			Home About us Contact

Induced Contraction (induced + contraction)

Distribution by Scientific Domains

Medical Sciences	80%
Life Sciences	16%

Selected Abstracts

Cloning and characterization of novel snake venom proteins that block smooth muscle contraction

FEBS JOURNAL, Issue 11 2002
Yasuo Yamazaki
In this study, we isolated a 25-kDa novel snake venom protein, designated ablomin, from the venom of the Japanese Mamushi snake (Agkistrodon blomhoffi). The amino-acid sequence of this protein was determined by peptide sequencing and cDNA cloning. The deduced sequence showed high similarity to helothermine from the Mexican beaded lizard (Heloderma horridum horridum), which blocks voltage-gated calcium and potassium channels, and ryanodine receptors. Ablomin blocked contraction of rat tail arterial smooth muscle elicited by high K+ -induced depolarization in the 0.1,1 µm range, but did not block caffeine-stimulated contraction. Furthermore, we isolated three other proteins from snake venoms that are homologous to ablomin and cloned the corresponding cDNAs. Two of these homologous proteins, triflin and latisemin, also inhibited high K+ -induced contraction of the artery. These results indicate that several snake venoms contain novel proteins with neurotoxin-like activity. [source]

Scutellarin-induced endothelium-independent relaxation in rat aorta

PHYTOTHERAPY RESEARCH, Issue 11 2008
Zhenwei Pan
Abstract Scutellarin is a flavonoid extracted from the traditional Chinese herb, Erigeron breviscapus Hand Mazz. In the present study, the vasorelaxant effects of scutellarin and the underlying mechanism were investigated in isolated rat aorta. Scutellarin (3, 10, 30, 100 µm) caused a dose-dependent relaxation in both endothelium-intact and endothelium-denuded rat aortic rings precontracted with noradrenaline bitartrate (IC50 = 7.7 ± 0.6 µm), but not with potassium chloride. Tetraethylammonium, glibenclamide, atropine, propranolol, indomethacin and N(G)-nitro- l -arginine methyl ester had no influence on the vasorelaxant effect of scutellarin, which further excluded the involvement of potassium channels, muscarinic receptor, nitric oxide pathway and prostaglandin in this effect. Pretreatment with scutellarin decreased the tonic phase, but not the phasic phase of the noradrenaline bitartrate induced tension increment. Scutellarin also alleviated Ca2+ -induced vasoconstriction in Ca2+ -depleted/noradrenaline bitartrate pretreated rings in the presence of voltage-dependent calcium channel blocker verapamil. The noradrenaline bitartrate evoked intracellular calcium increase was inhibited by scutellarin. Scutellarin had no effect on phorbol-12,13-diacetate induced contraction in a calcium-free bath solution. These results showed that scutellarin could relax thoracic artery rings in an endothelium-independent manner. The mechanism seems to be the inhibition of extracellular calcium influx independent of the voltage-dependent calcium channel. Copyright © 2008 John Wiley & Sons, Ltd. [source]

Nitric oxide-induced biphasic mechanism of vascular relaxation via dephosphorylation of CPI-17 and MYPT1

THE JOURNAL OF PHYSIOLOGY, Issue 14 2009
Toshio Kitazawa
Nitric oxide (NO) from endothelium is a major mediator of vasodilatation through cGMP/PKG signals that lead to a decrease in Ca2+ concentration. In addition, NO-mediated signals trigger an increase in myosin light chain phosphatase (MLCP) activity. To evaluate the mechanism of NO-induced relaxation through MLCP deinhibition, we compared time-dependent changes in Ca2+, myosin light chain (MLC) phosphorylation and contraction to changes in phosphorylation levels of CPI-17 at Thr38, RhoA at Ser188, and MYPT1 at Ser695, Thr696 and Thr853 in response to sodium nitroprusside (SNP)-induced relaxation in denuded rabbit femoral artery. During phenylephrine (PE)-induced contraction, SNP reduced CPI-17 phosphorylation to a minimal value within 15 s, in parallel with decreases in Ca2+ and MLC phosphorylation, followed by a reduction of contractile force having a latency period of about 15 s. MYPT1 phosphorylation at Ser695, the PKG-target site, increased concurrently with relaxation. Phosphorylation of RhoA, MYPT1 Thr696 and Thr853 differed significantly at 5 min but not within 1 min of SNP exposure. Inhibition of Ca2+ release delayed SNP-induced relaxation while inhibition of Ca2+ channel, BKCa channel or phosphodiesterase-5 did not. Pretreatment of resting artery with SNP suppressed an increase in Ca2+, contractile force and phosphorylation of MLC, CPI-17, MYPT1 Thr696 and Thr853 at 10 s after PE stimulation, but had no effect on phorbol ester-induced CPI-17 phosphorylation. Together, these results suggest that NO production suppresses Ca2+ release, which causes an inactivation of PKC and rapid CPI-17 dephosphorylation as well as MLCK inactivation, resulting in rapid MLC dephosphorylation and relaxation. [source]

c-Src tyrosine kinase, a critical component for 5-HT2A receptor-mediated contraction in rat aorta

