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1.
Pharmacol Rev ; 72(4): 910-968, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32962984

RESUMO

Prostaglandins are derived from arachidonic acid metabolism through cyclooxygenase activities. Among prostaglandins (PGs), prostacyclin (PGI2) and PGE2 are strongly involved in the regulation of homeostasis and main physiologic functions. In addition, the synthesis of these two prostaglandins is significantly increased during inflammation. PGI2 and PGE2 exert their biologic actions by binding to their respective receptors, namely prostacyclin receptor (IP) and prostaglandin E2 receptor (EP) 1-4, which belong to the family of G-protein-coupled receptors. IP and EP1-4 receptors are widely distributed in the body and thus play various physiologic and pathophysiologic roles. In this review, we discuss the recent advances in studies using pharmacological approaches, genetically modified animals, and genome-wide association studies regarding the roles of IP and EP1-4 receptors in the immune, cardiovascular, nervous, gastrointestinal, respiratory, genitourinary, and musculoskeletal systems. In particular, we highlight similarities and differences between human and rodents in terms of the specific roles of IP and EP1-4 receptors and their downstream signaling pathways, functions, and activities for each biologic system. We also highlight the potential novel therapeutic benefit of targeting IP and EP1-4 receptors in several diseases based on the scientific advances, animal models, and human studies. SIGNIFICANCE STATEMENT: In this review, we present an update of the pathophysiologic role of the prostacyclin receptor, prostaglandin E2 receptor (EP) 1, EP2, EP3, and EP4 receptors when activated by the two main prostaglandins, namely prostacyclin and prostaglandin E2, produced during inflammatory conditions in human and rodents. In addition, this comparison of the published results in each tissue and/or pathology should facilitate the choice of the most appropriate model for the future studies.


Assuntos
Receptores de Prostaglandina E/metabolismo , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Dinoprostona/imunologia , Dinoprostona/metabolismo , Epoprostenol/imunologia , Epoprostenol/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Camundongos , Polimorfismo de Nucleotídeo Único , Multimerização Proteica , Ratos , Receptores de Prostaglandina E/química , Receptores de Prostaglandina E/genética , Receptores de Prostaglandina E/imunologia , Especificidade da Espécie
2.
Prostaglandins Other Lipid Mediat ; 146: 106388, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31672620

RESUMO

Pulmonary hypertension (PH) is characterized by an elevation of mean pulmonary artery pressure and it is classified into five groups. Among these groups, PH Group-III is defined as PH due to lung disease or hypoxia. Prostacyclin (PGI2) analogues (iloprost, treprostinil) and endothelin-1 (ET-1) receptor antagonists (ERA) (used alone or in combination) are therapies used for treating PH. The mechanisms underlying the positive/negative effects of combination treatment are not well documented, and in this study, we tested the hypothesis that the combination of a PGI2 analogue (iloprost, treprostinil) and an ERA may be more effective than either drug alone to treat vasculopathies observed in PH Group-III patients. Using Western blotting, ETA and ETB receptor expression were determined in human pulmonary artery (HPA) preparations derived from control and PH Group-III patients, and the physiologic impact of altered expression ratios was assessed by measuring ET-1 induced contraction of ex vivo HPA and human pulmonary veins (HPV) in an isolated organ bath system. In addition, the effects of single agent or combination treatments with a PGI2 analogue and an ERA on ET-1 release and HPA smooth muscle cells (hPASMCs) proliferation were determined by ELISA and MTT techniques, respectively. Our results indicate that the increased ETA/ETB receptor expression ratio in HPA derived from PH Group-III patients is primarily governed by a greatly depressed ETB receptor expression. However, contractions induced by ET-1 are not impacted in HPA and HPV derived from PH Group-III patients as compared to controls. Also, we found that the combination of an ETA receptor antagonist (BQ123) with iloprost provides greater inhibition of hPASMCs proliferation (-48±14% control; -32±06% PH) than either agent alone. Of note, while the ETB receptor antagonist (BQ788) increases ET-1 production from PH Group-III patients' preparations (HPA, parenchyma), even under these more proliferative conditions, iloprost and treprostinil are still effective to inhibit hPASMCs proliferation (-22/-24%). Our findings may provide new insights for the treatment of PH Group-III by combining a PGI2 analogue and a selective ETA receptor antagonist.


