RESUMO
Atrial fibrillation (AF) is the commonest cardiac arrhythmia, affecting 3 million people in the USA and 8 million in the EU (according to the European Society of Cardiology). So, why is it that even with the best medical care, around a third of the patients are treatment resistant. Extensive research of its etiology showed that AF and its mechanisms are still debatable. Some of the AF origins are ascribed to functional and ionic heterogeneities of the heart tissue and possibly to additional triggering agents. But, have all AF origins been detected? Are all accepted origins, in fact, arrhythmogenic? In order to study these questions and specifically to check our new idea of intermittency as an arrhythmogenesis agent, we chose to employ a mathematical model which was as simple as possible, but which could still be used to observe the basic network processes of AF development. At this point we were not interested in the detailed ionic propagations nor in the actual shapes of the induced action potentials (APs) during the AF outbreaks. The model was checked by its ability to exactly recapture the basic AF developmental stages known from experimental cardiac observations and from more elaborate mathematical models. We use a simple cellular automata 2D mathematical model of N × N matrices to elucidate the field processes leading to AF in a tissue riddled with randomly distributed heterogeneities of different types, under sinus node operation, simulated by an initial line of briefly stimulated cells inducing a propagating wave, and with or without an additional active ectopic action potential pulse, in turn simulated by a transitory operation of a specific cell. Arrhythmogenic contributions, of three different types of local heterogeneities in myocytes and their collaborations, in inducing AF are examined. These are: a heterogeneity created by diffuse fibrosis, a heterogeneity created by myocytes having different refractory periods, and a new heterogeneity type, created by intermittent operation of some myocytes. The developmental stages (target waves and spirals) and the different probabilities of AF occurring under each condition, are shown. This model was established as being capable of reproducing the known AF origins and their basic development stages, and in addition has shown: (1) That diffuse fibrosis on its own is not arrhythmogenic but in combination with other arrhythmogenic agents it can either enhance or limit AF. (2) In general, combinations of heterogeneities can act synergistically, and, most importantly, (3) The new type of intermittency heterogeneity proves to be extremely arrhythmogenic. Both the intermittency risk and the fibrosis role in AF generation were established. Knowledge of the character of these arrhythmogenesis agents can be of real importance in AF treatment.
Assuntos
Fibrilação Atrial , Fármacos Cardiovasculares , Humanos , Nó Sinoatrial , Doença do Sistema de Condução Cardíaco , Células Musculares , Fármacos Cardiovasculares/metabolismo , Fibrose , Átrios do Coração , Potenciais de Ação , Miócitos Cardíacos/metabolismoRESUMO
Cardiovascular diseases remain the leading cause of death worldwide; hence there is an increasing focus on developing physiologically relevant in vitro cardiovascular tissue models suitable for studying personalized medicine and pre-clinical tests. Despite recent advances, models that reproduce both tissue complexity and maturation are still limited. We have established a scaffold-free protocol to generate multicellular, beating human cardiac microtissues in vitro from hiPSCs-namely human organotypic cardiac microtissues (hOCMTs)-that show some degree of self-organization and can be cultured for long term. This is achieved by the differentiation of hiPSC in 2D monolayer culture towards cardiovascular lineage, followed by further aggregation on low-attachment culture dishes in 3D. The generated hOCMTs contain multiple cell types that physiologically compose the heart and beat without external stimuli for more than 100 days. We have shown that 3D hOCMTs display improved cardiac specification, survival and metabolic maturation as compared to standard monolayer cardiac differentiation. We also confirmed the functionality of hOCMTs by their response to cardioactive drugs in long-term culture. Furthermore, we demonstrated that they could be used to study chemotherapy-induced cardiotoxicity. Due to showing a tendency for self-organization, cellular heterogeneity, and functionality in our 3D microtissues over extended culture time, we could also confirm these constructs as human cardiac organoids (hCOs). This study could help to develop more physiologically-relevant cardiac tissue models, and represent a powerful platform for future translational research in cardiovascular biology.
