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1.
Medicine (Baltimore) ; 100(1): e24146, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33429792

RESUMO

ABSTRACT: Since 2008, oral propranolol has evolved as the first-line therapy for infantile hemangiomas (IHs). Meanwhile, oral atenolol gradually shows comparative effectiveness versus oral propranolol with few side effects. Here, we conducted a mobile internal survey among a group of Chinese clinicians about how they choose the dosage, dose regimen, and dose escalation methods of propranolol and atenolol for the treatment of IH.A mobile-ready internal survey on the application of oral propranolol and oral atenolol for IH in mainland China was performed and distributed to 333 potential clinicians from different levels of healthcare institutions in mainland China. Eighty-one doctors responded to the survey. All the respondents had the experience of treating IH with oral propranolol and 32 had the experience with oral atenolol.Most of the doctors from tertiary hospitals chose 2 mg/kg/d twice daily, while most of those with the experience of propranolol from private hospitals chose 1 mg/kg/d once daily. More doctors from tertiary hospitals had the experience of atenolol than those from private hospitals.Oral atenolol has become another medication intervention option for IH in mainland China. This survey is helpful to standardize and develop a guideline of oral atenolol therapy for IH.


Assuntos
Atenolol/farmacologia , Hemangioma/tratamento farmacológico , Propranolol/farmacologia , Administração Oral , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Atenolol/uso terapêutico , China , Feminino , Hemangioma/complicações , Humanos , Lactente , Masculino , Propranolol/uso terapêutico , Inquéritos e Questionários , Resultado do Tratamento
2.
Biol Pharm Bull ; 43(4): 731-735, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32238715

RESUMO

Alzheimer's disease (AD) is characterized by the formation of extracellular amyloid plaques containing the amyloid ß-protein (Aß) within the parenchyma of the brain. Aß is considered to be the key pathogenic factor of AD. Recently, we showed that Angiotensin II type 1 receptor (AT1R), which regulates blood pressure, is involved in Aß production, and that telmisartan (Telm), which is an angiotensin II receptor blocker (ARB), increased Aß production via AT1R. However, the precise mechanism underlying how AT1R is involved in Aß production is unknown. Interestingly, AT1R, a G protein-coupled receptor, was strongly suggested to be involved in signal transduction by heterodimerization with ß2-adrenergic receptor (ß2-AR), which is also shown to be involved in Aß generation. Therefore, in this study, we aimed to clarify whether the interaction between AT1R and ß2-AR is involved in the regulation of Aß production. To address this, we analyzed whether the increase in Aß production by Telm treatment is affected by ß-AR antagonist using fibroblasts overexpressing amyloid precursor protein (APP). We found that the increase in Aß production by Telm treatment was decreased by the treatment of ß2-AR selective antagonist ICI-118551 more strongly than the treatment of ß1-AR selective antagonists. Furthermore, deficiency of AT1R abolished the effect of ß2-AR antagonist on the stimulation of Aß production caused by Telm. Taken together, the interaction between AT1R and ß2-AR is likely to be involved in Aß production.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Atenolol/farmacologia , Bisoprolol/farmacologia , Células Cultivadas , Camundongos Endogâmicos C57BL , Propanolaminas/farmacologia , Propranolol/farmacologia , Telmisartan/farmacologia
3.
Arq Bras Cardiol ; 114(2): 295-303, 2020 02.
Artigo em Inglês, Português | MEDLINE | ID: mdl-32215501

RESUMO

BACKGROUND: Cigarette smoking is usually associated with hypertension and may modify vasoconstrictor response. OBJECTIVE: The present study aimed to analyze and compare the interaction of passive cigarette smoking and hypertension on epinephrine and felypressin blood pressure effects after intravascular injection. METHOD: 45-day male Wistar rats had the main left renal artery partially constricted and the right kidney removed (1K1C model). Rats were placed in the chamber for exposition to passive cigarette smoking (10 cigarettes) during 10 min (6 days a week). Hypertensive rats received atenolol (90 mg/kg/day) by gavage for two weeks. Hypotensive and hypertensive response, response duration and heart rate were recorded from direct blood pressure values. The significance level was 5%. RESULTS: Passive cigarette smoking increased maximal hypertensive response to epinephrine in normotensive and 1K1C-atenolol treated rats and to felypressin only in 1K1C-atenolol treated rats; it also reduced epinephrine hypotensive response. Epinephrine increased heart rate in normotensive and hypertensive passive smokers or non-smoker rats. Comparing the two vasoconstrictors, epinephrine showed greater hypertensive response in normotensive smokers, 1K1C-atenolol treated smokers and non-smokers. However, in normotensive-nonsmoker rats, felypressin showed a greater and longer hypertensive effect. CONCLUSIONS: Our results suggest that passive cigarette smoking may reduce epinephrine vasodilation and increase hypertensive response when compared to felypressin. Therefore, felypressin may be safe for hypertensive patients to avoid tachycardia and atenolol interaction, but for normotensive and non-smoker patients, epinephrine may be safer than felypressin.


