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Rightward Shift (rightward + shift)
Selected AbstractsReducing conditions significantly attenuate the neuroprotective efficacy of competitive, but not other NMDA receptor antagonists in vitroEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2000Ashley K. Pringle Abstract Inappropriate activation of NMDA receptors during a period of cerebral ischaemia is a crucial event in the pathway leading to neuronal degeneration. However, significant research has failed to deliver a clinically active NMDA receptor antagonist, and competitive NMDA antagonists are ineffective in many experimental models of ischaemia. The NMDA receptor itself has a number of modulatory sites which may affect receptor function under ischaemic conditions. Using rat organotypic hippocampal slice cultures we have investigated whether the redox modulatory site affects the neuroprotective efficacy of NMDA receptor antagonists against excitotoxicity and experimental ischaemia (OGD). NMDA toxicity was significantly enhanced in cultures pretreated with a reducing agent. The noncompetitive antagonist MK-801 and a glycine-site blocker were equally neuroprotective in both normal and reduced conditions, but there was a significant rightward shift in the dose,response curves of the competitive antagonists APV and CPP and the uncompetitive antagonist memantine. OGD produced neuronal damage predominantly in the CA1 region, which was prevented by MK-801 and memantine, but not by APV or CPP. Inclusion of an oxidizing agent during the period of OGD had no effect alone, but significantly enhanced the neuroprotective potency of the competitive antagonists. These data clearly demonstrate that chemical reduction of the redox modulatory site of the NMDA receptor decreases the ability of competitive antagonists to block NMDA receptor-mediated neuronal damage, and that the reducing conditions which occur during simulated ischaemia are sufficient to produce a similar effect. This may have important implications for the design of future neuroprotective agents. [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] Synthesis and pharmacological evaluation of 5-dialkylaminomethyl-2-amino-2-oxazolines as H1 -antagonistsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2001J. J. Bosc New 5-dialkylaminomethyl-2-amino-2-oxazolines have been synthezised in two steps from the corresponding dialkylamines. They were evaluated in-vitro as H1 -antagonists. Compounds 1c, 1d and 1j significantly antagonized histamine-induced contraction of guinea-pig trachea with a rightward shift of the concentration-response curve to histamine. Compound 1f, 5-[(4-benzyl-1-piperidinyl)methyl]-2-amino-2-oxazoline, induced an increase in acetylcholine Emax (the maximal response to acetylcholine 10,3 M) and a shift to the left of the concentration-response curve. The lack of effect of this compound on histamine-induced contraction rules out a non-selective potentiation of the contraction mechanisms. Preliminary structure-activity results were reported partly based on physicochemical results. [source] Grave acidosis after severe anaphylactic bronchospasm: friend or foe?ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2007M. Pytte In a 20-year-old woman with known asthma, anaphylactic bronchospasm induced a grave combined respiratory and metabolic acidosis (pHa 6.66) with marked hypoxaemia (SaO2 45%). The beneficial effects of the rightward shift of the oxyhaemoglobin dissociation curve on tissue O2 unloading at such pH was more than offset by the negative effect on SaO2 at the reduced PaO2 (7.0 kPa) found in this patient. This case illustrates the detrimental effect of grave acidosis on arterial blood oxygen content at subnormal PaO2 values, the beneficial effect of a supranormal PaO2 on the SaO2 in such patients, and the rapid remission rate of life-threatening acidosis and blood lactate after adequate ventilation and tissue oxygenation were secured. The initial treatment of the patient and clinically relevant considerations are discussed. [source] (N)-methanocarba-2MeSADP (MRS2365) is a subtype-specific agonist that induces rapid desensitization of the P2Y1 receptor of human plateletsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2006D. M. BOURDON Summary., Adenosine