Assuntos
Endotelina-1/metabolismo , Epoprostenol/metabolismo , Hipertensão Pulmonar/metabolismo , Músculo Liso Vascular/metabolismo , Transdução de Sinais , Idoso , Endotelina-1/farmacologia , Epoprostenol/farmacologia , Feminino , Humanos , Hipertensão Pulmonar/patologia , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/patologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Veias Pulmonares/metabolismo , Veias Pulmonares/patologia , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo
4.
Int J Mol Sci ; 19(8)2018 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-30103548

RESUMO

Prostacyclins are extensively used to treat pulmonary arterial hypertension (PAH), a life-threatening disease involving the progressive thickening of small pulmonary arteries. Although these agents are considered to act therapeutically via the prostanoid IP receptor, treprostinil is the only prostacyclin mimetic that potently binds to the prostanoid EP2 receptor, the role of which is unknown in PAH. We hypothesised that EP2 receptors contribute to the anti-proliferative effects of treprostinil in human pulmonary arterial smooth muscle cells (PASMCs), contrasting with selexipag, a non-prostanoid selective IP agonist. Human PASMCs from PAH patients were used to assess prostanoid receptor expression, cell proliferation, and cyclic adenosine monophosphate (cAMP) levels following the addition of agonists, antagonists or EP2 receptor small interfering RNAs (siRNAs). Immunohistochemical staining was performed in lung sections from control and PAH patients. We demonstrate using selective IP (RO1138452) and EP2 (PF-04418948) antagonists that the anti-proliferative actions of treprostinil depend largely on EP2 receptors rather than IP receptors, unlike MRE-269 (selexipag-active metabolite). Likewise, EP2 receptor knockdown selectively reduced the functional responses to treprostinil but not MRE-269. Furthermore, EP2 receptor levels were enhanced in human PASMCs and in lung sections from PAH patients compared to controls. Thus, EP2 receptors represent a novel therapeutic target for treprostinil, highlighting key pharmacological differences between prostacyclin mimetics used in PAH.


Assuntos
Proliferação de Células/efeitos dos fármacos , Epoprostenol/análogos & derivados , Hipertensão Pulmonar/tratamento farmacológico , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Receptores de Prostaglandina E Subtipo EP2/biossíntese , Regulação para Cima/efeitos dos fármacos , Adolescente , Adulto , Criança , Epoprostenol/farmacologia , Feminino , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Masculino , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Receptores de Prostaglandina E Subtipo EP2/antagonistas & inibidores , Sistemas do Segundo Mensageiro/efeitos dos fármacos
5.
J Cardiovasc Pharmacol ; 69(1): 1-12, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27652910

RESUMO

BACKGROUND: Prostacyclin mimetics are vasodilatory agents used in the treatment of pulmonary arterial hypertension. The direct effects of prostanoids on right-ventricular (RV) function are unknown. We aimed to investigate the direct effects of prostacyclin mimetics on RV function in hearts with and without RV hypertrophy and failure. METHODS: Wistar rats were subjected to pulmonary trunk banding to induce compensated RV hypertrophy (n = 32) or manifest RV failure (n = 32). Rats without banding served as healthy controls (n = 30). The hearts were excised and perfused in a Langendorff system and subjected to iloprost, treprostinil, epoprostenol, or MRE-269 in increasing concentrations. The effect on RV function was evaluated using a balloon-tipped catheter inserted into the right ventricle. RESULTS: In control hearts, iloprost, treprostinil, and MRE-269 improved RV function. The effect was, however, absent in hearts with RV hypertrophy and failure. Treprostinil and MRE-269 even impaired RV function in hearts with manifest RV failure. CONCLUSIONS: Iloprost, treprostinil, and MRE-269 improved RV function in the healthy rat heart. RV hypertrophy abolished the positive inotropic effect, and in the failing right ventricle, MRE-269 and treprostinil impaired RV function. This may be related to changes in prostanoid receptor expression and reduced coronary flow reserve in the hypertrophic and failing right ventricle.


Assuntos
Cardiotônicos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Hipertrofia Ventricular Direita/tratamento farmacológico , Prostaglandinas I/uso terapêutico , Função Ventricular Direita/efeitos dos fármacos , Animais , Cardiotônicos/farmacologia , Insuficiência Cardíaca/fisiopatologia , Hipertrofia Ventricular Direita/fisiopatologia , Masculino , Técnicas de Cultura de Órgãos , Prostaglandinas I/farmacologia , Ratos , Ratos Wistar , Resultado do Tratamento , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico , Função Ventricular Direita/fisiologia
6.
Circulation ; 130(6): 496-507, 2014 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-24899690