Assuntos
Antineoplásicos , Fármacos Cardiovasculares , Células-Tronco Pluripotentes Induzidas , Humanos , Engenharia Tecidual/métodos , Coração/fisiologia , Diferenciação Celular/fisiologia , Fármacos Cardiovasculares/metabolismo , Antineoplásicos/metabolismo , Miócitos Cardíacos/metabolismoRESUMO
The particulate guanylyl cyclase A receptor (GC-A), via activation by its endogenous ligands atrial natriuretic peptide (ANP) and b-type natriuretic peptide (BNP), possesses beneficial biological properties such as blood pressure regulation, natriuresis, suppression of adverse remodeling, inhibition of the renin-angiotensin-aldosterone system, and favorable metabolic actions through the generation of its second messenger cyclic guanosine monophosphate (cGMP). Thus, the GC-A represents an important molecular therapeutic target for cardiovascular disease and its associated risk factors. However, a small molecule that is orally bioavailable and directly targets the GC-A to potentiate cGMP has yet to be discovered. Here, we performed a cell-based high-throughput screening campaign of the NIH Molecular Libraries Small Molecule Repository, and we successfully identified small molecule GC-A positive allosteric modulator (PAM) scaffolds. Further medicinal chemistry structure-activity relationship efforts of the lead scaffold resulted in the development of a GC-A PAM, MCUF-651, which enhanced ANP-mediated cGMP generation in human cardiac, renal, and fat cells and inhibited cardiomyocyte hypertrophy in vitro. Further, binding analysis confirmed MCUF-651 binds to GC-A and selectively enhances the binding of ANP to GC-A. Moreover, MCUF-651 is orally bioavailable in mice and enhances the ability of endogenous ANP and BNP, found in the plasma of normal subjects and patients with hypertension or heart failure, to generate GC-A-mediated cGMP ex vivo. In this work, we report the discovery and development of an oral, small molecule GC-A PAM that holds great potential as a therapeutic for cardiovascular, renal, and metabolic diseases.
Assuntos
Fármacos Cardiovasculares , Doenças Cardiovasculares/metabolismo , GMP Cíclico/metabolismo , Peptídeos Natriuréticos/metabolismo , Receptores do Fator Natriurético Atrial , Idoso , Regulação Alostérica , Animais , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/metabolismo , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/farmacologia , Células Cultivadas , Feminino , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Miócitos Cardíacos/metabolismo , Receptores do Fator Natriurético Atrial/química , Receptores do Fator Natriurético Atrial/efeitos dos fármacos , Receptores do Fator Natriurético Atrial/metabolismoRESUMO
ABSTRACT: Infarct size is a major determinant of outcomes after acute myocardial infarction (AMI). Carbon monoxide-releasing molecules (CORMs), which deliver nanomolar concentrations of carbon monoxide to tissues, have been shown to reduce infarct size in rodents. We evaluated efficacy and safety of CORM-A1 to reduce infarct size in a clinically relevant porcine model of AMI. We induced AMI in Yorkshire White pigs by inflating a coronary angioplasty balloon to completely occlude the left anterior descending artery for 60 minutes, followed by deflation of the balloon to mimic reperfusion. Fifteen minutes after balloon occlusion, animals were given an infusion of 4.27 mM CORM-A1 (n = 7) or sodium borate control (n = 6) over 60 minutes. Infarct size, cardiac biomarkers, ejection fraction, and hepatic and renal function were compared amongst the groups. Immunohistochemical analyses were performed to compare inflammation, cell proliferation, and apoptosis between the groups. CORM-A1-treated animals had significant reduction in absolute infarct area (158 ± 16 vs. 510 ± 91 mm2, P < 0.001) and infarct area corrected for area at risk (24.8% ± 2.6% vs. 45.2% ± 4.0%, P < 0.0001). Biochemical markers of myocardial injury also tended to be lower and left ventricular function tended to recover better in the CORM-A1 treated group. There was no evidence of hepatic or renal toxicity with the doses used. The cardioprotective effects of CORM-A1 were associated with a significant reduction in cell proliferation and inflammation. CORM-A1 reduces infarct size and improves left ventricular remodeling and function in a porcine model of reperfused MI by a reduction in inflammation. These potential cardioprotective effects of CORMs warrant further translational investigations.
