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Spontaneous Contractions (spontaneous + contraction)
Selected AbstractsThe actions of azelnidipine, a dihydropyridine-derivative Ca antagonist, on voltage-dependent Ba2+ currents in guinea-pig vascular smooth muscleBRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2006H-L Zhu Background and purpose: Although azelnidipine is used clinically to treat hypertension its effects on its target cells, Ca2+ channels, in smooth muscle have not been elucidated. Therefore, its effects on spontaneous contractions and voltage-dependent L-type Ca2+ channels were investigated in guinea-pig portal vein. Experimental approach: The inhibitory potency of azelnidipine on spontaneous contractions in guinea-pig portal vein was compared with those of other dihydropyridine (DHP)-derived Ca antagonists (amlodipine and nifedipine) by recording tension. Also its effects on voltage-dependent nifedipine-sensitive inward Ba2+ currents (IBa) in smooth muscle cells dispersed from guinea-pig portal vein were investigated by use of a conventional whole-cell patch-clamp technique. Key results: Spontaneous contractions in guinea-pig portal vein were reduced by all of the Ca antagonists (azelnidipine, Ki=153 nM; amlodipine, Ki=16 nM; nifedipine, Ki=7 nM). In the whole-cell experiments, azelnidipine inhibited the peak amplitude of IBa in a concentration- and voltage-dependent manner (-60 mV, Ki=282 nM; ,90 mV, Ki=2 ,M) and shifted the steady-state inactivation curve of IBa to the left at ,90 mV by 16 mV. The inhibitory effects of azelnidipine on IBa persisted after 7 min washout at ,60 mV. In contrast, IBa gradually recovered after being inhibited by amlodipine, but did not return to control levels. Both azelnidipine and amlodipine caused a resting block of IBa at -90 mV. Only nifedipine appeared to interact competitively with S(-)-Bay K 8644. Conclusions and implications: These results suggest that azelnidipine induces long-lasting vascular relaxation by inhibiting voltage-dependent L-type Ca2+ channels in vascular smooth muscle. British Journal of Pharmacology (2006) 149, 786,796. doi:10.1038/sj.bjp.0706919 [source] Real-time monitoring of intracellular calcium dynamic mobilization of a single cardiomyocyte in a microfluidic chip pertaining to drug discoveryELECTROPHORESIS, Issue 24 2007Xiujun Li Abstract A microfluidic method for real-time quantitative measurement of cellular response pertaining to drug discovery is reported. This method is capable of multiple-step liquid delivery for measuring the drug response of a single cardiomyocyte, due to the improved cell retention by a newly designed chip. The chip, which consists of a cell-retention chamber with a weir structure, was fabricated just by a one-photomask microfabrication procedure followed by on-chip etching. This method differs from the conventional method, which uses two-mask photolithography to fabricate the microchannel (deep etch) and the weir structure (shallow etch). The dimensions of the weir structure have been predicted by a mathematical model, and confirmed by confocal microscopy. Using this microfluidic method, the dynamic [Ca2+]i mobilization in a single cardiomyocyte during its spontaneous contraction was quantified. Furthermore, we measured the cellular response of a cardiomyocyte on (i) a known cardiotonic agent (caffeine), (ii) a cardiotoxic chemotherapeutic drug (daunorubicin), and (iii) an herbal anticancer drug candidate , isoliquiritigenin (IQ) based on the fluorescent calcium measurement. It was found that IQ had produced a less pronounced effect on calcium mobilization of the cardiomyocytes whereas caffeine and daunorubicin had much stronger effects on the cells. These three experiments on cardiomyocytes pertaining to drug discovery were only possible after the improved cell retention provided by the new chip design (MV2) required for multiple-step real-time cellular analysis on a microchip, as compared with our old chip design (MV1). [source] The regulation of acetylcholinesterase by cis -elements within intron I in cultured contracting myotubesJOURNAL OF NEUROCHEMISTRY, Issue 3 2006Tatiana V. Cohen Abstract The onset of spontaneous contraction in rat primary muscle cultures coincides with an increase in acetylcholinesterase (AChE) activity. In order to establish whether contractile activity modulates the rate of AChE transcript synthesis, and what elements of the gene are determinant, we examined the promoter and intron I in contracting muscle cultures. Ache genomic fragments attached to a