Abstract：
:The apelinergic system is an important player in the regulation of both vascular tone and cardiovascular function, making this physiological system an attractive target for drug development for hypertension, heart failure and ischemic heart disease. Indeed, apelin exerts a positive inotropic effect in humans whilst reducing peripheral vascular resistance. In this study, we investigated the signaling pathways through which apelin exerts its hypotensive action. We synthesized a series of apelin-13 analogs whereby the C-terminal Phe13 residue was replaced by natural or unnatural amino acids. In HEK293 cells expressing APJ, we evaluated the relative efficacy of these compounds to activate Gαi1 and GαoA G-proteins, recruit β-arrestins 1 and 2 (βarrs), and inhibit cAMP production. Calculating the transduction ratio for each pathway allowed us to identify several analogs with distinct signaling profiles. Furthermore, we found that these analogs delivered i.v. to Sprague-Dawley rats exerted a wide range of hypotensive responses. Indeed, two compounds lost their ability to lower blood pressure, while other analogs significantly reduced blood pressure as apelin-13. Interestingly, analogs that did not lower blood pressure were less effective at recruiting βarrs. Finally, using Spearman correlations, we established that the hypotensive response was significantly correlated with βarr recruitment but not with G protein-dependent signaling. In conclusion, our results demonstrated that the βarr recruitment potency is involved in the hypotensive efficacy of activated APJ.
journal_name
Pharmacol Resjournal_title
Pharmacological researchauthors
Besserer-Offroy É,Bérubé P,Côté J,Murza A,Longpré JM,Dumaine R,Lesur O,Auger-Messier M,Leduc R,Marsault É,Sarret Pdoi
10.1016/j.phrs.2018.02.032subject
Has Abstractpub_date
2018-05-01 00:00:00pages
7-16eissn
1043-6618issn
1096-1186pii
S1043-6618(17)31380-4journal_volume
131pub_type
杂志文章abstract：:Aminoglycoside antibiotics are employed clinically because of their potent bactericidal activities, less bacterial resistance, post-antibiotic effects and low cost. However, drugs belong to this class are well-known to cause nephrotoxicity, which limits their frequent clinical exploitation. Gentamicin, a commonly used...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2010.04.004
更新日期：2010-09-01 00:00:00
abstract：BACKGROUND:Many flavonoids have various beneficial actions like anti-inflammatory, anti-carcinogenic properties and many other clinical conditions. Astilbin is one such flavanoid compound having many physiological as well as pharmacological actions. PURPOSE:To summarize the important findings from the research conduct...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2020.104894
更新日期：2020-08-01 00:00:00
abstract：:A novel alkynylthiophene series of cannabinoid CB1 receptor antagonists has been described to exhibit distinct intrinsic activities with minimal substructure modifications. The three representatives, BPR0432, BPR0568 and BPR0569, functioning as a neutral antagonist, an inverse agonist and a partial agonist, respective...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2010.06.001
更新日期：2010-10-01 00:00:00
abstract：:The insulinotropic action of the meglitinide analogues KAD-1229, A-4166 and repaglinide was examined in rat pancreatic islets deprived of exogenous nutrient or incubated in the presence of nutrient secretagogues such as D-glucose and the methyl esters of pyruvic acid, succinic acid and glutamic acid. The meglitinide a...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1006/phrs.1996.0026
更新日期：1996-03-01 00:00:00
abstract：:DB-67 and its lactone homolog DB-91 are derivatives of topoisomerase I inhibitor camptothecin (CPT) with silyl moiety, which may exhibit a slower inactivation process by changed kinetics of protein binding and/or hydrolysis of its lactone ring and result in increased antitumor activity and decreased toxicity. Pharmaco...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2009.07.005
更新日期：2010-02-01 00:00:00
abstract：:Treatment of MC3T3E-1 osteoblast cultures with combined interferon- gamma(IFN- gamma), lipopolysaccharide (LPS) and tumor necrosis factor- alpha(TNF- alpha) induces expressions of inducible nitric oxide synthase (iNOS) and interleukin-6 (IL-6), resulting in sustained releases of large amounts of nitric oxide and IL-6....