Assuntos
Boranos/farmacologia , Monóxido de Carbono/metabolismo , Carbonatos/farmacologia , Fármacos Cardiovasculares/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Boranos/metabolismo , Carbonatos/metabolismo , Fármacos Cardiovasculares/metabolismo , Caspase 3/metabolismo , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Interleucina-1beta/metabolismo , Antígeno Ki-67/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Sus scrofa , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacosRESUMO
BACKGROUND: The oral application of drugs is the most popular route through which the systemic effect can be achieved. Nevertheless, oral administration is limited by difficulties related to the physicochemical properties of the drug molecule, including low aqueous solubility, instability, low permeability, and rapid metabolism, all of which result in low and irregular oral bioavailability. OBJECTIVE: The enhancement of oral bioavailability of drug molecules with such properties could lead to extreme complications in drug preparations. Oral lipid-based nanoparticles seem to possess extensive advantages due to their ability to increase the solubility, simplifying intestinal absorption and decrease or eradicate the effect of food on the absorption of low soluble, lipophilic drugs and therefore improving the oral bioavailability. METHODS: The present review provides a summary of the general theory of lipid-based nanoparticles, their preparation methods, as well as their oral applications. Moreover, oral drug delivery challenges are discussed. RESULTS: According to this review, the most frequent types of lipid-based nanoparticle, the solid lipid nanoparticles and nanostructured lipid carriers are potent oral carriers due to their ability to penetrate the oral drug adsorption barriers. Moreover, such lipid nanoparticles can be beneficial drug carriers against cardiovascular risk disorders as diabetes, hypertension, etc. Conclusion: In this review, the most current and promising studies involving Solid Lipid Nanoparticles and Nanostructured Lipid Carriers as oral drug carriers are reported aiming to assist researchers who focus their research on lipid-based nanoparticles.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Fatores de Risco de Doenças Cardíacas , Lipídeos/administração & dosagem , Nanopartículas/administração & dosagem , Administração Oral , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/metabolismo , Disponibilidade Biológica , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/metabolismo , Doenças Cardiovasculares/metabolismo , Portadores de Fármacos/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/metabolismo , Absorção Intestinal/efeitos dos fármacos , Absorção Intestinal/fisiologia , Nanopartículas/metabolismo , Permeabilidade , SolubilidadeRESUMO
Bone marrow-derived hematopoietic stem/progenitor cells are vasculogenic and play an important role in endothelial health and vascular homeostasis by participating in postnatal vasculogenesis. Progenitor cells are mobilized from bone marrow niches in response to remote ischemic injury and migrate to the areas of damage and stimulate revascularization largely by paracrine activation of angiogenic functions in the peri-ischemic vasculature. This innate vasoprotective mechanism is impaired in certain chronic clinical conditions, which leads to the development of cardiovascular complications. Members of the renin-angiotensin system-angiotensin-converting enzymes (ACEs) ACE and ACE2, angiotensin II (Ang II), Ang-(1-7), and receptors AT1 and Mas-are expressed in vasculogenic progenitor cells derived from humans and rodents. Ang-(1-7), generated by ACE2, is known to produce cardiovascular protective effects by acting on Mas receptor and is considered as a counter-regulatory mechanism to the detrimental effects of Ang II. Evidence has now been accumulating in support of the activation of the ACE2/Ang-(1-7)/Mas receptor pathway by pharmacologic or molecular maneuvers, which stimulates mobilization of progenitor cells from bone marrow, migration to areas of vascular damage, and revascularization of ischemic areas in pathologic conditions. This minireview summarizes recent studies that have enhanced our understanding of the physiology and pharmacology of vasoprotective axis in bone marrow-derived progenitor cells in health and disease. SIGNIFICANCE STATEMENT: Hematopoietic stem progenitor cells (HSPCs) stimulate revascularization of ischemic areas. However, the reparative potential is diminished in certain chronic clinical conditions, leading to the development of cardiovascular diseases. ACE2 and Mas receptor are key members of the alternative axis of the renin-angiotensin system and are expressed in HSPCs. Accumulating evidence points to activation of ACE2 or Mas receptor as a promising approach for restoring the reparative potential, thereby preventing the development of ischemic vascular diseases.