luciferase reporter were transfected into muscle cultures that were either electrically stimulated or paralyzed with tetrodotoxin to enhance or inhibit contractions, respectively. Cultures transfected with intron I-containing constructs showed a 2-fold increase in luciferase activity following electrical stimulation, compared to tetrodotoxin treatment, suggesting that this region contains elements responding to contractile activity. Deleting a 780 bp distal region within intron I, containing an N-box element at +890 bp, or introducing a 2-bp mutation within its core sequence, eliminated the contraction-induced response. In contrast, mutating an N-box element at +822 bp had no effect on the response. Furthermore, co-transfecting a dominant negative GA-binding protein (GABP), a transcription factor known to selectively bind N-box elements, reduced the stimulation-mediated increase. Our results suggest that the N-box within intron I at +890 bp is a regulatory element important in the transcriptional response of Ache to contractile activity in muscle. [source] Oxytocin receptor expressed on the smooth muscle mediates the excitatory effect of oxytocin on gastric motility in ratsNEUROGASTROENTEROLOGY & MOTILITY, Issue 4 2009J. Qin Abstract, The aim of this study was to localize oxytocin receptor (OTR) in the stomach and to investigate the effect of OT on gastric motility in rats. Western blot and immunohistochemistry methods were used to localize OTR in stomach. The motility of stomach was recorded in vivo (recording of the intragastric pressure), in vitro (recording of the contraction of muscle strips) and on isolated smooth muscle cells. OTR was expressed on cells of both circular and longitudinal muscle of stomach. Systemic administration of OT induced an early transient decrease and a subsequent increase on intragastric pressure. Devazepide (1 mg kg,1, i.v.), a cholecystokinin-1 (CCK1) receptor antagonist, completely abolished the transient response but did not influence the subsequent one. OT (10,9,10,6 mol L,1) dose-dependently increased the contraction of the muscle strips of gastric body, antrum, and pyloric sphincter, and decreased the average cell length of isolated smooth muscle cells. Tetrodotoxin and atropine did not influence the effect of OT on muscle strips. Pretreatment with atosiban, an OTR antagonist, inhibited the spontaneous contraction of muscle strips and abolished the excitatory effect of OT on the muscle strips and the isolated cells. These results suggest that the OTR is expressed on the smooth muscle of the stomach and mediates excitatory effect of OT on gastric motility. [source] Gastrointestinal, selective airways and urinary bladder relaxant effects of Hyoscyamus niger are mediated through dual blockade of muscarinic receptors and Ca2+ channelsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2008Anwarul 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] Increased intracellular [dATP] enhances cardiac contraction in embryonic chick cardiomyocytesJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2008Brenda Schoffstall Abstract Although ATP is the physiological substrate for cardiac contraction, cardiac contractility is significantly enhanced in vitro when only 10% of ATP substrate is replaced with 2,-deoxy-ATP (dATP). To determine the functional effects of increased intracellular [dATP] ([dATP]i) within living cardiac cells, we used hypertonic loading with varying exogenous dATP/ATP ratios, but constant total nucleotide concentration, to elevate [dATP]i in contractile monolayers of embryonic chick cardiomyocytes. The increase in [dATP]i was estimated from dilution of dye added in parallel with dATP. Cell viability, average contractile amplitude, rates of contraction/relaxation, spontaneous beat frequency, and Ca2+ transient amplitude and kinetics were examined. At total [dATP]i above ,70 µM, spontaneous contractions ceased, and above ,100 µM [dATP]i, membrane blebbing was also observed, consistent with apoptosis. Interestingly, [dATP]i of ,60 µM (,40% increase over basal [dATP]i levels) enhanced both amplitude of contraction and the rates of contraction and relaxation without affecting beat frequency. With total [dATP]i of ,60 µM or less, we found no significant change in Ca2+ transients. These data indicate that there is an "optimal" concentration of exogenously loaded [dATP]i that under controlled conditions can enhance contractility in living cardiomyocytes without affecting beat frequency or Ca2+ transients. J. Cell. Biochem. 