THE JOURNAL OF PHYSIOLOGY, Issue 16 2008
Rong Lu
Serotonin (5-hydroxytryptamine, 5-HT) receptors (5-HTRs) play critical roles in brain and cardiovascular functions. In the vasculature, 5-HT induces potent vasoconstrictions, which in aorta are mainly mediated by activation of the 5-HT2AR subtype. We previously proposed that one signalling mechanism of 5-HT-induced vasoconstriction could be c-Src, a member of the Src tyrosine kinase family. We now provide evidence for a central role of c-Src in 5-HT2AR-mediated contraction. Inhibition of Src kinase activity with 10 ,m 4-amino-5-(4-chlorophenyl)-7-(t -butyl)pyrazolo[3,4-d]pyrimidine (PP2) prior to contraction resulted in ,90,99% inhibition of contractions induced by 5-HT or by ,-methyl-5-HT (5-HT2R agonist). In contrast, PP2 pretreatment only partly inhibited contractions induced by angiotensin II and the thromboxane A2 mimetic, U46619, and had no significant action on phenylephrine-induced contractions. 5-Hydroxytryptamine increased Src kinase activity and PP2-sensitive tyrosine-phosphorylated proteins. As expected for c-Src identity, PP2 pretreatment inhibited 5-HT-induced contraction with an IC50 of ,1 ,m. Ketanserin (10 nm), a 5-HT2A antagonist, but not antagonists of 5-HT2BR (100 nm SB204741) or 5-HT2CR (20 nm RS102221), prevented 5-HT-induced contractions, mimicking PP2 and implicating 5-HT2AR as the major receptor subtype coupled to c-Src. In HEK 293T cells, c-Src and 5-HT2AR were reciprocally co-immunoprecipitated and co-localized at the cell periphery. Finally, 5-HT-induced Src activity was unaffected by inhibition of Rho kinase, supporting a role of c-Src upstream of Rho kinase. Together, the results highlight c-Src activation as one of the early and pivotal mechanisms in 5-HT2AR contractile signalling in aorta. [source]

The stimulant cathartic, emodin, contracts the rat isolated ileum by triggering release of endogenous acetylcholine

AUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2004
S. Ali
Summary 1 Anthraquinone stimulant cathartics, such as emodin, are believed to increase the rate of contraction of ileum tissue in vitro via multiple mechanisms. The aim of this study was to probe the effects of emodin on acetylcholine (ACh)-induced contraction of the rat isolated ileum preparation. 2 Ileal sections were incubated in Tyrode's solution and responses to methacholine, ACh and emodin obtained in the absence and presence of the muscarinic antagonist atropine and the choline uptake inhibitor hemicholinium (HC-3). Depletion of endogenous ACh in the presence of HC-3 was achieved by construction of an ACh dose,response curve, using exogenous ACh, prior to re-testing the effects of emodin in the presence of HC-3. 3 Emodin caused dose-dependent tissue contraction that was abolished by inclusion of atropine (1 ,m) in the buffer. Atropine (1 ,m) antagonized the response caused by methacholine. 4 Incubation of tissues with HC-3 (1 and 10 ,m) reduced the maximum response caused by emodin by 45% and 71% respectively, but had no effect on ACh-induced tissue contraction. 5 These data suggest that, emodin causes contraction of the ileum by triggering the release of endogenous ACh which acts on muscarinic receptors to cause contraction of the rat isolated ileum preparation. [source]

Enhanced Transcription of Contractile 5-Hydroxytryptamine 2A Receptors via Extracellular Signal-Regulated Kinase 1/2 after Organ Culture of Rat Mesenteric Artery

BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2005
Yong-Xiao Cao
The present study was designed to examine if vascular 5-HT2A receptors are up-regulated during organ culture and if the extracellular signal-regulated protein kinase 1/2 (ERK1/2) pathways are involved. Compared with fresh rat mesenteric artery ring segments, the contractile responses to 5-HT were significantly increased in the segments cultured for 6, 24 or 48 hr (P<0.05, P<0.01, P<0.01, respectively). The 5-HT-induced contraction occurred via 5-HT2A receptors, since the selective 5-HT2A antagonist ketanserin blocked the 5-HT-induced contraction in the fresh segments with a pA2 value 9.5 (slope was 0.98 with 95% confidence intervals from 0.8 to 1.1). A similar result was obtained in the segments cultured for 24 hr with a pA2 value of 9.43 (slope=0.91 and 95% confidence intervals between 0.45 to 2.3). In addition, the enhanced 5-HT2A receptor contraction occurred with a significant increase of 5-HT2A receptor mRNA (P<0.05). Organ culture of the mesenteric artery was found to activate ERK1/2 already within 1 and 3 hr. It is likely that the ERK1/2 pathways were involved as a initial switch, since the selective ERK1/2 pathway inhibitor SB386023 abolished both up-regulation of 5-HT2A mRNA transcription and the enhanced contractile response to 5-HT. These data reveal a role of ERK1/2 in up-regulation of 5-HT2A receptors and suggest a possibility to inhibit the enhanced responses to 5-HT by inhibition of the ERK1/2 pathway. [source]

Smooth muscle 5-HT2A receptors mediating contraction of porcine isolated proximal stomach strips

BRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2002
P Janssen
The aim of this study was to characterize the 5-HT receptors involved in the 5-HT-induced contraction of longitudinal muscle (LM) strips of porcine proximal stomach. This was done in a classical organ bath set-up for isotonic measurement. The concentration-contraction curve to 5-HT was not modified by 5-HT3 and 5-HT4 receptor antagonism. Methysergide, ketanserin and mesulergine antagonized the curve to 5-HT. Concomitantly, increasing concentrations of ketanserin and mesulergine progressively revealed a biphasic nature of the 5-HT curve. Ketanserin antagonized the low-affinity receptor while it did not modify the high-affinity receptor. Tetrodotoxin did not influence the concentration-contraction curve to 5-HT neither in the absence nor presence of ketanserin, indicating that nerves are not involved. Ketanserin competitively antagonized the monophasic concentration-response curve to ,-Methyl-5-HT, yielding a Schild slope that was not significantly different from unity. After constraining the Schild slope to unity, a pKB estimate of 8.23±0.90 was obtained. This affinity estimate of ketanserin closely approximates previously reported affinities at 5-HT2A receptors. In the presence of ketanserin (0.1 ,M; exposing the high-affinity receptor), a wide range of 5-HT receptor antagonists covering all 5-HT receptors known, was tested. Only methysergide and ritanserin inhibited the response to 5-HT, thus expressing affinity for the high-affinity receptor. This did not reveal the identity of the receptor involved. It can be concluded that 5-HT induces pig proximal stomach (LM) contraction via 5-HT2A receptors located on smooth muscle. A ketanserin-insensitive phase of contractions could not be characterized between the actually known classes of 5-HT receptors with the pharmacological tools that were used. British Journal of Pharmacology (2002) 137, 1217,1224. doi:10.1038/sj.bjp.0704992 [source]

Prostanoid EP1 - and TP-receptors involved in the contraction of human pulmonary veins

BRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2001
Laurence Walch
To characterize the prostanoid receptors (TP, FP, EP1 and/or EP3) involved in the vasoconstriction of human pulmonary veins, isolated venous preparations were challenged with different prostanoid-receptor agonists in the absence or presence of selective antagonists. The stable thromboxane A2 mimetic, U46619, was a potent constrictor agonist on human pulmonary veins (pEC50=8.60±0.11 and Emax=4.61±0.46 g; n=15). The affinity values for two selective TP-antagonists (BAY u3405 and GR32191B) versus U46619 were BAY u3405: pA2=8.94±0.23 (n=3) and GR32191B: apparent pKB=8.25±0.34 (n=3), respectively. These results are consistent with the involvement of TP-receptor in the U46619 induced contractions. The two EP1 -/EP3 - agonists (17-phenyl-PGE2 and sulprostone) induced contraction of human pumonary veins (pEC50=8.56±0.18; Emax=0.56±0.24 g; n=5 and pEC50=7.65±0.13; Emax=1.10±0.12 g; n=14, respectively). The potency ranking for these agonists: 17-phenyl-PGE2>sulprostone suggests the involvement of an EP1 -receptor rather than EP3. In addition, the contractions induced by sulprostone, 17-phenyl-PGE2 and the IP-/EP1 - agonist (iloprost) were blocked by the DP-/EP1 -/EP2 -receptor antagonist (AH6809) as well as by the EP1 antagonist (SC19220). PGF2, induced small contractions which were blocked by AH6809 while fluprostenol was ineffective. These results indicate that FP-receptors are not implicated in the contraction of human pulmonary veins. These data suggest that the contractions induced by prostanoids involved TP- and EP1 -receptors in human pulmonary venous smooth muscle. British Journal of Pharmacology (2001) 134, 1671,1678; doi:10.1038/sj.bjp.0704423 [source]

Endothelin-1 increases cholinergic nerve-mediated contraction of human bronchi via tachykinin synthesis induction

BRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2001
Bruno D'Agostino
In some asthmatics, muscarinic receptor antagonists are effective in limiting bronchoconstrictor response, suggesting an abnormal cholinergic drive in these subjects. There is a growing body of evidences indicating that cholinergic neurotransmission is also enhanced by endothelin-1 (ET-1) in rabbit bronchi, mouse trachea and in human isolated airway preparations. We investigated the role of secondary mediators in ET-1 induced potentiation of cholinergic nerve-mediated contraction in human bronchi, in particular the possible role of neuropeptides in this phenomenon. Bronchial tissues after endothelin treatment were exposed to a standard electrical field stimulation (EFS) (30% of EFS 30Hz)-induced contraction. In addition, in some experiments, preparations were treated with a tachykinin NK2 receptor antagonist and subsequently exposed to the same protocol. HPLC and RIA were performed on organ bath fluid samples. Moreover, the human bronchi were used for the ,-PPT (preprotachykinin) mRNA extraction and semiquantitative reverse transcription polymerase chain reaction (RT , PCR), prior to and 30 , 40 min following ET-1 challenge. The selective tachykinin NK2 receptor antagonist, SR48968, was effective to reduce ET-1 potentiation of EFS mediated contraction. HPLC or RIA showed significant increased quantities of NKA in organ bath effluents after EFS stimulation in bronchi pretreated with ET-1. Finally, ,-PPT mRNA level after stimulation of bronchi with ET-1 was increased about 2 fold respect to control untreated bronchi. In conclusion, this study demonstrated that, at least in part, the ET-1 potentiation of cholinergic nerve-mediated contraction is mediated by tachykinin release, suggesting that in addition to nerves, several type of cells, such as airway smooth muscle cell, may participate to neuropeptide production. British Journal of Pharmacology (2001) 134, 1447,1454; doi:10.1038/sj.bjp.0704395 [source]

The mechanism for the contraction induced by leukotriene C4 in guinea-pig taenia coli

BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2001
Satoshi Ieiri
The mechanism underlying the LTC4 -induced contraction of guinea-pig taenia coli was determined using the simultaneous measurements of [Ca2+]i and force in whole muscle preparations. Additional experiments were performed in receptor coupled permeabilized preparation. For comparison purposes, the contraction which was induced by a typical G-protein mediated agonist, carbachol was also characterized. LTC4 induced a contraction in the guinea-pig taenia coli in a concentration-dependent manner. The maximal response was obtained at 100 nM and the EC50 value was 5.4±1.9 nM. Both LTC4 and carbachol induced increases in [Ca2+]i and force. The maximum force induced by 100 nM LTC4 was significantly smaller than that induced by 10 ,M carbachol, although an increase in [Ca2+]i produced by both agonists was similar. In the permeabilized preparations, carbachol, but not LTC4, induced an additional force development at a fixed Ca2+ concentration. LTC4 induced no increase in [Ca2+]i and force in the Ca2+ -free solution, while carbachol induced transient increases in both [Ca2+]i and force in a Ca2+ -free solution. Both diltiazem and SK&F 96365 significantly inhibited the LTC4, and carbachol-induced increases in [Ca2+]i and force in normal PSS. The inhibitory pattern of [Ca2+]i by these drugs was also similar. We thus conclude that LTC4 induces the contraction of the guinea-pig taenia coli mainly through Ca2+ influx via both the diltiazem-sensitive and SK&F 96365-sensitive Ca2+ channels, without affecting either the Ca2+ -sensitivity or the intracellular Ca2+ release. These results indicated that the mechanism underlying the LTC4 -induced contraction differs greatly from that for conventional G-protein mediated agonists, such as carbachol. British Journal of Pharmacology (2001) 133, 529,538; doi:10.1038/sj.bjp.0704122 [source]

Role of Ca2+ mobilization and Ca2+ sensitization in 8-iso-PGF2, -induced contraction in airway smooth muscle

CLINICAL & EXPERIMENTAL ALLERGY, Issue 2 2009
A. Shiraki
Summary Background Isoprostanes are prostaglandin (PG)-like compounds synthesized by oxidative stress, not by cyclooxygenase, and increase in bronchoalveolar lavage fluid of patients with asthma. The airway inflammation implicated in this disease may be amplified by oxidants. Although isoprostanes are useful biomarkers for oxidative stress, the action of these agents on airways has not been fully elucidated. Objective This study was designed to determine the intracellular mechanisms underlying the effects of oxidative stress on airway smooth muscle, focused on Ca2+ signalling pathways involved in the effect of 8-iso-PGF2,. Methods Using simultaneous recording of isometric tension and F340/F380 (an indicator of intracellular concentrations of Ca2+, [Ca2+]i), we examined the correlation between tension and [Ca2+]i in response to 8-iso-PGF2, in the fura-2 loaded tracheal smooth muscle. Results Augmented tension and F340/F380 by 8-iso-PGF2, were attenuated by ICI-192605, an antagonist of thromboxane A2 receptors (TP receptors). Moreover, D609, an antagonist of phosphatidylcholine-specific phospholipase C, markedly reduced both the tension and F340/F380 induced by 8-iso-PGF2,, whereas U73122, an antagonist of phosphatidylinositol-specific phospholipase C, modestly inhibited them by 8-iso-PGF2,. SKF96365, a non-selective antagonist of Ca2+ channels, markedly reduced both tension and F340/F380 by 8-iso-PGF2,. However, diltiazem and verapamil, voltage-dependent Ca2+ channel inhibitors, modestly attenuated tension although their reduction of F340/F380 was not different from that by SKF96365. Y-27632, an inhibitor of Rho-kinase, significantly attenuated contraction induced by 8-iso-PGF2, without reducing F340/F380, whereas GF109203X and Go6983, protein kinase C inhibitors, did not markedly antagonize them although reducing F340/F380 with a potency similar to Y-27632. Conclusion 8-iso-PGF2, causes airway smooth muscle contraction via activation of TP receptors. Ca2+ mobilization by SKF96365- and D609-sensitive Ca2+ influx and Ca2+ sensitization by Rho-kinase contribute to the intracellular mechanisms underlying the action of 8-iso-PGF2,. Rho-kinase may be a therapeutic target for the physiologic abnormalities induced by oxidative stress in airways. [source]

PARTICIPATION OF VASOPRESSIN IN THE DEVELOPMENT OF CEREBRAL VASOSPASM IN A RAT MODEL OF SUBARACHNOID HAEMORRHAGE

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2004
Cristina C Trandafir
SUMMARY 1.,Previous studies have suggested the involvement of arginine vasopressin (AVP) and inflammation in the development of cerebral vasospasm after subarachnoid haemorrhage (SAH). The aim of the present study was to clarify the role of AVP in the arterial narrowing following cerebral haemorrhage by examining the effect of SR 49059 (a V1 receptor antagonist) on the diameter of rat basilar artery exposed to SAH. The effect of the 5-lipoxygenase inhibitor ZM 230487 on AVP-induced contraction of rat basilar arteries was also investigated. 2.,After 1 h and 2 days from SAH induction, brains were removed and pictures of the basilar arteries were taken. The external diameter of the basilar artery was measured in the presence and absence of SR 49059 (1 mg/kg, i.v.). For in vitro experiments, the basilar arteries isolated from control and SAH rats (at 1 h and at 2 days from SAH induction) were cut into spiral preparations and the AVP (0.3 nmol/L)-induced contraction in the presence of ZM 230487 was investigated. Each group analysed (i.e. control, SAH 1 h and SAH 2 days) consisted of eight rats. 3.,The diameter of rat basilar arteries decreased by 43 and 25% at 1 h and 2 days from SAH induction, respectively, compared with control. The administration of SR 49059 significantly reduced cerebral vasospasm. After SAH induction, the diameter of the basilar artery in SR 49059-treated groups decreased by only 22% (at 1 h) and by 3% (at 2 days) compared with the control group (P < 0.01). In basilar arterial strips, ZM 230487 attenuated the vasopressin-induced contraction in both control and SAH groups. However, SAH groups showed a significant resistance of the AVP-induced contraction in the presence of ZM 230487 compared with control (P < 0.05). 4.,The results suggest that the cerebral vasospasm in SAH rats is due, at least in part, to endogenous AVP and may involve an increase in the activity of 5-lipoxygenase. SR 49059 may represent a potential therapeutic strategy for the treatment of cerebral vasospasm. [source]