Assuntos
Angiotensina I/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Doenças Cardiovasculares/metabolismo , Sistemas de Liberação de Medicamentos/tendências , Células-Tronco Hematopoéticas/metabolismo , Fragmentos de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Proto-Oncogene Mas , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismoRESUMO
The natural isomers of resveratrol, cis- and trans-resveratrol, are natural phenolic substances synthetized via the shikimate pathway and found in many sources, including grapes, peanuts, blackberries, pistachios, cacao, cranberries, and jackfruits. They have functional and pharmacological properties such as anticarcinogenic, antidiabetic, anti-inflammatory, and cardioprotective activities. The aim of this article is to review the data published on resveratrol and its isomers, and their biosynthesis in plants, food sources, health and toxic effects, and the excretion of their metabolites. Due to its contribution to the promotion of human health, it is convenient to gather more knowledge about its functional properties, food sources, and the interactions with the human body during the processes of eating, digestion, absorption, biotransformation, and excretion, to combine this information to improve the understanding of these substances.
Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Fármacos Cardiovasculares/farmacologia , Alimentos , Hipoglicemiantes/farmacologia , Plantas/metabolismo , Resveratrol/farmacologia , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/toxicidade , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/toxicidade , Disponibilidade Biológica , Biotransformação , Fármacos Cardiovasculares/metabolismo , Fármacos Cardiovasculares/farmacocinética , Fármacos Cardiovasculares/toxicidade , Vias de Eliminação de Fármacos , Absorção Gastrointestinal , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/toxicidade , Isomerismo , Resveratrol/metabolismo , Resveratrol/farmacocinética , Resveratrol/toxicidadeRESUMO
All life forms typically possess homochirality, with rare exceptions. In the case of peptides and proteins, only L-amino acids are known to be encoded by genes. Nevertheless, D-amino acids have been identified in a variety of peptides, synthesized by animal cells. They include neuroexcitatory and neuroprotective peptides, cardioexcitatory peptides, hyperglycemic hormones, opioid peptides, antimicrobial peptides, natriuretic and defensin-like peptides, and fibrinopeptides. This article is a review of their occurrence, structure and bioactivity. It further explores the pharmacology and potential medical applications of some of the peptides.
Assuntos
Aminoácidos/química , Conotoxinas/química , Hormônios de Invertebrado/síntese química , Proteínas do Tecido Nervoso/química , Peptídeos Opioides/química , Proteínas Citotóxicas Formadoras de Poros/química , Sequência de Aminoácidos , Aminoácidos/metabolismo , Animais , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/metabolismo , Fármacos Cardiovasculares/farmacologia , Conotoxinas/biossíntese , Conotoxinas/farmacologia , Crustáceos/química , Crustáceos/metabolismo , Fibrinopeptídeo A/biossíntese , Fibrinopeptídeo A/química , Fibrinopeptídeo A/farmacologia , Humanos , Hormônios de Invertebrado/biossíntese , Hormônios de Invertebrado/química , Hormônios de Invertebrado/farmacologia , Moluscos/química , Moluscos/metabolismo , Peptídeos Natriuréticos/biossíntese , Peptídeos Natriuréticos/química , Peptídeos Natriuréticos/farmacologia , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/farmacologia , Peptídeos Opioides/biossíntese , Peptídeos Opioides/farmacologia , Proteínas Citotóxicas Formadoras de Poros/biossíntese , Proteínas Citotóxicas Formadoras de Poros/farmacologia , Especificidade da Espécie , Aranhas/química , Aranhas/metabolismo , EstereoisomerismoRESUMO
In this work, the aim of our study was to assess whether sesamin could influence the pharmacokinetics of ivabradine and its active metabolite N-desmethylivabradine in rats. At the begining, 12 healthy male Sprague-Dawley rats were randomly divided into two groups: The rats were received an oral administration of 1.0mg/kg ivabradine alone (the control group), and the rats were given 1.0mg/kg ivabradine co-administered with 50mg/kg sesamin by gavage (the test group). After that, blood samples were collected from the tail vein of rats, and ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) were used for determing the plasma concentrations of ivabradine and N-desmethylivabradine in rats. Finally, the pharmacokinetic parameters were estimated using DAS 2.0 software. As the results, the pharmacokinetic parameters (t1/2, Cmax, AUC (0-t) and AUC (0-oo)) of ivabradine in the control group were significantly lower than those in the test group (P<0.05). Moreover, sesamin significantly decreased t1/2, Cmax, AUC(0-t) and AUC(0-oo) of N-desmethylivabradine when compared to the control. These results demonstrated that sesamin increases plasma concentration of ivabradine and decreases N-desmethylivabradine conversely. Hence, our data indicated sesamin could influence the pharmacokinetic profile of ivabradine in rats, which might cause food-drug interaction in humans.