104: 2217,2227, 2008. © 2008 Wiley-Liss, Inc. [source] Influence of progesterone on myometrial contractility in pregnant mice treated with lipopolysaccharideJOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH (ELECTRONIC), Issue 6 2007Hiroshi Anbe Abstract Aim:, To evaluate the effect of progesterone on interleukin (IL)-6, prostaglandin (PG) E2 and nitric oxide (NO) metabolite (NOx) production and contractile activity by NO in pregnant mice treated with lipopolysaccharide (LPS). Methods:, Pregnant C57BL mice on day 14 of gestation were killed 6 h after i.p. injection of LPS (400 ,g/kg) or vehicle. Progesterone (2 mg) was subcutaneously injected 2 h before LPS treatment. Uterine rings were equilibrated in Krebs-Henseleit solution (37°C) bubbled with 20% O2 and 5% CO2 (pH 7.4) for sampling and isometric tension recording. IL-6, PGE2 and NOx productions were measured from the bathing solution. Changes in spontaneous contractile activity in response to cumulative concentrations of l -arginine, diethylamine/nitric oxide (DEA/NO, the NO donor), and 8-bromo-cGMP (8-br-cGMP) were compared. Integral contractile activity over 10 min after each concentration was calculated and expressed as percentage change from basal activity. Statistical analyses were performed using one-way anova followed by Dunnett's test (significance was defined as P < 0.05). Results:, Interleukin-6 (34.7 ± 6.0 pg/g tissue), PGE2 (66.8 ± 6.7 pg/g tissue) and NOx (51.0 ± 5.4 pmol/2 mL/g wet tissue) production were significantly stimulated by LPS treatment (138.2 ± 23.2, 147.0 ± 29.0, 98.6 ± 16.2, respectively; P < 0.05). l -arginine, DEA/NO and 8-br-cGMP concentration-dependently inhibited spontaneous contractions in uterine rings both in LPS-treated and -untreated animals. Treatment with LPS significantly attenuated the maximal inhibition induced by l -arginine, DEA/NO and 8-br-cGMP in uterine rings from pregnant mice. Progesterone significantly decreased the levels of IL-6 production (74.9 ± 12.1, P < 0.05), but not PGE2 and NOx production, and contractile responses by l -arginine, DEA/NO and 8-br-cGMP. Conclusions:, The administration of LPS is associated with increases in IL-6, PGE2 and NO, and these increases may or may not have a role to play in LPS-induced preterm labor. Progesterone reduced the LPS-induced increase in IL-6 production and this may be one of the ways that progesterone reduces the risk of preterm labor. [source] Effects of dofetilide on cardiovascular tissues from normo- and hypertensive ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2002Sheila A. Doggrell The aim was to test whether dofetilide has some potential for use in the treatment of heart failure. Dofetilide at ,3 times 10,5 M had no effect on the quiescent Wistar Kyoto (WKY) rat aorta, mesenteric and intralobar arteries, or the spontaneous contractions of the WKY rat portal vein. Dofetilide at 10,6 to 3 times 10,5 M relaxed the KCl-contracted aorta. Dofetilide at 10,9 -10,7 M augmented the force of contraction of left ventricle strips from 12- and 18-month-old WKY rats at 2 Hz. Spontaneously hypertensive rats (SHRs) at 12 and 17,21 months of age are models of cardiac hypertrophy and failure, respectively. The augmentation of force at 2 Hz with dofetilide was similar on 12-and 18-month-old WKY rats and 12-month-old SHRs but reduced on the 18-month-old SHR left ventricle. At a higher more physiological frequency, 4 Hz, the threshold concentration of dofetilide required to augment the force responses of 21-month-old SHR left ventricles was markedly increased and the maximum augmenting effect was decreased. Dofetilide at 10,7 -10,5 M reduced the rate of the 17-month-old WKY rat right atrium, and had a similar effect on age-matched SHR right atrium. In summary, dofetilide is a positive inotrope and negative chronotrope in the rat. However, as the positive inotropic effect is not observed with clinically relevant concentrations at a physiological rate in heart failure, dofetilide is unlikely to be useful as a positive inotrope in the treatment of heart failure. [source] Inhibitory effects of desflurane and sevoflurane on oxytocin-induced contractions of isolated pregnant human myometriumACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 9 2005K. Yildiz Background:, In this study, we investigated the inhibitory effects of desflurane and sevoflurane on oxytocin-induced contractions of isolated human myometrium. Methods:, Following delivery of the infant and placenta, a small segment of myometrium was excised from the upper incisional surface of the lower uterine segment and 