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2.
Molecules ; 26(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071328

RESUMO

Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete. Computational methodologies such as molecular mechanics (MM) and quantum mechanical (QM) methods play an important role in elucidating the detailed mechanisms of enzymatic reactions where experimental research measurements are not possible. Theories invoked by a variety of scientists indicate that enzymes work as structural scaffolds that serve to bring together and orient the reactants so that the reaction can proceed with minimum energy. Enzyme models can be utilized for mimicking enzyme catalysis and the development of novel prodrugs. Prodrugs are used to enhance the pharmacokinetics of drugs; classical prodrug approaches focus on alternating the physicochemical properties, while chemical modern approaches are based on the knowledge gained from the chemistry of enzyme models and correlations between experimental and calculated rate values of intramolecular processes (enzyme models). A large number of prodrugs have been designed and developed to improve the effectiveness and pharmacokinetics of commonly used drugs, such as anti-Parkinson (dopamine), antiviral (acyclovir), antimalarial (atovaquone), anticancer (azanucleosides), antifibrinolytic (tranexamic acid), antihyperlipidemia (statins), vasoconstrictors (phenylephrine), antihypertension (atenolol), antibacterial agents (amoxicillin, cephalexin, and cefuroxime axetil), paracetamol, and guaifenesin. This article describes the works done on enzyme models and the computational methods used to understand enzyme catalysis and to help in the development of efficient prodrugs.


Assuntos
Enzimas/química , Pró-Fármacos/química , Aciclovir/química , Atenolol/química , Atovaquona/química , Catálise , Química Farmacêutica/métodos , Decitabina/química , Dopamina/química , Concentração de Íons de Hidrogênio , Hidrólise , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Conformação Molecular , Nucleosídeos/química , Fenilefrina/química , Prótons , Teoria Quântica , Software , Tecnologia Farmacêutica/métodos , Temperatura , Ácido Tranexâmico/química
4.
Artigo em Alemão | MEDLINE | ID: mdl-34187073

RESUMO

Vasopressors are widely used in anaesthesiology and critical care medicine, to treat harmless (e.g. anaesthesia-induced hypotension) as well as life-threatening conditions (e.g. septic shock). Some clinically used vasopressors resemble endogenous substances - such as norepinephrine - while others have been artificially synthesized (e.g. phenylephrine). Most of the substances used in different clinical scenarios have various effects except for vasoconstriction alone. Therefore, a thorough understanding of the pharmacology and clinical profile of every single substance is of highest importance prior to practical usage. Furthermore, the fundamentals of vascular physiology and vasotonic regulation are mandatory to safely provide vasopressor-based therapies. This article covers the essentials of physiology and pharmacology of vasopressors, and the clinical settings they are used in (e.g. septic shock, vasoplegic shock after cardiac surgery, trauma-induced hypotension).


Assuntos
Choque Séptico , Choque , Humanos , Norepinefrina , Fenilefrina , Choque Séptico/tratamento farmacológico , Vasoconstritores/uso terapêutico
5.
Molecules ; 26(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064778

RESUMO

Kynurenic acid (KYNA) is derived from tryptophan, formed by the kynurenic pathway. KYNA is being widely studied as a biomarker for neurological and cardiovascular diseases, as it is found in ischemic conditions as a protective agent; however, little is known about its effect after ischemia-reperfusion in the vascular system. We induced ischemia for 30 min followed by 5 min reperfusion (I/R) in the rat aorta for KYNA evaluation using functional assays combined with proteomics. KYNA recovered the exacerbated contraction induced by phenylephrine and relaxation induced by acetylcholine or sodium nitroprussiate in the I/R aorta, with vessel responses returning to values observed without I/R. The functional recovery can be related to the antioxidant activity of KYNA, which may be acting on the endothelium-injury prevention, especially during reperfusion, and to proteins that regulate neurotransmission and cell repair/growth, expressed after the KYNA treatment. These proteins interacted in a network, confirming a protein profile expression for endothelium and neuron repair after I/R. Thus, the KYNA treatment had the ability to recover the functionality of injured ischemic-reperfusion aorta, by tissue repairing and control of neurotransmitter release, which reinforces its role in the post-ischemic condition, and can be useful in the treatment of such disease.


