Abstract:
BACKGROUND AND PURPOSE:Pulmonary hypertension (PH) is a devastating disease characterized by increased pulmonary arterial pressure, which progressively leads to right-heart failure and death. A dys-regulated renin angiotensin system (RAS) has been implicated in the development and progression of PH. However, the role of the angiotensin AT2 receptor in PH has not been fully elucidated. We have taken advantage of a recently identified non-peptide AT2 receptor agonist, Compound 21 (C21), to investigate its effects on the well-established monocrotaline (MCT) rat model of PH. EXPERIMENTAL APPROACH:A single s.c. injection of MCT (50 mg·kg(-1) ) was used to induce PH in 8-week-old male Sprague Dawley rats. After 2 weeks of MCT administration, a subset of animals began receiving either 0.03 mg·kg(-1) C21, 3 mg·kg(-1) PD-123319 or 0.5 mg·kg(-1) A779 for an additional 2 weeks, after which right ventricular haemodynamic parameters were measured and tissues were collected for gene expression and histological analyses. KEY RESULTS:Initiation of C21 treatment significantly attenuated much of the pathophysiology associated with MCT-induced PH. Most notably, C21 reversed pulmonary fibrosis and prevented right ventricular fibrosis. These beneficial effects were associated with improvement in right heart function, decreased pulmonary vessel wall thickness, reduced pro-inflammatory cytokines and favourable modulation of the lung RAS. Conversely, co-administration of the AT2 receptor antagonist, PD-123319, or the Mas antagonist, A779, abolished the protective actions of C21. CONCLUSIONS AND IMPLICATIONS:Taken together, our results suggest that the AT2 receptor agonist, C21, may hold promise for patients with PH.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Bruce E,Shenoy V,Rathinasabapathy A,Espejo A,Horowitz A,Oswalt A,Francis J,Nair A,Unger T,Raizada MK,Steckelings UM,Sumners C,Katovich MJdoi
10.1111/bph.13044subject
Has Abstractpub_date
2015-05-01 00:00:00pages
2219-31issue
9eissn
0007-1188issn
1476-5381journal_volume
172pub_type
杂志文章abstract::1. In the anaesthetized dog bombesin had a potent antidiuretic effect, and sometimes arrested urine flow completely. Threshold doses, by i.v. infusion, were of the order of 0.5-1 (ng/kg)/minute. Antidiuresis was the result of a reduction in glomerular filtration rate provoked by a fall in intraglomerular hydrostatic p...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1973.tb08352.x
更新日期:1973-07-01 00:00:00
abstract::1. Membrane effects of cromakalim (Crom; 50-300 microM) were examined in CA1 neurones recorded mainly by intracellular, single-electrode voltage-clamping in slices (from Sprague-Dawley rats) kept in an interface chamber at 33 degrees C. 2. In 14 cells held at -63 +/- 3.5 mV, in the presence of tetrodotoxin, kynurenic ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb17004.x
更新日期:1994-10-01 00:00:00
abstract::1. The effects of the spasmogenic agents, carbachol (CCh), histamine, 5-hydroxytryptamine (5-HT) and 9,11-epithio-11,12-methano-thromboxane A2 (STA2) were investigated on smooth muscle tissues of the dog trachea. 2. CCh (10 microM) produced a larger contraction than high K (128 mM), 10 microM histamine, 5-HT or STA2. ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1990.tb12049.x
更新日期:1990-05-01 00:00:00
abstract::1. N-methyl-gamma-aminobutyrate (N-methylGABA), N-methylglycine, N-methyltaurine and N-methylbeta-alanine diminished the frequency of spontaneous spike discharges in guinea-pig cerebellar slices. Usually a weak excitatory effect preceded the inhibition. 2. The inhibitory effects of N-methylGABA and N-methylbeta-alanin...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1977.tb07720.x
更新日期:1977-04-01 00:00:00
abstract::British Journal of Pharmacology (BJP) is pleased to publish a new set of guidelines for reporting research involving animals, simultaneously with several other journals; the 'ARRIVE' guidelines (Animals in Research: Reporting In Vivo Experiments). This editorial summarizes the background to the guidelines, gives our v...
