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Maximum Response (maximum + response)
Selected AbstractsDamaging properties of ground motions and prediction of maximum response of structures based on momentary energy responseEARTHQUAKE ENGINEERING AND STRUCTURAL DYNAMICS, Issue 9 2002Norio Hori Abstract Dynamic damaging potential of ground motions must be evaluated by the response behaviour of structures, and it is necessary to indicate what properties of ground motions are most appropriate for evaluation. For that purpose, the behaviour of energy input process and hysteretic energy dissipation are investigated in this study. It is found that the momentary input energy that is an index for the intensity of input energy is related to the characteristics of earthquakes such as cyclic or impulsive, and to the response displacement of structures immediately. On the basis of these results, a procedure is proposed to predict inelastic response displacement of structures by corresponding earthquake input energy to structural dissipated damping and hysteretic energy. In this procedure the earthquake response of structures is recognized as an input and dissipation process of energy, and therefore structural properties and damaging properties of ground motions can be taken into account more generally. Lastly, the studies of the pseudodynamic loading test of reinforced concrete structure specimens subjected to ground motions with different time duration are shown. The purpose of this test is to estimate the damaging properties of ground motions and the accuracy of the proposed prediction procedure. Copyright © 2002 John Wiley & Sons, Ltd. [source] Response to three-component seismic motion of arbitrary directionEARTHQUAKE ENGINEERING AND STRUCTURAL DYNAMICS, Issue 1 2002Julio J. Hernández Abstract This paper presents a response spectrum analysis procedure for the calculation of the maximum structural response to three translational seismic components that may act at any inclination relative to the reference axes of the structure. The formula GCQC3, a generalization of the known CQC3-rule, incorporates the correlation between the seismic components along the axes of the structure and the intensity disparities between them. Contrary to the CQC3-rule where a principal seismic component must be vertical, in the GCQC3-rule all components can have any direction. Besides, the GCQC3-rule is applicable if we impose restrictions to the maximum inclination and/or intensity of a principal seismic component; in this case two components may be quasi-horizontal and the third may be quasi-vertical. This paper demonstrates that the critical responses of the structure, defined as the maximum and minimum responses considering all possible directions of incidence of one seismic component, are given by the square root of the maximum and minimum eigenvalues of the response matrix R, of order 3×3, defined in this paper; the elements of R are established on the basis of the modal responses used in the well-known CQC-rule. The critical responses to the three principal seismic components with arbitrary directions in space are easily calculated by combining the eigenvalues of R and the intensities of those components. The ratio rmax/rSRSS between the maximum response and the SRSS response, the latter being the most unfavourable response to the principal seismic components acting along the axes of the structure, is bounded between 1 and ,(3,a2/(,a2 + ,b2 + ,c2)), where ,a,,b,,c are the relative intensities of the three seismic components with identical spectral shape. Copyright © 2001 John Wiley & Sons, Ltd. [source] Use of chemometric methodology in optimizing conditions for competitive binding partial filling affinity capillary electrophoresisELECTROPHORESIS, Issue 16 2008Ruth E. Montes Abstract This work expands the knowledge of the use of chemometric response surface methodology (RSM) in optimizing conditions for competitive binding partial filling ACE (PFACE). Specifically, RSM in the form of a Box,Behnken design was implemented in flow-through PFACE (FTPFACE) to effectively predict the significance of injection time, voltage, and neutral ligand (neutral arylsulfonamide) concentration, [Lo], on protein,neutral ligand binding. Statistical analysis results were used to create a model for response surface prediction via contour and surface plots at a given maximum response (,RMTR) to reach a targeted Kb,=,2.50×106,M,1. The adequacy of the model was then validated by experimental runs at the optimal predicted solution (injection time,=,2.3,min, voltage,=,11.6,kV, [Lo],=,1.4,,M). The achieved results greatly extend the usefulness of chemometrics in ACE and provide a valuable statistical tool for the study of other receptor,ligand combinations. [source] Response of zooplankton communities to liquid creosote in freshwater microcosmsENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 