RESUMO

BACKGROUND: Pulmonary hypertension (PH) is a life-threatening disorder characterized by increased pulmonary artery pressure, remodeling of the pulmonary vasculature, and right ventricular failure. Loss of endothelium-derived nitric oxide (NO) and prostacyclin contributes to PH pathogenesis, and current therapies are targeted to restore these pathways. Phosphodiesterases (PDEs) are a family of enzymes that break down cGMP and cAMP, which underpin the bioactivity of NO and prostacyclin. PDE5 inhibitors (eg, sildenafil) are licensed for PH, but a role for PDE2 in lung physiology and disease has yet to be established. Herein, we investigated whether PDE2 inhibition modulates pulmonary cyclic nucleotide signaling and ameliorates experimental PH. METHODS AND RESULTS: The selective PDE2 inhibitor BAY 60-7550 augmented atrial natriuretic peptide- and treprostinil-evoked pulmonary vascular relaxation in isolated arteries from chronically hypoxic rats. BAY 60-7550 prevented the onset of both hypoxia- and bleomycin-induced PH and produced a significantly greater reduction in disease severity when given in combination with a neutral endopeptidase inhibitor (enhances endogenous natriuretic peptides), trepostinil, inorganic nitrate (NO donor), or a PDE5 inhibitor. Proliferation of pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension was reduced by BAY 60-7550, an effect further enhanced in the presence of atrial natriuretic peptide, NO, and treprostinil. CONCLUSIONS: PDE2 inhibition elicits pulmonary dilation, prevents pulmonary vascular remodeling, and reduces the right ventricular hypertrophy characteristic of PH. This favorable pharmacodynamic profile is dependent on natriuretic peptide bioactivity and is additive with prostacyclin analogues, PDE5 inhibitor, and NO. PDE2 inhibition represents a viable, orally active therapy for PH.


Assuntos
AMP Cíclico/fisiologia , GMP Cíclico/fisiologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/antagonistas & inibidores , Hipertensão Pulmonar/enzimologia , Inibidores de Fosfodiesterase/uso terapêutico , Animais , Células Cultivadas , Nucleotídeo Cíclico Fosfodiesterase do Tipo 2/fisiologia , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Inibidores de Fosfodiesterase/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Triazinas/farmacologia , Triazinas/uso terapêutico
7.
Prostaglandins Other Lipid Mediat ; 120: 56-71, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25917921

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive disease of distal pulmonary arteries in which patients suffer from elevated pulmonary arterial pressure, extensive vascular remodelling and right ventricular failure. To date prostacyclin (PGI2) therapy remains the most efficacious treatment for PAH and is the only approved monotherapy to have a positive impact on long-term survival. A key thing to note is that improvement exceeds that predicted from vasodilator testing strongly suggesting that additional mechanisms contribute to the therapeutic benefit of prostacyclins in PAH. Given these agents have potent antiproliferative, anti-inflammatory and endothelial regenerating properties suggests therapeutic benefit might result from a slowing, stabilization or even some reversal of vascular remodelling in vivo. This review discusses evidence that the pharmacology of each prostacyclin (IP) receptor agonist so far developed is distinct, with non-IP receptor targets clearly contributing to the therapeutic and side effect profile of PGI2 (EP3), iloprost (EP1), treprostinil (EP2, DP1) along with a family of nuclear receptors known as peroxisome proliferator-activated receptors (PPARs), to which PGI2 and some analogues directly bind. These targets are functionally expressed to varying degrees in arteries, veins, platelets, fibroblasts and inflammatory cells and are likely to be involved in the biological actions of prostacylins. Recently, a highly selective IP agonist, selexipag has been developed for PAH. This agent should prove useful in distinguishing IP from other prostanoid receptors or PPAR binding effects in human tissue. It remains to be determined whether selectivity for the IP receptor gives rise to a superior or inferior clinical benefit in PAH.


Assuntos
Membrana Celular/efeitos dos fármacos , Epoprostenol/análogos & derivados , Epoprostenol/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Membrana Celular/metabolismo , Estabilidade de Medicamentos , Epoprostenol/uso terapêutico , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Remodelação Vascular/efeitos dos fármacos
8.
Prostaglandins Other Lipid Mediat ; 121(Pt A): 46-52, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26362969

