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Log EC50 (log + ec50)
Selected AbstractsEvidence against ,2 -adrenoceptors mediating relaxation in rat thoracic aortae: ,2 -agonists relaxation depends on interaction with ,1 -adrenoceptorsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2006Enrique F. Castillo Abstract In rat aorta, the presence of functional ,2 -adrenoceptors (,2 -AR) was investigated in ring preparations preconstricted with ,1 -adrenergic and non- ,1 -adrenergic agonists. Particularly, the hypothetical interference of ,2 -AR agonists with ,1 -AR-mediated vasoconstriction was evaluated. Relaxant and contractile responses to ,2 -AR agonists were obtained. In endothelium-intact and endothelium-denuded aortic rings preconstricted with phenylephrine (1 × 10,6 m), the imidazoline derivatives, clonidine and UK14304, induced relaxations with similar order of potencies (,log EC50) and maxima relaxant effects respectively. Pretreatment with the NO synthase inhibitor, NG -nitro- l -arginine methyl ester (l -NAME) had no effect on the relaxant responses to clonidine and UK14304. In phenylephrine-constricted rings with endothelium, relaxations to clonidine and UK 14304 were not antagonized by the selective ,2 -AR antagonist, rauwolscine (,1 × 10,6 m). Clonidine and UK 14304 induced only contractions on endothelium-intact and endothelium-denuded aortic rings contracted with prostaglandin F2, (3 × 10,7 m). Moreover, clonidine and UK 14304-induced relaxation of endothelium-denuded arteries precontracted with methoxamine but not with serotonin. Finally, the concentration,contraction curves to clonidine and UK 14304 in endothelium-denuded aortic rings were significantly shifted to the right by the ,1D -AR selective antagonist, BMY 7378, and rauwolscine. The pA2 and pKB values for BMY 7378 and rauwolscine, respectively, against endothelium-independent actions of clonidine and UK 14304 were characteristic of an effect on the ,1D -AR. The other selective ,2 -AR agonist tested BHT 933 (an azepine derivative), lacks considerable relaxant and contractile effects in rat aorta. The results provide no evidence for the presence of functional ,2 -AR in rat aorta. Respectively, the relaxant and contractile effects of the imidazoline derivatives, clonidine and UK 14304, may be due to an adjustable (in relation to the agonist-dependent active state of the ,1 -AR), inhibitory and excitatory, interaction with ,1 -ARs. [source] Evidence of ,1 -adrenoceptor functional changes in omental arteries of patients with end-stage renal diseaseAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2008M. P. Cruz-Domínguez Summary 1,1 -Adrenoceptor (,1 -AR) subtypes were characterized in isolated omental arteries obtained after abdominal surgery in patients with end-stage renal disease (ESRD) or with Diabetes Mellitus type 2 plus ESRD (ESRD-DM). 2 Omental arteries from patients with ESRD and ESRD-DM elicited a significant increase in sensitivity to phenylephrine with a pD2 (,log EC50) of 6.7 and 6.6, respectively, vs. the control (5.8, P < 0.001). 3 Stimulation with phenylephrine was conducted in the presence or absence of selective ,1 -AR competitive antagonists: 5-methylurapidil (,1A -), AH11110A (1-[biphenyl-2-yloxy]-4-imino-4-piperidin-1-yl-butan-2-ol; ,1B -) and BMY7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro [4.5] decane-7,9-dione; ,1D -). The relative abundance of mRNA for all three ,1 -ARs was determined. 4 The maximal contractile responses to phenylephrine were: Emax 1.59 ± 0.17, 1.48 ± 0.08 and 1.55 ± 0.14 g for the ESRD, ESRD-DM and control groups, respectively. 5 Functionally, there was an increment in the affinity for the ,1A -AR antagonist (pA2: control 7.45, ESRD 8.36, ESRD-DM 8.0; P < 0.01), and a reduction in the ,1B -AR antagonist affinity (8.3 for controls, 7.6 for ESRD and 7.3 for ESRD-DM; P < 0.01) associated with renal disease. The affinities for the ,1D -AR antagonist were similar among the studied groups (8.5 for the controls, 8.7 for the ESRD and 8.1 for the ESRD-DM groups). 6 Renal disease increased mRNA expression of ,1B -ARs and reduced both ,1A - and ,1D -ARs subtypes in ESRD and ESRD-DM patients. 7 The results suggest that human omental arteries exposed to chronic uraemia show vascular hypersensitivity to phenylephrine, because of functional ,1 -AR changes. [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] Beta-3 versus beta-2 adrenergic agonists and preterm labour: in vitro uterine relaxation effectsBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 6 2001Michael C. Dennedy Objective 1. To investigate the effects of the selective beta-3 adrenoreceptor agonist, BRL 37344, on human pregnant myometrial contractility in vitro. 2. to compare these effects with those of the beta-2 adrenoreceptor agonist, ritodrine. Methods Isometric tension recording was performed under physiological conditions in isolated myometrial strips from biopsies obtained at elective caesarean section. Following pre-incubation with oxytocin (10 -9 M), the effects of cumulative additions of BRL 37344 or ritodrine (10 -8,10 -3.5 M) on myometrial contractility were investigated. Results were expressed as -log EC50 (pD2) and mean maximal inhibition achieved for both drug compounds. Results BRL 37344 exerted a concentration dependant relaxant effect on myometrial contractions in all strips exposed [pD2, 7.26 (0.48) (SEM); mean maximal inhibition 61.98 (4.89%); n= 6]. Similarly, ritodrine exerted a concentration dependant inhibition of myometrial contractility in all strips exposed [pD2= 7.40 (0.28); mean maximal inhibition 59.49 (3.97%); n= 6]. There was no significant difference between calculated pD2 values (P= 0.65) or mean maximal inhibition achieved (P= 0.79). Conclusions The beta-3 adrenoreceptor agonist BRL 37344 induced relaxation of human myometrial contractions with similar potency to that of the most commonly used tocolytic agent ritodrine. This raises the possibility that the novel beta-3 adrenoreceptor agonists may have potential as therapeutic agents for human preterm labour. In view of their reported reduced cardiovascular side effects their potential clinical use requires further evaluation. [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] | ||||||||||