Assuntos
Anti-Hipertensivos/farmacologia , Atenolol/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Epinefrina/farmacologia , Felipressina/farmacologia , Poluição por Fumaça de Tabaco/efeitos adversos , Vasoconstritores/farmacologia , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipotensão , Masculino , Ratos Wistar , Fatores de Tempo , Vasodilatação/efeitos dos fármacos
4.
Biochem Pharmacol ; 171: 113731, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31783011

RESUMO

Stereoselectivity is well described for receptor binding and enzyme catalysis, but so far has only been scarcely investigated in carrier-mediated membrane transport. We thus studied transport kinetics of racemic (anti)adrenergic drugs by the organic cation transporters OCT1 (wild-type and allelic variants), OCT2, OCT3, MATE1, and MATE2-K with a focus on stereospecificity. OCT1 showed stereoselective uptake with up to 2-fold higher vmax over their corresponding counterpart enantiomers for (R,R)-fenoterol, (R,R)-formoterol, (S)-salbutamol, (S)-acebutolol, and (S)-atenolol. Orciprenaline and etilefrine were also transported stereoselectively. The Km was 2.1-fold and 1.5-fold lower for the (S,S)-enantiomers of fenoterol and formoterol, while no significant difference in Km was seen for the other aforementioned drugs. Common OCT1 variants showed similar enantiopreference to wild-type OCT1, with a few notable exceptions (e.g. a switch in enantiospecificity for fenoterol in OCT1*2 compared to the wild-type). Other cation transporters showed strong differences to OCT1 in stereoselectivity and transport activity: The closely related OCT2 displayed a 20-fold higher vmax for (S,S)-fenoterol compared to (R,R)-fenoterol and OCT2 and OCT3 showed 3.5-fold and 4.6-fold higher vmax for the pharmacologically active (R)-salbutamol over (S)-salbutamol. MATE1 and MATE2-K generally mediated transport with a higher capacity but lower affinity compared to OCT1, with moderate stereoselectivity. Our kinetic studies showed that significant stereoselectivity exists in solute carrier-mediated membrane transport of racemic beta-adrenergic drugs with surprising, and in some instances even opposing, preferences between closely related organic cation transporters. This may be relevant for drug therapy, given the strong involvement of these transporters in hepatic and renal drug elimination.


Assuntos
Agonistas Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/farmacologia , Proteínas de Transporte de Cátions Orgânicos/agonistas , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Acebutolol/química , Acebutolol/metabolismo , Acebutolol/farmacologia , Agonistas Adrenérgicos/química , Agonistas Adrenérgicos/metabolismo , Antagonistas Adrenérgicos/química , Antagonistas Adrenérgicos/metabolismo , Atenolol/química , Atenolol/farmacologia , Transporte Biológico , Fenoterol/química , Fenoterol/metabolismo , Fenoterol/farmacologia , Fumarato de Formoterol/química , Fumarato de Formoterol/metabolismo , Fumarato de Formoterol/farmacologia , Células HEK293 , Humanos , Cinética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Transportador 1 de Cátions Orgânicos/agonistas , Transportador 1 de Cátions Orgânicos/antagonistas & inibidores , Transportador 1 de Cátions Orgânicos/metabolismo , Transportador 2 de Cátion Orgânico/agonistas , Transportador 2 de Cátion Orgânico/antagonistas & inibidores , Transportador 2 de Cátion Orgânico/metabolismo , Estereoisomerismo
5.
J Physiol ; 597(24): 5835-5858, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31665811

RESUMO

KEY POINTS: Previous studies in fetuses with intrauterine growth restriction (IUGR) have shown that adrenergic dysregulation was associated with low insulin concentrations and greater insulin sensitivity. Although whole-body glucose clearance is normal, 1-month-old lambs with IUGR at birth have higher rates of hindlimb glucose uptake, which may compensate for myocyte deficiencies in glucose oxidation. Impaired glucose-stimulated insulin secretion in IUGR lambs is due to lower intra-islet insulin availability and not from glucose sensing. We investigated adrenergic receptor (ADR) ß2 desensitization by administering oral ADRß modifiers for the first month after birth to activate ADRß2 and antagonize ADRß1/3. In IUGR lambs ADRß2 activation increased whole-body glucose utilization rates and insulin sensitivity but had no effect on isolated islet or myocyte deficiencies. IUGR establishes risk for developing diabetes. In IUGR lambs we identified disparities in key aspects of glucose-stimulated insulin secretion and insulin-stimulated glucose oxidation, providing new insights into potential mechanisms for this risk. ABSTRACT: Placental insufficiency causes intrauterine growth restriction (IUGR) and disturbances in glucose homeostasis with associated ß adrenergic receptor (ADRß) desensitization. Our objectives were to measure insulin-sensitive glucose metabolism in neonatal lambs with IUGR and to determine whether daily treatment with ADRß2 agonist and ADRß1/ß3 antagonists for 1 month normalizes their glucose metabolism. Growth, glucose-stimulated insulin secretion (GSIS) and glucose utilization rates (GURs) were measured in control lambs, IUGR lambs and IUGR lambs treated with adrenergic receptor modifiers: clenbuterol atenolol and SR59230A (IUGR-AR). In IUGR lambs, islet insulin content and GSIS were less than in controls; however, insulin sensitivity and whole-body GUR were not different from controls. Of importance, ADRß2 stimulation with ß1/ß3 inhibition increases both insulin sensitivity and whole-body glucose utilization in IUGR lambs. In IUGR and IUGR-AR lambs, hindlimb GURs were greater but fractional glucose oxidation rates and ex vivo skeletal muscle glucose oxidation rates were lower than controls. Glucose transporter 4 (GLUT4) was lower in IUGR and IUGR-AR skeletal muscle than in controls but GLUT1 was greater in IUGR-AR. ADRß2, insulin receptor, glycogen content and citrate synthase activity were similar among groups. In IUGR and IUGR-AR lambs heart rates were greater, which was independent of cardiac ADRß1 activation. We conclude that targeted ADRß2 stimulation improved whole-body insulin sensitivity but minimally affected defects in GSIS and skeletal muscle glucose oxidation. We show that risk factors for developing diabetes are independent of postnatal catch-up growth in IUGR lambs as early as 1 month of age and are inherent to the islets and myocytes.