RESUMO

Prostacyclin (PGI2) mimetics (iloprost, treprostinil) are potent vasodilators (primarily via IP-receptor activation) and major therapeutic interventions for pulmonary hypertension (PH). Increased plasma levels of endothelin (ET-1), thromboxane (TxA2) and catecholamines have been demonstrated from patients with PH. In this study, we aimed to compare relaxant effects of iloprost and treprostinil on human (HPA) and rat pulmonary arteries precontracted with either ET-1, thromboxane (U46619) or an α-adrenergic receptor agonist (Norepinephrine, NE or phenylephrine, PE). Treprostinil and iloprost induced vasorelaxation of HPA precontracted with NE, ET-1 or U46619. We obtained greater relaxation response and sensitivity to treprostinil when ET-1 or U46619 were used to induce the precontraction in comparison to NE. In contrast, iloprost showed less relaxation response and sensitivity in HPA precontracted with U46619 versus NE. In the rat, treprostinil and iloprost induced vasorelaxation of pulmonary arteries precontracted with PE and U46619 but minimally with ET-1. However, in rat pulmonary arteries, PE-induced precontractions were comparatively low amplitude. Our study showed that the ex vivo relaxation or sensitivity of pulmonary arteries induced by PGI2 mimetics is highly dependent on both the pre-contraction agent and the species. To best extrapolate to effects on human tissue, our results suggest that U46619 is the appropriate contractile agent for assessing the relaxant effect of PGI2 mimetics in rat pulmonary arteries. Finally we suggest that in PH patients with high plasma concentration of TxA2, treprostinil (not iloprost) would be a preferential treatment. On the other hand, if the ET-1 plasmatic level is high, either treprostinil or iloprost will be effective.


Assuntos
Epoprostenol/análogos & derivados , Iloprosta/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Epoprostenol/farmacologia , Feminino , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
9.
Gen Physiol Biophys ; 32(4): 527-34, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23940092

RESUMO

The current study examined the responsiveness of blood vessels from diabetic rats to K+ channel openers and explored whether ROS might be involved in any changes. Responses were measured in aortic rings isolated from four weeks streptozotocin (65 mg/kg)-induced diabetic rats. Relaxation to levcromakalim (ATP-sensitive potassium channel KATP opener, 10(-9)-10(-5) mol/l) and (+/-)-naringenin (large conductance calcium-activated channel BKCa opener, 10(-8)-10(-3) mol/l) were recorded in phenylephrine (1 µmol/l) pre-contracted segments in the absence and presence of superoxide dismutase (SOD, 100 µmol/l) and apocynin (an antioxidant and inhibitor of NADPH oxidase, 100 µmol/l). Contractions to phenylephrine (10(-9)-10(-5) mol/l) and relaxation to acetylcholine (ACh, 10(-9)-10(-5) mol/l) were also recorded. Relaxation curves for levcromakalim, naringenin and ACh for the diabetic group were shifted to the right (p < 0.05) compared with the control. Contractions to phenylephrine were enhanced in the diabetic group (p < 0.01). SOD restored the ACh response but not those of K+ channel openers. On the other hand, apocynin restored the relaxation to naringenin but had no effect on both levcromakalim and ACh responses. The results suggest that both KATP and BKCa activities are attenuated in diabetes mellitus and that ROS appears to contribute only to the change in BKCa function.


Assuntos
Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/fisiopatologia , Diabetes Mellitus/fisiopatologia , Ativação do Canal Iônico/efeitos dos fármacos , Canais de Potássio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Acetofenonas/farmacologia , Acetilcolina/farmacologia , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Cromakalim/farmacologia , Diabetes Mellitus/metabolismo , Flavanonas/farmacologia , Sequestradores de Radicais Livres/farmacologia , Masculino , Fenilefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/farmacologia , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
10.
Nutrients ; 16(1)2023 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-38201945

RESUMO

Consumption of a high-carbohydrate diet has a critical role in the induction of weight gain and obesity-related pathologies. This study tested the hypothesis that a carbohydrate-rich diet induces weight gain, ectopic fat deposition, associated metabolic risks and development of non-alcoholic fatty liver disease (NAFLD), which are partially reversible following carbohydrate reduction. Sprague Dawley (SD) rats were fed a carbohydrate-enriched cafeteria diet (CAF) or normal chow (NC) ad libitum for 16-18 weeks. In the reversible group (REV), the CAF was replaced with NC for a further 3 weeks (18-21 weeks). Animals fed the CAF diet showed significantly increased body weight compared to those fed NC, accompanied by abnormal changes in their systemic insulin and triglycerides, elevation of hepatic triglyceride and hepatic steatosis. In the REV group, when the CAF diet was stopped, a modest, non-significant weight loss was associated with improvement in systemic insulin and appearance of the liver, with lower gross fatty deposits and hepatic triglyceride. In conclusion, a carbohydrate-enriched diet led to many features of metabolic syndrome, including hyperinsulinemia, while a dietary reduction in this macronutrient, even for a short period, was able to restore normoinsulinemia, and reversed some of the obesity-related hepatic abnormalities, without significant weight loss.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Ratos , Animais , Hepatopatia Gordurosa não Alcoólica/etiologia , Ratos Sprague-Dawley , Dieta/efeitos adversos , Obesidade/etiologia , Aumento de Peso , Insulina , Triglicerídeos , Redução de Peso , Carboidratos
11.
Vascul Pharmacol ; 151: 107194, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37442283

