ABSTRACT
Resumo Fundamento A hipertensão arterial (HTA) representa um grande fator de risco de morbidade e mortalidade cardiovascular. Ainda não se sabe que mecanismos moleculares específicos estão associados ao desenvolvimento de hipertensão essencial. Objetivo Neste trabalho, analisamos a associação entre expressão mRNA de monócito LRP1, expressão de proteína LRP1, e espessura íntima-média de carótida (EIMC) de pacientes com hipertensão essencial. Métodos A expressão mRNA de monócito LRP1 e os níveis de proteína e EIMC foram quantificados em 200 indivíduos mexicanos, sendo 91 normotensos (NT) e 109 hipertensos (HT) A significância estatística foi definida em p < 0,05. Resultados O grupo de pacientes HT tinha EIMC maior altamente significativa em comparação com os pacientes NT (p = 0,002), e isso está relacionado ao aumento na expressão mRNA de LRP1 (6,54 versus. 2,87) (p = 0,002) e expressão de proteína LRP1 (17,83 versus 6,25), respectivamente (p = 0,001). Essas diferenças foram mantidas mesmo quando dividimos nossos grupos de estudo, levando em consideração apenas aqueles que apresentavam dislipidemia na expressão de mRNA (p = 0,041) e de proteínas (p < 0,001). Também se identificou que a indução de LRP1 mediada por LRP1 em monócitos em de maneira dependente de dose e tempo, com diferença significativa em NT versus HT (0,195 ± 0,09 versus 0,226 ± 0,12, p = 0,046). Conclusão Foi encontrado um aumento em EIMC em indivíduos com hipertensão, associada a expressões de proteína LRP1 e mRNA mais altas em monócitos, independente da presença de dislipidemia em pacientes HT. Esses resultados que a upregulation de LRP1 em monócitos de pacientes hipertensos mexicanos poderia estar envolvida na diminuição da EIMC. (Arq Bras Cardiol. 2021; 116(1):56-65)
Abstract Background Arterial hypertension (HTA) represents a major risk factor for cardiovascular morbidity and mortality. It is not yet known which specific molecular mechanisms are associated with the development of essential hypertension. Objective In this study, we analyzed the association between LRP1 monocyte mRNA expression, LRP1 protein expression, and carotid intima media thickness (cIMT) of patients with essential hypertension. Methods The LRP1 monocyte mRNA expression and protein levels and cIMT were quantified in 200 Mexican subjects, 91 normotensive (NT) and 109 hypertensive (HT). Statistical significance was defined as p < 0.05. Results HT patients group had highly significant greater cIMT as compared to NT patients (p=0.002) and this correlated with an increase in the expression of LRP1 mRNA expression (6.54 vs. 2.87) (p = 0.002) and LRP1 protein expression (17.83 vs. 6.25), respectively (p = 0.001). These differences were maintained even when we divided our study groups, taking into account only those who presented dyslipidemia in both, mRNA (p = 0.041) and proteins expression (p < 0.001). It was also found that Ang II mediated LRP1 induction on monocytes in a dose and time dependent manner with significant difference in NT vs. HT (0.195 ± 0.09 vs. 0.226 ± 0.12, p = 0.046). Conclusion An increase in cIMT was found in subjects with hypertension, associated with higher mRNA and LRP1 protein expressions in monocytes, irrespective of the presence of dyslipidemias in HT patients. These results suggest that LRP1 upregulation in monocytes from Mexican hypertensive patients could be involved in the increased cIMT. (Arq Bras Cardiol. 2021; 116(1):56-65)
Subject(s)
Humans , Carotid Intima-Media Thickness , Hypertension , Monocytes , Risk Factors , Low Density Lipoprotein Receptor-Related Protein-1 , Lipoproteins, LDLABSTRACT
The I/D insertion/deletion polymorphism of the angiotensin-converting enzyme has been related to hypertension. This polymorphism also seems to have gender related implications. Angiotensin II contributes to the production and release of oxygen reactive species that react with nitric oxide, inactivating its effects. Objective: To establish whether the ACE I/D polymorphism correlates with nitric oxide plasma metabolites in healthy men and women. Methods: Among 896 subjects between 18 and 30 years of age range, 138 fulfilled inclusion criteria. The polymorphism was identified by polymerase chain reaction, and blood nitric oxide metabolites were analyzed following the method described by Bryan. Results: Both systolic and diastolic arterial pressures were higher in men than in women (107/67 vs. 101/65 mmHg, p < 0.001). In terms of the ACE gene, there were differences in the concentration of nitric oxide metabolites in men with the I/D and D/D genotypes when compared to carriers of the I/I genotype (33.55 and 29.23 vs. 53.74 pmol/ml; p = <0.05), while there were no significant differences in women when compared by genotype. Men with the D/D genotype had higher systolic blood pressure than I/D carriers (111 vs. 104 mmHg, p < 0.05). We observed no arterial blood pressure differences in women when grouped by ACE genotype. Conclusions: The ACE D/D genotype was associated with nitric oxide metabolite levels and systolic blood pressure in clinically healthy men while it had no effect in women.