diphosphate (ADP) initiates and maintains sustained aggregation of platelets through simultaneous activation of both the Gq -coupled P2Y1 receptor and the Gi -coupled P2Y12 receptor. We recently described the synthesis and P2Y1 receptor-specific agonist activity of (N)-methanocarba-2MeSADP (MRS2365). Consequences of selective activation of the P2Y1 receptor by MRS2365 have been further examined in human platelets. Whereas MRS2365 alone only induced shape change, addition of MRS2365 following epinephrine treatment, which activates the Gi/z -linked, ,2A -adrenergic receptor, resulted in sustained aggregation that was indistinguishable from that observed with ADP. Conversely, the platelet shape change promoted by ADP in the presence of the GPIIb/IIIa antagonist eptifibatide was similar to that promoted by MRS2365. Preaddition of the high affinity P2Y1 receptor antagonist MRS2500 inhibited the effect of MRS2365, whereas addition of MRS2500 subsequent to MRS2365 reversed the MRS2365-induced shape change. Preactivation of the P2Y1 receptor with MRS2365 for 2 min resulted in marked loss of capacity of ADP to induce aggregation as evidenced by a greater than 20-fold rightward shift in the concentration effect curve of ADP. This inhibitory effect of P2Y1 receptor activation was dependent on the concentration of MRS2365 (EC50 = 34 nm). The inhibitory effect of preincubation with MRS2365 was circumvented by activation of the Gq -coupled 5-HT2A receptor suggesting that MRS2365 induces loss of the ADP response as a consequence of desensitization of the Gq -coupled P2Y1 receptor. The time course of MRS2365-induced loss of aggregation response to epinephrine was similar to that observed with ADP. These results further demonstrate the P2Y1 receptor selectivity of MRS2365 and illustrate the occurrence of agonist-induced desensitization of the P2Y1 receptor of human platelets studied in the absence of P2Y12 receptor activation . [source] The Production Responses of the Competitive Firm to Three Conventional Distributional Shifts: a Unified PerspectiveMETROECONOMICA, Issue 2 2000Wayne Simpson This paper presents a unified perspective on the production responses of the competitive firm to three conventional distributional shifts: (i) a rightward shift of the distribution, (ii) a Rothschild,Stiglitz increase in risk, and (iii) a Menezes et al. increase in downside risk. In particular, assuming that the von Neumann,Morgenstern utility is increasing and concave, and assuming its higher-order derivatives are uniformly signed, we demonstrate that the production responses are unambiguous in the case of price less than or equal to marginal cost. In the alternative case of price greater than marginal cost, we then demonstrate that the production responses can be signed unambiguously by reference to sufficient conditions motivated by absolute risk aversion and by absolute prudence. [source] M2 mediated contractions of human bladder from organ donors is associated with an increase in urothelial muscarinic receptors,NEUROUROLOGY AND URODYNAMICS, Issue 1 2007Alan S. Braverman Abstract Aims Previous studies have shown increased density of M2 receptors in hypertrophied rat bladders that possess an M2 contractile phenotype. The aim of the current study is to determine whether human bladders with an M2 contractile phenotype also have a greater density of bladder M2 receptors. Materials and Methods Human bladders were obtained from 24 different organ transplant donors. Darifenacin and methoctramine affinity was determined by the rightward shift of cumulative carbachol concentration contractile response curves for each bladder. Radioligand binding and immunoprecipitation was used to quantify M2 and M3 subtypes in isolated detrusor muscle and urothelium. In addition, pig bladder muscle and urothelial receptors were quantified for comparison. Results In the human urothelium total, M2 and M3 muscarinic receptor density is significantly negatively correlated with the affinity of darifenacin for inhibition of contraction of the detrusor muscle. In the detrusor muscle there is no correlation between receptor density and darifenacin affinity for inhibition of contraction. Muscarinic receptor density is greater in the muscle than in the urothelium in human bladders whereas in the pig bladder the density