2 2001Paul K. Sibley Abstract In this study, the response of zooplankton communities to single applications of liquid creosote in model aquatic ecosystems (microcosms) was evaluated. Liquid creosote was applied to 14 microcosms at concentrations ranging from 0.06 to 109 mg/L. Two microcosms served as controls. Zooplankton samples were collected from each microcosm on days 7 and 1 before treatment and on days 2, 5, 7, 14, 21, 28, 43, 55, and 83 following treatment. Temporal changes (response-recovery) in composition of the zooplankton community were assessed using principal response curves (PRC). Creosote induced a rapid, concentrationdependent reduction in zooplankton abundance and number of taxa, with maximum response (50,100% reduction in population densities) occurring between 5 and 7 d after treatment. Taxa that dominated at the time of treatment experienced the greatest impact, as indicated by large, positive species weight values (>1) from the PRC analysis. Many of these taxa recovered to pretreatment or control levels during the posttreatment period, with the degree and duration of recovery being strongly dependent on concentration. Creosote had little effect on species composition at less than 1.1 mg/L, because changes in the types and relative proportion of species contributed from Cladocera, Rotifera, and Copepoda were comparable to those observed in control microcosms. However, a significant shift in species composition was observed at concentrations greater than 1.1 mg/L; these microcosms were generally dominated by low numbers of rotifers, some of which had not been collected before treatment. Community-level effect concentrations (EC50s) were 44.6 and 46.6 ,g/L at 5 and 7 d, respectively, based on nominal creosote. Corresponding no-effect concentrations were 13.9 and 5.6 ,g/L. The results of this field study indicate that creosote may pose a significant risk to zooplankton communities at environmental concentrations potentially encountered during spills and/or leaching events. [source] Ouabain stimulates endothelin release and expression in human endothelial cells without inhibiting the sodium pumpFEBS JOURNAL, Issue 5 2004Robert Saunders Ouabain, a sodium pump (Na+/,K+ -ATPase) inhibitor, has been shown to act as a hormone and is possibly involved in the pathogenesis of hypertension. The mechanism by which ouabain may act was investigated using primary cultures of human umbilical artery endothelial cells (HUAECs), which are known to express and release the vasoconstrictive hormone endothelin (ET-1). Five minutes after application, low concentrations of ouabain induced Ca2+ oscillations and stimulated ET-1 release from endothelial cells into the medium. To investigate whether the observed effects were due to inhibition of the sodium pump, the effects of ouabain on the uptake of 86Rb+ by HUAECs were examined. Unexpectedly, ouabain concentrations below 10 nm stimulated 86Rb+ uptake by 15,20%, and in some experiments by 50%, results that are consistent with a stimulation of the pump. Within the concentration range 1,10 nm, ouabain induced a 2.5-fold stimulation (phosphorylation) of mitogen-activated protein kinase (MAP kinase). After incubation of HUAECs with ouabain for 12 h, the glycoside stimulated cell growth by 49 ± 4%, as measured by cell number, with a maximum response at 5 nm. At similar concentrations, ouabain also increased ET-1 mRNA abundance by 19.5 ± 3.1%. The results indicate that, by influencing ET-1 expression and release, ouabain may contribute to the regulation of vascular tone. The data also confirm that it is not a global inhibition of the sodium pump that is involved in the mechanism of action of this cardiac glycoside. [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] OPTIMIZATION OF VACUUM PULSE OSMOTIC DEHYDRATION OF CANTALOUPE USING RESPONSE SURFACE METHODOLOGYJOURNAL OF FOOD PROCESSING AND PRESERVATION, Issue 1 2005WILMER J. FERMIN ABSTRACT The optimum levels of vacuum pressure, concentration of osmotic solution and dehydration time for vacuum pulse osmotic dehydration of cantaloupe were determined by response surface methodology (RSM). The response surface equations ( P < 0.05 and lack of fit > 0.1) explain the 97.6, 88.0 and 97.1% of the variability in weight loss, water loss and °Brix increase, respectively, at 95% confidence level. The canonical analysis for each response indicated that the stationary point is a saddle point for weight loss and °Brix increase, and a point of maximum response for water loss. The region that best satisfied all the constraints (low values in weight loss and °Brix increase, and high value in water loss) is located within the intervals from 49.5 °Brix to 52.5 °Brix for concentration and from 75 min to 84 min for dehydration time at a vacuum pulse of 740 mbar. [source] Insurmountable antagonism of AT-1015, a 5-HT2 antagonist, on