20 strips, randomly assigned into two groups (n = 10), were obtained from 20 non-laboring term parturients. The study protocol consisted of a 60-min period of spontaneous contractions, control recording with oxytocin 2 × 109 m (10-min period), washout interval of 10 min, volatile administration (three times per 15-min period) of 0.5, 1 and 2 minimum alveolar concentration (MAC), response to oxytocin (10-min period), a further washout interval (10-min period) and subsequent control recording with oxytocin without anesthetics. Results:, After oxytocin administration, the frequency and amplitude of contractions increased (P < 0.05) and the duration decreased (P < 0.05). The frequency and amplitude of contractions induced with oxytocin decreased significantly at 0.5, 1 and 2 MAC of desflurane and sevoflurane (P < 0.05). The amplitude of contractions was significantly different at 1 MAC between the two groups (P < 0.05). The duration of contractions at 2 MAC decreased in both groups (P < 0.05). Conclusions:, Desflurane and sevoflurane at 0.5, 1 and 2 MAC inhibit the frequency and amplitude of myometrial contractions induced with oxytocin in a dose-dependent manner. However, desflurane inhibits the amplitude less than sevoflurane at 1 MAC. We suggest that 0.5 MAC of both agents and 1 MAC of desflurane may be safely used in the presence of oxytocin following delivery of the infant and placenta during Cesarean section without fear of uterine atony and hemorrhage. [source] Effects of imatinib mesylate (Glivec®) as a c-kit tyrosine kinase inhibitor in the guinea-pig urinary bladderNEUROUROLOGY AND URODYNAMICS, Issue 3 2006Yasue Kubota Abstract Aims In the gastrointestinal tract, slow wave activity in smooth muscle is generated by the interstitial cells of Cajal (ICC). Detrusor smooth muscle strips of most species show spontaneous contractions which are triggered by action potential bursts, however, the pacemaker mechanisms for the detrusor are still unknown. Recently, ICC-like cells have been found in guinea-pig bladder, using antibodies to the c-kit receptor. We have investigated the effects of Glivec, a c-kit tyrosine kinase inhibitor, on spontaneous action potentials in guinea-pig detrusor and intravesical pressure of isolated guinea-pig bladders. Methods Changes in the membrane potential were measured in guinea-pig detrusor smooth muscle using conventional microelectrode techniques. Pressure changes in the bladder were recorded using whole organ bath techniques. Results Smooth muscle cells in detrusor muscle bundles exhibited spontaneous action potentials, and spontaneous pressure rises occurred in isolated bladders. Glivec (10 ,M) converted action potential bursts into continuous firing with no effects on the shape of individual action potentials. Glivec (>50 ,M) reduced the amplitude of spontaneous pressure rises in the whole bladder in a dose dependent manner and abolished spontaneous action potentials in detrusor smooth muscle cells. Conclusions The results suggest that ICC-like cells may be responsible for generating bursts of action potentials and contractions in detrusor smooth muscle. Drugs inhibiting the c-kit receptor may prove useful for treating the overactive bladder. Neurourol. Urodynam. © 2006 Wiley-Liss, Inc. [source] Contractile properties of the proximal urethra and bladder in female pig: Morphology and functionNEUROUROLOGY AND URODYNAMICS, Issue 1 2006J.J.M. Pel Abstract Aims To compare the contractile properties of proximal urethral and bladder muscle of the female pig. Materials and Methods In two proximal segments (I and II) of the urethra, small muscle bundles were excised to measure the force-length (maximum force) and the force-velocity (unloaded shortening velocity) relation using the stop-test. The rate of force development was calculated using phase plots. Contractile properties of urethral and bladder segments were statistically compared using the Mann,Whitney U -test. Immunohistochemical staining of whole circumference urethral cross sections was used to identify the location of smooth and striated muscle fibres. Results On isometric force development, the urethral muscle bundles revealed a fast (,0.5 sec) and a slow (,2.1 sec) time constant, whereas in bladder only a slow (,2.3 sec) component was measured. On average, isometric force was highest in bladder. The length range over which force was produced was smallest in urethral segment II, followed by urethral segment I and finally bladder. The unloaded shortening velocity was 0.15, 0.25 and 0.35 1/sec, respectively. Histological