Assuntos
Retardo do Crescimento Fetal/tratamento farmacológico , Resistência à Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Receptores Adrenérgicos beta 2/metabolismo , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Antagonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Antagonistas de Receptores Adrenérgicos beta 2/farmacocinética , Antagonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Animais , Atenolol/administração & dosagem , Atenolol/farmacologia , Atenolol/uso terapêutico , Células Cultivadas , Clembuterol/administração & dosagem , Clembuterol/farmacologia , Clembuterol/uso terapêutico , Feminino , Retardo do Crescimento Fetal/metabolismo , Glucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Músculo Esquelético/metabolismo , Ovinos
6.
Pak J Pharm Sci ; 32(4): 1643-1648, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31608885

RESUMO

Murraya koenigii (L.) spreng (curry leaves) have traditionally been used for its various medicinal properties. The current study was conducted to assess the comparative effect of Murraya koenigii (L.) spreng (curry leaves) and market available beta blocker drug Atenolol on cardiac enzyme (CK-MB) level in male albino rats. Out of total 26 locally bred male Albino Wistar rats (180 to 200gm weight) two rats were treated with only voltral for dose adjustment. Remaining 24 rats were randomly categorized into following 1 control (C) group and 3 experimental groups Model (M), Test 1 (T1) and Test 2 (T2) containing 6 rats in each group. Rats in C group were orally fed by 0.9% saline solution while rats of M and both test groups T1 and T2 were orally treated with voltral tablet (30mg /kg body weight) for three weeks to increase the level of CK-MB heart enzyme. After voltral treatment rats in test group T1 were treated orally with Atenolol (30 mg/kg body weight) and T2 with Murraya koenigii (L.) spreng (curry leaves) extract (180 mg/kg body weight) for last three weeks. Results show that rats treated with Atenolol showed a decrease in level of heart enzyme as compare to M group, while Murraya koenigii (L.) spreng treated rats group T2 showed more significant decrease of heart enzyme (CK-MB) level as compared to M and T1 groups with significantly improved behavioral activity including increased locomotor activity, short-term memory and reduction in depression. These results demonstrate that natural herbal treatment by curry leaves extract play an effective role in lowering the cardiac enzyme (CK-MB) level to its normal range which helps reducing the risk of CVD and CHD.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Atenolol/farmacologia , Creatina Quinase Forma MB/sangue , Murraya/química , Preparações de Plantas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Miocárdio/enzimologia , Folhas de Planta/química , Ratos Wistar
7.
Cell Physiol Biochem ; 53(4): 587-605, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31535830

RESUMO

BACKGROUND/AIMS: To investigate the role of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in renal ischemia/reperfusion-induced (I/R) cardiac inflammatoryprofile. METHODS: Left kidney ischemia was induced in male C57BL/6 mice for 60 min, followed by reperfusion for 12 days, and treatment with or without atenolol, losartan, or enalapril. The expression of vimentin in kidney and atrial natriuretic factor (ANF) in the heart has been investigated by RT-PCR. In cardiac tissue, levels of ß1-adrenoreceptors, adenylyl cyclase, cyclic AMP-dependent protein kinase (PKA), noradrenaline, adrenaline (components of SNS), type 1 angiotensin II receptors (AT1R), angiotensinogen/Ang II and renin (components of RAS) have been measured by Western blotting and HPLC analysis. A panel of cytokines - tumour necrosis factor (TNF-α), interleukin IL-6, and interferon gamma (IFN-γ) - was selected as cardiac inflammatory markers. RESULTS: Renal vimentin mRNA levels increased by >10 times in I/R mice, indicative of kidney injury. ANF, a marker of cardiac lesion, increased after renal I/R, the values being restored to the level of Sham group after atenolol or enalapril treatment. The cardiac inflammatory profile was confirmed by the marked increase in the levels of mRNAs of TNF-α, IL-6, and IFN-γ. Atenolol and losartan reversed the upregulation of TNF-α expression, whereas enalapril restored IL-6 levels to Sham levels; both atenolol and enalapril normalized IFN-γ levels. I/R mice showed upregulation of ß1-adrenoreceptors, adenylyl cyclase, PKA and noradrenaline. Renal I/R increased cardiac levels of AT1R, which decreased after losartan or enalapril treatment. Renin expression also increased, with the upregulation returning to Sham levels after treatment with SNS and RAS blockers. Angiotensinogen/Ang II levels in heart were unaffected by renal I/R, but they were significantly decreased after treatment with losartan and enalapril, whereas increase in renin levels decreased. CONCLUSION: Renal I/R-induced cardiac inflammatory events provoked by the simultaneous upregulation of SNS and RAS in the heart, possibly underpin the mechanism involved in the development of cardiorenal syndrome.


