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EFS-evoked Contractions (EFS-evok + contraction)
Selected AbstractsGABAB receptor function in the ileum and urinary bladder of wildtype and GABAB1 subunit null miceAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2002G. J. Sanger Summary1 GABAB1 receptor subunit knockout mice were generated and the effects of the GABAB receptor agonist, baclofen, were evaluated within the peripheral nervous system (PNS) of wildtype (+/+), heterozygote (+/,) and knockout (,/,) animals. For this purpose, neuronally-mediated responses were evoked in both the isolated ileum and urinary bladder, using selective electrical field stimulation (EFS). 2 In ileum resected from 4,8-week-old-mice, low frequencies of EFS (0.5 Hz) evoked irregular muscle contractions which were prevented by atropine 1 ,M and reduced by baclofen (33.4 ± 5.6%, 100 ,m). The latter effect was antagonized by the GABAB receptor antagonist CGP54626 0.2 ,m. Baclofen 100 ,m did not affect contractions of similar amplitude induced by carbachol, indicating that the ability of baclofen to inhibit cholinergic function in mouse ileum may be due to an action at prejunctional GABAB receptors. 3 To avoid the development of grand mal seizure by GABAB1 (,/,) mice, a behaviour observed when the mice were greater than 3 weeks old, it was necessary to study the effects of this knockout in 1,3-week-old-animals. However, at this age, EFS at 0.5 Hz did not evoke robust muscle contractions. Consequently we used EFS at 5 Hz, which did evoke cholinergically mediated contractions, found to be of similar amplitude in (+/+) and (+/,) mice, of both 1,3 weeks and 4,8 weeks of age. At this frequency of EFS, baclofen reduced the amplitude of the evoked contractions [n=6 (+/+) and n=5 (+/,), IC50 19.2 ± 4.8 ,m) and this effect was greatly reduced in the presence of CGP54626 0.2 ,m. 4 In urinary bladder from 1,3-week-old-mice, using higher frequencies of EFS to evoke clear, nerve-mediated contractions (10 Hz), baclofen 10,300 ,m concentration-dependently inhibited contractions in (+/+) mice (IC50 9.6 ± 3.8 ,m). This effect was inhibited by CGP54626 (0.2 ,m, 46.2 ± 13.6% inhibition, 300 ,m baclofen n=7) a concentration which, by itself, had no effect on the EFS-evoked contractions. 5 The effects of baclofen in both ileum and urinary bladder were absent in the GABAB1 receptor subunit (,/,) mice; however, responses to EFS were unaffected in (,/,) when compared to the (+/+) mice. 6 Our data suggest that, as in the central nervous system (CNS), the GABAB1 receptor subunit is an essential requirement for GABAB receptor function in the enteric and PNS. As such, these data do not provide a structural explanation for the existence of putative subtypes of GABAB receptor, suggested by studies such as those in which different rank-orders of GABAB agonist affinity have been reported in different tissues. [source] Differences between the abilities of tegaserod and motilin receptor agonists to stimulate gastric motility in vitroBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2007E M Jarvie Background and purpose: Motilin or 5-HT4 receptor agonists stimulate gastrointestinal motility. Differences in activity are suggested but direct comparisons are few. A method was devised to directly compare the gastric prokinetic activities of motilin, the motilin receptor agonist, erythromycin, and the 5-HT4 receptor agonist, tegaserod. Experimental approach: Gastric prokinetic-like activity was assessed by measuring the ability to facilitate cholinergically-mediated contractions evoked by electrical field stimulation (EFS) in rabbit isolated stomach. Comparisons were made between potency, maximal activity and duration of responses. Key results: Rabbit motilin (r.motilin) 0.003,0.3,M, [Nle13]motilin 0.003,0.3,M, erythromycin 0.3,10,M and tegaserod 0.1,10,M caused concentration , dependent potentiation of EFS-evoked contractions. The potency ranking was r.motilin = [Nle13]motilin > tegaserod > erythromycin. The Emax ranking was r.motilin = [Nle13]motilin = erythromycin > tegaserod. Responses to r.motilin and [Nle13]motilin faded rapidly (t1/2 9 and 11 min, respectively) whereas those to erythromycin and tegaserod were maintained longer (t1/2 24 and 28 min). The difference did not appear to be due to peptide degradation. A second application of [Nle13]motilin was excitatory after 60 min contact and fade of the initial response (responses to 0.03 and 0.1,M [Nle13]motilin were not different from those caused by the first application). Conclusions and implications: Prokinetic-like activities of the 5-HT4 agonist tegaserod and the motilin receptor agonists were compared by measuring changes in cholinergically-mediated contractions. This novel approach highlighted important differences between classes (greater Emax of motilin, compared with tegaserod) and for the first time, within each class (short t1/2 for motilin, compared with erythromycin). British Journal of Pharmacology (2007) 150, 455,462. doi:10.1038/sj.bjp.0707118 [source] 5-HT4 receptors on cholinergic nerves involved in contractility of canine and human large intestine longitudinal muscleBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2000N H Prins 5-HT4 receptors mediate circular muscle relaxation in both human and canine large intestine, but this phenomenon alone can not explain the improvement in colonic motility induced by selective 5-HT4 receptor agonists in vivo. We set out to characterize 5-HT4 receptor-mediated effects in longitudinal muscle strips of canine and human large intestine. Electrical field stimulation (EFS) was applied providing submaximal isotonic contractions. L -NOARG (0.1 mM) was continuously present in the organ bath to preclude nitric oxide-induced relaxation to EFS. The selective 5-HT4 receptor agonist prucalopride (0.3 ,M) enhanced EFS-evoked contractions, that were antagonized in both preparations by the selective 5-HT4 receptor antagonist GR 113808 (0.1 ,M). The prucalopride-induced increase was present in canine ascending and descending colon, but absent in rectum. Regional differences in response to prucalopride were not observed in human ascending and sigmoid colon and rectum. Incubation with atropine (1 ,M) or tetrodotoxin (0.3 ,M) inhibited EFS-induced contractions, which were then unaffected by prucalopride (0.3 ,M) in both tissues. In the presence of methysergide (3 ,M; both tissues) and granisetron (0.3 ,M; only human tissues), 5-HT (0.3 ,M) enhanced EFS-induced contractions, an effect that was antagonized by GR 113808 (0.1 ,M). In the presence of atropine or tetrodotoxin, EFS-induced contractions were inhibited, leaving 5-HT (0.3 ,M) ineffective in both preparations. This study demonstrates for the first time that in human and canine large intestine, 5-HT4 receptors are located on cholinergic neurones, presumably mediating facilitating release of acetylcholine, resulting in enhanced longitudinal muscle contractility. This study and previous circular muscle strip studies suggest that 5-HT4 receptor agonism facilitates colonic propulsion via a coordinated combination of inhibition of circumferential resistance and enhancement of longitudinal muscle contractility. British Journal of Pharmacology (2000) 131, 927,932; doi:10.1038/sj.bjp.0703615 [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] | ||||||||||