preparations showed that smooth as well as striated muscle was present in proximal urethra. In urethral muscle bundles, spontaneous contractions were measured with a frequency of 0.4 Hz. Conclusions Differences in contractility found between urethra and bladder may be ascribed to the presence of striated muscle in the proximal urethra. The regulation of tone and spontaneous contractions may be part of the continence mechanism in the female pig urinary tract. © 2005 Wiley-Liss, Inc. [source] Pycnogenol increases the probability of the contraction state in chick embryonic cardiomyocytes, indicating inotropic effectsPHYTOTHERAPY RESEARCH, Issue 2 2007Noboru Hasegawa Abstract The influence of pycnogenol on the probability of contraction was studied in chick cardiomyocytes. Ventricles from 9,11 day chicken embryos were cultured. After 10,11 days in culture, stable spontaneous contractions were recorded and the contraction kinetics analysed. Isoproterenol and pycnogenol increased the probability of the contraction state. After pretreatment with the , -receptor antagonist, propranolol reduced the isoproterenol- and pycnogenol-increased probability of contraction state. These data suggested that pycnogenol has inotropic effects via stimulation of , -receptor mediated activity. Copyright © 2006 John Wiley & Sons, Ltd. [source] Effect of a dysmenorrhea Chinese medicinal prescription on uterus contractility in vitroPHYTOTHERAPY RESEARCH, Issue 7 2003Chun-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] Role of the cholinergic system and of apamin-sensitive Ca2+ -activated K+ channels on rabbit jejunum spontaneous activity and on the inhibitory effects of adrenoceptor agonistsAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 2 2003L. Romanelli Summary 1 One reason why rabbit jejunum is suitable for studying the mechanisms underlying the actions of the various neurotransmitters and their interactions is its spontaneous motility. The main regulator of spontaneous motility is the cholinergic system. How the cholinergic system regulates the spontaneous activity in the rabbit jejunum and how it affects the inhibitory action of , - and , -adrenoceptor agonists remains unclear. 2 We studied the influence of the cholinergic system and apamin-sensitive Ca2+ -activated K+ channels on spontaneous contractions in the rabbit jejunum and on the inhibitory effects of,1 - and , -adrenoceptor agonists. 3 In naïve tissues, atropine (ATR, 7.4 × 10,8 m) and tetrodotoxin (8 × 10,8 m) almost completely inhibited , to a similar extent , the amplitude of spontaneous activity. Despite the presence of ATR or TDX, tissue contraction gradually recovered to about 50% of the baseline amplitude within 5,10 min. When ATR or TDX, respectively, were added to the TDX- or ATR-treated tissues, the recovered activity decreased weakly but significantly. After washout and a 45-min rest the contraction amplitude returned to baseline values. A further exposure to ATR or TDX reduced the contraction to a level significantly lower than the one obtained after TDX or ATR added 5 min after ATR or TDX, respectively. In preparations prestimulated for 10 min with acetylcholine (ACh), ATR abolished the TDX-resistant recovered spontaneous activity. 4 Adrenaline (ADR, 0.5,5 × 10,7 m) and phenylephrine (PHE, 1,10 × 10,7 m) inhibited tissue motility in naïve and in ATR- and in TDX-exposed preparations. But whereas in naïve preparations the ,1 -adrenoceptor antagonists completely antagonized inhibition induced by both drugs, in ATR- and TDX-exposed tissues they did so only partially for ADR. Agonist-induced inhibition had a rapid onset but rapidly faded; pendular movements took significantly longer to recover in ATR- and TDX-treated tissues than in naïve tissues. In tissues exposed for 2 min to ADR (0.5,5 × 10,7 m) or PHE (1,10 × 10,7 m), washout or addition of ,1 -adrenoceptor antagonists caused an immediate short-lasting increase in contraction amplitude. 5 Apamin (APAM, 5 × 10,9 m) caused a rapid and persistent increase in the amplitude of contractions. It also blocked the inhibitory responses to ADR and PHE, and removed washout-induced contractions. The APAM-induced increase in the contraction amplitude correlated with the increase obtained by washing out ADR or PHE. 6 Isoprenaline (at concentrations up to 2.8 × 10,7 m) produced no inhibitory response in naïve tissues, but it invariably blocked (at a concentration of 0.7 × 10,7 m) the recovered spontaneous activity (and sometimes depressed muscletone) in tissues exposed to ATR or TDX. Neither propranolol (3.4 × 10,7 m) nor APAM (5 × 10,9 m) counteracted these inhibitory effects. 