Assuntos
Rim/metabolismo , Miocárdio/metabolismo , Sistema Renina-Angiotensina , Sistema Nervoso Simpático/metabolismo , Animais , Atenolol/farmacologia , Atenolol/uso terapêutico , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Catecolaminas/metabolismo , Enalapril/farmacologia , Enalapril/uso terapêutico , Interleucina-6/metabolismo , Losartan/farmacologia , Losartan/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Sistema Nervoso Simpático/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Vimentina/genética , Vimentina/metabolismo
8.
J Pharm Pharmacol ; 71(10): 1576-1583, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31347707

RESUMO

OBJECTIVES: Paraoxonase-1 (PON1) enzyme is related to high-density lipoprotein (HDL), which is calcium dependent. It has essential roles such as protecting LDL against oxidation and detoxification of highly toxic substances. It is a significant risk to reduce the levels of this enzyme in patients with diabetes mellitus, cardiovascular diseases, hyperthyroidism and chronic renal failure. METHODS: Here, it was reported that the purification of human serum PON1 using straightforward methods and determination of the interactions between some antihypertension drugs and the enzyme. KEY FINDING: It was found that these drugs exhibit potential inhibitor properties for human serum PON1 with IC50 values in the range of 131.40-369.40 µm and Ki values in the range of 56.24 ± 6.75-286.74 ± 28.28 µm. These drugs showed different inhibition mechanisms. It was determined that midodrine and nadolol were exhibited competitive inhibition, but atenolol and pindolol were exhibited non-competitive inhibition. CONCLUSION: Usage of these drugs would be hazardous in some cases.


Assuntos
Anti-Hipertensivos/farmacologia , Arildialquilfosfatase/sangue , Aterosclerose/sangue , Aterosclerose/tratamento farmacológico , Atenolol/farmacologia , Humanos , Lipoproteínas HDL/sangue , Midodrina/farmacologia , Nadolol/farmacologia , Pindolol/farmacologia
9.
Chemosphere ; 236: 124318, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31319310

RESUMO

The present paper deals with the atenolol (ATL) degradation by advanced anodic oxidation using a boron-doped diamond anode supported on niobium (Nb/BDD). Cyclic voltammetry performed on this electrode revealed that it presents a high quality (diamond-sp3/sp2-carbon ratio), high potential for OER and that ATL can be oxidized directly and/or indirectly by the electrogenerated oxidants, such as hydroxyl radicals, persulfate ions and sulfate radicals. Electrolysis experiments demonstrated that ATL degradation and mineralization follow a mixed (first and zero) order kinetics depending on the applied current density. At high applied current densities, the amount of OH radicals is very high and the overall reaction is limited by the transport of ATL (pseudo first-order kinetics) whereas for low applied current densities, the rate of OH radicals generation at the anode is slower than the rate of arrival of ATL molecules (pseudo-zero order kinetics). Estimated values of kzero and kfirst based on the assumption of pseudo-zero or pseudo-first order kinetics were carried oud as a function of the supporting electrolyte concentration, indicating that both parameters increased with its concentration due the higher production of sulfate reactive species that play an important role in degradation. Finally, MCE increased with the decrease of current density, due to the lower amount of OH present in solution, since this species could be rapidly wasted in parasitic reactions; and the increase of sulfate concentration due to the more efficient production of persulfate.


Assuntos
Atenolol/uso terapêutico , Eletrólise/métodos , Nióbio/química , Atenolol/farmacologia , Eletrodos
10.
Acta Cir Bras ; 34(5): e201900505, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31166461

RESUMO

PURPOSE: To evaluate the cardioprotective response of the pharmacological modulation of ß-adrenergic receptors (ß-AR) in animal model of cardiac ischemia and reperfusion (CIR), in spontaneously hypertensive (SHR) and normotensive (NWR) rats. METHODS: CIR was induced by the occlusion of left anterior descendent coronary artery (10 min) and reperfusion (75 min). The SHR was treated with ß-AR antagonist atenolol (AT, 10 mg/kg, IV) 5 min before CIR, and NWR were treated with ß-AR agonist isoproterenol (ISO, 0.5 mg/kg, IV) 5 min before CIR. RESULTS: The treatment with AT increased the incidence of VA, AVB and LET in SHR, suggesting that spontaneous cardioprotection in hypertensive animals was abolished by blockade of ß-AR. In contrast, the treatment with ISO significantly reduced the incidence of ventricular arrhythmia, atrioventricular blockade and lethality in NWR (30%, 20% and 20%, respectively), suggesting that the activation of ß-AR stimulate cardioprotection in normotensive animals. Serum CK-MB were higher in SHR/CIR and NWR/CIR compared to respective SHAM group (not altered by treatment with AT or ISO). CONCLUSION: The pharmacological modulation of ß-AR could be a new cardioprotective strategy for the therapy of myocardial dysfunctions induced by CIR related to cardiac surgery and cardiovascular diseases.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Atenolol/farmacologia , Cardiotônicos/farmacologia , Isoproterenol/farmacologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Receptores Adrenérgicos beta/efeitos dos fármacos , Animais , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Creatina Quinase Forma MB/sangue , Testes de Função Cardíaca , Masculino , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Ratos Endogâmicos SHR , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento
11.
J Clin Pharmacol ; 59(11): 1462-1470, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31090079