Assuntos
Dioxóis/farmacologia , Ivabradina/farmacocinética , Lignanas/farmacologia , Administração Oral , Animais , Área Sob a Curva , Fármacos Cardiovasculares/sangue , Fármacos Cardiovasculares/metabolismo , Fármacos Cardiovasculares/farmacocinética , Cromatografia Líquida de Alta Pressão , Dioxóis/administração & dosagem , Dioxóis/farmacocinética , Ivabradina/sangue , Ivabradina/metabolismo , Lignanas/administração & dosagem , Lignanas/farmacocinética , Masculino , Ratos Sprague-Dawley , Espectrometria de Massas em TandemAssuntos
Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/metabolismo , Sistemas de Liberação de Medicamentos/tendências , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/metabolismo , Animais , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/metabolismo , Humanos , CamundongosRESUMO
We hypothesized that ranolazine-induced adenosine release is responsible for its beneficial effects in ischemic heart disease. Sixteen open-chest anesthetized dogs with noncritical coronary stenosis were studied at rest, during dobutamine stress, and during dobutamine stress with ranolazine. Six additional dogs without stenosis were studied only at rest. Regional myocardial function and perfusion were assessed. Coronary venous blood was drawn. Murine endothelial cells and cardiomyocytes were incubated with ranolazine and adenosine metabolic enzyme inhibitors, and adenosine levels were measured. Cardiomyocytes were also exposed to dobutamine and dobutamine with ranolazine. Modeling was employed to determine whether ranolazine can bind to an enzyme that alters adenosine stores. Ranolazine was associated with increased adenosine levels in the absence (21.7 ± 3.0 vs. 9.4 ± 2.1 ng/mL, P < 0.05) and presence of ischemia (43.1 ± 13.2 vs. 23.4 ± 5.3 ng/mL, P < 0.05). Left ventricular end-systolic wall stress decreased (49.85 ± 4.68 vs. 57.42 ± 3.73 dyn/cm2, P < 0.05) and endocardial-to-epicardial myocardial blood flow ratio tended to normalize (0.89 ± 0.08 vs. 0.76 ± 0.10, P = nonsignificant). Adenosine levels increased in cardiac endothelial cells and cardiomyocytes when incubated with ranolazine that was reversed when cytosolic-5'-nucleotidase (cN-II) was inhibited. Point mutation of cN-II aborted an increase in its specific activity by ranolazine. Similarly, adenosine levels did not increase when cardiomyocytes were incubated with dobutamine. Modeling demonstrated plausible binding of ranolazine to cN-II with a docking energy of -11.7 kcal/mol. We conclude that the anti-adrenergic and cardioprotective effects of ranolazine-induced increase in tissue adenosine levels, likely mediated by increasing cN-II activity, may contribute to its beneficial effects in ischemic heart disease.NEW & NOTEWORTHY Ranolazine is a drug used for treatment of angina pectoris in patients with ischemic heart disease. We discovered a novel mechanism by which this drug may exhibit its beneficial effects. It increases coronary venous levels of adenosine both at rest and during dobutamine-induced myocardial ischemia. Ranolazine also increases adenosine levels in endothelial cells and cardiomyocytes in vitro, by principally increasing activity of the enzyme cytosolic-5'-nucleotidase. Adenosine has well-known myocardial protective and anti-adrenergic properties that may explain, in part, ranolazine's beneficial effect in ischemic heart disease.