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1006/phrs.2000.0778
更新日期：2001-03-01 00:00:00
abstract：:Cancer cell mutations can be identified by genomic and transcriptomic techniques. However, they are not sufficient to understand the full complexity of cancer heterogeneity. Analyses of proteins expressed in cancers and their modification profiles show how these mutations could be translated at the functional level. P...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2020.105091
更新日期：2020-10-01 00:00:00
abstract：:Exogenous hydrogen sulfide (H2S) protects against myocardial ischemia/reperfusion injury but the mechanism of action is unclear. The present study investigated the effect of GYY4137, a slow-releasing H2S donor, on myocardial infarction given specifically at reperfusion and the signalling pathway involved. Thiobutabarb...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2016.06.028
更新日期：2016-09-01 00:00:00
abstract：:Lipid peroxidation increased both in the liver homogenates and in the hepatic mitochondrial fraction of bile duct ligated (BDL)-rats. Although mitochondrial superoxide dismutase (SOD) activity did not change in the liver, glutathione (GSH) levels and glutathione peroxidase (GSH-Px) activity decreased in hepatic mitoch...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1006/phrs.1997.0225
更新日期：1997-09-01 00:00:00
abstract：:Epidemiological, clinical and animal studies revealed that sex differences exist in the manifestation and outcome of cardiovascular disease (CVD). The underlying molecular mechanisms implicated in these sex differences are not fully understood. The reasons for sex differences in CVD are definitely multifactorial, but ...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2017.01.019
更新日期：2017-05-01 00:00:00
abstract：AIM:Acute myocardial infarction and subsequent post-infarction heart failure are among the leading causes of mortality worldwide. The endocannabinoid system has emerged as an important modulator of cardiovascular disease, however the role of endocannabinoid metabolic enzymes in heart failure is still elusive. Herein, w...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2019.104578
更新日期：2020-01-01 00:00:00
abstract：:In recent years, natural products have reemerged as biotherapeutic options, with several dietary carotenoids, viz. astaxanthin, fucoxanthin, siphonaxanthin, β-cryptoxanthin, α-carotene, β-carotene, and lycopene, developing as potential candidates for chemoprevention and chemotherapeutics of breast, colorectal, lung, a...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2020.104830
更新日期：2020-07-01 00:00:00
abstract：:Hydrogen sulfide (H2S) is an endogenously produced signaling molecule synthesized by cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). Given that H2S exerts significant effects on bioenergetics and metabolism, the goal of the current study was to determine th...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2017.09.023
更新日期：2018-02-01 00:00:00
abstract：BACKGROUND AND PURPOSE:Chronic obstructive pulmonary disease (COPD) is characterized by progressive alveolar damage and generally irreversible airflow limitation. Nuclear factor-κB (NF-κB) plays a critical role in COPD pathogenesis. Receptor-interacting protein 2 (Rip2), a 60 kDa adaptor protein, is a positive regulato...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2018.10.016
更新日期：2019-01-01 00:00:00
abstract：:The potential for modulating gene expression by the use of antisense oligonucleotides has become increasingly interesting in recent years. Antisense oligonucleotides are complementary nucleic acid fragments that hybridize to target sequences within RNA to form a DNA-RNA duplex, resulting in the block of translation of...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1006/phrs.1997.0227
更新日期：1997-09-01 00:00:00
abstract：:We have shown previously that the antitumor drug, hydroxyurea (HU) is able to induce dose-dependent increases in plasma corticosterone levels in the rat. The drug was administered early in the morning, when the levels of circulating glucocorticoids are low in this species. Normally, in humans under physiological condi...