7 These results indicate that spontaneous motility in the rabbit jejunum is predominantly mediated by neuronal release of ACh and by some other unidentified neuronal activity. Released ACh inhibits myogenic activity and strongly antagonizes , -adrenoceptor-induced APAM-insensitive inhibition but leaves ,1 agonist-induced APAM-sensitive inhibition unchanged. [source] Rupture of the uterine scar during term labour: contractility or biochemistry?BJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 1 2005Catalin S. Buhimschi Objective Vaginal birth after a prior low transverse caesarean section (VBAC) is advocated as a safe and effective method to reduce the total caesarean section rate. However, the risk of uterine rupture has dampened the enthusiasm of practising clinicians for VBAC. Uterine rupture occurs more frequently in women receiving prostaglandins in preparation for the induction of labour. We hypothesised that similar to the cervix, prostaglandins induces biochemical changes in the uterine scar favouring dissolution, predisposing the uterus to rupture at the scar of the lower segment as opposed to elsewhere. Design We tested aspects of this hypothesis by investigating the location of uterine rupture associated with prostaglandins and compared it with the sites of rupture in the absence of prostaglandins. Settings Two North American University Hospitals. Population Twenty-six women with a prior caesarean section, experiencing uterine rupture in active labour. Methods Retrospective review of all pregnancies complicated by uterine rupture at two North American teaching hospitals from 1991 to 2000. Main outcome measure Site of the uterine rupture. Results Thirty-four women experienced rupture after a previous caesarean section with low transverse uterine incision. Ten of the women who ruptured (29%) received prostaglandins for cervical ripening (dinoprostone: n= 8 or misoprostol: n= 2) followed by either spontaneous contractions (n= 3) or oxytocin augmentation during labour (n= 7). In 16 women (47%), oxytocin alone was sufficient for the induction/augmentation of labour. Eight (23%) women ruptured at term before reaching the active phase of labour in the absence of pro-contractile agents or attempted VBAC. There were no differences among the groups in terms of age, body mass index, parity, gestational age, fetal weight or umbilical cord pH measurements. Women treated with prostaglandins experienced rupture at the site of their old scar more frequently than women in the oxytocin-alone group whose rupture tended to occur remote from their old scar (prostaglandins 90%vs oxytocin 44%; OR: 11.6, 95% CI: 1.2,114.3). Conclusion Women in active labour treated with prostaglandins for cervical ripening appear more likely to rupture at the site of their old scar than women augmented without prostaglandins. We propose that prostaglandins induce local, biochemical modifications that weaken the scar, predisposing it to rupture. [source] Contraction kinetics of isolated human myometrium during menstrual cycle and pregnancyBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 1 2000Mikhail Tchirikov Objective To investigate the interaction between actin and myosin in the myometrium by studying the contraction kinetics of isolated samples of human myometrium. Design Experimental and observational cross-sectional study. Setting Eppendorf University Hospital, Hamburg. Samples Myometrium samples were taken from women in the follicular phase (n= 6) or luteal phase (n= 6) of the menstrual cycle and during pregnancy at term (n= 25). Methods The frequency, extent and rate of force development were determined in spontaneously active myometrial preparations. From a resting force of 2 mN, sustained tonic contractions were induced by K+ -depolarisation (124 mM), or by protein kinase C activation (19.9 ,M indolactam). The steady force was reversibly interrupted by rapid length changes (100 Hz sinus vibrations lasting 1 s, 5% of muscle length). Extent (steady plateau), as well as rate of force increase after cessation of vibrations, were derived from bi-exponential functions fitted to the time course of force recovery. Results Frequency of spontaneous contractions was higher in the follicular phase [mean (SD) 18.3 contractions/hour (1.0)] than in the luteal phase [13.4 contractions/hour (8.1)] or in pregnancy at term [8.8 contractions/hour (7.6)]. During indolactam treatment, steady force in pregnancy at term was significantly