Abstract:
BACKGROUND AND PURPOSE:Insulin resistance is often found to be associated with high blood pressure. We propose that in insulin-resistant hypertension, endothelial dysfunction is the consequence of increased activity of vascular MMP-2. As MMP-2 proteolytically cleaves a number of extracellular matrix proteins, we hypothesized that MMP-2 impairs endothelial function by proteolytic degradation of endothelial NOS (eNOS) or its cofactor, heat shock protein 90 (HSP90). EXPERIMENTAL APPROACH:We tested our hypothesis in bovine coronary artery endothelial cells and fructose-fed hypertensive rats (FHR), a model of acquired systolic hypertension and insulin resistance. KEY RESULTS:Treatment of FHRs with the MMP inhibitor doxycycline, preserved endothelial function as well as prevented the development of hypertension, suggesting that MMPs impair endothelial function. Furthermore, incubating endothelial cells in vitro with a recombinant MMP-2 decreased NO production in a dose-dependent manner. Using substrate cleavage assays and immunofluorescence microscopy studies, we found that MMP-2 not only cleaves and degrades HSP90, an eNOS cofactor but also co-localizes with both eNOS and HSP90 in endothelial cells, suggesting that MMPs functionally interact with the eNOS system. Treatment of FHRs with doxycycline attenuated the decrease in eNOS and HSP90 expression but did not improve insulin sensitivity. CONCLUSIONS AND IMPLICATIONS:Our data suggest that increased activity of MMP-2 in FHRs impairs endothelial function and promotes hypertension. Inhibition of MMP-2 could be a potential therapeutic strategy for the management of hypertension.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Nagareddy PR,Rajput PS,Vasudevan H,McClure B,Kumar U,Macleod KM,McNeill JHdoi
10.1111/j.1476-5381.2011.01583.xsubject
Has Abstractpub_date
2012-02-01 00:00:00pages
705-15issue
3eissn
0007-1188issn
1476-5381journal_volume
165pub_type
杂志文章abstract::1. The role of nitric oxide in the coronary circulation under basal conditions and when exposed to various vasodilator stimuli was studied in instrumented, anaesthetized goats, by examining the action of inhibiting endogenous nitric oxide production with NG-nitro-L-arginine methyl ester (L-NAME). 2. In 12 goats, left ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1992.tb14375.x
更新日期:1992-07-01 00:00:00
abstract::1 To evaluate the role of prostaglandin I(2) (PGI(2)) in allergic inflammation, allergic responses in the airway, skin and T cells were studied in mice lacking the receptor for PGI(2) (the prostanoid IP receptor) through gene disruption. 2 Three inhalations of antigen caused an increase in plasma extravasation, leukoc...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0704872
更新日期:2002-10-01 00:00:00
abstract::1. Losigamone is a novel anticonvulsant the mechanism of action of which is not known. This study investigated the effect of losigamone on spontaneous, NMDA- and AMPA-induced depolarizations in the cortical wedge preparation of the DBA/2 mouse (which are susceptible to sound-induced seizures) and on endogenous amino a...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0701539
更新日期:1997-12-01 00:00:00
abstract::Experiments were undertaken to determine whether the site of the hypoglycaemic action of 5-hydroxytryptophan (5-HTP), a direct precursor of 5-hydroxytryptamine (5-HT), was in the central nervous system or in the liver. The fall in blood glucose followed the rapid increase in the amount of 5-HT both in the brain and li...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1985.tb10553.x
更新日期:1985-07-01 00:00:00
abstract:BACKGROUND AND PURPOSE:The human kinome consists of roughly 500 kinases, including 150 that have been proposed as therapeutic targets. Protein kinases regulate an array of signalling pathways that control metabolism, cell cycle progression, cell death, differentiation and survival. It is not surprising, then, that new ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.14062
更新日期:2017-12-01 00:00:00
abstract::1. Histamine (2-4 micrograms kg-1 i.v.) increased airways resistance (Raw) and decreased dynamic lung compliance (Cdyn) in urethane-anaesthetized guinea-pigs. The effects on Raw were almost abolished by atropine (0.1 mg kg-1 i.v.) and reduced by vagal cooling (11-16 degrees C). 2. Histamine-induced changes in Raw and ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1988.tb11555.x
更新日期:1988-06-01 00:00:00