RESUMO

ß-Blockers' heart rate (HR)-lowering effect is an important determinant of the effectiveness for this class of drugs, yet it is variable among ß-blocker-treated patients. To date, genetic studies have revealed several genetic signals associated with HR response to ß-blockers. However, these genetic signals have not been consistently replicated across multiple independent cohorts. Here we sought to use data from 3 hypertension clinical trials to validate single-nucleotide polymorphisms (SNPs) previously associated with the HR response to ß-blockers. Using linear regression analysis, we investigated the effects of 6 SNPs in 3 genes, including ADRB1, ADRB2, and GNB3, relative to the HR response following ß-blocker used in the PEAR (n = 757), PEAR-2 (n = 368), and INVEST (n = 1401) trials, adjusting for baseline HR, age, sex, and ancestry. Atenolol was used in PEAR and INVEST, and metoprolol was used in PEAR-2. We found that rs1042714 and rs1042713 in ADRB2 were significantly associated with HR response to both ß-blockers in whites (rs1042714 C-allele carriers, meta-analysis ß = -0.95 beats per minute [bpm], meta-analysis P = 3×10-4 ; rs1042713 A-allele carriers, meta-analysis ß = -1.15 bpm, meta-analysis P = 2×10-3 ). In conclusion, the results of our analyses provide strong evidence to support the hypothesis that rs1042714 and rs1042713 in the ADRB2 gene are important predictors of HR response to cardioselective ß-blockade in hypertensive patient cohorts.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Frequência Cardíaca/genética , Receptores Adrenérgicos beta 2/genética , Grupo com Ancestrais do Continente Africano , Alelos , Atenolol/farmacologia , Grupo com Ancestrais do Continente Europeu , Feminino , Genótipo , Frequência Cardíaca/efeitos dos fármacos , Proteínas Heterotriméricas de Ligação ao GTP/genética , Humanos , Hipertensão/tratamento farmacológico , Masculino , Metoprolol/farmacologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores Adrenérgicos beta 1/genética
12.
Clin Transl Sci ; 12(5): 497-504, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31033190

RESUMO

European Americans (EA) have a better antihypertensive response to ß-blockers when compared with African Americans, albeit with some variability. We undertook a genomewide association study to elucidate the underlying genetic determinants in EA contributing to this variability in blood pressure (BP) response. A discovery genomewide association study of change in BP post-metoprolol treatment was performed in EA participants (n = 201) from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) study and tested for replication in the atenolol-treated EA from the PEAR study (n = 233). Rs294610 in the FGD5, which encodes for FYVE, RhoGEF and PH Domain Containing 5, (expression quantitative trait loci for FGD5 in the small intestine) was significantly associated with increased diastolic BP response to ß-blockers in the PEAR-2 study (P = 3.41 × 10-6 , ß = -2.70) and replicated (P = 0.01, ß = -1.17) in the PEAR study. Post-meta-analysis of these studies, an additional single nucleotide polymorphism rs45545233 in the SLC4A1, encoding for Solute Carrier Family 4 Member 1, (expression quantitative trait loci for dual specificity phosphatase 3 in the artery tibial) was identified that was significantly associated with a poor response to ß-blockers (P = 3.43 × 10-6 , ß = 4.57) and was replicated in the atenolol add-on cohort (P = 0.007, ß = 4.97). We identified variants in FGD5 and SLC4A1, which have been previously cited as candidate genes for hypertension, to be associated with a ß-blocker BP response in EA. Further elucidation is warranted of the underlying mechanisms of these variants and genes by which they influence the BP response to ß-blockers.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Pressão Sanguínea/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Atenolol/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Estudos de Coortes , Diástole/efeitos dos fármacos , Feminino , Humanos , Desequilíbrio de Ligação/genética , Masculino , Metanálise como Assunto , Metoprolol/farmacologia , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
13.
Eur J Pharm Sci ; 131: 93-98, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30753892

RESUMO

ß-blockers show variable efficacy as antihypertensives. Herein, we evaluated plasma miRNAs as biomarkers for defining antihypertensive response to ß-blockers. Expression of 22 ß-blocker pharmacodynamics-related miRNAs was assessed in baseline plasma samples from 30 responders and 30 non-responders to metoprolol from the PEAR-2 study (Discovery). Logistic regression was performed to identify miRNAs significantly associated with metoprolol response. Those miRNAs were profiled in baseline plasma samples from 25 responders and 25 non-responders to atenolol from the PEAR study (validation). In discovery, miR-101, miR-27a, miR-22, miR-19a, and let-7e were significantly associated with metoprolol response (P = 0.01, 0.017, 0.025, 0.025, and 0.04, respectively). In validation, miR-19a was significantly associated with atenolol response (P = 0.038). Meta-analysis between PEAR-2 and PEAR revealed significant association between miR-19a (P = 0.004), miR-101 (P = 0.006), and let-7e (P = 0.012) and ß-blocker response. Hence, miR-19a, miR-101, and let-7e, which regulate ß1-adrenergic receptor and other ß-blocker pharmacodynamics-related genes, may be biomarkers for antihypertensive response to ß-blockers.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Anti-Hipertensivos/farmacologia , Atenolol/farmacologia , Metoprolol/farmacologia , MicroRNAs/sangue , Adulto , Feminino , Humanos , Hipertensão/sangue , Hipertensão/genética , Masculino , Pessoa de Meia-Idade
14.
Am J Vet Res ; 80(3): 270-274, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30801219

