Browsing by Author "Jalil Milad, Jorge Emilio"
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- ItemAngiotensin I-converting enzyme gene polymorphism influences chronic hypertensive response in the rat Goldblatt model(LIPPINCOTT WILLIAMS & WILKINS, 2002) Ocaranza Jeraldino, María Paz; Piddo, Ana M.; Faundez, Perla; Lavandero, Sergio; Jalil Milad, Jorge EmilioBackground and objective In humans, the insertion/ deletion polymorphism in the anglotensin (Ang) I converting enzyme (ACE) gene significantly determines ACE activity. The deletion allele induces higher ACE levels and is associated with hypertension in men. In the rat, a microsatellite marker in the ACE gene allows differentiation of the ACE alleles among strains with different ACE levels. We evaluated the effect of genetically determined ACE expression on the development of renovascular hypertension in the rat.
- ItemAngiotensin I-converting enzyme gene polymorphism influences chronic hypertensive response in the rat Goldblatt model(LIPPINCOTT WILLIAMS & WILKINS, 2002) Ocaranza Jeraldino, María Paz; Piddo, Ana M.; Faundez, Perla; Lavandero, Sergio; Jalil Milad, Jorge EmilioBackground and objective In humans, the insertion/ deletion polymorphism in the anglotensin (Ang) I converting enzyme (ACE) gene significantly determines ACE activity. The deletion allele induces higher ACE levels and is associated with hypertension in men. In the rat, a microsatellite marker in the ACE gene allows differentiation of the ACE alleles among strains with different ACE levels. We evaluated the effect of genetically determined ACE expression on the development of renovascular hypertension in the rat.
- ItemAngiotensin I-converting enzyme insertion/deletion polymorphism and adrenergic response to exercise in hypertensive patients.(2002) Braun Jones, Vivian Sandra; Chamorro Spikin, Gastón Alberto; Cordova Alvestegui, Samuel Edmundo; Fardella Bello, Carlos Enrique; Jalil Milad, Jorge Emilio; Lavandero, Sergio; Ocaranza Jeraldino, María Paz; Schumacher, ErwinBackgroundThe insertion/deletion ACE polymorphism (ACE I/D) regulates different levels of circulating and tissue ACE activities, which may induce diverse adrenergic responses to physiological stimuli. The aim of this study was to evaluate the influence of
- ItemGenotipos del sistema renina-angiotensina-aldosterona: a la búsqueda de enfermedades cardiovasculares(2002) Jalil Milad, Jorge Emilio; Ocaranza Jeraldino, María Paz
- ItemHydrochlorothiazide Reduces Cardiac Hypertrophy, Fibrosis and Rho-Kinase Activation in DOCA-Salt Induced Hypertension(2021) Mondaca Ruff, David Gonzalo; Araos Valdebenito, Fernando Patricio; Yañez, Cristián; Novoa, Ulises F.; Mora, Ítalo G.; Ocaranza Jeraldino, María Paz; Jalil Milad, Jorge EmilioBackground: Thiazides are one of the most common antihypertensive drugs used for hypertension treatment and hydrochlorothiazide (HCTZ) is the most frequently used diuretic for hypertension treatment. The Rho/Rho-kinase (ROCK) path plays a key function in cardiovascular remodeling. We hypothesized that in preclinical hypertension HCTZ reduces myocardial ROCK activation and consequent myocardial remodeling. Methods: The preclinical model of deoxycorticosterone (DOCA)-salt hypertension was used (Sprague–Dawley male rats). After 3 weeks, in 3 different groups: HCTZ, the ROCK inhibitor fasudil or spironolactone was added (3 weeks). After 6 weeks myocardial hypertrophy and fibrosis, cardiac levels of profibrotic proteins, mRNA levels (RT PCR) of pro remodeling and pro oxidative molecules and ROCK activity were determined. Results: Blood pressure, myocardial hypertrophy and fibrosis were reduced significantly by HCTZ, fasudil and spironolactone. In the heart, increased levels of the pro-fibrotic proteins Col-I, Col-III and TGF-β1 and gene expression of pro-remodeling molecules TGF-β1, CTGF, MCP-1 and PAI-1 and the pro-oxidative molecules gp91phox and p22phox were significantly reduced by HCTZ, fasudil and spironolactone. ROCK activity in the myocardium was increased by 54% (P < 0.05) as related to the sham group and HCTZ, spironolactone and fasudil, reduced ROCK activation to control levels. Conclusions: HCTZ reduced pathologic LVH by controlling blood pressure, hypertrophy and myocardial fibrosis and by decreasing myocardial ROCK activation, expression of pro remodeling, pro fibrotic and pro oxidative genes. In hypertension, the observed effects of HCTZ on the myocardium might explain preventive outcomes of thiazides in hypertension, specifically on LVH regression and incident heart failure.