Assuntos
Aorta/patologia , Ácido Cinurênico/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Proteômica , Acetilcolina/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Modelos Animais de Doenças , Ácido Cinurênico/farmacologia , Contração Miocárdica/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Nitroprussiato/farmacologia , Fenilefrina/farmacologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Ratos Sprague-Dawley , Vasodilatação/efeitos dos fármacos
6.
Am J Physiol Regul Integr Comp Physiol ; 321(1): R62-R78, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33978481

RESUMO

Obese Zucker rats (OZRs) develop hypertension and hyperinsulinemia by 3 mo of age. Male OZRs also have diminished baroreflex-mediated activation of nucleus tractus solitarius (NTS) and bradycardia, which are improved by correcting their hyperglycemia. Conversely, 3-mo-old female OZRs and lean Zucker rats (LZRs) have equivalent baroreflex-mediated bradycardia that is impaired in 6-mo-old OZRs. We hypothesized that 3-mo-old female OZRs maintain NTS activation and baroreflexes coincident with glycemic control. We also hypothesized that 6-mo-old female OZRs develop impaired baroreflexes with hyperglycemia and diminished NTS activation. In 12- to 16-wk-old females, sympathetic nerve activity (SNA) and arterial pressure (AP) were higher in OZRs than LZRs. However, baroreflex-mediated inhibition of SNA and bradycardia were equivalent in female OZRs and LZRs. Unlike deficits in male OZRs, female OZRs and LZRs had no differences in phenylephrine-induced c-Fos expression in NTS or decreases in SNA and AP evoked by glutamate into NTS. Compared with hyperglycemia in male OZRs (217.9 ± 34.4 mg/dL), female OZRs had normal fed blood glucose levels (108.2 ± 1.6 mg/dL in LZRs and 113.6 ± 3.5 mg/dL in OZRs) with emerging glucose intolerance. Conscious 24- to 27-wk-old female OZRs had impaired baroreflex-mediated bradycardia, but fed blood glucose was modestly elevated (124.2 ± 5.2 mg/dL) and phenylephrine-induced c-Fos expression in NTS was comparable to LZRs. These data suggest that better glycemic control in 3-mo-old female OZRs prevents diminished NTS activation and baroreflexes, supporting the notion that hyperglycemia impairs these responses in male OZRs. However, 6-mo-old female OZRs had impaired baroreflex efficacy without diminished NTS activation or pronounced hyperglycemia, suggesting baroreflex deficits develop by different mechanisms in female and male OZRs.


Assuntos
Barorreflexo/fisiologia , Glicemia/metabolismo , Controle Glicêmico , Hipertensão , Obesidade , Envelhecimento , Animais , Colesterol/sangue , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperinsulinismo , Insulina/sangue , Masculino , Fenilefrina/farmacologia , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Zucker , Fatores Sexuais , Sistema Nervoso Simpático , Triglicerídeos/sangue
9.
Anal Chem ; 93(15): 6034-6042, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33830731

RESUMO

The novel fluorescent agonists were discovered herein for α1-adrenergic receptors (α1-ARs) based on photoinduced electron transfer (PeT) off-on switch by conjugating the fluorophore 7-(diethylamino)coumarin-3-carboxylic acid with phenylephrine. After careful evaluation, these probes exhibited efficient binding affinity with α1-ARs and could be applied to selectively imaging α1-ARs or successfully tracing the dynamic process of α1-AR internalization in living cells. Meanwhile, a bioluminescence resonance energy transfer binding assay with these new probes has been well-established and applied. Therefore, these PeT-based on-off agonists may serve as powerful tools for the α1-AR-associated study during drug discovery.