serotonin-induced endothelium-dependent relaxation in porcine coronary arteryJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2003Mamunur Rashid The purpose of this study was to examine the inhibitory effects of AT-1015, a newly synthesized 5-HT2 receptor antagonist, on serotonin-induced endothelium-dependent relaxation in U 46619 (5 times 10,9m)-precontracted porcine coronary artery pre-incubated with ketanserin (3 times 10,6m), and then compare its effects with another potent 5-HT2 antagonist, ritanserin. The investigation showed that AT-1015 (10,8,10,6m) caused rightward shift with significant inhibition of maximum relaxation response induced by serotonin in porcine coronary artery with endothelium. Ritanserin caused a rightward shift of serotonin-induced relaxation without decreasing maximum response at 10,9 and 10,8m, but it inhibited the maximum relaxation response at 10,7m. The study showed that AT-1015 and ritanserin had no inhibitory effect on bradykinin-induced relaxation in porcine coronary artery with endothelium. Thus, these findings suggested that AT-1015 at concentrations of 10,8,10,6m caused noncompetitive blockade of serotonin-induced endothelium-dependent relaxation in porcine coronary artery. The antagonistic effects of AT-1015 on serotonin-induced relaxation were different from that of ritanserin, except at 10,7m ritanserin. The variation of inhibitory effects between these two 5-HT2 antagonists may be due to the different chemical structure and/or interaction sites at the receptor. [source] Immunochemical detection of Lonomia obliqua caterpillar venom in ratsMICROSCOPY RESEARCH AND TECHNIQUE, Issue 6 2004Gustavo Henrique Da Silva Abstract Severe cases of human envenoming by caterpillars of the saturniid moth Lonomia obliqua in Brazil can result in renal damage, leading to renal failure, and intracerebral hemorrhaging. In this work, we used immunohistochemical staining with rabbit antiserum raised against L. obliqua venom to examine venom distribution in selected tissues of the brain (cerebellum and hippocampus), kidneys, and liver of male Wistar rats injected with a single dose of venom (200 ,g/kg, i.v.) and sacrificed 6, 18, 24, and 72 hours later. The immunolabeling of GFAP was also examined to assess the venom effects on perivascular astrocytic end-feet in the microvasculature of the hippocampus and cerebellum. Venom was detected in the kidneys (6 and 18 hours) and in the liver (6 hours) but not in the brain at any of the time intervals examined. In contrast, immunolabeling for GFAP revealed astrogliosis in the cerebellum and enhanced expression of this protein in the glial processes of the cerebellum and hippocampus, with a maximum response from 24 hours onwards. The high immunoreactivity seen in the kidneys agreed with the renal damage and dysfunction reported for some patients. The lack of venom detection in the brain, despite the altered expression of GFAP in astrocytes, suggested either that the venom does not enter this organ or that its entrance is transient and fast. Alternatively, the circulating venom may induce the release of mediators that could serve as second messengers to provoke the late astrocytic reactivity and astrogliosis. It is possible that both of these mechanisms may contribute to the effects observed. Microsc. Res. Tech. 65:276,281, 2004. © 2005 Wiley-Liss, Inc. [source] Experimental verification of the relation between the radar cross section and the list angle of surface vesselsMICROWAVE AND OPTICAL TECHNOLOGY LETTERS, Issue 11 2006J. F. Pérez Ojeda Abstract In this paper, the effect of ship angular motions on the radar cross section is addressed. To this end, a set of measurements for different ships were conducted from a shore-based instrumental radar. The targets execute oblique straight trajectories with respect to the radar line of sight with induced roll. The analysis of the dependence between target reflectivity and the roll angle shows that, for conventional vessels, the maximum response at low grazing angles is achieved in steady conditions, and it varies significantly according to the sign of the roll angle referred to the radar location. This result is confirmed by the comparison of measurements of a ship performing turning circles at several speeds, thus inducing different roll angles. © 2006 Wiley Periodicals, Inc. Microwave Opt Technol Lett 48: 2237,2241, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.21932 [source] Threshold analysis of selected dose-response data for endocrine active chemicals,APMIS, Issue 3 2001Robert M. Blair Using a biologically relevant mathematical model, the Michaelis-Menten equation, we examined published data from endocrine active chemicals for evidence of no-threshold dose-response curves. Data were fit to a modified Michaelis-Menten equation which accounted for total background response. Subsequently, the data sets were analyzed