Assuntos
Adenosina/metabolismo , Fármacos Cardiovasculares/farmacologia , Estenose Coronária/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Ranolazina/farmacologia , 5'-Nucleotidase/química , 5'-Nucleotidase/metabolismo , Animais , Sítios de Ligação , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/metabolismo , Células Cultivadas , Estenose Coronária/metabolismo , Estenose Coronária/fisiopatologia , Modelos Animais de Doenças , Cães , Hemodinâmica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Miócitos Cardíacos/metabolismo , Ligação Proteica , Conformação Proteica , Ranolazina/química , Ranolazina/metabolismo , Relação Estrutura-Atividade , Regulação para Cima , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Urocortin-2 (Ucn-2) is a peptide of the corticotrophin releasing factor-related family with several effects within the cardiovascular system. A variety of molecular mechanisms has been proposed to underlie some of these effects, although others remain mostly hypothetical. Growing interest in the cardiovascular properties of this peptide promoted several pre-clinical studies in the settings of heart failure and ischemia, as well as some experiments in the fields of systemic and pulmonary arterial hypertension. Most of these studies report promising results, with Ucn-2 showing therapeutic potential in these settings, and few clinical trials to date are trying to translate this potential to human cardiovascular disease. Ucn-2 also appears to have potential as a biomarker of diagnostic/prognostic relevance in cardiovascular disease, this being a recent field in the study of this peptide needing further corroboration. Regarding the increasing amount of evidence in Ucn-2 investigation, this work aims to make an updated review on its cardiovascular effects and molecular mechanisms of action and therapeutic potential, and to identify some research barriers and gaps in the study of this cardioprotective peptide.
Assuntos
Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Sistema Cardiovascular/efeitos dos fármacos , Hormônio Liberador da Corticotropina/uso terapêutico , Urocortinas/uso terapêutico , Animais , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Hormônio Liberador da Corticotropina/efeitos adversos , Hormônio Liberador da Corticotropina/metabolismo , Hemodinâmica/efeitos dos fármacos , Humanos , Resultado do Tratamento , Urocortinas/efeitos adversos , Urocortinas/metabolismo , Função Ventricular/efeitos dos fármacosRESUMO
The gut microbiome is emerging as an important contributor to both cardiovascular disease risk and metabolism of xenobiotics. Alterations in the intestinal microbiota are associated with atherosclerosis, dyslipidemia, hypertension, and heart failure. The microbiota have the ability to metabolize medications, which can results in altered drug pharmacokinetics and pharmacodynamics or formation of toxic metabolites which can interfere with drug response. Early evidence suggests that the gut microbiome modulates response to statins and antihypertensive medications. In this review, we will highlight mechanisms by which the gut microbiome facilitates the biotransformation of drugs and impacts pharmacological efficacy. A better understanding of the complex interactions of the gut microbiome, host factors, and response to medications will be important for the development of novel precision therapeutics for targeting CVD.
Assuntos
Bactérias/metabolismo , Fármacos Cardiovasculares/administração & dosagem , Microbioma Gastrointestinal , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Biotransformação , Fármacos Cardiovasculares/metabolismo , Fármacos Cardiovasculares/farmacocinética , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , HumanosRESUMO
D-Danshensu (D-DSS), a traditional Chinese medicine, is used to treat cardiovascular and cerebrovascular diseases. However, current isolation protocols for D-DSS both natural and synthetic are not ideal; therefore, in this study, we have developed a whole-cell biotransformation method to produce D-DSS from L-DOPA. This was done by co-expressing L-amino acid deaminase (aadL), D-lactate dehydrogenase (ldhD), and glucose dehydrogenase (gdh). To begin to optimize the production of D-DSS, varying copy number plasmids were used to express each of the required genes. The resulting strain, Escherichia coli ALG7, which strongly overexpressed aadL, ldhD, and weakly overexpressed gdh, yielded a 378% increase in D-DSS production compared to E. coli ALG1. Furthermore, the optimal reaction conditions for the production of D-DSS were found to be a pH of 7.5, temperature at 35 °C, and 50 g/L wet cells for 12 h. Under these optimized conditions, the D-DSS amount achieved 119.1 mM with an excellent ee (> 99.9%) and a productivity of 9.9 mM/h.