RESUMO

Pulmonary arterial hypertension (PAH) is a rare cardiopulmonary disorder, involving the remodelling of the small pulmonary arteries. Underlying this remodelling is the hyper-proliferation of pulmonary arterial smooth muscle cells within the medial layers of these arteries and their encroachment on the lumen. Previous studies have demonstrated an association between excessive mitochondrial fragmentation, a consequence of increased expression and post-translational activation of the mitochondrial fission protein dynamin-related protein 1 (DRP1), and pathological proliferation in PASMCs derived from PAH patients. However, the impact of prostacyclin mimetics, widely used in the treatment of PAH, on this pathological mitochondrial fragmentation remains unexplored. We hypothesise that these agents, which are known to attenuate the proliferative phenotype of PAH PASMCs, do so in part by inhibiting mitochondrial fragmentation. In this study, we confirmed the previously reported increase in DRP1-mediated mitochondrial hyper-fragmentation in PAH PASMCs. We then showed that the prostacyclin mimetic treprostinil signals via either the Gs-coupled IP or EP2 receptor to inhibit mitochondrial fragmentation and the associated hyper-proliferation in a manner analogous to the DRP1 inhibitor Mdivi-1. We also showed that treprostinil recruits either the IP or EP2 receptor to activate PKA and induce the phosphorylation of DRP1 at the inhibitory residue S637 and inhibit that at the stimulatory residue S616, both of which are suggestive of reduced DRP1 fission activity. Like treprostinil, MRE-269, an IP receptor agonist, and butaprost, an EP2 receptor agonist, attenuated DRP1-mediated mitochondrial fragmentation through PKA. We conclude that prostacyclin mimetics produce their anti-proliferative effects on PAH PASMCs in part by inhibiting DRP1-mediated mitochondrial fragmentation.


Assuntos
Hipertensão Arterial Pulmonar , Humanos , Hipertensão Arterial Pulmonar/metabolismo , Proliferação de Células , Dinaminas/metabolismo , Dinaminas/farmacologia , Artéria Pulmonar/metabolismo , Dinâmica Mitocondrial
12.
Br J Pharmacol ; 180 Suppl 2: S23-S144, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-38123151

RESUMO

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.16177. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.


Assuntos
Bases de Dados de Produtos Farmacêuticos , Receptores Acoplados a Proteínas G , Humanos , Ligantes , Canais Iônicos/química , Receptores Citoplasmáticos e Nucleares
13.
Crit Care Med ; 40(4): 1261-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22425821

RESUMO

OBJECTIVE: Excessive opening of the adenosine triphosphate-sensitive potassium channel in vascular smooth muscle is implicated in the vasodilation and vascular hyporeactivity underlying septic shock. Therapeutic channel inhibition using sulfonylurea agents has proved disappointing, although agents acting on its pore appear more promising. We thus investigated the hemodynamic effects of adenosine triphosphate-sensitive potassium channel pore inhibition in awake, fluid-resuscitated septic rats, and the extent to which these responses are modulated by the high sympathetic tone present in sepsis. Temporal changes in ex-vivo channel activity and subunit gene expression were also investigated. DESIGN: In vivo and ex vivo animal study. SETTING: University research laboratory. SUBJECTS: Male adult Wistar rats. INTERVENTIONS AND MEASUREMENTS: Fecal peritonitis was induced in conscious, fluid-resuscitated rats. Pressor responses to norepinephrine and PNU-37883A (a vascular adenosine triphosphate-sensitive potassium channel inhibitor acting on the Kir6.1 pore-forming subunit) were measured at 6 or 24 hrs, in the absence or presence of the autonomic ganglion blocker, pentolinium. The aorta and mesenteric artery were examined ex vivo for rubidium efflux as a marker of adenosine triphosphate-sensitive potassium channel activity, and for adenosine triphosphate-sensitive potassium channel subunit gene expression using quantitative reverse transcription-polymerase chain reaction. MAIN RESULTS: A total of 120 rats (50 sham-operated controls, 70 septic) were included. Septic rats became hypotensive after 12 hrs, with a 24-hr mortality of 51.7% (0% in controls). At 6 hrs, there was an attenuated pressor response to norepinephrine (p < .01) despite blood pressure being elevated (p < .01). PNU-37883A had no pressor effect, except in the presence of pentolinium (p < .01). Kir6.1 subunit mRNA increased significantly in the mesenteric artery while rubidium efflux was increased in both the aorta and mesenteric artery at 24 hrs. CONCLUSIONS: Despite evidence of increased adenosine triphosphate-sensitive potassium channel activity in sepsis, it appears to be inhibited in vivo by high sympathetic tone. This may explain, at least in part, the reduced efficacy of adenosine triphosphate-sensitive potassium channel blockers in human septic shock.