using non-linear regression in order to estimate the four parameters of interest (non-hormone controlled background (Bnh), maximum response (Rmax), endogenous hormone level (D0), and the dose at which a half-maximal response was observed (ED50)) and to determine the fit to the fully modified Michaelis-Menten equation. Subsequently, response data were adjusted to account for Bnh and then normalized to Rmax, while dose data were adjusted to account for D0 and then normalized to the ED50. This data set was combined into a single, composite data set and fit to the fully modified Michaelis-Menten equation. We examined 31 data sets (24 endpoints) from studies on 9 different chemical/hormone treatments. Twenty-six of the data sets fit the modified Michaelis-Menten equation with high multiple correlation coefficients (r>0.90). The normalized data demonstrated a good fit to the modified Michaelis-Menten equation. These results indicate that a variety of biological responses fit the modified Michaelis-Menten equation, which does not have a threshold dose term. [source] A very low response rate in an on-line survey of medical practitionersAUSTRALIAN AND NEW ZEALAND JOURNAL OF PUBLIC HEALTH, Issue 3 2008Campbell Aitken Abstract Objective: To report on the response rate achieved in a survey of medical practitioners and discuss the reasons for it. Method: An on-line (internet-based) survey of all 609 registered pharmacotherapy prescribers in Victoria and Queensland; invitations to participate were sent by mail in late April 2007, and one reminder letter in late May 2007. Results: Six hundred and nine invitation letters were mailed, nine were returned to sender, and 52 questionnaires completed, making the overall response rate 52/600 = 8.7%. The response rate in Queensland was 13.2% (16/121), and in Victoria 7.5% (36/479). Conclusion(s): Despite utilising sound techniques, our response rate was much lower than those achieved in recent Australian paper-based surveys of medical practitioners. It is possible that the issue being addressed (injecting-related injuries and diseases) was not of high priority for many invitees, leading to reduced response. Implications: On-line surveys are not yet an effective method of collecting data from Australian medical practitioners; researchers should continue to use paper questionnaires for maximum response. [source] Cholinergic responses of ileal longitudinal muscle under short-lasting exposure to cupric ionsAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2008Ch. Nachev Summary 1 The effect of short-term exposure to cupric ions (Cu2+) on electric field-stimulated (EFS) or agonist-induced contractions of guinea-pig isolated ileum was studied. 2 EFS elicited tetrodotoxin- and atropine-sensitive contractions that were concentration dependently inhibited by Cu2+ (IC50 = 14.7 ± 4.2 ,m). Maximal inhibition (90.4 ± 3.1% of baseline contractions) was attained with 30 ,m Cu2+. 3 Carbachol induced concentration-dependent contractions (EC50 = 0.021 ± 0.004 ,m) that were inhibited by 0.3 ,m atropine to a non-competitive manner (decreased maximal response, EC50 value = 0.26 ± 0.04 ,m, Ke = 0.026 ,m). Cu2+ (15 ,m) potentiated contractions induced by carbachol, such that the maximum response was increased by 30.3 ± 10.4%. 4 Histamine induced concentration-dependent contractions of the longitudinal muscle (EC50 = 0.11 ± 0.03 ,m). Dyphenhydramine (0.1 ,m) decreased the maximum response to histamine and shifted the curve to the right (EC50 value = 4.71 ± 0.35 ,m, Ke = 0.0024 ,m). Cu2+ (15 ,m) caused a rightward shift of the histamine concentration,response curve (EC50 = 0.61 ± 0.1 ,m) without changing the maximum response. Serotonin induced concentration-dependent contractions at concentrations higher than 10 nM (EC50 value of 0.34 ± 0.12 ,m) were not significantly affected by 15 ,m Cu2+. 5 Our results suggest that in ileal longitudinal muscle, Cu2+ inhibits cholinergic neurotransmission but also facilitates postsynaptic muscarinic receptor responses. [source] ,1A -Adrenoceptors predominate in the control of blood pressure in mouse mesenteric vascular bedAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2007S. G. Martínez-Salas Summary 1,The pressor action of the ,1A -adrenoceptor agonist, A61603 (N -[5-(4,5-dihydro-1H -imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl] methanesulfonamide) or the ,1 -adrenoceptor agonist phenylephrine, and their blockade by selective ,1 -adrenoceptor antagonists in the mouse isolated mesenteric vascular bed were evaluated. 2,A61603 showed a , 235-fold higher potency in elevating perfusion pressure in mesenteric bed compared to phenylephrine. 3,The ,1A -adrenoceptor selective antagonist RS 100329 (5-methyl-3-[3-[4-[2-(2,2,2,-trifluoroethoxy) phenyl]-1-piperazinyl] propyl]-2,4-(1H)-pyrimidinedione), displaced with high affinity agonist concentration,response curves to the right in a concentration-dependent manner. 