El polimorfismo inserción/deleción del gen de la enzima convertidora de la angiotensina (polimorfismo I/D de la ECA), se relaciona con hipertensión y sus efectos podrían estar asociados al género. La angiotensina II contribuye a la producción y liberación de especies reactivas de oxígeno, que reaccionan con el óxido nítrico (ON), inactivándolo. Objetivo: Conocer si existen diferencias en la concentración de metabolitos de ON en hombres y mujeres sanos que puedan estar influidas por el polimorfismo I/D de la ECA. Métodos: De 896 sujetos de entre 18 y 30 años, 138 cumplieron los criterios de inclusión. El polimorfismo fue identificado usando reacción en cadena de la polimerasa y los metabolitos de ON fueron analizados en sangre usando el método de Bryan. Resultados: Las presiones sistólica y diastólica fueron más elevadas en hombres que en mujeres (107/67 vs. 101/65 mmHg p < 0.001). En relación con el genotipo, existieron diferencias significativas en la concentración de metabolitos de ON en los hombres con genotipos I/D, D/D comparados con los portadores del genotipo I/I (33.55 y 29.23 vs. 53.74 pmol/ml, respectivamente; p = <0.05). No hubo diferencias significativas en las mujeres portadoras de los diferentes genotipos. Respecto a la presión arterial, los hombres con genotipo D/D presentaron mayor presión arterial sistólica que aquellos portadores de I/D (111 vs. 104 mmHg, p < 0.05). En las mujeres no se observaron diferencias significativas comparándolas por genotipo. Conclusiones: El genotipo D/D de la ECA está asociado con el nivel de metabolitos de ON en plasma y la presión arterial sistólica en hombres clínicamente sanos; esta asociación no se observa en las mujeres.
Subject(s)
Adolescent , Adult , Female , Humans , Male , Young Adult , Blood Pressure , Nitric Oxide/blood , Polymorphism, Genetic , Peptidyl-Dipeptidase A/genetics , Genotype , Mexico , Nitric Oxide/metabolismABSTRACT
Objetivo:Reforzar el conocimiento sobre la fisiopatología de la estenosis aórtica. Métodos: Se compararon los niveles urinarios de angiotensina II y angiotensina-(1-7) entre dos muestras: a) 45 pacientes con estenosis aórtica de importante repercusión hemodinámica, sin hipertensión arterial sistémica y con funciones renal y sistólica ventricular izquierda normales; b) grupo de control con 21 voluntarios sin patología cardiovascular. Hipótesis nula: no habría diferencia entre los niveles urinarios. Resultados:El promedio de la concentración urinaria de angiotensina-(1-7) en pacientes con estenosis aórtica fue 2.102 pmoles/mL y de 5.591 pmoles/mL para el grupo control. La media obtenida en concentración urinaria de angiotensina II fue de 0.704 pmoles/mL en los pacientes con estenosis aórtica y 0.185 pmoles/mL en el grupo control. Utilizando la prueba t de Student determinamos que la diferencia en la concentración urinaria de angiotensina-(1-7) (p = 0.633) y la diferencia en la concentración urinaria de angiotensina II (p = 0.631), fueron estadísticamente significativas. Conclusión:Se documentó una diferencia estadísticamente significativa en los niveles urinarios de angiotensina II y angiotensina-(1-7) dentro del grupo de pacientes con estenosis aórtica de importante repercusión hemodinámica.