Tonic Potentiation And Attenuation Produced By Membrane Depolarization In Guinea-Pig Trachealis

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2000
Kenichi Yamaki
SUMMARY 1. We studied how membrane depolarization directly affected intracellular Ca2+ signalling when voltage-operated Ca2+ channels (VOCC) were not available in guinea-pig tracheal smooth muscle. To block VOCC, we used 3 ,mol/L verapamil, which completely abolished high K+ (20,60 mmol/L)-induced contraction, and elevation of fura-2 signal. 2. Muscle tone was generated by adding Ca2+ to the extracellular Ca2+ -free solution containing prostaglandin (PG)E2 (100 nmol/L) after abolishing basal tone with indomethacin (1 ,mol/L). 3. In the absence of verapamil, high K+ (20,60 mmol/L) solution potentiated 2.4 mmol/L Ca2+ -induced sustained contractions. Even in the presence of 3 ,mol/L verapamil, replacement with 20 and 40 mmol/L K+ solution induced tonic potentiation, which was changed to attenuation with a higher K+ solution (60 mmol/L), lower extracellular Ca2+ concentration ([Ca2+]o) and pretreatment with cyclopiazonic acid (10 ,mol/L), a Ca2+ sequestration inhibitor. 4. These results indicate that the balance between depolarization-dependent Ca2+ release and receptor-operated cation channel inhibition may determine whether tonic potentiation or attenuation is manifested, depending on the availability of VOCC, the magnitude of the depolarization, [Ca2+]o and Ca2+ content in the sarcoplasmic reticulum. [source]

2,2,-Nitrophenylisatogen potentiates P2X1 receptor mediated vascular contraction and blood pressure elevation

DRUG DEVELOPMENT RESEARCH, Issue 1 2003
Anna-Karin Wihlborg
Abstract The objective of this research was to examine the effects of chemical compounds with possible P2 receptor modulating effects and to characterize the potentiating effects of 2,2,-nitrophenylisatogen (NPI) on P2X1 receptors in vitro and in vivo. Chemical compounds were tested in an in vitro pharmacological assay using vascular segments from the rat mesenteric artery stimulated by P2 receptor-specific agonists. Contractions were expressed as a percentage of 60 mM K+ -induced contractions. Blood pressure was evaluated in pithed rats. NPI (30 ,M) added 15 min before addition of the P2X1 receptor-specific agonist ,,-MeATP increased the maximum vasoconstriction from 23% to 49% (an increase of 113%). Furthermore, NPI prevented the desensitization of repeated ,,-MeATP contractions. Related compounds were examined, and 2-(3-methoxy-phenyl)-1-oxy-indol-3-one (MPI) had similar effects as NPI, but several others lacked effect. NPI had no effect on ADP,S (P2Y1) or acetylcholine-mediated vasodilatation, nor on UTP (P2Y2/4), UDP (P2Y6), or noradrenaline-mediated contractions. In pithed rats, the blood pressure response to 50 nmol/kg-infusion of ,,-MeATP was increased from 50±6 to 63±5 mmHg (P<0.05), but had no effect on basal blood pressure or on the cardiovascular response to preganglionic nerve stimulation. In conclusion, NPI and MPI potentiates P2X1 receptor vascular contractions in vitro and (NPI) blood pressure effects in vivo. It is possible that the effect is mediated by an inhibition of P2X1 receptor desensitization. Drug Dev. Res. 59:82,87, 2003. © 2003 Wiley-Liss, Inc. [source]

Ovalbumin-induced sensitization affects non-quantal acetylcholine release from motor nerve terminals and alters contractility of skeletal muscles in mice

EXPERIMENTAL PHYSIOLOGY, Issue 2 2009
Alexander Y. Teplov
Skeletal muscles play key roles in the development of various pathologies, including bronchial asthma and several types of auto-immune disorders, e.g. polymyositis. Since most of these maladies have an immunological/allergic element, this paper is devoted to assessing the impact of immunobiological reorganization on the functional properties of isolated skeletal muscles in mice. A combination of two methods (myography and electrophysiology) was used to evaluate extensor digitorum longus (EDL) and diaphragmatic muscle (DM) in this regard. Conventional myographic technique showed that ovalbumin-induced sensitization (OS) produced different changes in the contractile properties of EDL and DM. The amplitudes of carbachol (CCh)-induced contractions increased in DM but decreased in EDL. Those changes were inversely related to OS-mediated changes of non-quantal acetylcholine (ACh) release intensity within the muscle endplate, as shown by the electrophysiologically measured H-effect. These results clearly show that OS-mediated changes of non-quantal ACh release alter the functional properties of postjunctional ACh receptors and therefore contribute to the disturbance of CCh-induced contractility of skeletal muscles. Other mechanisms of OS-mediated changes of skeletal muscle contractility are also proposed and discussed. [source]