4,The ,1D -adrenoceptor selective antagonist BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5] decane-7,9-dione), did not displace A61603 nor did it block the phenylephrine-induced pressor response. 5,The ,1B/D -adrenoceptor alkylating antagonist chloroethylclonidine (CEC), caused a rightward shift of the phenylephrine concentration,response curve and reduced its maximum response; however, CEC only slightly modified A61603 evoked contraction. 6,The results indicate that the isolated mouse mesenteric vascular bed expresses ,1A -adrenoceptors and suggest a very discrete role for 1B -adrenoceptors. [source] Contractile activity of ATP and diadenosine tetraphosphate on urinary bladder in the rats: role of superoxide anion and urotheliumAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 2 2006M. M. Khattab Summary 1 Both ATP and diadenosine tetraphosphate (AP4A) produced a dose-dependent contraction of rat isolated urinary bladder rings. The AP4A dose,response curve was to the left of that of ATP, and the maximum response was greater than that produced by ATP. 2 Mechanical removal of the urothelium increased the contractile response to ATP by between 53% and 71%, and that to AP4A by 42% (at highest AP4A concentration) to 68% at lower concentration. 3 Inhibition of Cu/Zn superoxide dismutase with diethylthiocarbamate (DETCA, 5 mm) significantly reduced the ATP-evoked contraction by 31% (at high ATP concentration) to 40% at low ATP concentration. Similarly, the AP4A-induced contractions were significantly decreased by 27% at low AP4A level to 38% at higher concentrations. 4 Induction of exogenous superoxide anion stress by the use of the superoxide anion generator, pyrogallol (0.5 mm), significantly decreased both ATP- and AP4A-induced contractions of the rat urinary bladder over the whole dose range. Contractile responses to ATP decreased by 36,40%, and those to AP4A by 44,49%. 5 In conclusion, the urinary bladder urothelium exerts an inhibitory control over the purinergic contractility produced by adenine mononucleotides and dinucleotides. Superoxide anion stress, whether endogenous or exogenous, attenuates the ATP-induced as well as AP4A-induced contractility. [source] The stimulant cathartic, emodin, contracts the rat isolated ileum by triggering release of endogenous acetylcholineAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2004S. 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] Functional importance of the actin cytoskeleton in contraction of bovine iris sphincter muscleAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2002J. A. C. Filipe Summary 1 The contractile capacity of smooth muscle cells depends on the cytoskeletal framework of the cell. The aim of this study was to determine the functional importance of both the actin and the tubulin components of the cytoskeleton in contractile responses of the bovine isolated iris sphincter muscle. 2 In each preparation, two contractions to the muscarinic agonist carbachol were obtained. The maximum responses of the first contractions were taken as 100%. The second contractions to carbachol were elicited in the presence of either cytochalasin B (50 and 5 ,m), an inhibitor of the actin cytoskeleton, or colchicine (100 ,m), an inhibitor of the tubulin cytoskeleton (30 min incubation). 3 Cytochalasin B, at a concentration of 50 ,m, significantly decreased the contractions induced by carbachol, with the maximum response reduced to 21.8 ± 6.6% (n = 12) of the initial maximum. The maximal contractions to carbachol in the presence of colchicine reached 96.2 ± 7.9% (n = 9) of the initial contraction, which was not significantly different from control second responses to carbachol with neither drug present, which reached 113.3 ± 7.6% (n = 7). 4 The effect of cytochalasin B was dose-dependent, since at a lower concentration of 5 ,m, the drug decreased the maximum contraction to carbachol to 60.3 ± 8.8% (n = 6). The effect of cytochalasin B was at least partially reversible, since after the use of the higher concentration of 50 ,m, contractions to carbachol increased to 62.3 ± 15.5% (n = 4) of the maximal response, after 1 h repeated washing of the preparations. 5 Cytochalasin D, at a concentration of 50 ,m, completely abolished the contractions induced by carbachol (n = 4). 6 These findings suggest that in bovine iris sphincter muscle, contractions to carbachol are highly dependent, from a functional point of view, on actin polymerization, and not, to any important degree, on the polymerization of tubulin. [source] 2-Phenylmelatonin: A Partial Agonist at Enteric Melatonin ReceptorsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2000Maria Grazia Santagostino-Barbone The effect of the melatonin receptor ligand, 2-phenylmelatonin, has been assessed in isolated strips of the guinea-pig proximal colon. 