journal_title:British journal of pharmacology
pub_type: 社论
doi:10.1111/j.1476-5381.2010.00873.x
更新日期:2010-08-01 00:00:00
abstract::1. The bovine pulmonary vein contracts in response to acetylcholine, histamine, 5-hydroxytryptamine and bradykinin. The tissue is particularly sensitive to 5-hydroxytryptamine (>0.1 ng/ml). Specific Schultz-Dale reactions were elicited in the pulmonary vein in response to horse plasma.2. The Schultz-Dale reaction is i...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:
更新日期:1971-10-01 00:00:00
abstract::1. The effects of the nitrosothiol, S-nitroso N-acetylpenicillamine (SNAP) which liberates nitric oxide (NO), on ethanol-mediated gastric damage, blood flow and cyclic GMP levels in siaoloadenectomized (SALX) rats have been investigated. 2. Intraluminal instillation of ethanol (5-50% w/v) dose-dependently induced haem...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1995.tb15883.x
更新日期:1995-05-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Down's syndrome is a common genetic cause of intellectual disability, for which there are no drug therapies. Mechanistic studies in a model of Down's syndrome [Ts65Dn (TS) mice] demonstrated that impaired cognitive function was due to excessive neuronal inhibitory tone. These deficits were normal...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.12169
更新日期:2013-07-01 00:00:00
abstract::G protein-coupled receptors are the largest group of membrane proteins and are the targets for approximately 30% of drugs currently used therapeutically. These 7-transmembrane-spanning proteins continue to provide new opportunities to develop therapeutics based on emerging knowledge of their structure, signalling prop...
journal_title:British journal of pharmacology
pub_type: 社论
doi:10.1111/j.1476-5381.2010.00695.x
更新日期:2010-03-01 00:00:00
abstract::1. The binding of 2-[125I]-iodomelatonin to chicken brain membranes, and the inhibition of binding by melatonin, N-acetyltryptamine and luzindole, were examined at temperatures between 4 degrees C and 37 degrees C. 2. At all temperatures studied, the binding affinity (Kd or Ki) for 2-[125I]-iodomelatonin, melatonin (b...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb14059.x
更新日期:1994-01-01 00:00:00
abstract::1 gamma-Aminobutyric acid (GABA, 0.1 to 1 mM) had no significant effect on the amplitude, rise time, half decay time or frequency of miniature endplate potentials (m.e.p.ps) at the frog or mouse neuromuscular junctions in vitro. 2 Addition of GABA (1 mM) to preparations previously treated with 11 mM K+-Ringer did not ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1980.tb10937.x
更新日期:1980-01-01 00:00:00
abstract::1. We studied the effect of intracellular angiotensin II (Ang II) and related peptides on rat aortic contraction, whether this effect is pharmacologically distinguishable from that induced by extracellular stimulation, and determined the Ca2+ source involved. 2. Compounds were delivered into the cytoplasm of de-endoth...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702421
更新日期:1999-03-01 00:00:00
abstract::1 The mechanism underlying the enhancement by superoxide dismutase (SOD) of endothelium-dependent relaxation was investigated in rabbit mesenteric resistance arteries. 2 SOD (200 U ml(-1)) increased the production of H(2)O(2) in smooth muscle cells (as indicated by the use of an H(2)O(2)-sensitive fluorescent dye). 3 ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705255
更新日期:2003-05-01 00:00:00
abstract::1 The present study comprised treatment of healthy male rats with Delta(9)-tetrahydrocannabinol (THC, 10 mg kg(-1), p.o.), and combinations of THC with benzoflavone moiety (BZF, 10 and 20 mg kg(-1), p.o.) isolated from Passiflora incarnata Linneaus, over a period of 30 days. 2 Upon 30-days chronic administrations, the...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705015
更新日期:2003-01-01 00:00:00
abstract::1. In order to define the electrophysiological mechanism(s) responsible for bradykinin (BK)-induced positive inotropic and chronotropic responses in isolated guinea-pig atria, effects of BK on the membrane currents were examined in isolated atrial cells using patch clamp techniques. 2. BK (0.1-1000 nM) increased the L...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702060
更新日期:1998-09-01 00:00:00
abstract::1. Bepridil (BPD) is a pharmacological compound able to bind to the Ca2+ sensor protein troponin C (TnC), which triggers skeletal muscle contraction upon Ca2+-binding. BPD can thereby modulate the Ca2+-affinity of this protein. 2. The Ca2+-sensitizing action of bepridil was investigated on slow and fast isoforms of Tn...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702820
更新日期:1999-10-01 00:00:00
abstract::delta 9-Tetrahydrocannabinol (delta 9-THC) was injected into the preoptic area of the anterior hypothalamus or into the third or fourth cerebral ventricle of the conscious mouse through a chronically implanted cannula and the effects on body temperature and oxygen consumption rate were measured. At an ambient temperat...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1982.tb08802.x
更新日期:1982-02-01 00:00:00