is greater in the urothelium than in the muscle. Conclusions The greater density of urothelial muscarinic receptors in human bladders with lower darifenacin affinity, indicative of a greater contribution of M2 receptors to the contractile response, points towards a possible role of the urothelium in controlling M2 mediated contractile phenotype. In comparison between human and pig bladders, the distribution of muscarinic receptor subtypes in the muscle and urothelium are quite different. Neurourol. Urodynam. © 2006 Wiley-Liss, Inc. [source] Flavonoids as antagonists at A1 adenosine receptorsPHYTOTHERAPY RESEARCH, Issue 11 2006Stephen P. H. Alexander Abstract This study aimed to investigate the potential for ,avonoid action at A1 adenosine receptors in vitro. In a radioligand binding assay for A1 adenosine receptor occupancy in particulate preparations from guinea-pig cerebral cortex, flavonoids competed in concentration-dependent manners with Hill slopes typically not different from unity. Of the ,avonoids tested, quercetin showed highest affinity (pKi value of 5.33). At a concentration of 28 mm, quercetin evoked a rightward shift in the N6 -cyclopentyladenosine-induced inhibition of electrically evoked contractions of the guinea-pig isolated ileum, allowing the calculation of a pKi value of 4.71. These data suggest, therefore, that ,avonoids represent an additional dietary source of A1 adenosine receptor antagonists (beyond the methylxanthines, caffeine and theophylline). Copyright © 2006 John Wiley & Sons, Ltd. [source] Studies on spasmogenic and spasmolytic activities of Calendula officinalis flowersPHYTOTHERAPY RESEARCH, Issue 10 2006Samra 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] Z-Score for Benchmarking Reader Competence in a Central ECG LaboratoryANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 1 2009Gopi Krishna Panicker B.H.M.S., P.G.D.C.R. Background: ECGs from thorough QT studies must be read in a central laboratory by trained experts. Standards of expertise are not presently defined. We, therefore, studied the use of Z-scores to define reader competence. Methods: Two hundred ECGs were read by 24 experts and the mean and standard deviation (SD) of QT measurements calculated for each ECG. Z-scores ([QTreader, mean QTexperts]/ SDexperts) for each ECG and mean of absolute Z-scores of all ECGs read by a reader were calculated. The highest mean absolute Z-score of experts was considered the cutoff to define competence. Hundred of these standardized ECGs were used to assess performance of readers from the central laboratory. Results: All experts had mean absolute Z-scores , 1.5. Using this cutoff, one of 28 experienced readers and 7 of 15 trainees had unacceptable Z-scores. After re-training, all achieved Z-scores <1.5. Comparing histograms of actual Z-scores of the 100 ECGs of readers with unacceptable scores with that of the reader with the best Z-score showed two patterns. Readers with histograms having a peak and tails similar to that of the best reader, but with leftward or rightward shift, consistently made shorter or longer QT measurements, respectively. A histogram with a flatter peak and wider tails, suggested that measurements were long in some ECGs and short in others. Conclusion: Mean absolute Z-score is useful to assess competence for measuring the QT interval on ECGs. Analysis of histograms can pinpoint problems in QT measurements. [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] Pharmacological characterization of a novel investigational antimuscarinic drug, fesoterodine, in vitro and in vivoBJU INTERNATIONAL, Issue 8 2008Peter Ney OBJECTIVE To investigate the primary pharmacology of fesoterodine (a novel antimuscarinic drug developed for treating overactive bladder) and SPM 7605 (its active metabolite, considered to be the main pharmacologically active principle of fesoterodine in man) against human muscarinic receptor subtypes, and to investigate in vitro and in vivo functional activity of these agents on the rat bladder compared with existing standard agents. MATERIALS AND METHODS The displacement of radioligand binding by fesoterodine, SPM 7605 and standard agents in membrane preparations of Chinese hamster ovary (CHO) cells expressing the different human muscarinic receptors (M1,M5) was