RESUMO

OBJECTIVE To test the hypothesis that once-daily oral administration of atenolol would attenuate the heart rate response to isoproterenol for 24 hours. ANIMALS 20 healthy dogs. PROCEDURES A double-blind randomized placebo-controlled crossover study was conducted. Dogs were assigned to receive atenolol (1 mg/kg, PO, q 24 h) or a placebo for 5 to 7 days. After a washout period of 7 days, dogs then received the other treatment. Heart rate at rest (HRr) and heart rate induced by administration of isoproterenol (HRi) as a constant rate infusion (0.2 µg/kg/min for 5 to 7 minutes) were obtained by use of ECG 0, 0.25, 3, 6, 12, 18, and 24 hours after administration of the final dose of atenolol or the placebo. A mixed-model ANOVA was used to evaluate effects of treatment, time after drug or placebo administration, treatment-by-time interaction, period, and sequence on HRr and HRi. RESULTS Effects of sequence or period were not detected. There was a significant effect of treatment and the treatment-by-time interaction on HRi. Atenolol significantly attenuated HRi for 24 hours but did so maximally at 3 hours (least squares mean ± SE, 146 ± 5 beats/min and 208 ± 5 beats/min for atenolol and placebo, respectively). The effect at 24 hours was small (193 ± 5 beats/min and 206 ± 5 beats/min for atenolol and placebo, respectively). Atenolol had a small but significant effect on HRr. CONCLUSIONS AND CLINICAL RELEVANCE This study of healthy dogs receiving atenolol supported a recommendation for a dosing interval < 24 hours.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Agonistas Adrenérgicos beta , Atenolol/farmacologia , Cães , Isoproterenol/antagonistas & inibidores , Administração Oral , Animais , Pressão Sanguínea/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Frequência Cardíaca/efeitos dos fármacos , Masculino , Distribuição Aleatória
15.
J Physiol ; 597(7): 1819-1831, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30693527

RESUMO

KEY POINTS: The prevailing dogma about neurogenic regulation of vascular tone consists of major vasodilatation caused by CGRP (and possibly substance P) released from sensory-motor nerves and vasoconstriction caused by noradrenaline, ATP and neuropeptode Y release from sympathetic nerves. Most studies on perivascular nerve-mediated vasodilatation are made in vitro. In the present study, we provide evidence indicating that in vivo electrical perivascular nerve stimulation in rat mesenteric small arteries causes a large ß1-adrenoceptor-mediated vasodilatation, which contrasts with a smaller vasodilatation caused by endogenous CGRP that is only visible after inhibition of Y1 NPY receptors. ABSTRACT: Mesenteric arteries are densely innervated and the nerves are important regulators of vascular tone and hence blood pressure and blood flow. Perivascular sensory-motor nerves have been shown to cause vasodilatation in vitro. However, less is known about their function in vivo. Male Wistar rats (10-12 weeks old; n = 72) were anaesthetized with ketamine (3 mg kg-1 ) and xylazine (0.75 mg kg-1 ) or pentobarbital (60 mg kg-1 ). After a laparotomy, a section of second-order mesenteric artery was visualized in an organ bath after minimal removal of perivascular adipose tissue. The effects of electrical field stimulation (EFS) and drugs on artery diameter and blood flow were recorded with intravital microscopy and laser speckle imaging. EFS caused vasodilatation in arteries constricted with 1 µm U46619 in the presence of 140 µm suramin and 1 µm prazosin. The vasodilatation was inhibited by 1 µm tetrodotoxin and 5 µm guanethidine, although not by the 1 µm of the CGRP receptor antagonist BIBN4096bs. In the presence of 0.3 µm Y1 receptor antagonist BIBP3226, BIBN4096bs partly inhibited the vasodilatation. Atenolol at a concentration 1 µm inhibited the vasodilatation, whereas 0.1 µm of the ß2 -adrenoceptor selective antagonist ICI-118,551 had no effect. Increasing the extracellular [K+ ] to 20 mm caused vasodilatation but was converted to vasoconstriction in the presence of 1 µm BIBN4096bs, and constriction to 30 mm potassium was potentiated by BIBN4096bs. Atenolol but not BIBN4096bs increased contraction to EFS in the absence of suramin and prazosin. In mesenteric small arteries of anaesthetized rats, EFS failed to stimulate major dilatation via sensory-motor nerves but induced sympathetic ß1 -adrenoceptor-mediated dilatation.


Assuntos
Artérias Mesentéricas/fisiologia , Receptores Adrenérgicos beta 1/fisiologia , Vasodilatação/fisiologia , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Animais , Antinematódeos/farmacologia , Atenolol/farmacologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Piperazinas/farmacologia , Prazosina/farmacologia , Quinazolinas/farmacologia , Ratos , Ratos Wistar , Suramina/farmacologia , Técnicas de Cultura de Tecidos , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia , Vasodilatação/efeitos dos fármacos
16.
Drug Res (Stuttg) ; 69(2): 83-92, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29996172