2-Phenylmelatonin (0.01 nM-1 ,M) caused a concentration-dependent contractile response. The potency value (,log EC50) was 9.3±1.0. The maximum effect was 25±4% of that elicited by the maximally effective concentration (0.3 ,M) of 5-HT and 43±3% of that by the maximally effective concentration (10 ,M) of melatonin. When used as an antagonist, 2-phenylmelatonin (0.01 nM and 0.1 nM) concentration-dependently inhibited melatonin-induced contractions with depression of the maximum response by 25% and 54%, respectively. Higher (1 nM) 2-phenylmelatonin concentrations failed to antagonize melatonin-induced response. Prazosin (0.3 ,M), a selective antagonist of melatonin MT3 sites, antagonized melatonin-induced contractions to an extent similar to that induced by 0.01 nM 2-phenylmelatonin (with 30% reduction of the maximum effect to melatonin). The combination of 0.3 ,M prazosin and 0.01 nM 2-phenylmelatonin caused antagonism similar in extent to that caused by each individual antagonist. 2-Phenylmelatonin at subnanomolar concentrations behaves as an antagonist of melatonin-induced contractile responses while at nanomolar/micromolar concentrations it behaves as a weak contractile agonist. [source] Electrophysiological effects of 5-hydroxytryptamine on isolated human atrial myocytes, and the influence of chronic , -adrenoceptor blockadeBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2003Davide Pau 5-Hydroxytryptamine (5-HT) has been postulated to play a proarrhythmic role in the human atria via stimulation of 5-HT4 receptors. The aims of this study were to examine the effects of 5-HT on the L-type Ca2+ current (ICaL) action potential duration (APD), the effective refractory period (ERP) and arrhythmic activity in human atrial cells, and to assess the effects of prior treatment with , -adrenoceptor antagonists. Isolated myocytes, from the right atrial appendage of 27 consenting patients undergoing cardiac surgery who were in sinus rhythm, were studied using the whole-cell perforated patch-clamp technique at 37°C. 5-HT (1 nM,10 ,M) caused a concentration-dependent increase in ICaL, which was potentiated in cells from , -blocked (maximum response to 5-HT, Emax=299±12% increase above control) compared to non- , -blocked patients (Emax=220±6%, P<0.05), but with no change in either the potency (log EC50: ,7.09±0.07 vs ,7.26±0.06) or Hill coefficient (nH: 1.5±0.6 vs 1.5±0.3) of the 5-HT concentration,response curve. 5-HT (10 ,M) produced a greater increase in the APD at 50% repolarisation (APD50) in cells from , -blocked patients (of 37±10 ms, i.e. 589±197%) vs non- , -blocked patients (of 10±4 ms, i.e. 157±54%; P<0.05). Both the APD90 and the ERP were unaffected by 5-HT. Arrhythmic activity was observed in response to 5-HT in five of 17 cells (29%) studied from , -blocked, compared to zero of 16 cells from the non- , -blocked patients (P<0.05). In summary, the 5-HT-induced increase in calcium current was associated with a prolonged early plateau phase of repolarisation, but not late repolarisation or refractoriness, and the enhancement of these effects by chronic , -adrenoceptor blockade was associated with arrhythmic potential. British Journal of Pharmacology (2003) 140, 1434,1441. doi:10.1038/sj.bjp.0705553 [source] Receptor signaling mechanisms underlying muscarinic agonist-evoked contraction in guinea-pig ileal longitudinal smooth muscleBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2003T Unno In guinea-pig ileal longitudinal muscle, muscarinic partial agonists, 4-(N -[3-chlorophenyl]-carbomoyloxy)-2-butynyl-trimethylammonium (McN-A343) and pilocarpine, each produced parallel increases in tension and cytosolic Ca2+ concentration ([Ca2+]c) with a higher EC50 than that of the full agonist carbachol. The maximum response of [Ca2+]c or tension was not much different among the three agonists. The Ca2+ channel blocker nicardipine markedly inhibited the effects of all three agonists The contractile response to any agonist was antagonized in a competitive manner by M2 receptor selective antagonists (N,N,- bis[6-[[(2-methoyphenyl)methyl]amino]hexyl]-1,8-octanediamine tetrahydrochloride and 11-[[2-[(diethlamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4] benzodiazepine-6-one), and the apparent order of M2 antagonist sensitivity was McN-A343>pilocarpine>carbachol. M3 receptor selective antagonists, 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide and darifenacin, both severely depressed the maximum response for McN-A343, while darifenacin had a similar action in the case of pilocarpine. Both M3 antagonists behaved in a competitive manner in the case of the carbachol response. McN-A343 failed to release Ca2+ from the intracellular stores, and the Ca2+ -releasing action of pilocarpine was very weak compared with that of carbachol. All three agonists were capable of increasing Ca2+ sensitivity of the contractile proteins. McN-A343 rarely produced