characterized. Agonistic and antagonistic activities were studied using different CHO cell lines stably expressing the human recombinant muscarinic receptor subtypes. The effects of fesoterodine and SPM 7605 on isolated bladder strips contracted by carbachol or electrical field stimulation (EFS) were investigated. In vivo the effects of fesoterodine and SPM 7605 on micturition variables were assessed using continuous cystometry in conscious female Sprague-Dawley rats, and compared to those of oxybutynin and atropine. RESULTS In vitro SPM 7605 potently inhibited radioligand binding at all five human muscarinic receptor subtypes with equal affinity across all five. Fesoterodine had a similar balanced selectivity profile but was less potent than SPM 7605. Both substances were competitive antagonists of cholinergic agonist-stimulated responses in human M1-M5 cell lines and had a similar potency and selectivity profile to the radioligand-binding studies. In rat bladder strips, fesoterodine and SPM 7605 caused a rightward shift of the concentration-response curve for carbachol with no depression of the maximum, and concentration-dependently reduced contractions induced by EFS. The potency of both drugs was similar to that of atropine and oxybutynin. In the presence of the esterase inhibitor neostigmine, the concentration-response curve of fesoterodine was shifted to the right, suggesting that part of the activity was caused by metabolism to SPM 7605 by tissue enzymes. In vivo, low doses (0.01 mg/kg) of fesoterodine and SPM 7605 reduced micturition pressure and increased intercontraction intervals and bladder capacity, but did not affect residual volume. CONCLUSIONS Fesoterodine and its active metabolite, SPM 7605, are nonsubtype selective, competitive antagonists of human muscarinic receptors, but SPM 7605 has greater potency than the parent compound. Pharmacodynamic studies in the rat bladder in vitro confirm the competitive muscarinic antagonist profile of these agents in a native tissue preparation, and in vivo studies in the rat showed effects on bladder function consistent with a muscarinic antagonist profile. [source] Noncompetitive antagonism of BIBN4096BS on CGRP-induced responses in human subcutaneous arteriesBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2004Majid Sheykhzade We investigated the antagonistic effect of 1-piperidinecarboxamide, N -[2-[[5amino-l-[[4-(4-pyridinyl)-l-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl) (BIBN4096BS) on the calcitonin gene-related peptide (CGRP)-induced responses by using isometric myograph and FURA-2 technique in human subcutaneous arteries removed in association with abdominal surgery. BIBN4096BS, at the concentration of 1 pM, had no significant effect on the CGRP-induced relaxation in these vessels. At the concentration of 10 pM, BIBN4096BS had a competitive antagonistic-like behaviour characterized by parallel rightward shift in the log CGRP concentration-tension curve with no depression of the Emax. At the higher concentrations (0.1 and 1 nM), BIBN4096BS had a concentration-dependent noncompetitive antagonistic effect on the CGRP-induced responses. The efficacy and potency of CGRP was significantly greater in the smaller (lumen diameter ,200 ,m) human subcutaneous arteries compared to the larger ones. The apparent agonist equilibrium dissociation constant, KA, for CGRP1 receptors in the human subcutaneous arteries was approximately 1 nM. Analysis of the relationship between receptor occupancy and response to CGRP indicates that the receptor reserve is relatively small. Using reverse transcriptase-polymerase chain reaction (RT-PCR), the presence of mRNA sequences encoding the calcitonin receptor-like receptor, receptor activity modifying protein (RAMP1, RAMP2, RAMP3) and receptor component protein were demonstrated in human subcutaneous arteries, indicating the presence of CGRP1 -like receptor and the necessary component for the receptor activation. In conclusion, the inhibitory action of BIBN4096BS at the low concentration (10 pM) on the CGRP-tension curve (but not intracellular calcium concentration ([Ca2+]i) resembles what is seen with a reversible competitive antagonist. However, at the higher concentrations (0.1 and 1 nM), BIBN4096BS acts as a selective noncompetitive inhibitor at CGRP1 receptors