Assuntos
Vasos Sanguíneos/fisiopatologia , Sepse/fisiopatologia , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Adamantano/análogos & derivados , Adamantano/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/metabolismo , Bloqueadores Ganglionares/farmacologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiopatologia , Morfolinas/farmacologia , Norepinefrina/farmacologia , Tartarato de Pentolínio/farmacologia , Ratos , Ratos Wistar , Sepse/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismo , ATPase Trocadora de Sódio-Potássio/fisiologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia
14.
Clin Epigenetics ; 14(1): 98, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35915507

RESUMO

Histone 3 lysine 27 (H3K27) demethylation constitutes an important epigenetic mechanism of gene activation. It is mediated by the Jumonji C domain-containing lysine demethylases KDM6A and KDM6B, both of which have been implicated in a wide myriad of diseases, including blood and solid tumours, autoimmune and inflammatory disorders, and infectious diseases. Here, we review and summarise the pre-clinical evidence, both in vitro and in vivo, in support of the therapeutic potential of inhibiting H3K27-targeting demethylases, with a focus on the small-molecule inhibitor GSK-J4. In malignancies, KDM6A/B inhibition possesses the ability to inhibit proliferation, induce apoptosis, promote differentiation, and heighten sensitivity to currently employed chemotherapeutics. KDM6A/B inhibition also comprises a potent anti-inflammatory approach in inflammatory and autoimmune disorders associated with inappropriately exuberant inflammatory and autoimmune responses, restoring immunological homeostasis to inflamed tissues. With respect to infectious diseases, KDM6A/B inhibition can suppress the growth of infectious pathogens and attenuate the immunopathology precipitated by these pathogens. The pre-clinical in vitro and in vivo data, summarised in this review, suggest that inhibiting H3K27 demethylases holds immense therapeutic potential in many diseases.


Assuntos
Histonas , Neoplasias , Metilação de DNA , Epigênese Genética , Histona Desmetilases/genética , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Lisina/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética
15.
Am J Respir Crit Care Med ; 182(9): 1161-70, 2010 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-20622039

RESUMO

RATIONALE: Prostacyclin analogs, used to treat idiopathic pulmonary arterial hypertension (IPAH), are assumed to work through prostacyclin (IP) receptors linked to cyclic AMP (cAMP) generation, although the potential to signal through peroxisome proliferator-activated receptor-γ (PPARγ) exists. OBJECTIVES: IP receptor and PPARγ expression may be depressed in IPAH. We wished to determine if pathways remain functional and if analogs continue to inhibit smooth muscle proliferation. METHODS: We used Western blotting to determine IP receptor expression in peripheral pulmonary arterial smooth muscle cells (PASMCs) from normal and IPAH lungs and immunohistochemistry to evaluate IP receptor and PPARγ expression in distal arteries. MEASUREMENTS AND MAIN RESULTS: Cell proliferation and cAMP assays assessed analog responses in human and mouse PASMCs and HEK-293 cells. Proliferative rates of IPAH cells were greater than normal human PASMCs. IP receptor protein levels were lower in PASMCs from patients with IPAH, but treprostinil reduced replication and treprostinil-induced cAMP elevation appeared normal. Responses to prostacyclin analogs were largely dependent on the IP receptor and cAMP in normal PASMCs, although in IP(-/-) receptor cells analogs inhibited growth in a cAMP-independent, PPARγ-dependent manner. In IPAH cells, antiproliferative responses to analogs were insensitive to IP receptor or adenylyl cyclase antagonists but were potentiated by a PPARγ agonist and inhibited (∼ 60%) by the PPARγ antagonist GW9662. This coincided with increased PPARγ expression in the medial layer of acinar arteries. CONCLUSIONS: The antiproliferative effects of prostacyclin analogs are preserved in IPAH despite IP receptor down-regulation and abnormal coupling. PPARγ may represent a previously unrecognized pathway by which these agents inhibit smooth muscle proliferation.