Assuntos
Elétrons , Receptores Adrenérgicos alfa 1 , Transporte de Elétrons , Corantes Fluorescentes , Células HEK293 , Humanos , Fenilefrina , Receptores Adrenérgicos alfa 1/metabolismo
10.
Biomed Pharmacother ; 139: 111567, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33848773

RESUMO

This study was designed to determine the effectiveness of 5-(3-Hydroxybenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-5), 5-(4-Hydroxybenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-8), 5-(3-Chlorobenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-9) and 5-(4-Chlorobenzylidene)-2, 4, 6(1H, 3H, 5H)-pyrimidinetrione (SR-10) against hypertension. In deoxycorticosterone acetate-salt rats, SR-5, SR-8, SR-9, and SR-10 reduced blood pressure and normalized renal functions. In isolated rat aortic rings, SR-5, SR-8, SR-9, and SR-10 relaxed phenylephrine (PE) and K+-induced contractions. The vasodilator effect was endothelium-independent. Test compounds caused a rightward shift of Ca++ and PE concentration-response curves with a reduction of maximum response. SR-5, SR-8, SR-9, and SR-10 inhibited PE peak contractions in a Ca++ free medium. In guinea-pig atria, SR5, SR-8, SR-9, and SR-10 caused a mild-to-moderate inhibition of force and rate of contractions. In the aorta and heart tissues, the test compounds enhanced glutathione-s-transferase, reduced glutathione and catalase levels, improved cellular architecture, and decreased lipid peroxidation and expression of inflammatory markers: cyclooxygenase 2, tumor necrosis factor alpha, phosphorylated c-Jun N-terminal kinase, and phosphorylated-nuclear factor kappa B, evidenced in the immunohistochemistry, enzyme-linked immunosorbent assay, western blot molecular investigations and a decreased mRNA expression of calcium channel in RT-PCR analysis. SR-5, SR-8, SR-9, and SR-10 increased the urinary output in rats and inhibited the human platelet aggregation. This study revealed that SR-5, SR-8, SR-9, and SR-10 possess BP lowering, reno-protective, vasodilatory (mediated via Ca++ antagonist, antioxidant and anti-inflammatory pathways), partial cardio-suppressant, diuretic, and antiplatelet effects, demonstrating their therapeutic potential in hypertension management.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Pirimidinas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Hipertensivos/uso terapêutico , Antioxidantes/farmacologia , Aorta/efeitos dos fármacos , Cálcio/farmacologia , Desoxicorticosterona , Feminino , Cobaias , Humanos , Hipertensão/induzido quimicamente , Testes de Função Renal , Masculino , Camundongos , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Fenilefrina/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Pirimidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Vasodilatadores/farmacologia
11.
BMJ Case Rep ; 14(4)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795288

RESUMO

This case report summarises the case of a 56-year-old man with low-flow, ischaemic priapism requiring urgent insertion of a penile prosthesis following prophylactic anticoagulation with tinzaparin. Low-molecular-weight heparin (LMWH) has been proposed as a cause of ischaemic priapism, although reported cases of this are rare. This particular side effect of tinzaparin has been reported once in a case report in 2018, and there are scant other reports of LMWH-induced priapism. This case was refractory to the full treatment algorithm, including multiple aspirations, phenylephrine injection, cavernosal shunt and required transfer for implantation of a penile prosthesis. Only one other case of such a severe case of priapism has been documented, involving LMWH and warfarin. Documented evidence of possible causes of priapism are vital, given the rarity of this condition, the frequency of LMWH and the potentially devastating complications.


Assuntos
Prótese de Pênis , Priapismo , Heparina de Baixo Peso Molecular/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Pênis , Fenilefrina , Priapismo/induzido quimicamente , Tinzaparina
12.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807195

RESUMO

(1) Background: The exact mechanism(s) underlying pathological changes in a heart in transition to hypertrophy and failure are not yet fully understood. However, alterations in cardiac energy metabolism seem to be an important contributor. We characterized an in vitro model of adrenergic stimulation-induced cardiac hypertrophy for studying metabolic, structural, and functional changes over time. Accordingly, we investigated whether metabolic interventions prevent cardiac structural and functional changes; (2) Methods: Primary rat cardiomyocytes were treated with phenylephrine (PE) for 16 h, 24 h, or 48 h, whereafter hypertrophic marker expression, protein synthesis rate, glucose uptake, and contractile function were assessed; (3) Results: 24 h PE treatment increased expression of hypertrophic markers, phosphorylation of hypertrophy-related signaling kinases, protein synthesis, and glucose uptake. Importantly, the increased glucose uptake preceded structural and functional changes, suggesting a causal role for metabolism in the onset of PE-induced hypertrophy. Indeed, PE treatment in the presence of a PAN-Akt inhibitor or of a GLUT4 inhibitor dipyridamole prevented PE-induced increases in cellular glucose uptake and ameliorated PE-induced contractile alterations; (4) Conclusions: Pharmacological interventions, forcing substrate metabolism away from glucose utilization, improved contractile properties in PE-treated cardiomyocytes, suggesting that targeting glucose uptake, independent from protein synthesis, forms a promising strategy to prevent hypertrophy and hypertrophy-induced cardiac dysfunction.