- ItemLa vía de señalización Rho/Rho-cinasa en la enfermedad y el remodelado cardiovascular(EDICIONES DOYMA S/L, 2005) Jalil Milad, Jorge Emilio; Lavandero, Sergio; Chiong, Mario; Ocaranza Jeraldino, María PazThe small guanosine triphosphatase Rho and its target, Rho kinase, play important roles in both blood pressure regulation and vascular smooth muscle contraction. Rho is activated by agonists of receptors coupled to cell membrane G protein, such as angiotensin II and phenylephrine. Once Rho is activated, it translocates to the cell membrane where it, in turn, activates Rho kinase. Activated Rho kinase phosphorylates myosin light chain phosphatase, which is then inhibited. This sequence stimulates vascular smooth muscle contraction, stress fiber formation, and cell migration. In this way, Rho and Rho kinase activation have important effects on several cardiovascular diseases. Currently available substances that specifically inhibit this signaling pathway could offer clinical benefits in several cardiovascular, as well as non-cardiovascular, diseases, such as arterial hypertension, pulmonary hypertension, cerebral or coronary spasm, post-angioplasty restenosis, and erectile dysfunction.
- ItemLevels of plasma angiotensin-(1-7) in patients with hypertension who have the angiotensin–I-converting enzyme deletion/deletion genotype(2003) Chiong, Mario; Godoy Jorquera, Iván Esteban; Jalil Milad, Jorge Emilio; Lavandero, Sergio; Ocaranza Jeraldino, María Paz; Palomera, Cristián; Román, MaritzaIn patients with hypertension who have the DD-ACE genotype (higher angiotensin-converting enzyme [ACE] activity), plasma levels of angiotensin-(1-7) are 4 times lower than in patients with the II-ACE genotype (lower ACE levels). Angiotensin II levels are
- ItemOn endogenous Angiotensin II antagonism in hypertension(Lippincott Williams and Wilkins, 2016) Ocaranza Jeraldino, María Paz; Jalil Milad, Jorge Emilio
- ItemPrevencion Precoz de Hipertrofia Ventricular Izquierda en la Hipertension Experimental y Concentraciones de Angiotensina II(2001) Gálvez, Anita; Ocaranza Jeraldino, María Paz; Lavandero, Sergio; Jalil Milad, Jorge EmilioIntroducción.Las concentraciones de angiotensina IIpueden inhibirse parcialmente durante la administracióncrónica de inhibidores de la enzima conversiva de la an-giotensina (ECA), limitando desde el punto de vista clíni-co su eficacia en el tratamiento de la hipertensión arterial.Existen pocos estudios que relacionan directamente laactividad de la ECA y la prevención precoz de hipertrofiaventricular izquierda (HVI) secundaria a hipertensión arte-rial durante la administración de un inhibidor de la ECA(IECA). Objetivo.Evaluar los efectos de la inhibición precoz dela ECA con perindopril sobre el desarrollo de hiperten-sión, HVI y concentraciones de angiotensina II plasmáticay en el ventrículo izquierdo en el modelo Goldblatt en larata (Gb; 2 riñones-un pinzado) a las 2 semanas de la ci-rugía. Resultados.La presión arterial sistólica y la masa ven-tricular izquierda relativa aumentaron un 42 y un 20%,respectivamente, en el grupo Gb (p < 0,001). Las acti-vidades de ECA circulante y en el ventrículo izquierdofueron significativamente mayores en las ratas Gb com-paradas con los controles. Las concentraciones de angio-tensina II plasmática y en el ventrículo izquierdo tambiénaumentaron un 129 y un 800%, respectivamente. El pe-rindopril previno la aparición de hipertensión y el desarro-llo de HVI, ya que inhibió la ECA plasmática (y en el ven-trículo izquiedo), además de la angiotensina II circulantey en el ventrículo izquierdo.Conclusiones. En este modelo experimental de HVIhipertensiva existe una activación temprana de la ECAplasmática y cardíaca. La administración precoz de unIECA previene el desarrollo de hipertensión e HVI al inhi-bir el aumento de angiontensina II en el plasma y el ven-trículo izquierdo.