in human subcutaneous arteries. British Journal of Pharmacology (2004) 143, 1066,1073. doi:10.1038/sj.bjp.0705967 [source] The Na-K-ATPase is a target for an EDHF displaying characteristics similar to potassium ions in the porcine renal interlobar arteryBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2002Eckhart Büssemaker The present study was performed to determine the characteristics of the endothelium-derived hyperpolarizing factor (EDHF) that mediates the nitric oxide (NO)- and prostacyclin (PGI2)-independent hyperpolarization and relaxation of porcine renal interlobar arteries. Bradykinin-induced changes in isometric force or smooth muscle membrane potential were assessed in rings of porcine renal interlobar artery preconstricted with the thromboxane analogue U46619 in the continuous presence of N, -nitro- L -arginine and diclofenac to inhibit NO synthases and cyclo-oxygenases. Inhibition of NO- and PGI2 -production induced a rightward shift in the concentration-relaxation curve to bradykinin without affecting maximal relaxation. EDHF-mediated relaxation was abolished by a depolarizing concentration of KCl (40 mM) as well as by a combination of charybdotoxin and apamin (each 100 nM), two inhibitors of calcium-dependent K+ (K+Ca) channels. Charybdotoxin and apamin also reduced the bradykinin-induced, EDHF-mediated hyperpolarization of smooth muscle cells from 13.7±1.3 mV to 5.7±1.2 mV. In addition to the ubiquitous ,1 subunit of the Na-K-ATPase, the interlobar artery expressed the , subunit as well as the ouabain-sensitive ,2, ,3 subunits. A low concentration of ouabain (100 nM) abolished the EDHF-mediated relaxation and reduced the bradykinin-induced hyperpolarization of smooth muscle cells (13.6±2.8 mV versus 5.20±1.39 mV in the absence and presence of ouabain). Chelation of K+, using cryptate 2.2.2., inhibited EDHF-mediated relaxation, without affecting NO-mediated responses. Elevating extracellular KCl (from 4 to 14 mM) elicited a transient, ouabain-sensitive hyperpolarization and relaxation that was endothelium-independent and insensitive to charybdotoxin and apamin. These results indicate that in the renal interlobar artery, EDHF-mediated responses display the pharmacological characteristics of K+ ions released from endothelial K+Ca channels. Smooth muscle cell hyperpolarization and relaxation appear to be dependent on the activation of highly ouabain-sensitive subunits of the Na-K-ATPase. British Journal of Pharmacology (2002) 137, 647,654. doi:10.1038/sj.bjp.0704919 [source] Agmatine, an endogenous ligand at imidazoline binding sites, does not antagonize the clonidine-mediated blood pressure reactionBRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2002Walter Raasch Since agmatine has been identified as a clonidine displacing substance (CDS), the aim of this study was to investigate whether agmatine can mimic CDS-induced cardiovascular reactions in organ bath experiments, pithed spontaneously hypertensive rats (SHR) and anaesthetized SHR. Intravenously-administered agmatine significantly reduced the blood pressure and heart rate of anaesthetized SHR at doses higher than 1 and 3 mg kg,1, respectively. These effects are probably mediated via central mechanisms, since there was an approximate 8 fold rightward shift of the dose-response curve in the pithed SHR (indicating a weakened cardiovascular effect). Moreover, in organ bath experiments, agmatine failed to alter the contractility of intact or endothelium-denuded aortal rings. When agmatine was administered i.c.v. to anaesthetized SHR, blood pressure was increased without any alteration of heart rate, whereas blood pressure was unchanged and heart rate was increased after injection into the 4th brain ventricle. This suggests that haemodynamic reaction patterns after central application are related to distinct influences on central cardiovascular mechanisms. Agmatine reduces noradrenaline release in pithed SHR while ,2 -adrenoceptors are irreversibly blocked with phenoxybenzamine, but not while I1 -binding sites are selectively blocked with AGN192403. This suggests that agmatine may modulate noradrenaline release in the same way that clonidine does, i.e. via imidazoline binding sites; this involves a reduction in sympathetic tone which in turn reduces blood pressure and heart