Assuntos
Cardiomegalia/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Metabolismo Energético , Glucose/metabolismo , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Miócitos Cardíacos/efeitos dos fármacos , Fenilefrina/farmacologia , Fosforilação , Ratos , Transdução de Sinais/efeitos dos fármacos
13.
Biosci Biotechnol Biochem ; 85(5): 1128-1139, 2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33693487

RESUMO

The C-terminal of G protein-coupled receptors is now recognized as being important for G protein activation and signaling function. To detect the role of C-terminal tail in receptor activation, we used the α1b-AR, which has a long C-terminal of 164 amino acids. We constructed the intramolecular FRET sensors, in which the C-terminal was truncated to 10 (∆C-10), 20 (∆C-20), 30 (∆C-30), 50 (∆C-50), 70 (∆C-70), or 90 (∆C-90). The truncated mutants of ∆C-10, ∆C-20, or ∆C-30 cannot induce FRET signal changes and downstream ERK1/2 phosphorylation. However, the truncated mutants of ∆C-50, ∆C-70, or ∆C-90 induce significant FRET signal changes and downstream ERK1/2 phosphorylation, especially ∆C-90. This is particularly true in the case of the ∆C-90, ∆C-70, or ∆C-50 which retained the potential phosphorylation sites (Ser401, Ser404, Ser408, or Ser410). The ∆C-90 showed an increase in agonist-induced FRET signal changes and ERK1/2 phosphorylation in PKC- or endocytosis-dependent and EGFR-, src-, or ß-arrestin2-independent.


Assuntos
Técnicas Biossensoriais , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Processamento de Proteína Pós-Traducional , Receptores Adrenérgicos alfa 1/química , beta-Arrestina 2/genética , Animais , Transferência Ressonante de Energia de Fluorescência , Expressão Gênica , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Mesocricetus , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Fenilefrina/farmacologia , Fosforilação/efeitos dos fármacos , Plasmídeos/química , Plasmídeos/metabolismo , Domínios Proteicos , Engenharia de Proteínas/métodos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores Adrenérgicos alfa 1/genética , Receptores Adrenérgicos alfa 1/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Serina/metabolismo , beta-Arrestina 2/antagonistas & inibidores , beta-Arrestina 2/metabolismo
14.
Ther Deliv ; 12(3): 201-214, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33715382

RESUMO

Design: Prospective, double-masked, controlled, cross-over superiority studies. Materials & methods: Eligible volunteers in two pooled Phase III trials received microdosed mydriatics. MIST-1 study subjects received fixed-combination TR-PH, phenylephrine 2.5% (PH) or tropicamide 1% (TR). MIST-2 study subjects received TR-PH or placebo. Mean change from baseline in pupil diameter was measured by digital pupillometry at 35 min postadministration. Results: Pooled efficacy analysis included 131 subjects. Compared with TR-PH, treatment group difference in 35-min change in mean pupil dilation from baseline was 0.58 mm (p < 0.0001) with TR, 3.87 mm (p < 0.0001) with PH and 4.65 mm (p < 0.0001) with placebo. Adverse events reported were infrequent, transient and mostly mild. Conclusion: TR-PH demonstrated superior pupil dilation compared with each component and placebo. TR-PH was safe & well-tolerated.