Objective:Strengthen knowledge about the pathophysiology of aortic stenosis. Methods: Urinary levels of angiotensin-(1-7) and angiotensin II were compared between two samples: A) forty five patients with severe aortic stenosis, without systemic arterial hypertension and with normal kidney and normal left ventricular systolic function; B) control group: twenty one persons without cardiovascular disease. Null hypothesis: there would be no difference between urinary levels. Results: The average of angiotensin-(1-7) urinary concentration in severe aortic stenosis patients was 2.102 pmol/mL and 5.591 pmol/mL for the control group. The average of Ang II was 0.704 pmol/mL and 0.185 pmol/mL respectively. Using t-Student test, we determine that the difference in urinary concentration of angiotensin-(1-7) [p = 0.633] and the difference of angiotensin II (p = 0.631), were statistically significant. Conclusion:documented a statistically significant difference in urinary levels angiotensin II and angiotensin-(1-7) within the group of patients with severe aortic stenosis.
Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , Young Adult , Angiotensin I/urine , Angiotensin II/urine , Aortic Valve Stenosis/urine , Peptide Fragments/urine , Case-Control Studies , Cross-Sectional Studies , Prospective Studies , Severity of Illness IndexABSTRACT
OBJECTIVE: To study the antiarrhythmic effect of remifentanil in experimental arrhythmias in dogs. METHODS: We used dogs weighing 12 kg-18 kg anesthetized with 30 mg/kg sodium pentobarbital given intravenously. Ventricular arrhythmia, ventricular fibrillation and death were induced with digoxin (9 microg/kg/min). In another model, two types of arrhythmia were induced in the right atrium, one of them with aconitine crystals placed on the right atrium and the other was induced in the basement of the right atrium by electrical stimulation. The potential antiarrhythmic action of remifentaniL was investigated in ventricular and atrial arrhythmias by the administration of an intravenous bolus after toxic signs were evident. Thus, two arrhythmias with different mechanisms were generated. Leads DII, unipolar left intraventricular and right atrial leads, and left ventricular pressure were used to record control tracings and tracings in presence of remifentanil, during ventricular arrhythmia. RESULTS: Remifentanil abolished toxic effects of digoxin, it eliminated the A-V dissociation and ventricular extrasystoles, reverting to sinus rhythm in each case. Remifentanil extended the time to reach lethal doses from 63.25 +/- 11.3 to 100 +/- 11.8 min. These effects were blocked by naloxone (0.01 microg/kg) applied before remifentanil. In the two arrhythmias model, remifentanil suppressed both, ectopic focus and atrial flutter. CONCLUSIONS: Remifentanil elicits antiarrhythmic and cardioprotective effects in experimental ventricular arrhythmias induced by digoxin and in a model of two atrial arrhythmias induced by aconitine and by electrical stimulation.
Subject(s)
Animals , Dogs , Female , Male , Analgesics, Opioid , Arrhythmias, Cardiac , Heart Diseases , Piperidines , AnesthesiaABSTRACT
PURPOSE: The endothelial function is the cornerstone of several cardiovascular disease. In this trial we compared how the Nitric Oxide (NO) and Oxidative Stress (OS) serum levels, as surrogate markers of endothelial function, change in patients who received (or not) rosuvastatin during the first seven days of an acute coronary syndrome (ACS). METHODS: Twenty-two patients with ACS (age:66 +/- 9 years, gender: ten female and 12 male) were randomized in two groups. Patients in the first group (G1) received the conventional treatment for an ACS, plus placebo. The other group (G2) additionally received a daily oral dose of 40 mg of rosuvastatin. We measured the blood levels of nitrates and OS in both groups twice: at baseline (admission to Intensive care unit) and seven days after. The statistical analysis was performed using the paired t-test or the Chi2 test depending of the variables. Statistical significance was considered with a p < 0.05. RESULTS: Groups (G1 and G2) differed statistically on age (G1=71 years +/- 10 vs. G2 63 +/- 9 years, p=0.04). After 7 days of the ACS onset, ON levels diminished on 21% (p=0.17) in G1, but raised on 24% in the group who re- ceived rosuvastatin (p=0.005), with statistically difference between groups (p=0.005). On the other hand, the OS, augmented statistically on both groups: G1 (17%, p<0.001) and G2 (13%, p<0.001), without any difference between groups (p=0.77). Conclusion: The endothelial dysfunction in the first days of an ACS is accentuated, but with the use of rosuvastatina, the endothelial function improves. In contrast, the OS increase in both groups, without differences between groups.
