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101.
ML Jensen KA Wafford AR Brown D Belelli JJ Lambert NR Mirza 《British journal of pharmacology》2013,168(5):1118-1132
Background and Purpose
Most GABAA receptor subtypes comprise 2α, 2β and 1γ subunit, although for some isoforms, a δ replaces a γ-subunit. Extrasynaptic δ-GABAA receptors are important therapeutic targets, but there are few suitable pharmacological tools. We profiled DS2, the purported positive allosteric modulator (PAM) of δ-GABAA receptors to better understand subtype selectivity, mechanism/site of action and activity at native δ-GABAA receptors.Experimental Approach
Subunit specificity of DS2 was determined using electrophysiological recordings of Xenopus laevis oocytes expressing human recombinant GABAA receptor isoforms. Effects of DS2 on GABA concentration–response curves were assessed to define mechanisms of action. Radioligand binding and electrophysiology utilising mutant receptors and pharmacology were used to define site of action. Using brain-slice electrophysiology, we assessed the influence of DS2 on thalamic inhibition in wild-type and δ0/0 mice.Key Results
Actions of DS2 were primarily determined by the δ-subunit but were additionally influenced by the α, but not the β, subunit (α4/6βxδ > α1βxδ >> γ2-GABAA receptors > α4β3). For δ-GABAA receptors, DS2 enhanced maximum responses to GABA, with minimal influence on GABA potency. (iii) DS2 did not act via the orthosteric, or known modulatory sites on GABAA receptors. (iv) DS2 enhanced tonic currents of thalamocortical neurones from wild-type but not δ0/0 mice.Conclusions and Implications
DS2 is the first PAM selective for α4/6βxδ receptors, providing a novel tool to investigate extrasynaptic δ-GABAA receptors. The effects of DS2 are mediated by an unknown site leading to GABAA receptor isoform selectivity. 相似文献102.
103.
Soluble urokinase plasminogen activator receptor (suPAR) is a novel,independent predictive marker of myocardial infarction in HIV‐1‐infected patients: a nested case‐control study
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IC Moraes‐Silva RN De La Fuente C Mostarda K Rosa K Flues NR Damaceno‐Rodrigues EG Caldini K De Angelis EM Krieger MC Irigoyen 《Clinical and experimental pharmacology & physiology》2010,37(3):e114-e120
1. Baroreceptors regulate moment‐to‐moment blood pressure (BP) variations, but their long‐term effect on the cardiovascular system remains unclear. Baroreceptor deficit accompanying hypertension contributes to increased BP variability (BPV) and sympathetic activity, whereas exercise training has been associated with an improvement in these baroreflex‐mediated changes. The aim of the present study was to evaluate the autonomic, haemodynamic and cardiac morphofunctional effects of long‐term sinoaortic baroreceptor denervation (SAD) in trained and sedentary spontaneously hypertensive rats (SHR). 2. Rats were subjected to SAD or sham surgery and were then further divided into sedentary and trained groups. Exercise training was performed on a treadmill (five times per week, 50–70% maximal running speed). All groups were studied after 10 weeks. 3. Sinoaortic baroreceptor denervation in SHR had no effect on basal heart rate (HR) or BP, but did augment BPV, impairing the cardiac function associated with increased cardiac hypertrophy and collagen deposition. Exercise training reduced BP and HR, re‐established baroreflex sensitivity and improved both HR variability and BPV. However, SAD in trained SHR blunted all these improvements. Moreover, the systolic and diastolic hypertensive dysfunction, reduced left ventricular chamber diameter and increased cardiac collagen deposition seen in SHR were improved after the training protocol. These benefits were attenuated in trained SAD SHR. 4. In conclusion, the present study has demonstrated that the arterial baroreflex mediates cardiac disturbances associated with hypertension and is crucial for the beneficial cardiovascular morphofunctional and autonomic adaptations induced by chronic exercise in hypertension. 相似文献
106.
Recombinant DNA technology has revolutionized our understanding of many
biological systems. However, such techniques and their application have not
been fully exploited in the study of sperm zona interaction. Using examples
from other biological systems, we ourline several experimental approaches
that are likely to significantly enhance our understanding of the gamete
recognition process.
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Pilot study of MK-462 in migraine 总被引:1,自引:0,他引:1
NR Cutler J Claghorn JJ Sramek G Block D Parebianco H Cheng TV Olah SA Reines 《Cephalalgia : an international journal of headache》1996,16(2):113-116
MK-462 is a potent, selective 5HT1D receptor agonist which may be useful in treating acute migraine. We conducted a double-blind placebo-controlled inpatient study to assess the preliminary efficacy and safety of oral doses of MK-462 20 mg ( n = 8) and 40 mg ( n =36) vs placebo ( n =21), administered to 65 male and post-menopausal female migraine patients aged 22–51 with moderate or severe migraine headache. Headache severity and functional disability were measured at 0.5, 1, 1.5, and 2 h post-dose. The 20 mg dose was well tolerated and 4/8 patients obtained relief in headache severity at the 2 h time point. The 40 mg dose was well tolerated and was significantly ( p <0.05) superior to placebo at the 1.5 and 2 h time points (with 27/36 or 75% obtaining relief at 2 h compared to 7/21 or 33% for placebo). Adverse events occurred in 50% of patients on 20 mg MK-462, 72% of those on 40 mg MK-462, and in 52% of placebo-treated subjects. The most common adverse events associated with MK-462 were drowsiness (20 mg 12%; 40 mg 44%; placebo 24%), dry mouth (10 mg 36%; placebo 19%), and lightheadedness/dizziness (40 mg 17%; placebo 10%). Based on these preliminary results, MK-462 appears worthy of continued study for the treatment of acute migraine. 相似文献