Assuntos
Midríase , Tropicamida , Humanos , Soluções Oftálmicas , Fenilefrina , Estudos Prospectivos , Pupila
15.
Chin Med J (Engl) ; 134(7): 792-799, 2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33661141

RESUMO

BACKGROUND: Norepinephrine infusion decreases hypotension after spinal anesthesia during cesarean section. This study aimed to compare the efficacy of norepinephrine infusion and ephedrine bolus against post-spinal hypotension in parturients. METHODS: In this double-blinded, randomized controlled clinical trial, parturients scheduled for elective cesarean section were randomly allocated to receive norepinephrine infusion (0.05 µg·kg-1·min-1) just before spinal anesthesia continuing for 30 min or ephedrine bolus (0.15 mg/kg) just before spinal anesthesia. A rescue bolus (5 µg norepinephrine for the norepinephrine group, and 5 mg ephedrine for the ephedrine group) was administered whenever hypotension occurred. Our primary outcome was the incidence of hypotension within 30 min of spinal anesthesia administration. Secondary outcomes included maternal and neonatal outcomes 30 min after spinal block, and neonatal cerebral oxygenation 10 min after birth. RESULTS: In total, 190 patients were enrolled; of these patients, 177 were included in the final analysis. Fewer patients suffered hypotension in the norepinephrine group than in the ephedrine group (29.5% vs. 44.9%, odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.28-0.95, P = 0.034). Moreover, the tachycardia frequency was lower in the norepinephrine group than in the ephedrine group (OR: 0.22, 95% CI: 0.11-0.44, P < 0.001), and patients suffered less nausea and vomiting (OR: 0.28, 95% CI: 0.11-0.70, P = 0.004). There was no difference in Apgar scores and umbilical arterial blood gas analysis between the two groups. However, neonatal cerebral regional saturations were significantly higher after birth in the norepinephrine group than in the ephedrine group (mean difference: 2.0%, 95% CI: 0.55%-3.45%, P = 0.008). CONCLUSION: In patients undergoing elective cesarean section with spinal anesthesia, norepinephrine infusion compared to ephedrine bolus resulted in less hypotension and tachycardia, and exhibited potential neonatal benefits. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02542748; https://clinicaltrials.gov/ct2/show/record/NCT02542748.


Assuntos
Raquianestesia , Hipotensão , Raquianestesia/efeitos adversos , Cesárea/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Hipotensão/tratamento farmacológico , Hipotensão/prevenção & controle , Recém-Nascido , Fenilefrina , Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto , Vasoconstritores/uso terapêutico
17.
J Ethnopharmacol ; 272: 113920, 2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-33607200

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Pinoresinol diglucoside (PDG), the active compound extracted from Eucommia ulmoides, Styrax sp. and Forsythia suspensa, plays the roles in regulating hypertension, inflammation and oxidative stress. AIMS: Considering that hypertension and inflammation has been proved to contribute to cardiac remodeling, we tested the effects of PDG on cardiac hypertrophy (CM). METHODS: Male Sprague Dawley (SD) rats were used to construct hypertrophic rats by partial abdominal aortic constriction (AAC)-surgery. PDG solution (2 mg/ml) was used to treat AAC-induced rats by intraperitoneal injection at low dose (L-PDG, 2.5 mg/kg per day), medium dose (M-PDG, 5 mg/kg per day), and high dose (H-PDG, 7.5 mg/kg per day) for 3 weeks post AAC-surgery. CM was evaluated by the ratio of left ventricular weight to body weight ratio (LVW/BW), left ventricular wall thickness by H&E staining, and collagen content deposit by Masson's staining. Further, isoproterenol (ISO) and phenylephrine (PE) were used to produce cellular models of CM in neonatal rat ventricular cardiomyocytes (NRVMs). PDG pre-treated NRVMs 2 h at low dose (L-PDG, 2.5 µg/ml), medium dose (M-PDG, 5 µg/ml), and high dose (H-PDG, 7.5 µg/ml) for 24 h with or without PE- and ISO-stimulation. CM was evaluated by the expressions of hypertrophic biomarkers. Next, the hypertrophic biomarkers and pro-inflammatory cytokines were measured using quantitative real-time PCR (qRT-PCR), the expressions of protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/transcription factor nuclear factor-kappa B (NF-kB) signaling pathway were determined by Western blotting. RESULTS: PDG treatment prevented cardiac histomorphology damages, decreased upregulations of hypertrophic biomarkers, and prevented fibrosis and inflammation after pressure overload resulting from AAC-surgery. Consistently, PDG remarkably inhibited the changes of cardiomyocyte hypertrophic biomarkers and inflammatory responses in cellular models of CM. Interestingly, PDG administration inhibited the activation of AKT/mTOR/NF-kB signaling pathway both in vivo and in vitro. CONCLUSIONS: PDG prevents AAC-induced CM in vivo, PE- and ISO-induced CM in vitro. The AKT/mTOR/NF-kB signaling pathway could be the potential therapeutic target involved in the protection of PDG. These findings provide novel evidence that PDG might be a promising therapeutic strategy for CM.