membrane depolarization, but always accelerated electrical spike discharge. Pilocarpine effect was more often accompanied by membrane depolarization, as was usually seen using carbachol. The results suggest that muscarinic agonist-evoked contractions result primarily from the integration of Ca2+ entry associated with the increased spike discharge and myofilaments Ca2+ sensitization, and that Ca2+ store release may contribute to the contraction indirectly via potentiation of the electrical membrane responses. They may also support the idea that an interaction of M2 and M3 receptors plays a crucial role in mediating the contraction response. British Journal of Pharmacology (2003) 139, 337,350. doi:10.1038/sj.bjp.0705267 [source] Anandamide-induced relaxation of sheep coronary arteries: the role of the vascular endothelium, arachidonic acid metabolites and potassium channelsBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2001J Grainger The effects of the endocannabinoid, anandamide, and its metabolically stable analogue, methanandamide, on induced tone were examined in sheep coronary artery rings in vitro. In endothelium-intact rings precontracted to the thromboxane A2 mimetic, U46619, anandamide (0.01 , 30 ,M) induced slowly developing concentration-dependent relaxations (pEC50 [negative log of EC50]=6.1±0.1; Rmax [maximum response]=81±4%). Endothelium denudation caused a 10 fold rightward shift of the anandamide concentration-relaxation curve without modifying Rmax. Methanandamide was without effect on U46619-induced tone. The anandamide-induced relaxation was unaffected by the cannabinoid receptor antagonist, SR 141716A (3 ,M), the vanilloid receptor antagonist, capsazepine (3 and 10 ,M) or the nitric oxide synthase inhibitor, L -NAME (100 ,M). The cyclo-oxygenase inhibitor, indomethacin (3 and 10 ,M) and the anandamide amidohydrolase inhibitor, PMSF (70 and 200 ,M), markedly attenuated the anandamide response. The anandamide transport inhibitor, AM 404 (10 and 30 ,M), shifted the anandamide concentration-response curve to the right. Precontraction of endothelium-intact rings with 25 mM KCl attenuated the anandamide-induced relaxations (Rmax=7±7%), as did K+ channel blockade with tetraethylammonium (TEA; 3 ,M) or iberiotoxin (100 nM). Blockade of small conductance, Ca2+ -activated K+ channels, delayed rectifier K+ channels, KATP channels or inward rectifier K+ channels was without effect. These data suggest that the relaxant effects of anandamide in sheep coronary arteries are mediated in part via the endothelium and result from the cellular uptake and conversion of anandamide to a vasodilatory prostanoid. This, in turn, causes vasorelaxation, in part, by opening potassium channels. British Journal of Pharmacology (2001) 134, 1003,1012; doi:10.1038/sj.bjp.0704340 [source] Race and ethnicity impact on the maximum proliferative response in peripheral blood lymphocytes from HIV-seropositive individualsHIV MEDICINE, Issue 6 2007MA Kolber Summary The effects of race and ethnicity on immunological function have not been fully studied in patients infected with HIV-1. To study such differences, 54 patients on virally suppressive highly active antiretroviral therapy (HAART) with CD4 counts >200 cells/,L had their peripheral blood lymphocytes (PBL) evaluated for response to recall antigen. Significant differences were found in the maximum responses for PBL from black individuals compared with those from white individuals, and the differences were highly significant when responses for African-Americans were compared with those for white-Hispanics. These findings support work delineating ethnicity and race as significant variables to be taken into account when looking at vaccination strategies and responsiveness to therapeutic pharmacological interventions. [source] Selectivity of lynx proteins on insect nicotinic acetylcholine receptors in the brown planthopper, Nilaparvata lugensINSECT MOLECULAR BIOLOGY, Issue 3 2010B. Yang Abstract Neuronal nicotinic acetylcholine receptors (nAChRs) are major excitatory neurotransmitter receptors in both vertebrates and invertebrates. Two lynx proteins (Nl-lynx1 and Nl-lynx2) have been identified in the brown planthopper, Nilaparvata lugens, which act as modulators on insect nAChRs. In the present study, two lynx proteins were found to act on the triplet receptor Nl,1/Nl,2/,2 expressed in Xenopus oocytes, increasing agonist-evoked macroscopic currents, but not changing agonist sensitivity and desensitization properties. Nl-lynx1 and Nl-lynx2 increased Imax (maximum responses) of acetylcholine to 4.85-fold and 2.40-fold of that of Nl,1/Nl,2/,2 alone, and they also increased Imax of imidacloprid to 2.57-fold and 1.25-fold. Although, on another triplet nAChRs Nl,3/Nl,8/,2, Nl-lynx2 increased Imax of acetylcholine and imidacloprid to 3.63-fold and 2.16-fold, Nl-lynx1 had no effects on Imax of either