abstract::1. The signal transduction pathway for vasorelaxation induced by human alpha-calcitonin gene-related peptide (human alpha-CGRP) was studied in rat thoracic aortic rings preconstricted with noradrenaline (10(-7) M). 2. Vasorelaxation by human alpha-CGRP was inhibited by haemoglobin (10(-6) M) and methylene blue (10(-5)...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1992.tb14508.x
更新日期:1992-11-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Normal pregnancy is associated with decreased vascular resistance and increased release of vasodilators. Endothelin-1 (ET-1) causes vasoconstriction via endothelin receptor type A (ET(A)R), but could activate ET(B)R in the endothelium and release vasodilator substances. However, the roles of ET(B...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.12225
更新日期:2013-07-01 00:00:00
abstract::Halothane has many effects on the resting membrane potential (V(m)) of excitable cells and exerts numerous effects on skeletal muscle one of which is the enhancement of Ca(2+) release by the sarcoplasmic reticulum (SR) resulting in a sustained contracture. The aim of this study was to analyse the effects of clinical d...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0703330
更新日期:2000-06-01 00:00:00
abstract::We have performed a systematic mutagenesis of three hydrophobic rings (17', 13' and 9') within transmembrane region (TM) 2 of the alpha9alpha10 nicotinic cholinergic receptor (nAChR) to a hydrophilic (threonine) residue and compared the properties of mutant receptors reconstituted in Xenopus laevis oocytes. Phenotypic...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0706224
更新日期:2005-08-01 00:00:00
abstract::1. Endotoxaemia causes an enhanced formation of reactive oxygen species (ROS) which contribute to the multiple organ dysfunction syndrome (MODS) in septic shock. Here we investigate (i) the effects of endotoxin on the expression of two isoforms of superoxide dismutase (SOD), namely Cu/Zn-SOD (cytosol) and Mn-SOD (mito...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702123
更新日期:1998-10-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Nitric oxide (NO) is known to activate NO-sensitive guanylyl cyclase (NO-GC) and to elicit cGMP production. However, NO has also been proposed to induce cGMP-independent effects. It is accepted practice to use specific NO-GC inhibitors, such as ODQ or NS2028, to assess cGMP-dependent NO effects. ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.12275
更新日期:2013-09-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Inflammasomes are multimeric complexes that facilitate caspase-1-mediated processing of the pro-inflammatory cytokines IL-1β and IL-18. Clinical hypertension is associated with renal inflammation and elevated circulating levels of IL-1β and IL-18. Therefore, we investigated whether hypertension i...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13230
更新日期:2016-02-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Parabens are commonly added in pharmaceutical, cosmetic and food products because of their wide antibacterial properties, low toxicity, inertness and chemical stability, although the molecular mechanism of their antibacterial effect is not fully understood. Some agonists of the transient receptor...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0707219
更新日期:2007-05-01 00:00:00
abstract::1. The electrical activity of guinea-pig pelvic ganglion cells following iontophoretically applied cholinergic drugs, alone and during orthodromic nerve stimulation via the hypogastric nerve, has been recorded intracellularly.2. Iontophoretic application of nicotine (Nic) and acetylcholine (ACh) reduced membrane resis...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1971.tb09932.x
更新日期:1971-01-01 00:00:00
abstract:BACKGROUND AND PURPOSE:The dietary trace amines tyramine and beta-phenylethylamine (beta-PEA) can increase blood pressure. However, the mechanisms involved in the vascular effect of trace amines have not been fully established. The purpose of this study was to evaluate whether trace amine-dependent vasoconstriction was...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/bjp.2008.286
更新日期:2008-10-01 00:00:00
abstract:BACKGROUND AND PURPOSE:QT prolongation is commonly used as a surrogate marker for Torsade de Pointes (TdP) risk of non-cardiovascular drugs. However, use of this indirect marker often leads to misinterpretation of the realistic TdP risk, as tested compounds may cause QT prolongation without evoking TdP in humans. A neg...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2011.01795.x
更新日期:2012-05-01 00:00:00
abstract::1. The present study was designed to test the hypothesis that beneficial effects of angiotensin converting enzyme (ACE)inhibitors are independent of a fall in blood pressure in rat experimental heart failure following coronary ligation. 2. The animals were assigned randomly to six groups; sham operation, controls subj...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb13155.x
更新日期:1994-07-01 00:00:00
abstract::1. The effects of fenoverine, an antispasmodic drug, have been studied on the Ca2+ channel currents of isolated cells from rat portal vein and pregnant myometrium by the patch-clamp technique (whole-cell configuration). 2. Fenoverine inhibited both fast and slow Ca2+ channel currents in a concentration-dependent manne...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1991.tb12386.x
更新日期:1991-09-01 00:00:00