Assuntos
Cardiomegalia/tratamento farmacológico , Lignanas/farmacocinética , Lignanas/uso terapêutico , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Animais Recém-Nascidos , Aorta Abdominal/cirurgia , Cardiomegalia/etiologia , Cardiomegalia/patologia , Constrição Patológica , Modelos Animais de Doenças , Fibrose/prevenção & controle , Inflamação/prevenção & controle , Isoproterenol/toxicidade , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Fenilefrina/toxicidade , Pressão , Cultura Primária de Células , Ratos Sprague-Dawley , Remodelação Ventricular/efeitos dos fármacos
18.
Am J Physiol Heart Circ Physiol ; 320(5): H2112-H2129, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33606584

RESUMO

Electronic cigarette (e-cig) vaping (ECV) has been proposed as a safer alternative to tobacco cigarette smoking (TCS); however, this remains controversial due to a lack of long-term comparative studies. Therefore, we developed a chronic mouse exposure model that mimics human vaping and allows comparison with TCS. Longitudinal studies were performed to evaluate alterations in cardiovascular function with TCS and ECV exposure durations of up to 60 wk. For ECV, e-cig liquid with box-mod were used and for TCS, 3R4F-cigarettes. C57/BL6 male mice were exposed 2 h/day, 5 days/wk to TCS, ECV, or air control. The role of vape nicotine levels was evaluated using e-cig-liquids with 0, 6, or 24 mg/mL nicotine. Following 16-wk exposure, increased constriction to phenylephrine and impaired endothelium-dependent and endothelium-independent vasodilation were observed in aortic segents, paralleling the onset of systemic hypertension, with elevations in systemic vascular resistance. Following 32 wk, TCS and ECV induced cardiac hypertrophy. All of these abnormalities further increased out to 60 wk of exposure, with elevated heart weight and aortic thickness along with increased superoxide production in vessels and cardiac tissues of both ECV and TCS mice. While ECV-induced abnormalities were seen in the absence of nicotine, these occurred earlier and were more severe with higher nicotine exposure. Thus, long-term vaping of e-cig can induce cardiovascular disease similar to TCS, and the severity of this toxicity increases with exposure duration and vape nicotine content.NEW & NOTEWORTHY A chronic mouse exposure model that mimics human e-cigarette vaping and allows comparison with tobacco cigarette smoking was developed and utilized to perform longitudinal studies of alterations in cardiovascular function. E-cigarette exposure led to the onset of cardiovascular disease similar to that with tobacco cigarette smoking. Impaired endothelium-dependent and endothelium-independent vasodilation with increased adrenergic vasoconstriction were observed, paralleling the onset of systemic hypertension and subsequent cardiac hypertrophy. This cardiovascular toxicity was dependent on exposure duration and nicotine dose.