Assuntos
Biotecnologia/métodos , Fármacos Cardiovasculares/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Lactatos/metabolismo , Levodopa/metabolismo , Engenharia Metabólica/métodos , Biotransformação , Enzimas/genética , Enzimas/metabolismo , Expressão Gênica , Concentração de Íons de Hidrogênio , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , TemperaturaRESUMO
Cardiac remodeling is the response of the heart to a range of pathological stimuli. Cardiac remodeling is initially adaptive; however, if sustained, it ultimately causes adverse clinical outcomes. Cardiomyocyte loss or hypertrophy, inflammation and fibrosis are hallmarks of cardiac remodeling. Proteoglycans, which are composed of glycosaminoglycans and a core protein, are a non-structural component of the extracellular matrix. The lack of proteoglycans results in cardiovascular defects during development. Moreover, emerging evidence has indicated that proteoglycans act as significant modifiers in ischemia and pressure overload-related cardiac remodeling. Proteoglycans may also provide novel therapeutic strategies for further improvement in the prognosis of cardiovascular diseases.
Assuntos
Insuficiência Cardíaca/metabolismo , Isquemia Miocárdica/metabolismo , Proteoglicanas/metabolismo , Remodelação Ventricular/fisiologia , Animais , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/fisiopatologia , Remodelação Ventricular/efeitos dos fármacosRESUMO
The last two centuries have witnessed countless discoveries in the field of medicine that found their roots in the up growing development of technology as well as in the visionary ideas of brilliant scientists and research groups. One of the most important discoveries in the field of cardiovascular medicine allowed to break the paradigm identifying the heart with mere mechanical pump and to characterize its intriguing endocrine properties. Indeed, the discovery of hormones produced by the cardiac chambers, the natriuretic peptides, represents one of the milestones of the current conception of complexity of integrated human physiology. In the last four decades, the role of these hormones in the regulation of the cardiovascular system, in physiology and diseases, has been defined piece after piece. From diagnostic and prognostic markers, natriuretic peptides have become one of the most relevant clinical biomarker and a reliable target for establishing the efficacy of therapies. Recently and successfully, natriuretic peptide-based strategies are proposed as therapeutic weapons to improve outcome in heart failure. The future will witness potential further therapeutic application of natriuretic peptides that are currently being actively investigated.
Assuntos
Fármacos Cardiovasculares/metabolismo , Insuficiência Cardíaca/metabolismo , Peptídeos Natriuréticos/metabolismo , Animais , Biomarcadores/metabolismo , Fármacos Cardiovasculares/administração & dosagem , Previsões , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologiaRESUMO
Pulmonary hypertension (PH) due to left ventricular heart failure (LV-HF) is a disabling and life-threatening disease for which there is currently no single marketed pharmacological agent approved. Despite recent advances in the pathophysiological understanding, there is as yet no prospect of cure, and the majority of patients continue to progress to right ventricular failure and die. There is, therefore an urgent unmet need to identify novel pharmacological agents that will prevent or reverse the increase in pulmonary artery pressures while enhancing cardiac performance in PH due to LV-HF. In the present article, we first focused on the Natriuretic Peptide Receptor type C (NPR-C) based therapeutic strategies aimed at lowering pulmonary artery pressure. Second, we reviewed potential NPR-C therapeutic strategies to reverse or least halt the detrimental effects of diastolic dysfunction and impaired nitic oxide signalling pathways, as well as possibilities for neurohumoral modulation.