increased [8.8 mN (4.0)], compared with the follicular phase [3.7 mN (0.9)]. Force recovery was distinctly slower in pregnancy at term during indolactam treatment [time constant 99.2 s (57.9); P < 0.005] than during K+ -depolarisation [time constant 29.1 s (5.9)], whereas in the follicular phase the rate of force recovery was faster with indolactam [16.8 s (7.1)] than with K+ depolarisation [24.4 s (5.9); P < 0.005]. Conclusions The responses of human myometrium to contraction stimuli differ according to the reproductive state. Membrane depolarisation causes similar responses in all myometrial strips. In contrast, near term stimulation of protein kinase C generates a large tonic force and slow contraction kinetics, whereas early in the menstrual cycle contraction kinetics are fast. [source] Effects of excitatory and inhibitory neurotransmission on motor patterns of human sigmoid colon in vitroBRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2008M Aulí Background and purpose: To characterize the in vitro motor patterns and the neurotransmitters released by enteric motor neurons (EMNs) in the human sigmoid colon. Experimental approach: Sigmoid circular strips were studied in organ baths. EMNs were stimulated by electrical field stimulation (EFS) and through nicotinic ACh receptors. Key results: Strips developed weak spontaneous rhythmic contractions (3.67±0.49 g, 2.54±0.15 min) unaffected by the neurotoxin tetrodotoxin (TTX; 1 ,M). EFS induced strong contractions during (on, 56%) or after electrical stimulus (off, 44%), both abolished by TTX. Nicotine (1,100 ,M) inhibited spontaneous contractions. Latency of off-contractions and nicotine responses were reduced by NG -nitro- L -arginine (1 mM) and blocked after further addition of apamin (1 ,M) or the P2Y1 receptor antagonist MRS 2179 (10 ,M) and were unaffected by the P2X antagonist NF279 (10 ,M) or ,-chymotrypsin (10 U mL,1). Amplitude of on- and off-contractions was reduced by atropine (1 ,M) and the selective NK2 receptor antagonist Bz-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (1 ,M). MRS 2179 reduced the amplitude of EFS on- and off-contractions without altering direct muscular contractions induced by ACh (1 nM,1 mM) or substance P (1 nM,10 ,M). Conclusions and implications: Latency of EFS-induced off-contractions and inhibition of spontaneous motility by nicotine are caused by stimulation of inhibitory EMNs coreleasing NO and a purine acting at muscular P2Y1 receptors through apamin-sensitive K+ channels. EFS-induced on- and off-contractions are caused by stimulation of excitatory EMNs coreleasing ACh and tachykinins acting on muscular muscarinic and NK2 receptors. Prejunctional P2Y1 receptors might modulate the activity of excitatory EMNs. P2Y1 and NK2 receptors might be therapeutic targets for colonic motor disorders. British Journal of Pharmacology (2008) 155, 1043,1055; doi:10.1038/bjp.2008.332; published online 1 September 2008 [source] Evolving mechanisms of action of alverine citrate on phasic smooth musclesBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2007M Hayase Background and purpose: We have investigated the mechanisms underlying the paradoxical ability of the antispasmodic, alverine, to enhance spontaneous activity in smooth muscles while suppressing evoked activity. Experimental approach: The effects of alverine on spontaneous and induced contractile activity were examined in preliminary experiments with various smooth muscles. More detailed effects were also investigated by recording membrane potential, intracellular Ca2+ concentration ([Ca2+]i) and tension from single-bundle detrusor smooth muscle (DSM) of the guinea-pig urinary bladder. Key results: Alverine (10 ,M) increased the frequency and amplitude of spontaneous action potentials, transient increases in [Ca2+]i and associated contractions. Alverine also decreased action potential rate of decay, suggesting inhibition of L -type Ca channel inactivation. Charybdotoxin (50 nM) but neither cyclopiazonic acid (10 ,M) nor Bay K 8644 (10 ,M) attenuated alverine-induced enhancement of spontaneous contractions. Alverine suppressed contractions produced by high K (40 mM) or ACh (10 ,M), without affecting electrical responses and with little suppression of increases in [Ca2+]i. This feature was very similar to that of the effects of the Rho kinase inhibitor Y-27632 (10 ,M). Conclusions and implications: Alverine may increase Ca influx during action potentials due to inhibition of the inactivation of L -type Ca channels, but may also suppress evoked