Gastrointestinal, selective airways and urinary bladder relaxant effects of Hyoscyamus niger are mediated through dual blockade of muscarinic receptors and Ca2+ channels

FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2008
Anwarul Hassan Gilani
Abstract This study describes the spasmolytic, antidiarrhoeal, antisecretory, bronchodilatory and urinary bladder relaxant properties of Hyoscyamus niger to rationalize some of its medicinal uses. The crude extract of H. niger seeds (Hn.Cr) caused a complete concentration-dependent relaxation of spontaneous contractions of rabbit jejunum, similar to that caused by verapamil, whereas atropine produced partial inhibition. Hn.Cr inhibited contractions induced by carbachol (1 ,m) and K+ (80 mm) in a pattern similar to that of dicyclomine, but different from verapamil and atropine. Hn.Cr shifted the Ca2+ concentration,response curves to the right, similar to that caused by verapamil and dicyclomine, suggesting a Ca2+ channel-blocking mechanism in addition to an anticholinergic effect. In the guinea-pig ileum, Hn.Cr produced a rightward parallel shift of the acetylcholine curves, followed by a non-parallel shift with suppression of the maximum response at a higher concentration, similar to that caused by dicyclomine, but different from that of verapamil and atropine. Hn.Cr exhibited antidiarrhoeal and antisecretory effects against castor oil-induced diarrhoea and intestinal fluid accumulation in mice. In guinea-pig trachea and rabbit urinary bladder tissues, Hn.Cr caused relaxation of carbachol (1 ,m) and K+ (80 mm) induced contractions at around 10 and 25 times lower concentrations than in gut, respectively, and shifted carbachol curves to the right. Only the organic fractions of the extract had a Ca2+ antagonist effect, whereas both organic and aqueous fractions had anticholinergic effect. A constituent, ,-sitosterol exhibited Ca2+ channel-blocking action. These results suggest that the antispasmodic effect of H. niger is mediated through a combination of anticholinergic and Ca2+ antagonist mechanisms. The relaxant effects of Hn.Cr occur at much lower concentrations in the trachea and bladder. This study offers explanations for the medicinal use of H. niger in treating gastrointestinal and respiratory disorders and bladder hyperactivity. [source]

Effects of ouabain on contractions induced by manganese ions in Ca2+ -free, isotonic solutions with varying concentrations of K+ in guinea-pig taenia coli

FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2005
Tetsuyuki Nasu
Abstract The action of ouabain, a cell membrane Na+, K+ -ATPase blocker, on contractions induced by manganese ions (Mn2+) in Ca2+ -free, isotonic solutions with varying concentrations of K+ in the external medium were investigated in order to evaluate the underlying role of external Na+ in Mn2+ -induced contractions in isolated taenia coli of the guinea-pig. Mn2+ at 5 mm induced greater contractions as external isotonic K+ concentrations progressively increased from 10 to 100 mm. Ouabain (2 × 10,4 m) completely inhibited tension development stimulated by 5 mm Mn2+ in isotonic, 30 mm K+ (96 mm Na+) medium. Whereas, the tension inhibitory effects of ouabain became progressively weaker as isotonic, external K+ concentrations increased to 60 mm, which successively decreased external Na+ concentrations. Eventually, ouabain failed to affect contractions stimulated by Mn2+ in isotonic, 126 mm K+, Na+ -deficient medium. Ouabain caused progressively greater increase in cellular Na+ concentrations as the Na+ concentrations increased in the isotonic, K+ medium. While, pyruvate, which penetrates cell independently of external Na+, reversed the inhibition of tension by ouabain in isotonic, 30 mm K+, Na+ -sufficient (96 mm) medium containing 5 mm Mn2+. These results suggested that Mn2+ induced the contraction, which was maintained by glucose transport depending on external Na+, in the case of Na+ -sufficient medium in K+ -depolarized taenia coli. However, it induced the contraction independent of external Na+, in the case of Na+ -deficient, K+ medium. Ouabain might exhibit greater inhibition of the contraction induced by Mn2+ as the decrease in the Na+ gradient across the cell membranes continues. [source]

Characterization of myenteric neuropathy in the jejunum of spontaneously diabetic BB-rats

NEUROGASTROENTEROLOGY & MOTILITY, Issue 7 2008
M. Zandecki
Abstract, Decreased gastric expression and function of neuronal nitric oxide synthase (nNOS) has been proposed as a potential mechanism underlying diabetic gastroparesis. As gastric nNOS expression is vagally controlled, these changes might occur secondarily to vagal neuropathy. In addition, it is unclear whether other inhibitory neurotransmitters are also involved. We used the type 1 diabetic BioBreeding (BB)-rat model to study jejunal motor control and nNOS expression, which is independent of the vagus. Jejunal segments were used for in vitro contractility studies, and measurement of nNOS expression after 8 or 16 weeks of diabetes compared with age- and sex-matched controls. Unlike electrical field stimulation and acetylcholine (ACh)-induced contractions, non-adrenergic non-cholinergic (NANC) relaxations were significantly reduced in diabetic rats. In contrast to control rats, NANC relaxations in diabetic rats were N, -nitro- l -arginine methyl ester (l -NAME) insensitive. Jejunal nNOS expression was significantly decreased in diabetic rats. Both in diabetic and in control animals, l -NAME resistant relaxations were sensitive to P2 -receptor antagonists. In the jejunum of spontaneously diabetic rats, decreased nitric oxide responsiveness and decreased nNOS protein expression occur while purinergic transmission is unaffected. These findings indicate that nitrergic enteric neuropathy may be a primary dysfunction in diabetes, independent from vagal dysfunction. [source]