- ItemProtective Role of the ACE2/Ang-(1-9) Axis in Cardiovascular Remodeling(2012) Jalil Milad, Jorge Emilio; Ocaranza Jeraldino, María PazDespite reduction in cardiovascular (CV) events and end-organ damage with the current pharmacologic strategies, CV disease remains the primary cause of death in the world. Pharmacological therapies based on the renin angiotensin system (RAS) blockade are used extensively for the treatment of hypertension, heart failure, and CV remodeling but in spite of their success the prevalence of end-organ damage and residual risk remain still high. Novel approaches must be discovered for a more effective treatment of residual CV remodeling and risk. The ACE2/Ang-(1–9) axis is a new and important target to counterbalance the vasoconstrictive/proliferative RAS axis. Ang-(1–9) is hydrolyzed slower than Ang-(1–7) and is able to bind the Ang II type 2 receptor. We review here the current experimental evidence suggesting that activation of the ACE2/Ang-(1–9) axis protects the heart and vessels (and possibly the kidney) from adverse cardiovascular remodeling in hypertension as well as in heart failure.
- ItemRecent insights and therapeutic perspectives of angiotensin-(1-9) in the cardiovascular system(2014) Ocaranza Jeraldino, María Paz; Michea, Luis; Chiong, Mario; Lagos Arévalo, Carlos Fernando; Lavandero, Sergio; Jalil Milad, Jorge EmilioChronic RAS (renin-angiotensin system) activation by both AngII (angiotensin II) and aldosterone leads to hypertension and perpetuates a cascade of pro-hypertrophic, pro-inflammatory, pro-thrombotic and atherogenic effects associated with cardiovascular damage. In 2000, a new pathway consisting of ACE2 (angiotensin-converting enzyme2), Ang-(1-9) [angiotensin-(1-9)], Ang-(1-7) [angiotensin-(1-7)] and the Mas receptor was discovered. Activation of this novel pathway stimulates vasodilation, anti-hypertrophy and anti-hyperplasia. For some time, studies have focused mainly on ACE2, Ang-(1-7) and the Mas receptor, and their biological properties that counterbalance the ACE/AngII/AT(1)R (angiotensin type 1 receptor) axis. No previous information about Ang-(1-9) suggested that this peptide had biological properties. However, recent data suggest that Ang-(1-9) protects the heart and blood vessels (and possibly the kidney) from adverse cardiovascular remodelling in patients with hypertension and/or heart failure. These beneficial effects are not modified by the Mas receptor antagonist A779 [an Ang-(1-7) receptor blocker], but they are abolished by-the AT(2)R (angiotensin type 2 receptor) antagonist PD123319. Current information suggests that the beneficial effects of Ang-(1-9) are mediated via the AT2R. In the present review, we summarize the biological effects of the novel vasoactive peptide Ang-(1-9), providing new evidence of its cardiovascular-protective activity. We also discuss the potential mechanism by which this peptide prevents and ameliorates the cardiovascular damage induced by RAS activation.