journal_title：Pharmacological research
pub_type： 临床试验,杂志文章
doi：10.1006/phrs.2000.0709
更新日期：2000-10-01 00:00:00
abstract：:Receptor concentrations for adrenaline, steroid hormones, PGF2alpha, LH and FSH were measured in the hypophysis and ovary of dairy cows with ovarian cysts and the results were compared with those of healthy animals. Significant modifications were found in all receptor concentrations, either between follicular and lute...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1006/phrs.1998.0442
更新日期：1999-04-01 00:00:00
abstract：:Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used as analgesics. Although the results of clinical studies indicate considerable disparity in the analgesic efficacy of NSAIDs, the pre-clinical models generally used for the study of nociception do not allow a clear distinction to be made between the ana...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1006/phrs.2001.0921
更新日期：2002-02-01 00:00:00
abstract：:Vanillin is one of the most widely used flavor compounds in food and personal products. It has been reported that vanillin is able to inhibit mutagenesis induced by chemical and physical mutagens, and to suppress the invasion and migration of cancer cells. Herein we used the oligonucleotide microarray approach to stud...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2007.09.009
更新日期：2007-12-01 00:00:00
abstract：:Tachykinins are important in the development of pulmonary inflammation in mice but the tachykinin receptor subtype mediating this response has not been defined. To elucidate the role of tachykinin NK3-receptors on allergen-induced pulmonary inflammation, studies were performed on ovalbumin (OVA) sensitized and challen...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2004.07.002
更新日期：2004-12-01 00:00:00
abstract：:In the present study, we have investigated the effects of centrally administered ginsenoside Rc and Rg1 on the modulation of the NMDA receptor and GABA(A)receptor binding in rat brain. The NMDA receptor binding was analysed by quantitative autoradiography using [(3)H]MK-801 binding, and the GABA(A)receptor bindings we...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1006/phrs.2001.0809
更新日期：2001-05-01 00:00:00
abstract：:Endocannabinoids are part of a bioactive lipid signaling system, not only in the central nervous system but also in various peripheral organs. Accumulating evidence implicates dysregulation of the endocannabinoid system (ECS) in the pathogenesis of various cardiovascular diseases, including hypertension, atheroscleros...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2009.04.003
更新日期：2009-08-01 00:00:00
abstract：:The pharmacokinetics of single intravenous and intramuscular administrations and milk antimicrobial equivalent activity of enrofloxacin at a dose of 5 mg per kilogram body weight were studied in clinically healthy lactating goats which were either not treated or had received 7.5 mg per kilogram body weight of albendaz...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/s1043-6618(03)00179-8
更新日期：2003-10-01 00:00:00
abstract：:As a function of the structural modification of the steroid nucleus, the inhibitory interaction of 11 progesterone derivatives with human Na/K-ATPase (Na+/K(+)-transporting ATPase, EC 3.6.1.37), through C3-O-rhamnosylation, is either much decreased or weakly up to strongly increased, so that the rhamnosyl residue cont...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/s1043-6618(05)80102-1
更新日期：1991-01-01 00:00:00
abstract：:The concept of compartment evolved in the contexts of radioactivity, physiology, pharmacology and tracer kinetics. Recently compartmental models have been compared with 'physiological models', even though in most cases the same, or stricter hypotheses, are necessary for the validity of these latter models. This paper ...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1006/phrs.2001.0873
更新日期：2001-10-01 00:00:00
abstract：:The clear importance of mutated KRAS as a therapeutic target has driven the investigation of multiple approaches to inhibit oncogenic KRAS signaling at different molecular levels. However, no KRAS-targeted therapy has reached the clinic to date, which underlies the intrinsic difficulty in developing effective, direct ...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2017.01.006
更新日期：2017-03-01 00:00:00
abstract：:This brief overview is focused on the inherent duality of immune responses: on the one hand they may induce inflammation and precipitate injury, on the other, a number of examples of participation in organ and tissue repair are growing. These processes will be reviewed from the nephrological stand-point. Specifically,...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1016/j.phrs.2008.05.011
更新日期：2008-08-01 00:00:00
abstract：:In the present study the effect of ketamine on the contractions caused by propoxur and phoxim on the isolated guinea pig ileum was investigated. Ketamine was found able to inhibit in a concentration-dependent manner the contractile responses of the ileum to propoxur and phoxim, while it did not significantly modify th...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/1043-6618(94)80003-0
更新日期：1994-08-01 00:00:00
abstract：:Nebivolol is a new selective beta 1-adrenergic blocking agent, that possesses a peculiar pharmacodynamic profile and an original chemical structure, by which it differs from traditional beta 1-blockers. Nebivolol is a racemic mixture of two enantiomers in equal ratios. It is endowed with a highly selective beta 1-bloc...
journal_title：Pharmacological research
pub_type： 杂志文章,评审
doi：10.1006/phrs.1998.0387
更新日期：1998-12-01 00:00:00
abstract：:Neuroinflammation plays an important role in the progression of various neurodegenerative diseases. In this study, we investigated the anti-inflammatory effects of lonchocarpine, a natural compound isolated from Abrus precatorius, under in vitro and in vivo neuroinflammatory conditions induced by challenge with lipopo...
journal_title：Pharmacological research
pub_type： 杂志文章
doi：10.1016/j.phrs.2017.02.027
更新日期：2017-05-01 00:00:00