Studies on spasmogenic and spasmolytic activities of Calendula officinalis flowers

PHYTOTHERAPY RESEARCH, Issue 10 2006
Samra Bashir
Abstract The aqueous-ethanol extract of Calendula officinalis flowers (Co.Cr) was studied for its possible spasmolytic and spasmogenic effects in isolated gut preparations. In rabbit jejunum, Co.Cr caused a dose-dependent (0.03,3.0 mg/mL) relaxation of spontaneous and K+-induced contractions, suggestive of calcium channel blockade (CCB). In a few preparations, a mild non-reproducible spasmogenic effect was observed at lower doses, followed by relaxation. The CCB effect was confirmed when pretreatment of the jejunum preparations with Co.Cr produced a dose-dependent rightward shift in the Ca++ dose-response curves, similar to that of verapamil. Activity-directed fractionation revealed that the spasmolytic activity of the plant was concentrated in its organic fractions. The aqueous fraction exhibited a marked atropine sensitive spasmogenic effect but was found to be devoid of any spasmolytic effect. These data indicate that the crude extract of Calendula officinalis flowers contains both spasmolytic and spasmogenic constituents, exhibiting these effects through calcium channel blocking and cholinergic activities and this study provides a scientific base for its traditional use in abdominal cramps and constipation. Copyright © 2006 John Wiley & Sons, Ltd. [source]

Effect of a dysmenorrhea Chinese medicinal prescription on uterus contractility in vitro

PHYTOTHERAPY RESEARCH, Issue 7 2003
Chun-Sen Hsu
Abstract Dysmenorrhea is a common gynecologic complaint. After their ,rst menstrual period, 30%,60% of American women suffer from some level of discomfort. It is estimated that 6 billion work hours are lost in this manner every year in the United States which equals an economic loss of nearly US$200 million. Dysmenorrhea is not only a problem for women but also one which affects quality of life and even reduces productivity in general. Dysmenorrhea is directly related to elevated levels of PGF2, (prostaglandins F2,) and is treated using nonsteroid anti-in,ammatory drugs in Western medicine. Though ef,cacy of the latter is rapid, there are many side effects to the liver, kidney, and digestive system. The anti-in,ammatory effect is temporary, and such drugs are unable to provide a long-term cure. Because of this, Chinese medicinal therapy is being considered as a feasible alternative medicine. In this study, Wen-Jing Tang (one of the dysmenorrhea Chinese medicinal prescriptions) was selected. A 50% alcoholic solution was used to extract active ingredients and create a freeze-dried product. At ,rst, Wen-Jing Tang was used to suppress spontaneous contractions and prostaglandins F2, -induced contractions of rat uterine smooth muscle in vitro. Then, an assessment was performed to determine the mechanism of the prescription. Acetylcholine, ergonovine, propranolol, oxytocin, and KCl were used to analyze the physiological mechanisms of WJT. The results show that antagonism of both PGF2, and ACh are the major mechanisms for treating dysmenorrhea by Wen-Jing Tang. Furthermore, the antagonistic effect of KCl-depolarization contractions may be an auxiliary mechanism of the curative effect. Copyright © 2003 John Wiley & Sons, Ltd. [source]

c-Src tyrosine kinase, a critical component for 5-HT2A receptor-mediated contraction in rat aorta

Actions of R- and S-verapamil and nifedipine on rat vascular and intestinal smooth muscle

AUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2004
L. Cleary
Summary 1 We have investigated the actions of the calcium entry blockers nifedipine, R-verapamil and S-verapamil in rat aorta, colon and vas deferens. 2 In aorta and colon, these agents produced concentration-dependent relaxations of KCl (80 mm)-induced contractions. In both tissues, the order of potency was nifedipine > S-verapamil > R-verapamil. However, nifedipine showed selectivity for aorta (potency ratio, colon/aorta: 4.36), S-verapamil showed no selectivity (0.62), but R-verapamil showed selectivity for colon (0.19). 3 In prostatic portions of rat vas deferens, nifedipine (10 ,m) abolished the contraction to a single electrical stimulus, but R- and S-verapamil were without effect. In epididymal portions of rat vas deferens, R- and S-verapamil inhibited ,1 -adrenoceptor-mediated contractions to a single electrical stimulus at concentrations of 10 ,m and above. 4 In conclusion, R-verapamil may prove useful as an intestinal selective calcium entry blocker in the treatment of intestinal disease with a hypermotility component, e.g. irritable bowel syndrome. [source]

Opposite effects of endogenous nitric oxide and prostaglandin F2, in the rat mesenteric bed

AUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2003
H. A. Peredo
Summary 1 The relationship between the effects of endogenous nitric oxide (NO) and prostanoids on the noradrenaline (NA)-induced contractions and the mechanisms involved were investigated in the rat perfused mesenteric bed, using NG -nitro- l -arginine methyl ester (l -NAME), a NO synthase inhibitor and sodium nitroprusside (SNP), a NO donor. 2 The constrictor responses to NA were reduced to 50% by the cyclooxygenase inhibitor 10 ,m indomethacin as well as by 1 ,m SNP. When indomethacin and SNP were perfused simultaneously the contractions were further reduced. 3 The NA-induced contractions were increased by the addition of 400 ,ml -NAME and the addition of either indomethacin or SNP abolished such increases. The simultaneous perfusion of both agents further reduced the contractions. 4 Removal of the endothelium increased NA-induced contractions to a similar extent as l -NAME and this increase was abolished by indomethacin as well as by SNP. 5 The perfusion of 10 ,m NA augmented the release of prostaglandin (PG) F2, by the mesenteric bed without modifications in any other prostanoid. In the presence of l -NAME, this effect was further increased. However, SNP abolished the NA-induced stimulation of PGF2, release. 6 In de-endothelialized preparations NA also stimulated PGF2, production as observed in intact preparations. This effect was more marked in the presence of l -NAME; in contrast, SNP abolished the stimulation. 7 In conclusion, the present results suggest an opposite action between NO and PGF2, on the NA-induced contractions in the rat mesenteric bed. [source]

Characterization of the 5-hydroxytryptamine receptors mediating contraction in the pig isolated intravesical ureter

BRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2003
Medardo Hernández
This study was designed to investigate the effect of 5-hydroxytryptamine (5-HT) and to characterize the 5-HT receptors involved in 5-HT responses in the pig intravesical ureter. 5-HT (0.01,10 ,M) concentration-dependently increased the tone of intravesical ureteral strips, whereas the increases in phasic contractions were concentration-independent. The 5-HT2 receptor agonist ,-methyl 5-HT, mimicked the effect on tone whereas weak or no response was obtained with 5-CT, 8-OH-DPAT, m -chlorophenylbiguanide and RS 67333, 5-HT1, 5-HT1A, 5-HT3 and 5-HT4 receptor agonists, respectively. 5-HT did not induce relaxation of U46619-contracted ureteral preparations. Pargyline (100 ,M), a monoaminooxidase A/B activity inhibitor, produced leftward displacements of the concentration-response curves for 5-HT. 5-HT-induced tone was reduced by the 5-HT2 and 5-HT2A receptor antagonists ritanserine (0.1 ,M) and spiperone (0.2 ,M), respectively. However, 5-HT contraction was not antagonized by cyanopindolol (2 ,M), SDZ,SER 082 (1 ,M), Y-25130 (1 ,M) and GR 113808 (0.1 ,M), which are respectively, 5-HT1A/1B, 5-HT2B/2C, 5-HT3, and 5-HT4 selective receptor antagonists. Removal of the urothelium did not modify 5-HT-induced contractions. Blockade of neuronal voltage-activated sodium channels, ,-adrenergic receptors and adrenergic neurotransmission with tetrodotoxin (1 ,M), phentolamine (0.3 ,M) and guanethidine (10 ,M), respectively, reduced the contractions to 5-HT. However, physostigmine (1 ,M), atropine (0.1 ,M) and suramin (30 ,M), inhibitors of cholinesterase activity, muscarinic- and purinergic P2 -receptors, respectively, failed to modify the contractions to 5-HT. These results suggest that 5-HT increases the tone of the pig intravesical ureter through 5-HT2A receptors located at the smooth muscle. Part of the 5-HT contraction is indirectly mediated via noradrenaline release from sympathetic nerves. British Journal of Pharmacology (2003) 138, 137,144. doi:10.1038/sj.bjp.0705019 [source]

Inhibitory effect of 1,8-cineole on guinea-pig airway challenged with ovalbumin involves a preferential action on electromechanical coupling

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 11 2009
Vasco PD Bastos
Summary 11,8-Cineole is a terpenoid constituent of essential oils with anti-inflammatory properties. It reduces the neural excitability, functions as an antinociceptive agent and has myorelaxant actions in guinea-pig airways. The aim of the present study was to investigate the mechanism underlying the myorelaxant effects of 1,8-cineole in guinea-pig isolated trachea from either naïve guinea-pigs or ovalbumin (OVA)-sensitized animals subjected to antigenic challenge. 2Isometric recordings were made of the tone of isolated tracheal rings. Rings with an intact epithelium relaxed beyond basal tone in the presence of 1,8-cineole (6.5 × 10,6 to 2 × 10,2 mol/L) in a concentration-dependent manner (P < 0.001, anova) with a pD2 value of 2.23 (95% confidence interval 2.10,2.37). Removal of the epithelium or pretreatment of intact tissue for 15 min with 50 µmol/L NG -nitro- l -arginine methyl ester, 5 mmol/L tetraethylammonium, 0.5 µmol/L tetrodotoxin or 5 µmol/L propranolol did not alter the potency (pD2) or the maximal myorelaxant effect (Emax) of 1,8-cineole. 31,8-Cineole also significantly decreased the Schultz-Dale contraction induced by OVA, mainly in preparations from OVA-sensitized animals submitted to antigen challenge. 1,8-Cineole decreased tracheal hyperresponsiveness to KCl and carbachol caused by antigen challenge and almost abolished the concentration,response curves to KCl, whereas it had little effect on the concentration,response curves to carbachol. Under Ca2+ -free conditions and in the presence of 10,4 mol/L acetylcholine, neither 1,8-cineole (6.5 × 10,3 mol/L) nor verapamil (1 × 10,5 mol/L) affected Ca2+ -induced contractions, but they almost abolished Ba2+ -induced contractions. 4In conclusion, the findings of the present study show that 1,8-cineole is a tracheal myorelaxant that acts preferentially on contractile responses elicited electromechanically. [source]