RESUMO

There is a growing global interest in hypertension due to its associated complications including renal dysfunction in patients. The thyroid system reportedly regulates renal function in both animal and human. The present study investigated the therapeutic efficacy of taurine on renal and thyroid dysfunctions in hypertensive rats. Hypertension was induced by oral administration of nitric oxide synthase inhibitor, N-nitro L-arginine-methyl-ester (L-NAME), at 40 mg/kg body weight to the male Wistar rats for 14 consecutive days. The hypertensive rats were subsequently treated with either taurine (100 and 200 mg/kg) or reference drug atenolol (10 mg/kg) for another 14 consecutive days. Hypertensive rats showed renal damage evidenced by elevated plasma creatinine and urea levels when compared with normotensive control rats. Furthermore, L-NAME-induced hypertensive rats showed decreased circulatory concentrations of thyroid stimulating hormone, thyroxine, triiodothyronine and the ratio of triiodothyronine to thyroxine. The marked decrease in the renal antioxidant enzyme activities and nitric oxide level was accompanied by significant increase in myeloperoxidase activity and biomarkers of oxidative stress in hypertensive rats. Histological examination of kidneys from hypertensive rats revealed congestion of blood vessels, hemorrhagic lesion and disorganized glomerular structure. However, treatment with taurine or atenolol significantly reversed the suppression of thyroid function, ameliorated renal oxidative stress and histopathological lesions in L-NAME-induced hypertensive rats. Taurine may be a useful chemotherapeutic supplement in enhancing renal and thyroid functions in hypertensive patients.


Assuntos
Hipertensão/complicações , Insuficiência Renal/prevenção & controle , Taurina/administração & dosagem , Glândula Tireoide/fisiopatologia , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Atenolol/farmacologia , Atenolol/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Suplementos Nutricionais , Modelos Animais de Doenças , Humanos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/patologia , Masculino , NG-Nitroarginina Metil Éster/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Insuficiência Renal/etiologia , Insuficiência Renal/patologia , Glândula Tireoide/efeitos dos fármacos
17.
Acta cir. bras ; 34(5): e201900505, 2019. graf
Artigo em Inglês | LILACS | ID: biblio-1010872

RESUMO

Abstract Purpose: To evaluate the cardioprotective response of the pharmacological modulation of β-adrenergic receptors (β-AR) in animal model of cardiac ischemia and reperfusion (CIR), in spontaneously hypertensive (SHR) and normotensive (NWR) rats. Methods: CIR was induced by the occlusion of left anterior descendent coronary artery (10 min) and reperfusion (75 min). The SHR was treated with β-AR antagonist atenolol (AT, 10 mg/kg, IV) 5 min before CIR, and NWR were treated with β-AR agonist isoproterenol (ISO, 0.5 mg/kg, IV) 5 min before CIR. Results: The treatment with AT increased the incidence of VA, AVB and LET in SHR, suggesting that spontaneous cardioprotection in hypertensive animals was abolished by blockade of β-AR. In contrast, the treatment with ISO significantly reduced the incidence of ventricular arrhythmia, atrioventricular blockade and lethality in NWR (30%, 20% and 20%, respectively), suggesting that the activation of β-AR stimulate cardioprotection in normotensive animals. Serum CK-MB were higher in SHR/CIR and NWR/CIR compared to respective SHAM group (not altered by treatment with AT or ISO). Conclusion: The pharmacological modulation of β-AR could be a new cardioprotective strategy for the therapy of myocardial dysfunctions induced by CIR related to cardiac surgery and cardiovascular diseases.


Assuntos
Animais , Masculino , Atenolol/farmacologia , Cardiotônicos/farmacologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Receptores Adrenérgicos beta/efeitos dos fármacos , Agonistas Adrenérgicos beta/farmacologia , Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Isoproterenol/farmacologia , Ratos Endogâmicos SHR , Fatores de Tempo , Pressão Sanguínea/efeitos dos fármacos , Biomarcadores/sangue , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/sangue , Reprodutibilidade dos Testes , Resultado do Tratamento , Creatina Quinase Forma MB/sangue , Testes de Função Cardíaca
18.
Acta cir. bras ; 33(12): 1061-1066, Dec. 2018. tab
Artigo em Inglês | LILACS | ID: biblio-973491

RESUMO

Abstract Purpose: To investigate the role of atenolol in the gene expression of caspase 1 (Casp1) and Bcl2L1 on vascular endothelium of rat intestine after ischemia and reperfusion (IR). Methods: Eighteen adult male Wistar rats were randomly divided into 3 groups (n=6): SG (Sham group): no clamping of the superior mesenteric artery; IRG: IR plus saline group: IRG+At: IR plus Atenolol group. Rats from IRG and IRG+At were subjected to 60 min of intestinal ischemia and 120 min of reperfusion. Atenolol (2mg/kg) or saline were injected in the femoral vein 5 min before ischemia, 5 min and 55 min after reperfusion. Thereafter, intestinal segments were appropriately removed and processed for Endothelial Cell Biology Rat RT2 Profiler PCR Array. Results: the anti-apoptotic Bcl2L1 gene expression was significantly down-regulated (-1.10) in the IRG and significantly up-regulated in the IRG+At (+14.15). Meanwhile, despite Casp1 gene expression was upregulated in both groups, it was significantly higher in the IRG (+35.06) than the IRG+At (+6.68). Conclusions: Atenolol presents antiapoptotic effects on rat intestine subjected to IR partly by the up-regulation of the anti-apoptotic Bcl2L1 gene expression. Moreover, atenolol can mitigate the pro-apoptotic and pro-inflammatory effects of Casp1 gene on rat intestine after IR.