Assuntos
Hipertensão Pulmonar/fisiopatologia , Músculo Liso Vascular/citologia , PPAR gama/fisiologia , Receptores de Epoprostenol/fisiologia , Animais , Anti-Hipertensivos/farmacologia , Western Blotting , Proliferação de Células , Regulação para Baixo/fisiologia , Epoprostenol/análogos & derivados , Epoprostenol/farmacologia , Células HEK293 , Humanos , Iloprosta/farmacologia , Imuno-Histoquímica , Camundongos , PPAR gama/metabolismo , Prostaglandinas Sintéticas/farmacologia , Rosiglitazona , Tiazolidinedionas/farmacologia , Vasodilatadores/farmacologia
16.
Front Pharmacol ; 12: 705421, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34267666

RESUMO

Pulmonary arterial hypertension (PAH) is an aggressive vascular remodeling disease that carries a high morbidity and mortality rate. Treprostinil (Remodulin) is a stable prostacyclin analogue with potent vasodilatory and anti-proliferative activity, approved by the FDA and WHO as a treatment for PAH. A limitation of this therapy is the severe subcutaneous site pain and other forms of pain experienced by some patients, which can lead to significant non-compliance. TWIK-related potassium channels (TREK-1 and TREK-2) are highly expressed in sensory neurons, where they play a role in regulating sensory neuron excitability. Downregulation, inhibition or mutation of these channels leads to enhanced pain sensitivity. Using whole-cell patch-clamp electrophysiological recordings, we show, for the first time, that treprostinil is a potent antagonist of human TREK-1 and TREK-2 channels but not of TASK-1 channels. An increase in TASK-1 channel current was observed with prolonged incubation, consistent with its therapeutic role in PAH. To investigate treprostinil-induced inhibition of TREK, site-directed mutagenesis of a number of amino acids, identified as important for the action of other regulatory compounds, was carried out. We found that a gain of function mutation of TREK-1 (Y284A) attenuated treprostinil inhibition, while a selective activator of TREK channels, BL-1249, overcame the inhibitory effect of treprostinil. Our data suggests that subcutaneous site pain experienced during treprostinil therapy may result from inhibition of TREK channels near the injection site and that pre-activation of these channels prior to treatment has the potential to alleviate this nociceptive activity.

17.
Br J Pharmacol ; 178 Suppl 1: S27-S156, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34529832

RESUMO

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.


Assuntos
Bases de Dados de Produtos Farmacêuticos , Farmacologia , Humanos , Canais Iônicos , Ligantes , Receptores Citoplasmáticos e Nucleares , Receptores Acoplados a Proteínas G
18.
Nature ; 427(6977): 853-8, 2004 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-14985765

RESUMO

Neutrophil leukocytes have a pivotal function in innate immunity. Dogma dictates that the lethal blow is delivered to microbes by reactive oxygen species (ROS) and halogens, products of the NADPH oxidase, whose impairment causes immunodeficiency. However, recent evidence indicates that the microbes might be killed by proteases, activated by the oxidase through the generation of a hypertonic, K+-rich and alkaline environment in the phagocytic vacuole. Here we show that K+ crosses the membrane through large-conductance Ca2+-activated K+ (BK(Ca)) channels. Specific inhibitors of these channels, iberiotoxin and paxilline, blocked oxidase-induced 86Rb+ fluxes and alkalinization of the phagocytic vacuole, whereas NS1619, a BK(Ca) channel opener, enhanced both. Characteristic outwardly rectifying K+ currents, reversibly inhibited by iberiotoxin, were demonstrated in neutrophils and eosinophils and the expression of the alpha-subunit of the BK channel was confirmed by western blotting. The channels were opened by the combination of membrane depolarization and elevated Ca2+ concentration, both consequences of oxidase activity. Remarkably, microbial killing and digestion were abolished when the BK(Ca) channel was blocked, revealing an essential and unexpected function for this K+ channel in the microbicidal process.


