EFS EJPs; the last effects were prevented by nordihydroguaiaretic acid. These and other studies suggest that LTs are synthesized by canine bronchi and have receptors on canine bronchial smooth muscle but that contractions to LTC4 and LTD4 in the canine airway are usually not observed because of the presence of inhibitory prostanoids (PGE2 and PGI2). We suggest that decreases in PGE2 and PGI2 in models of airway disease in combination with increases in LTC4, LTD4, and thromboxane A2 may contribute to airway hyperresponsiveness in vitro.

Potentiation of acetylcholine release from tracheal parasympathetic nerves by cAMP

1996 ◽  
Vol 270 (4) ◽  
pp. L541-L546 ◽  
Author(s):  
X. Y. Zhang ◽  
N. E. Robinson ◽  
F. X. Zhu
Keyword(s):  
High Performance ◽  
Acetylcholine Release ◽  
Electrical Field Stimulation ◽  
Maximal Effect ◽  
Dependent Manner ◽  
Ach Release ◽  
Electrical Field ◽  
Concentration Dependent Manner ◽  
Cyclic Monophosphate ◽  
Parasympathetic Nerves

We tested the hypothesis that increasing intracellular levels of adenosine 3', 5'-cyclic monophosphate (cAMP) increases acetylcholine (ACh) release from airway parasympathetic nerves. Muscle strips from equine trachea were preincubated for 60 min with 10(-7)M atropine, 10(-6)M neostigmine, and 10(-5) M guanethidine. The ACh release was evoked by electrical field stimulation (EFS, 20 V, 0.5 ms, 0.5 Hz) and measured by high-performance liquid chromatography with electrochemical detection. Agents known to increase cAMP, i.e., forskolin (10(-6) - 10(-4) M), 8-bromoadenosine 3', 5'-cyclic monophosphate (8-BrcAMP; 10(-5)-10(-3) M), and 3-isobutyl-1-methylxanthine (IBMX ; 10(-5)-10(-3)M) was potentiated by IBMX but not mimicked by 1,9 dideoxyforskolin. To determine if the augmentation of Ach release facilitated EFS-induced ACh release in a concentration-dependent manner. Forskolin-induced augmentation of ACh release induced by activation of beta 2-adrenoceptors is mediated via cAMP-dependent pathways, we also examined the additive effects of 8-BrcAMP, forskolin, and IBMX with 10(-6)M isoproterenol (ISO), the concentration that maximally augments ACh release. Neither forskolin nor 8-BrcAMP potentiated the maximal augmentation produced by ISO, but inhibition of phosphodiesterase with IBMX (10(-4) and 10(-3)M) augmented the maximal effect of ISO. These observations indicate that neuronal cAMP is a physiological modulator of ACh release from airway parasympathetic nerves and mediates ISO-induced augmentation of ACh release. Bronchodilators that increase cAMP may therefore paradoxically augment ACh release while relaxing smooth muscle.

Bovine gallbladder muscularis: source of a myogenic receptor for cholecystokinin

1988 ◽  
Vol 254 (3) ◽  
pp. G294-G299 ◽  
Author(s):  
B. Schjoldager ◽  
M. J. Shaw ◽  
S. P. Powers ◽  
P. F. Schmalz ◽  
J. Szurszewski ◽  
...  
Keyword(s):  
Biochemical Characterization ◽  
Neuronal Response ◽  
Electrical Field Stimulation ◽  
Adrenergic Blockade ◽  
Dependent Manner ◽  
Field Stimulation ◽  
Electrical Field ◽  
Concentration Dependent Manner ◽  
High Affinity

Despite being a classic target for the gastrointestinal peptide hormone, cholecystokinin (CCK), the gallbladder CCK receptor is not well characterized. Pharmacological studies of small species suggest that CCK action can be mediated by direct myogenic or by both myogenic and neurogenic receptors. To prepare for the biochemical characterization of a gallbladder CCK receptor and to define the subtype of the receptor being studied, we have performed autoradiographic localization and pharmacological characterization of CCK receptors on bovine gallbladder. Autoradiography demonstrated high-affinity specific CCK-binding sites only on the muscularis. CCK-8 stimulated tonic contraction of longitudinal strips of gallbladder muscularis in a concentration-dependent manner, with an ED50 of 0.2 nM. Antagonism at the cholinergic receptor with 1 microM atropine or axonal transmission with 1 microM tetrodotoxin did not modify CCK-induced contraction, supporting a direct myogenic effect of this hormone. Optimal electrical field stimulation (10 V, 10 Hz, 500 microseconds) to elicit a neuronal response resulted in muscle strip relaxation, which was abolished with adrenergic blockade (1 microM phentolamine, 1 microM propranolol). Although acetylcholine administration stimulated contraction, electrical field stimulation did not, even in the presence of phentolamine, propranolol, and/or CCK. Thus, in bovine gallbladder muscularis, there is evidence for a functional CCK receptor only on smooth muscle cells. Demonstration of a single, high-affinity specific CCK-binding site on an enriched plasma membrane preparation of bovine gallbladder muscularis is consistent with this representing a myogenic CCK receptor.

Catecholamine affects acetylcholine release in trachea: alpha 2-mediated inhibition and beta 2-mediated augmentation

1995 ◽  
Vol 268 (3) ◽  
pp. L368-L373 ◽  
Author(s):  
X. Y. Zhang ◽  
N. E. Robinson ◽  
Z. W. Wang ◽  
M. C. Lu
Keyword(s):  
High Performance ◽  
Electrical Field Stimulation ◽  
Dependent Manner ◽  
Ach Release ◽  
Electrical Field ◽  
Concentration Dependent Manner ◽  
Parasympathetic Nerves ◽  
Adrenoceptor Antagonist ◽  
Ici 118,551 ◽  
Beta 2

We investigated the effects of catecholamines on acetylcholine (ACh) release from equine airway parasympathetic nerves. Trachealis strips were suspended in 2-ml tissue baths with Krebs-Henseleit solution containing atropine (10(-7) M), neostigmine (10(-6) M), and guanethidine (10(-5) M). Electrical field stimulation (20 V, 0.5 ms, 0.5 Hz, for 15 min) was applied, and ACh was measured by high-performance liquid chromatography with electrochemical detection. Epinephrine (Epi) and norepinephrine (NE) inhibited ACh release in a concentration-dependent manner. Inhibition was attenuated by the alpha 2-adrenoceptor antagonist idazoxan (10(-6) M) but not by the alpha 1-antagonist prazosin (10(-6) M). After alpha 2-blockade with idazoxan (10(-5) to 10(-4) M), Epi but not NE augmented ACh release. Isoproterenol (10(-7) to 10(-5) M) increased ACh release, an effect that was reversed by the beta 2-adrenoceptor antagonist ICI-118,551 (10(-5) M) but not by the beta 1-adrenoceptor antagonist atenolol (10(-5) M). Our results indicate that horse airway cholinergic nerves are modulated by both alpha 2-inhibitory and beta 2-excitatory adrenoceptors, with the former being predominant.

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