Assuntos
Animais , Masculino , Atenolol/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Expressão Gênica/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Caspase 1/efeitos dos fármacos , Proteína bcl-X/efeitos dos fármacos , Intestino Delgado/irrigação sanguínea , Fatores de Tempo , Endotélio Vascular , Distribuição Aleatória , Regulação para Baixo/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Reação em Cadeia da Polimerase , Reprodutibilidade dos Testes , Resultado do Tratamento , Ratos Wistar , Artéria Mesentérica Superior , Apoptose/efeitos dos fármacos , Constrição , Citoproteção/efeitos dos fármacos , Caspase 1/genética , Proteína bcl-X/genética , Isquemia Mesentérica/prevenção & controle
19.
J Clin Hypertens (Greenwich) ; 20(10): 1464-1472, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30289609

RESUMO

A quantitative survey was completed by 103 primary care physicians (PCPs) and 59 cardiologists who regularly prescribed ß-blockers to assess knowledge and use of this heterogeneous drug class for hypertension. More cardiologists than PCPs chose ß-blockers as initial antihypertensive therapy (30% vs 17%, P < 0.01). Metoprolol and carvedilol were the most commonly prescribed ß-blockers. Cardiologists rated "impact on energy" and "arterial vasodilation" as more important than PCPs (P < 0.05/<0.01, respectively). Awareness of vasodilation was greater for carvedilol (52%) than nebivolol (31%). Association between ß-blockers and clinical variables included nebivolol with ß1 -selectivity, nebivolol and carvedilol with vasodilation and efficacy in older patients and African Americans, metoprolol with heart rate reduction, and atenolol and metoprolol with weight gain and hyperglycemia. Physicians preferred prescribing ß-blockers with lower risk of incident diabetes. Clinical practice guidelines influenced physician prescribing more than formularies or performance metrics. This survey captures physicians' perceptions/use of various ß-blockers and clinically relevant knowledge gaps.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Cardiologistas/estatística & dados numéricos , Hipertensão/tratamento farmacológico , Médicos de Atenção Primária/estatística & dados numéricos , Antagonistas Adrenérgicos beta/efeitos adversos , Antagonistas Adrenérgicos beta/uso terapêutico , Afro-Americanos/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/uso terapêutico , Atenolol/efeitos adversos , Atenolol/farmacologia , Cardiologistas/psicologia , Carvedilol/efeitos adversos , Carvedilol/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/epidemiologia , Hipertensão/mortalidade , Metoprolol/efeitos adversos , Metoprolol/farmacologia , Nebivolol/efeitos adversos , Nebivolol/farmacologia , Percepção , Médicos de Atenção Primária/psicologia , Guias de Prática Clínica como Assunto , Inquéritos e Questionários , Vasodilatação/efeitos dos fármacos
20.
J Clin Hypertens (Greenwich) ; 20(11): 1603-1609, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30267456

RESUMO

Beta-blockers are one of the most commonly prescribed classes of antihypertensive medications during pregnancy. Previous studies reported an association between beta-blocker exposure and intrauterine growth restriction. Whether some beta-blocker subtypes may be associated with higher risk is not known. This is a retrospective cohort study of pregnant women exposed to beta-blockers in the Kaiser Permanente Southern California Region between 2003 and 2014. Logistic regression models were used to evaluate association between exposure to different beta-blocker agents and risk of low fetal birth weights. In a cohort of 379 238 singleton pregnancies, 4847 (1.3%) were exposed to beta-blockers. The four most commonly prescribed beta-blockers were labetalol (n = 3357), atenolol (n = 638), propranolol (n = 489), and metoprolol (n = 324). Mean birth weight and % low birth weight (<2500 g) were 2926 ± 841 g and 24.4% for labetalol, 3058 ± 748 g and 18.0% for atenolol, 3163 ± 702 g and 13.3% for metoprolol, 3286 ± 651 g and 7.6% for propranolol, and 3353 ± 554 g and 5.2% for non-exposed controls. Exposure to atenolol and labetalol were associated with increased risks of infant born small for gestational age (SGA) (atenolol: adjusted OR 2.4, 95% CI: 1.7-3.3; labetalol: adjusted OR 2.9, 95% CI: 2.6-3.2). Risk of SGA associated with metoprolol or propranolol exposure was not significantly different from the non-exposed group (metoprolol: adjusted OR 1.5, 95% CI: 0.9-2.3; propranolol: adjusted OR 1.3, 95% CI: 0.9-1.9). Association between beta-blocker exposure and SGA does not appear to be a class effect. Variations in pharmacodynamics and confounding by indication may explain these findings.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Anti-Hipertensivos/farmacologia , Peso ao Nascer/efeitos dos fármacos , Retardo do Crescimento Fetal/induzido quimicamente , Antagonistas Adrenérgicos beta/efeitos adversos , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Atenolol/efeitos adversos , Atenolol/farmacologia , Atenolol/uso terapêutico , California/epidemiologia , Feminino , Retardo do Crescimento Fetal/epidemiologia , Retardo do Crescimento Fetal/etnologia , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Labetalol/efeitos adversos , Labetalol/farmacologia , Labetalol/uso terapêutico , Masculino , Metoprolol/efeitos adversos , Metoprolol/farmacologia , Metoprolol/uso terapêutico , Gravidez , Prevalência , Propranolol/efeitos adversos , Propranolol/farmacologia , Propranolol/uso terapêutico , Estudos Retrospectivos
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