Assuntos
Imunidade Inata , Canais de Potássio Cálcio-Ativados/metabolismo , Cálcio/metabolismo , Condutividade Elétrica , Eosinófilos/citologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Imunidade Inata/efeitos dos fármacos , Transporte de Íons/efeitos dos fármacos , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta , Canais de Potássio Ativados por Cálcio de Condutância Alta , Potenciais da Membrana/efeitos dos fármacos , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Potássio/metabolismo , Canais de Potássio Cálcio-Ativados/antagonistas & inibidores , Radioisótopos de Rubídio , Staphylococcus aureus/imunologia , Acetato de Tetradecanoilforbol/farmacologia , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismo
19.
Br J Pharmacol ; 177(1): 161-174, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31476020

RESUMO

BACKGROUND AND PURPOSE: In patients with pulmonary hypertension (PH) associated with lung disease and/or hypoxia (Group III), decreased pulmonary vascular tone and tissue hypoxia is therapeutically beneficial. PGE2 and PGI2 induce potent relaxation of human bronchi from non-PH (control) patients via EP4 and IP receptors, respectively. However, the effects of PGE2 /PGI2 and their mimetics on human bronchi from PH patients are unknown. Here, we have compared relaxant effects of several PGI2 -mimetics approved for treating PH Group I with several PGE2 -mimetics, in bronchial preparations derived from PH Group III and control patients. EXPERIMENTAL APPROACH: Relaxation of bronchial muscle was assessed in samples isolated from control and PH Group III patients. Expression of prostanoid receptors was analysed by western blot and real-time PCR, and endogenous PGE2 , PGI2 , and cAMP levels were determined by ELISA. KEY RESULTS: Maximal relaxations induced by different EP4 receptor agonists (PGE2 , L-902688, and ONO-AE1-329) were decreased in human bronchi from PH patients, compared with controls. However, maximal relaxations produced by PGI2 -mimetics (iloprost, treprostinil, and beraprost) were similar for both groups of patients. Both EP4 and IP receptor protein and mRNA expressions were significantly lower in human bronchi from PH patients. cAMP levels significantly correlated with PGI2 but not with PGE2 levels. CONCLUSION AND IMPLICATIONS: The PGI2 -mimetics retained maximal bronchodilation in PH Group III patients, whereas bronchodilation induced by EP4 receptor agonists was decreased. Restoration of EP4 receptor expression in airways of PH Group III patients with respiratory diseases could bring additional therapeutic benefit.


Assuntos
Brônquios/metabolismo , Broncodilatadores/metabolismo , Broncodilatadores/uso terapêutico , Dinoprostona/metabolismo , Dinoprostona/uso terapêutico , Hipertensão Pulmonar/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Brônquios/efeitos dos fármacos , Brônquios/patologia , Broncodilatadores/farmacologia , Dinoprostona/farmacologia , Relação Dose-Resposta a Droga , Epoprostenol/análogos & derivados , Epoprostenol/metabolismo , Epoprostenol/farmacologia , Epoprostenol/uso terapêutico , Feminino , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/patologia , Iloprosta/metabolismo , Iloprosta/farmacologia , Iloprosta/uso terapêutico , Masculino , Pessoa de Meia-Idade , Técnicas de Cultura de Órgãos , Pirrolidinonas/metabolismo , Pirrolidinonas/farmacologia , Pirrolidinonas/uso terapêutico , Receptores de Prostaglandina E Subtipo EP4/agonistas , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Tetrazóis/metabolismo , Tetrazóis/farmacologia , Tetrazóis/uso terapêutico , Vasodilatadores/metabolismo , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico , Adulto Jovem
20.
Drug Healthc Patient Saf ; 11: 55-64, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496830

RESUMO

Selexipag is a compound that was designed to overcome the issues associated with oral administration of prostanoid compounds, beraprost and treprostinil in the treatment of pulmonary hypertension (PAH). As a selective IP agonist, it was designed to avoid the off-target prostanoid effects especially in the gastrointestinal system. To place this compound in context, this paper briefly reviews the efficacy, tolerability, and safety of subcutaneous, inhaled, and oral prostanoid preparations and comparesthemto selexipag. Selexipag is the first agent targeting a prostanoid receptor where a reduction in the primary efficacy morbidity/mortality composite end-point has been demonstrated. While safety outcomes favor selexipag over placebo, tolerability issues remain. Efficacy in terms of improvement in effort tolerance, hemodynamic and mortality benefit is less than seen with IV therapy. This is the first prostanoid demonstrated in a clinical trial to have added benefit in those on background double combination therapy and the first non IV prostanoid to demonstrate outcome benefit in the connective tissue disease (CTD) population in a randomized controlled trial.

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