rate. Finally, CDS-like cardiovascular activity appears not to be due to agmatine, since (i) blood pressure in anaesthetized SHR is decreased by agmatine and clonidine, and (ii) agmatine did not antagonize the blood pressure reaction to clonidine in pithed or anaesthetized SHR. British Journal of Pharmacology (2002) 135, 663,672; doi:10.1038/sj.bjp.0704513 [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] Effect of caffeine on response of rabbit isolated corpus cavernosum to high K+ solution, noradrenaline and transmural electrical stimulationCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2004Adebowale Adebiyi Summary 1.,Caffeine has wide-ranging activities on smooth muscles, including contractile and relaxant effects. The aim of the present study was to examine the activity of caffeine on rabbit corpus cavernosum (RCC). 2.,The effects of caffeine (0.5,4.0 mmol/L) on the response of RCC to high K+ solution, noradrenaline (NA) and transmural electrical stimulation (EFS) were studied in a tissue bath system. 3.,Caffeine did not contract the RCC. However, 0.5,4.0 mmol/L caffeine caused concentration-dependent relaxation of tension development in high-K+ (120 mmol/L) solution in contrast with the solvent control. At 4.0 mmol/L caffeine, high-K+ solution-induced tone of the RCC was reduced by 73.4 ± 7.3%. Caffeine (0.5,4.0 mmol/L) also concentration-dependently relaxed NA (12.5 µmol/L)-induced tonic contraction of the RCC. At 4.0 mmol/L caffeine, NA-induced tone of the RCC was reduced by 41.1 ± 7.0%. Incubation of RCC in 2.0 mmol/L caffeine for 30 min prior to EFS (1,40 Hz) caused a marked rightward shift in the frequency,response curve. 4.,The results of the present study suggest that caffeine exhibits relaxant activity on rabbit cavernosal smooth muscle and the mechanism of this activity possibly involves inhibition of Ca2+ signalling. [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] EFFECT OF THE PHOSPHODIESTERASE 5 INHIBITORS SILDENAFIL, TADALAFIL AND VARDENAFIL ON RAT ANOCOCCYGEUS MUSCLE: FUNCTIONAL AND BIOCHEMICAL ASPECTSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2009Haroldo A Toque SUMMARY 1The anococcygeus muscle is part of the erectile machinery in male rodents. Phosphodiesterase (PDE) 5 inhibitors enhance and prolong the effects of cGMP, which has a key role in penile erection. The aim of the present study was to provide a functional and biochemical comparison of the three PDE5 inhibitors, namely sildenafil, tadalafil and vardenafil, in the rat anococcygeus muscle. 2Muscle strips were mounted in 4 mL organ baths and isometric force recorded. Levels of cGMP were measured using an enzyme immunoassay kit. Western blots were used to determine PDE5 protein expression. 3The PDE5 inhibitors concentration-dependently relaxed carbachol-precontracted anococcygeus muscle; however, vardenafil was more potent (pEC50 = 8.11 ± 0.05) than sildenafil (7.72 ± 0.06) or tadalafil (7.69 ± 0.05). Addition of NG -nitro- l -arginine methyl ester (100 µmol/L) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 µmol/L) to the organ baths caused significant rightward shifts in concentration,response curves for all PDE5 inhibitors. 4Sildenafil, tadalafil and vardenafil (all at 0.1 µmol/L) caused leftward shifts in the glyceryl trinitrate (GTN) concentration-response curves (by 4.0-, 3.7- and 5.5-fold, respectively). In addition, all three PDE5 inhibitors significantly potentiated relaxation responses to both GTN (0.01,10 µmol/L) and electrical field stimulation (EFS; 1,32 Hz), with vardenafil having more pronounced effects. 5All three PDE5 inhibitors reduced EFS-evoked contractions in a concentration-dependent manner over the concentration range 0.001,1 µmol/L. There were no significant differences between the effects of the three PDE5 inhibitors. 6Vardenafil (0.01,0.1 µmol/L) was more potent in preventing cGMP degradation in vitro than sildenafil (0.01,0.1 µmol/L) and tadalafil (0.01,0.1 µmol/L). 7Under control conditions, the expression of PDE5 was higher in the anococcygeus muscle than in the corpus cavernosum. 8In conclusion, PDE5 inhibitors enhance exogenous and endogenous nitric oxide-mediated relaxation in the rat anococcygeus muscle. The potency of vardenafil was greater than that of either sildenafil or tadalafil. [source] | |||||||||||||