Subject(s)
Aged , Female , Humans , Male , Middle Aged , Acute Coronary Syndrome , Endothelium, Vascular , Fluorobenzenes , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Nitric Oxide/blood , Oxidative Stress , Pyrimidines , Sulfonamides , Acute Coronary Syndrome/bloodABSTRACT
It has been suggested that dietary intake of flavonoids may reduce the risk of cardiovascular diseases. On the other hand, in vitro and in vivo studies shows that flavonoids has a vast array of biological activities. Our aim in this review is to put in evidence the effect of flavonoids on several enzymatic systems that could act as potential therapeutic targets, based on the reports of diverse research groups, leaders in the natural products research area, have published through the years, and with the goal of consolidating those results with the findings provided by some epidemiological studies, could support the introduction of these compounds into the clinic.
Subject(s)
Adult , Aged , Aged, 80 and over , Humans , Middle Aged , Antioxidants , Cardiovascular Diseases , Flavonoids , Phytotherapy , Platelet Aggregation Inhibitors , Antioxidants , Antioxidants , Clinical Trials as Topic , Cardiovascular Diseases , Cardiovascular Diseases/mortality , Enzymes , Flavonoids , Flavonoids , Flavonoids , Platelet Aggregation Inhibitors , Platelet Aggregation Inhibitors , Quercetin , Quercetin , Research , Time FactorsABSTRACT
The pharmacological effect of a Viscum album aqueous extract was evaluated on the Langendorff isolated and perfused heart model in normotense male guinea pig hearts. Coronary vascular resistance, left intraventricular pressure, nitric oxide release in the perfusion liquid, cyclic guanosine monophosphate production, and analysis of inducible and endothelial nitric oxide synthases expression by Western Blot in ventricular tissue were recorded in absence and presence of blockers and inhibitors, such as 3 microM gadolinium chloride, 100 microM N(omega)-nitro-L-arginine methyl ester and 10 microM 1H-[1,2,4]oxadiazolo[4,2-a]quinoxalin-1-one. V. album aqueous extract exerts a significant decrease in the coronary vascular resistance, which courses with significant increases in nitric oxide and cyclic guanosine monophosphate production. Analysis of the expression of both nitric oxide synthases revealed that this extract significantly induces the expression of both isoforms in guinea pig hearts. These effects were inhibited by the presence of blockers and inhibitors. The coronary vasodilation induced by the extract is mediated by the nitric oxide/soluble guanylyl cyclase pathway. In addition, this extract shows a positive inotropic effect which that is tyramine-mediated by means of beta1-adrenergic stimulation.
Subject(s)
Animals , Guinea Pigs , Coronary Vessels , Coronary Vessels/physiology , Heart , In Vitro Techniques , Myocardium/enzymology , Nitric Oxide Synthase Type II/biosynthesis , Nitric Oxide Synthase Type III/biosynthesis , Plant Extracts , Viscum album , Vasodilation , PerfusionABSTRACT
Se evaluó farmacológicamente los extractos de diversas variedades de Magnolia grandiflora sobre el músculo cardíaco. Se recolectó en el período de marzo a julio hojas y flores de Magnolia grandiflora nativa del Instituto Nacional de Cardiología "Ignacio Chávez", de la zona norte, poniente y oriente del Distrito Federal, de los estados de Puebla, Colima y Chiapas. Éstas se procesaron por separado y los extractos se obtuvieron por maceración con una mezcla de etanol-agua (1:3 v/v) a 4°C durante dos semanas. El análisis cualitativo se realizó por cromatografía en capa fina, columna y de líquidos de alta resolución (CLAR). El análisis funcional y molecular se efectuó por reactividad química específica y resonancia magnética protónica (RMN ¹H). La evaluación farmacológica se realizó en corazones aislados de cobayo macho. Los extractos, fracciones y compuestos se administraron en bolos seriados bajo un estudio de curvas dosis-respuesta gradual en donde se midió la presión intraventricular izquierda y la presión de perfusión coronaria, evaluando así el efecto inotrópico positivo y vasodilatador de los extractos de Magnolia grandiflora. Se identificó y aisló vulgarenol y 2-p-hidroxifenil-2-OH-etilamina, por lo que los resultados sugieren que su efecto vasodilatador e inotrópico positivo, se deben a la presencia de estas sustancias, las cuales se complementan con magnograndiólido y tiramina.