- ItemReproducibility of plasma angiotensin-converting enzyme activity in human subjects determined by fluorimetry with Z-phenylalanine-histidyl-leucine as substrate(MOSBY-YEAR BOOK INC, 1999) Jalil Milad, Jorge Emilio; Ocaranza Jeraldino, María Paz; Piddo, Ana MaríaDespite the major physiologic role of angiotensin-converting enzyme (ACE), few studies have evaluated the ideal conditions for measuring human plasma ACE activity, specifically when using Z-phenylalanine-histidyl-leucine as substrate. This study, performed in volunteer patients, assessed the reproducibility of human plasma ACE activity measured by fluorimetry with Z-phenyl-histidyl-leucine as the substrate. After blood centrifugation, plasma was stored under different conditions until processing. The following sources of variability were evaluated: (1) the interval to centrifugation of blood after collection, (2) the temperature and (3) safe time for storing the plasma after cold centrifugation, (4) the effect of fasting. Plasma ACE activity was 20.6 ± 7.7 U/mL, 20.9 ± 8 U/mL, and 20.5 ± 7.9 U/mL (n = 25) when samples were centrifuged immediately, after 1 hour of blood sampling, and after 3 hours of blood sampling, respectively (not significant). In plasma kept at –20°C, ACE activity was not different after 1 week (17.4 ± 4.3 U/mL) nor after 1 month (17.9 ± 4 U/mL), whereas baseline ACE was 16.7 ± 4.3 U/mL (n = 10). In plasma stored at –80°C, ACE activity was 15.5 ± 5.7 U/mL after 1 month (baseline 15 ± 5.3 U/mL; not significant; n = 12). No evidence for hydrolysis of the reaction product of ACE (his-leu dipeptide) was observed in plasma samples kept for 1 month at –20°C or at –80°C (by high-performance liquid chromatography analysis). In plasma obtained before breakfast, ACE activity was 12.8 ± 7.1 U/mL, and it was 12.3 ± 7.5 U/mL 2 hours afterwards (not significant; n = 12). Thus, to determine human plasma ACE activity by fluorimetry with reliability, with Z-phenylalanine-histidyl-leucine used as a substrate, there is a safe interval of at least 3 hours before blood centrifugation at –4°C. Plasma may be kept at –20°C or at –80°C for at least 4 weeks before final processing. Fasting does not influence its enzymatic activity. (J Lab Clin Med 1999;133:501-6)
- ItemReverse Remodeling in Human Heart Failure after Cardiac Resynchronization Therapy Is Associated With Reduced RHO-Kinase Activation(2021) Ocaranza Jeraldino, Maria Paz; Jalil Milad, Jorge Emilio; Altamirano Assad, Rodrigo Patricio; De León Soto, Ana María; Moya López, Jackeline Trinidad; Lonis Álvarez, María Alejandra; Gabrielli Nervi, Luigi Arnaldo; Mac Nab, Paul; Cordova Alvestegui, Samuel Edmundo; Paredes, Alejandro; Vergara Saavedra, Ismael Antonio; Bittner Braemer, Alex Gerhard; Sabat Sarras, Karime Alejandra; Pastorini, Karla["Background: Reverse remodeling is a clinically relevant endpoint in heart failure with reduced ejection fraction (HFrEF). Rho-kinase (ROCK) signaling cascade activation correlates with cardiac remodeling and left ventricular (LV) systolic dysfunction in HFrEF patients. Cardiac resynchronization therapy (CRT) is effective in HFrEF, especially when there is a left bundle block, as this treatment may stimulate reverse remodeling, thereby improving quality of life and prolonging survival for patients with this severe condition. Here, we evaluate the hypothesis that ROCK activation is reduced after effective CRT in HFrEF.", "Methods: ROCK activation in circulating leukocytes was evaluated in 28 HFrHF patients, using Western blot (myosin light chain phosphatase subunit 1 phosphorylation, MYPT1p/t), before and three months after initiation of CRT. LV systolic function and remodeling were assessed by echocardiography.", "Results: Three months after CRT, LV ejection fraction increased an average of 14.5% (p < 0.001) in 13 patients (responders), while no change was observed in 15 patients (non-responders). End-systolic diameter decreased 16% (p < 0.001) in responders, with no change in non-responders. ROCK activation in PBMCs decreased 66% in responders (p < 0.05) but increased 10% in non-responders (NS). LV end-diastolic diameter was also 5.2 mm larger in non-responders vs. responders (p = 0.058). LV ejection fraction, systolic diameter, and ROCK activation levels were similar in both groups at baseline.", "Conclusion: In HFrEF patients, 3 months of effective CRT induced reverse myocardial remodeling, and ROCK activation was significantly decreased in circulating leukocytes. Thus, decreased ROCK activation in circulating leukocytes may reflect reverse cardiac remodeling in patients with heart failure."]