Assuntos
Aorta/efeitos dos fármacos , Doenças Cardiovasculares/induzido quimicamente , Nicotina/administração & dosagem , Vaping/efeitos adversos , Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Animais , Aorta/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/fisiopatologia , Sistemas Eletrônicos de Liberação de Nicotina , Masculino , Camundongos , Fenilefrina/farmacologia , Fatores de Tempo , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia
19.
Oxid Med Cell Longev ; 2021: 3109294, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33623633

RESUMO

Diabetes mellitus contributes to macro- and microvascular complications, leading to adverse cardiovascular events. This study examined the effects of vitamin D deficiency on the vascular function and tissue oxidative status in the microcirculation of diabetic rats and to determine whether these effects can be reversed with calcitriol (active vitamin D metabolite) supplementation. Streptozotocin-induced diabetic rats were fed for 10 weeks with control diet (DC) or vitamin D-deficient diet without (DD) or with oral calcitriol supplementation (0.15 µg/kg) in the last four weeks (DDS) (10 rats each group). A nondiabetic rat group that received control diet was also included (NR). After 10 weeks, rats were sacrificed; mesenteric arterial rings with and without endothelium were studied using wire myograph. Western blotting of the mesenteric arterial tissue was performed to determine the protein expression of endothelial nitric oxide synthase (eNOS) enzyme. Antioxidant enzyme superoxide dismutase (SOD) activity and oxidative stress marker malondialdehyde (MDA) levels in the mesenteric arterial tissue were also measured. The DC group had significantly lower acetylcholine-induced relaxation and augmented endothelium-dependent contraction, with reduced eNOS expression, compared to NR rats. In mesenteric arteries of DD, acetylcholine-induced endothelium-dependent and sodium nitroprusside-induced endothelium-independent relaxations were lower than those in DC. Calcitriol supplementation in DDS restored endothelium-dependent relaxation. Mesenteric artery endothelium-dependent contraction of DD was greater than DC; it was not affected by calcitriol supplementation. The eNOS protein expression and SOD activity were significantly lower while MDA levels were greater in DD compared to DC; these effects were not observed in DDS that received calcitriol supplementation. In conclusion, vitamin D deficiency causes eNOS downregulation and oxidative stress, thereby impairing the vascular function and posing an additional risk for microvascular complications in diabetes. Calcitriol supplementation to diabetics with vitamin D deficiency could potentially be useful in the management of or as an adjunct to diabetes-related cardiovascular complications.


Assuntos
Calcitriol/farmacologia , Diabetes Mellitus Experimental/enzimologia , Endotélio Vascular/fisiopatologia , Microvasos/fisiopatologia , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Regulação para Cima , Deficiência de Vitamina D/complicações , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Suplementos Nutricionais , Endotélio Vascular/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/enzimologia , Artérias Mesentéricas/fisiopatologia , Microvasos/efeitos dos fármacos , Nitroprussiato/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fenilefrina/farmacologia , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Regulação para Cima/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
20.
J Cataract Refract Surg ; 47(8): 982-990, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33577273

RESUMO

PURPOSE: To investigate the economic impact of an intracameral mydriatics and anesthetic agent (ICMA), topical mydriatics, and a mydriatic ocular insert in cataract patients. SETTING: One public hospital in the Netherlands. DESIGN: Prospective cohort study. METHODS: Resource use data were collected from a healthcare and societal perspective on the day of surgery. Other outcome parameters included pupil size, surgeon satisfaction, postoperative pain, and Catquest-9SF scores. RESULTS: A total of 368 patients were included, the mean costs per patient were €506 in the ICMA group (n = 122), €474 in the ocular insert group (n = 115), and €451 in the topical group (n = 131). The acquisition cost of ICMA was highest and resulted in longer surgical time. After correction for an imbalance in the distribution of fast and slow surgeons, the mean costs in the ocular insert and topical groups were comparable (€450 vs €444). There was no statistically significant difference in the use of additional mydriatics intraoperatively (P = .521). The mean ratio of pupil size to white-to-white distance was lower in the ICMA group during all intraoperative measurements (P < .001) but similar between the topical and ocular insert groups (P range .11-.82). CONCLUSIONS: In the investigated setting in the Netherlands, ICMA was the most costly strategy. In addition, pupil size was lowest in the ICMA group but did not result in more additional mydriasis measures intraoperatively. The ocular insert was comparable with topical mydriatics in costs and pupil size. Implementation of ICMA could be considered when availability of nurses or physical space for perioperative care is limited.


Assuntos
Catarata , Midríase , Facoemulsificação , Custos e Análise de Custo , Humanos , Lidocaína , Midriáticos , Países Baixos , Fenilefrina , Estudos Prospectivos , Pupila
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