Several extracts from diverse Magnolia grandiflora varieties were pharmacological evaluated in the cardiac muscle. From March to July, flowers and leaves from Magnolia grandiflora, native from the National Institute of Cardiology "Ignacio Chávez", from north, west, and orient zones from Mexico City, and from Puebla, Colima and Chiapas states were collected. They were separately processed and the extracts were obtained by maceration with ethanol-water (1:3 v/v) at 4°C during two weeks. Qualitative analysis was accomplished with thin-layer, column and high-performance liquid chromatographies (HPLC). Functional and molecular analysis was made by specific chemical reactivity and by protonic magnetic resonance (RMN ¹H). Pharmacological evaluation was completed in isolated and perfused male guinea pigs hearts. Extracts, fractions, and compounds were administrated by serial bolus in a gradual dose-response curves study in which left intraventricular pressure and coronary perfusion pressure were recorded, evaluating by such the positive inotropic and vasodilator effects of Magnolia grandifloraextracts. Vulgarenol and 2-p-hydroxyphenyl-2-hydroxy-ethylamine were isolated and identified, and the obtained results suggest that its positive inotropic and vasodilator effects are owed to these substances, being complemented by magnograndiolide and tyramine.
Subject(s)
Animals , Guinea Pigs , Male , Heart/drug effects , Magnolia , Plant Extracts/pharmacology , Case-Control Studies , Chromatography, Gel , Coronary Vessels/drug effects , Coronary Vessels/physiology , Heart/physiology , Magnetic Resonance Spectroscopy , Myocardium/metabolism , Ventricular Function, Left/drug effects , Ventricular Function, Left/physiology , Ventricular Pressure/drug effects , Ventricular Pressure/physiologyABSTRACT
Pese a su reducido margen de seguridad, los digitálicos siguen utilizándose en el tratamiento de la insuficiencia cardiaca congestiva y la fibrilación auricular crónica. Con el descubrimiento de su estructura, se han realizado remodelaciones para disminuir su toxicidad. Investigaciones recientes reportan que la eficacia digitálica radica en la electronegatividad del anillo "D" esteroideo, generada por la lactona e hidroxilo que poseen estos compuestos. En el presente trabajo, damos cuenta de la importancia que tiene esta propiedad molecular, que aunada a la conformación estructural, dan lugar a cambios significativos en las propiedades farmacológicas como el inotropismo y el margen de seguridad. Así, evaluamos una serie de once compuestos derivados de digitoxigenina, con grupos que sustituyen sobre el anillo "D" al hidroxilo y/o la lactona, los cuales denominamos -OH, -Lac, D-01, D-02, D-03, D-07, D-14, D-15, D-20, D-21 y D-22. La electronegatividad y la energía conformacional de cada compuesto se determinaron por el método Duhamm. El estudio farmacológico se realizó en corazones aislados de cobayo con base en el modelo de Langendorff y, en corazón de perro conforme al modelo cardiopulmonar de Starling. Los resultados permiten observar que la modulación de la acción digitálica está centrada, estructuralmente, en los sustituyentes de la fracción "D". El efecto inotrópico positivo y el margen de seguridad, medido como el cociente de la dosis tóxica sobre la dosis inotrópica, están relacionados con el aumento de electronegatividad y con una disminución de las energías rotacional y translacional que definen la conformación molecular; en consecuencia, estas propiedades son imprescindibles en la eficacia digitálica.
In spite their reduced therapeutic index, digitalis-type drugs continue being used for treating diseases such as congestive heart failure and chronic atrial fibrillation. Thanks to the development of several methods, their structural determination has been feasible, so, structural modifications have been worked out to modulate their toxicity. Several reports realizes that efficacy for these digitalis-type drugs lies on the electronegativity centered on the steroidal moiety (D-ring) generated by either lactone and hydroxyl sub-stituents attached to the steroidal moiety. In this work, we report how electronegativity, and so structural conformation, does modify their pharmacological properties, e.g., inotropism and safety margin. Thus, we evaluated a series of eleven drugs derived from digitoxigenin, named -OH, -Lac, D-01, D-02, D-03, D-07, D-14, D-15, D-20, D-21 and D-22, with groups that substitute both lactone and hydroxyl groups on the steroidal D-ring. Electronegativity and conformational energy were determined by Duhamm's method. The pharmacological evaluation for these drugs was accomplished in guinea pigs isolated hearts (according to the model proposed by Langendorff) and dog's isolated heart (as established by Starling's in vivo model). The results may suggest that digitalis-like action lies on the substituents attached to the D-ring. Positive inotropic effect and therapeutic index are related with increases in electronegativity as well with decreases in rotational and traslational energies; therefore, these molecular properties have such importance for the digitalis efficacy. (Arch Cardiol Mex 2003; 73:11-17).