abstract::1 The responses of the smooth muscle of the capsule and blood vessels of the isolated, blood-perfused spleen of the dog to angiotensin, oxytocin and vasopressin have been investigated and compared to the actions of the catecholamines, adrenaline and noradrenaline.2 Increasing doses of each of the three polypeptides ca...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1975.tb06930.x
更新日期:1975-06-01 00:00:00
abstract::1. Studies in rats suggest that PACAP modulates gastric acid secretion through the release of both histamine and somatostatin. 2. We characterized the effects of exogenous PACAP on gastric acid secretion in urethane-anesthetized mice implanted with a gastric cannula and in conscious 2-h pylorus ligated mice, and deter...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705739
更新日期:2004-05-01 00:00:00
abstract::1. The effects of bretylium were investigated on purified Na,K-ATPase from guinea-pig heart and on the Na/K pump in trout erythrocytes, with a view to further identifying the mechanism(s) associated with its antiarrhythmic effects. 2. Na,K-ATPase activity of the thiocyanate-dispersed enzyme was determined by the measu...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1991.tb12523.x
更新日期:1991-12-01 00:00:00
abstract::1. We have studied the transcellular biosynthesis of bioactive leukotrienes (LTs), generated upon blood cell-vascular wall interactions and their functional consequences, in the spontaneously beating, cell-perfused, heart of the rabbit. Rabbit isolated hearts were perfused under recirculating conditions (50 ml) with 5...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1993.tb13943.x
更新日期:1993-11-01 00:00:00
abstract::1. Whole-cell patch-clamp recordings were made from smooth muscle cells isolated from the longitudinal muscle layer of guinea-pig ileum. Carbachol (acting at muscarinic receptors) or histamine (acting at H1 histamine receptors) suppressed Ca2+ channel current. The effect of either agonist had an initial transient comp...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0702112
更新日期:1998-10-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Biased GPCR ligands are able to engage with their target receptor in a manner that preferentially activates distinct downstream signalling and offers potential for next generation therapeutics. However, accurate quantification of ligand bias in vitro is complex, and current best practice is not a...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.13441
更新日期:2016-04-01 00:00:00
abstract::1 The possible involvement of N-methyl-D-aspartate (NMDA)-receptors in epileptiform synaptic activity in the kainic acid (KA) lesioned hippocampus was investigated. In this chronic model of epilepsy there is a loss of both the early and the late components of synaptic inhibition as well as changes in the membrane prop...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1987.tb11280.x
更新日期:1987-08-01 00:00:00
abstract::1. We aimed to determine whether nitric oxide (NO) and/or the endothelium is involved in cholinergic neurogenic vasodilatation in the rat isolated hindquarters. 2. The abdominal aorta was cannulated for perfusion of the rat hindquarters with Krebs bicarbonate solution containing phenylephrine, to induce basal constric...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb13121.x
更新日期:1994-06-01 00:00:00
abstract::1. Thoracic aortae, isolated from rats supplemented with dietary vitamin E after vitamin E deficiency, were analysed for changes in vascular reactivity. 2. Following 4 or 12 months of dietary vitamin E deficiency, endothelium-dependent vasodilator responses to acetylcholine were significantly impaired. However, when a...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb13103.x
更新日期:1994-06-01 00:00:00
abstract::1. Juvenile male rats treated with parachlorophenylalanine showed hair loss round the head and neck extending down the chest and abdomen.2. Treated isolated rats did not have this loss of hair, while untreated animals living in the same cage as treated rats lost their hair. The loss therefore seems to be caused by inc...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1970.tb08518.x
更新日期:1970-02-01 00:00:00
abstract::Cholesterol and oxysterol sulfates are important regulators of lipid metabolism, inflammation, cell apoptosis, and cell survival. Among the sulfate-based lipids, cholesterol sulfate (CS) is the most studied lipid both quantitatively and functionally. Despite the importance, very few studies have analysed and linked th...
journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1111/bph.15227
更新日期:2020-08-06 00:00:00
abstract::1. A synthetic oxytocin analogue, [1-N-carbamoyl-hemicystine-2-O-methyltyrosine]-oxytocin (carbamoyl-methyloxytocin), has been tested as an antagonist to the actions of oxytocin and vasopressin on the uterus, the mammary gland and blood pressure.2. The analogue inhibited the response of the isolated rat uterus to both...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1970.tb09927.x
更新日期:1970-10-01 00:00:00
abstract::Arthritis-associated inflammatory pain represents a serious medical problem worldwide. Current treatments for arthritic pain are not very effective and cause unwanted side effects. Resolvins, including the resolvin D and resolvin E series, are a family of novel endogenous lipid mediators derived from ω-3 polyunsaturat...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.2011.01348.x
更新日期:2011-09-01 00:00:00
abstract::Previous studies have provided evidence for the presence on B cell membrane of adenosine receptors (P1-purinoceptors) of the A1-subtype which inhibit insulin secretion. In this work we have investigated the implication of a guanosine triphosphate (GTP) binding protein (G protein) in the A1 purinoceptor-induced inhibit...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1989.tb11775.x
更新日期:1989-01-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Selective cannabinoid CB2 receptor agonists have demonstrated analgesic activity across multiple preclinical pain models. AM1241 is an indole derivative that exhibits high affinity and selectivity for the CB2 binding site and broad spectrum analgesic activity in rodent models, but is not an antag...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0707568
更新日期:2008-01-01 00:00:00
abstract::1. The effects of balloon injury on the reactivity of ipsilateral and contralateral carotid arteries were compared to those observed in arteries from intact animals (control arteries). 2. Carotid arteries were obtained from Wistar rats 2, 4, 7, 15, 30 or 45 days after injury and mounted in an isolated organ bath. Reac...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1038/sj.bjp.0705732
更新日期:2004-05-01 00:00:00
abstract::1. The use of pharmacological inhibitors of nitric oxide (NO) synthesis to treat patients with septic shock is limited by the observation that they cause a fall in cardiac output in some subjects. The aim of this work was to investigate this fall and to test whether it was reversible by subsequent administration of ni...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb13089.x
更新日期:1994-06-01 00:00:00
abstract:BACKGROUND AND PURPOSE:Immunomodulatory tetracyclines are well-characterized drugs with a pharmacological potential beyond their antibiotic properties. Specifically, minocycline and doxycycline have shown beneficial effects in experimental colitis, although pro-inflammatory actions have also been described in macrophag...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/bph.14494
更新日期:2018-12-01 00:00:00
abstract::Burimamide, an H(2)-receptor blocking agent, has been shown capable of blocking the uptake and metabolism of [(14)C]-histamine, both in the guinea-pig isolated atrium and in murine neoplastic mast cells. This occurs even at concentrations far below the dose range capable of blocking the positive chronotropic effect of...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1973.tb08384.x
更新日期:1973-10-01 00:00:00
abstract::1. The alpha 1-adrenoceptor subtypes mediating contractions of the smooth muscle in human prostatic urethra and branches of internal iliac artery were characterized in isometric contraction experiments. 2. Phenylephrine produced concentration-dependent contractions in both the urethra and artery. These responses were ...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1994.tb17053.x
更新日期:1994-11-01 00:00:00
abstract::1. Mouse islets were used to define the characteristics and study the mechanisms of the stimulation of insulin release by compound AZ-DF 265, 4-[[N-(alpha-phenyl-2-piperidino-benzyl) carbamoyl]methyl] benzoic acid, a substituted benzoic acid with an asymmetric carbon atom. 2. At a non-stimulatory concentration of gluc...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1988.tb11405.x
更新日期:1988-01-01 00:00:00
abstract::The histamine H3 receptor, first described in 1983 as a histamine autoreceptor and later shown to also function as a heteroreceptor that regulates the release of other neurotransmitters, has been the focus of research by numerous laboratories as it represents an attractive drug target for a number of indications inclu...
journal_title:British journal of pharmacology
pub_type: 杂志文章,评审
doi:10.1038/bjp.2008.147
更新日期:2008-07-01 00:00:00
abstract::1 Atrial pacing at progressively increasing frequencies was performed on unanaesthetized dogs through electrodes placed aseptically in the wall of the right atrium and exteriorized in the neck region. 2 Heart rate and two atrioventricular conduction (AVC) parameters, namely the Wenckebach Point (one or two systole blo...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1982.tb09300.x
更新日期:1982-10-01 00:00:00
abstract::1 Prostaglandin and thromboxane release from the term pregnant (Day 22) rat uterus in vitro has been measured by radioimmunoassay and gas chromatography combined with mass spectrometry. 2 Prostacyclin (prostaglandin I2, PGI2) and thromboxane A2 (TXA2) (measured as their metabolites, 6-oxo-PGF1 alpha and TXB2, respecti...
journal_title:British journal of pharmacology
pub_type: 杂志文章
doi:10.1111/j.1476-5381.1981.tb16773.x
更新日期:1981-05-01 00:00:00