Assuntos
Fármacos Cardiovasculares/metabolismo , Insuficiência Cardíaca/metabolismo , Hipertensão Pulmonar/metabolismo , Peptídeo Natriurético Tipo C/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Animais , Fármacos Cardiovasculares/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Resultado do Tratamento , Disfunção Ventricular Esquerda/tratamento farmacológicoAssuntos
Ácido Acético/administração & dosagem , Antineoplásicos/administração & dosagem , Fármacos Cardiovasculares/administração & dosagem , Cardiopatias/prevenção & controle , Neoplasias/prevenção & controle , Ácido Acético/efeitos adversos , Ácido Acético/metabolismo , Antineoplásicos/efeitos adversos , Antineoplásicos/metabolismo , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/metabolismo , Cardiopatias/diagnóstico , Cardiopatias/metabolismo , Humanos , Neoplasias/diagnóstico , Neoplasias/metabolismo , Oxalatos/metabolismoRESUMO
BACKGROUND: While direct-acting antivirals have been approved for treating hepatitis C, the guidelines highlight the importance of considering potential drug-drug interactions between DAAs and concomitant medications. AIM: To assess comorbidity prevalence, concomitant medication use and potential drug-drug interactions between DAAs and concomitant medications for hepatitis C patients in Taiwan. METHODS: This cross-sectional study enrolled 822 patients from May to August 2016 in Taiwan. Patient demographics, comorbidities and concomitant medications were evaluated by physician surveys. RESULTS: A total of 709 (86.3%) patients had ≥1 comorbidity; the most prevalent comorbidity categories were diseases of the digestive system (40.1%), circulatory system (38.7%) and endocrine/nutritional/metabolic diseases (35.2%). Elderly patients had more comorbidities. A total of 622 (75.7%) patients received ≥1 concomitant medication; the average number of concomitant medications was 3.2. The most common concomitant medication classes were cardiovascular (34.4%), gastrointestinal (25.7%) and central nervous system drugs (22.7%). Among patients without cirrhosis or with compensated cirrhosis, contraindications were most prevalent with paritaprevir/ritonavir/ombitasvir plus dasabuvir, daclatasvir/asunaprevir and glecaprevir/pibrentasvir (13.3%, 6.0% and 5.4% respectively), and least prevalent with sofosbuvir, sofosbuvir/daclatasvir, sofosbuvir/ledipasvir and sofosbuvir/velpatasvir (0.8%, 1.3%, 1.4% and 2.1% respectively). Sofosbuvir-based regimens had no contraindications in patients with decompensated cirrhosis. CONCLUSION: Our population represented an elderly demographic, with a high prevalence of comorbidities and widespread use of concomitant medications. The potential drug-drug interactions between these concomitant medications and DAA regimens differed, with the fewest potential interactions with sofosbuvir-based regimens.
Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Sofosbuvir/uso terapêutico , Uridina Monofosfato/análogos & derivados , Idoso , Anti-Infecciosos/metabolismo , Anti-Infecciosos/uso terapêutico , Antivirais/metabolismo , Benzimidazóis/metabolismo , Fármacos Cardiovasculares/metabolismo , Fármacos Cardiovasculares/uso terapêutico , Comorbidade , Estudos Transversais , Interações Medicamentosas/fisiologia , Feminino , Fluorenos/metabolismo , Hepatite C Crônica/metabolismo , Humanos , Interferons/metabolismo , Interferons/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sofosbuvir/metabolismo , Taiwan/epidemiologia , Uridina Monofosfato/metabolismo , Uridina Monofosfato/uso terapêuticoRESUMO
The consumption of cocoa products rich in (-)-epicatechin is associated with reduced cardiovascular risk and improved vascular function. However, little is known about (-)-epicatechin's effects on aged endothelium. In order to characterize the health restoring effects of (-)-epicatechin on aged endothelium and identify the underlying mechanisms, we utilized high passage number (i.e. aged) bovine coronary artery endothelial cells and aortas of 3 and 18 month old rats. We evaluated cell senescence (ß-galactosidase), nitric oxide (NO) production through the endothelial nitric oxide synthase pathway, mitochondria related endpoints, citrate synthase activity and vascular relaxation. Cells were treated with water or (-)-epicatechin (1 µM) for 48 h and rats orally with either water or (-)-epicatechin (1 mg kg-1 day-1) for 15 days. Senescence associated ß-galactosidase levels doubled in aged cells while those treated with (-)-epicatechin only evidenced an â¼40% increase. NO levels in cells decreased by â¼33% with aging and (-)-epicatechin normalized them. Endothelial nitric oxide synthase phosphorylation levels paralleled these results. Aging increased total protein and synthase acetylation levels and (-)-epicatechin partially restored them to those of young cells by stimulating sirtuin-1 binding to the synthase. Phosphorylated sirtuin-1, mitofilin, oxidative phosphorylation complexes and transcriptional factor for mitochondria were reduced by â¼40% with aging and were restored by (-)-epicatechin. (-)-Epicatechin enhanced acetylcholine induced aged aorta vasodilation and stimulated NO levels while reducing blood pressure. In conclusion, (-)-epicatechin reverses endothelial cell aging and restores key control elements of vascular function. These actions may partly explain the epidemiological evidence for the beneficial effects of cocoa consumption on the incidence of cardiac and vascular diseases.