acetylcholine or imidacloprid. The results demonstrate the selectivity of lynx proteins for different insect nAChR subtypes. This selectivity was also identified in native N. Lugens. Co-immunoprecipitation was found between Nl,1/Nl,2-containing receptors and both Nl-lynx1 and Nl-lynx2, but was only found between Nl,3/Nl,8-containing receptors and Nl-lynx2. When the previously identified Nl,1Y151S and Nl,3Y151S mutations were included (Nl,1Y151S/Nl,2/,2 and Nl,3Y151S/Nl,8/,2), the increase in Imax of imidacloprid, but not acetylcholine, caused by co-expression of Nl-lynx1 and Nl-lynx2 was more noticeable than that of their wildtype counterparts. Taken together, these data suggest that two modulators, Nl-lynx1 and Nl-lynx2, might serve as an influencing factor in target site insensitivity in N. lugens, such as Y151S mutation. [source] Responsiveness, affinity constants and receptor reserves for serotonin on aortae of aged normotensive and hypertensive ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2001Sheila A. Doggrell We have previously shown that the potency and affinity constants (KA values) for serotonin (5-HT) are greater, and the 5-HT2A -receptor reserve is lesser, on the aorta of 6-month-old spontaneously hypertensive rats (SHRs) compared with age-matched Wistar Kyoto normotensive (WKY) rats. The present study was undertaken to investigate whether these parameters are altered on the aorta with ageing and as hypertension progresses to heart failure. The effects of phenoxybenzamine on the serotonergic responses of the aortae of 24-month-old WKY rats and SHRs were determined. On WKY rat aorta, ageing from 6 to 24 months was associated with an increase in sensitivity and affinity for serotonin, and a loss of 5-HT2A -receptor reserve. On SHR aorta, ageing from 6 to 24 months was also associated with an increase in sensitivity and affinity for serotonin, but a loss of 5-HT2A -receptor reserve. The sensitivity to serotonin was greater on the 24-month-old SHR aorta (pD2 6.53) than age-matched WKY rat aorta (pD2 5.89). On the aorta of the 24-month-old WKY rats, the KA value for serotonin was 4.5 times 10,6 M, and the receptor occupancies required for 20 and 50% maximum responses were 12 and 29%, respectively. There was a similar affinity, but greater receptor reserves, for serotonin on the aorta of age-matched SHRs. In summary, we have shown changes in sensitivity, affinity and 5-HT2A -receptor reserves for serotonin on the aorta with ageing and in hypertension/heart failure. [source] Alpha1A/L -adrenoceptors mediate contraction of the circular smooth muscle of the pig urethraAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2006K. Bagot Summary 1 Sympathetically mediated urethral tone is essential for the maintenance of continence and involves the activation of postjunctional ,1 -adrenoceptors. This study characterizes the ,1 -adrenoceptor subtypes responsible for mediating contraction of the urethral circular smooth muscle of the pig. 2 The potency order of a number of agonists and the affinities of several receptor selective antagonists were determined on pig-isolated circular smooth muscle strips in the presence of cocaine (1 ,m) and corticosterone (10 ,m) to inhibit amine uptake and propranolol (1 ,m) to antagonize , -adrenoceptors. 3 The potency order for agonists was N -[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulphonamide (A61603) > noradrenaline = phenylephrine = M6434 > methoxamine with pEC50 values of 7.3, 5.8, 5.7, 5.6 and 5.0 respectively. 4 The ,1D -adrenoceptor-selective antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione (BMY7378) caused rightward shifts of the concentration,response curves to noradrenaline, yielding a low affinity estimate (6.6) for the urethral receptor. The ,1A -adrenoceptor-selective antagonists, RS100329 and 5-methylurapidil, gave relatively high affinity estimates (9.6 and 8.8 respectively) for this receptor. All three antagonists produced Schild plots with slopes close to unity but did reduce maximum responses at higher concentrations. Prazosin antagonized responses of the urethra to noradrenaline, yielding a mean affinity estimate of 9.0. Although the Schild plot for prazosin again had a slope of unity, this drug also reduced maximum responses to noradrenaline at all concentrations examined (10,100 nm). N -[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro- ,,, -dimethyl-1H-indole-3-ethanamide (RS17053), which discriminates between responses mediated via ,1A (high affinity) and ,1L -adrenoceptors (low affinity) at concentrations up to 3 ,m, failed to antagonize responses of the urethra. 5 These results suggest that contraction of urethral circular smooth muscle in the pig is mediated via a single population of adrenoceptors with the pharmacological characteristics of the ,1A/L -adrenoceptor, most probably the ,1L -adrenoceptor. [source] | |||||||||||||||||||