activity by inhibiting the sensitivity of contractile proteins to Ca2+. The proportional contribution of Ca-dependent and Ca-independent contractions in DSM may differ between spontaneous and evoked activity, necessitating further investigations into the interactions between these pathways for assessing the therapeutic potential of alverine to treat DSM dysfunction. British Journal of Pharmacology (2007) 152, 1228,1238; doi:10.1038/sj.bjp.0707496; published online 15 October 2007 [source] The actions of azelnidipine, a dihydropyridine-derivative Ca antagonist, on voltage-dependent Ba2+ currents in guinea-pig vascular smooth muscleBRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2006H-L Zhu Background and purpose: Although azelnidipine is used clinically to treat hypertension its effects on its target cells, Ca2+ channels, in smooth muscle have not been elucidated. Therefore, its effects on spontaneous contractions and voltage-dependent L-type Ca2+ channels were investigated in guinea-pig portal vein. Experimental approach: The inhibitory potency of azelnidipine on spontaneous contractions in guinea-pig portal vein was compared with those of other dihydropyridine (DHP)-derived Ca antagonists (amlodipine and nifedipine) by recording tension. Also its effects on voltage-dependent nifedipine-sensitive inward Ba2+ currents (IBa) in smooth muscle cells dispersed from guinea-pig portal vein were investigated by use of a conventional whole-cell patch-clamp technique. Key results: Spontaneous contractions in guinea-pig portal vein were reduced by all of the Ca antagonists (azelnidipine, Ki=153 nM; amlodipine, Ki=16 nM; nifedipine, Ki=7 nM). In the whole-cell experiments, azelnidipine inhibited the peak amplitude of IBa in a concentration- and voltage-dependent manner (-60 mV, Ki=282 nM; ,90 mV, Ki=2 ,M) and shifted the steady-state inactivation curve of IBa to the left at ,90 mV by 16 mV. The inhibitory effects of azelnidipine on IBa persisted after 7 min washout at ,60 mV. In contrast, IBa gradually recovered after being inhibited by amlodipine, but did not return to control levels. Both azelnidipine and amlodipine caused a resting block of IBa at -90 mV. Only nifedipine appeared to interact competitively with S(-)-Bay K 8644. Conclusions and implications: These results suggest that azelnidipine induces long-lasting vascular relaxation by inhibiting voltage-dependent L-type Ca2+ channels in vascular smooth muscle. British Journal of Pharmacology (2006) 149, 786,796. doi:10.1038/sj.bjp.0706919 [source] Intrinsic vasomotricity and adrenergic effects in a model of isolated rabbit eyeACTA OPHTHALMOLOGICA, Issue 4 2009Esmeralda Delgado Abstract. Purpose:, We aimed to investigate the responsiveness of the ocular arteries to adrenergic drugs in a model of perfused isolated rabbit eye. Methods:, Rabbit external ophthalmic arteries (n = 15) in a head-mounted preparation were cannulated and the retinal and uveal vasculature perfused at a constant flow with warmed tyrode. The three-way polypropylene catheter was further connected to a pressure transducer and intraluminal pressure was taken as a measure of vascular resistance. Effects of intra-arterial injections of phenylephrine (group A, n = 5), prazosin (group B, n = 5) and phentolamine (group C, n = 5) on the recorded pressure were obtained. Student's paired- t test and one-way analysis of variance were used for statistical analysis (p < 0.05). Results:, Intrinsic vasomotricity was observed in all preparations prior to any drug administration. Phenylephrine produced an increase in total vascular resistance. Intrinsic vasomotricity became more evident, showing a lower frequency but higher amplitude of oscillations. Evoked vasomotor responses with phenylephrine (250 ,g/ml) were inhibited by intra-arterial administration of the selective ,1 -adrenergic antagonist, prazosin (0.5 mg/ml), as well as the non-selective ,-adrenergic antagonist phentolamine (6 mg/ml). Conclusions:, Rabbit external ophthalmic arteries showed spontaneous contractions under constant perfusion. Phenylephrine elicited a vasoconstrictor response that was inhibited by adrenergic antagonists. In addition, the intrinsic vasomotricity was enhanced by phenylephrine and blocked by adrenergic antagonists. These results show that under in vitro perfusion the territory presents similar responses to adrenergic drugs to those observed in in vivo models and also provides evidence of myogenic autoregulatory properties in the rabbit ophthalmic artery and/or choroid. [source] | |||||||||||||||||||||||||