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1.
Clin Sci (Lond) ; 135(18): 2197-2216, 2021 09 30.
Artículo en Inglés | MEDLINE | ID: mdl-34494083

RESUMEN

Activation of the angiotensin (Ang)-converting enzyme (ACE) 2/Ang-(1-7)/MAS receptor pathway of the renin-angiotensin system (RAS) induces protective mechanisms in different diseases. Herein, we describe the cardiovascular phenotype of a new transgenic rat line (TG7371) that expresses an Ang-(1-7)-producing fusion protein. The transgene-specific mRNA and the corresponding protein were shown to be present in all evaluated tissues of TG7371 with the highest expression in aorta and brain. Plasma Ang-(1-7) levels, measured by radioimmunoassay (RIA) were similar to control Sprague-Dawley (SD) rats, however high Ang-(1-7) levels were found in the hypothalamus. TG7371 showed lower baseline mean arterial pressure (MAP), assessed in conscious or anesthetized rats by telemetry or short-term recordings, associated with increased plasma atrial natriuretic peptide (ANP) and higher urinary sodium concentration. Moreover, evaluation of regional blood flow and hemodynamic parameters with fluorescent microspheres showed a significant increase in blood flow in different tissues (kidneys, mesentery, muscle, spleen, brown fat, heart and skin), with a resulting decrease in total peripheral resistance (TPR). TG7371 rats, on the other hand, also presented increased cardiac and global sympathetic tone, increased plasma vasopressin (AVP) levels and decreased free water clearance. Altogether, our data show that expression of an Ang-(1-7)-producing fusion protein induced a hypotensive phenotype due to widespread vasodilation and consequent fall in peripheral resistance. This phenotype was associated with an increase in ANP together with an increase in AVP and sympathetic drive, which did not fully compensate the lower blood pressure (BP). Here we present the hemodynamic impact of long-term increase in tissue expression of an Ang-(1-7)-fusion protein and provide a new tool to investigate this peptide in different pathophysiological conditions.


Asunto(s)
Angiotensina I/metabolismo , Sistema Cardiovascular/metabolismo , Hemodinámica , Hipertensión/prevención & control , Fragmentos de Péptidos/metabolismo , Sistema Nervioso Simpático/metabolismo , Angiotensina I/genética , Animales , Arginina Vasopresina/metabolismo , Factor Natriurético Atrial/metabolismo , Velocidad del Flujo Sanguíneo , Presión Sanguínea , Sistema Cardiovascular/fisiopatología , Modelos Animales de Enfermedad , Genotipo , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Hemodinámica/genética , Hipertensión/genética , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Fragmentos de Péptidos/genética , Fenotipo , Ratas Sprague-Dawley , Ratas Transgénicas , Proteínas Recombinantes de Fusión/metabolismo , Flujo Sanguíneo Regional , Sistema Nervioso Simpático/fisiopatología , Factores de Tiempo , Resistencia Vascular
2.
Clin Exp Pharmacol Physiol ; 47(2): 213-219, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31643111

RESUMEN

Diminazene aceturate (DIZE) is an anti-protozoan compound that has been previously reported to increase the activity of the angiotensin-converting enzyme 2 (ACE2) and thus increase Angiotensin-(1-7) production, leading to cardioprotection against post-myocardial infarction dysfunction and structural remodelling. Moreover, DIZE is able to ameliorate morpho-functional changes after myocardial infarction by enhancing ACE2 activity, thus increasing Angiotensin-(1-7) production (a benefic peptide of the renin-angiotensin system). However, despite the improvement in cardiac function/structure, little is known about DIZE effects on arrhythmia suppression, contraction/excitable aspects of the heart and importantly its mechanisms of action. Thus, our aim was to test the acute effect of DIZE cardioprotection at the specific level of potential antiarrhythmic effects and modulation in excitation-contraction coupling. For this, we performed in vitro and in vivo techniques for arrhythmia induction followed by an acute administration of DIZE. For the first time, we described that DIZE can reduce arrhythmias which is explained by modulation of cardiomyocyte contraction and excitability. Such effects were independent of Mas receptor and nitric oxide release. Development of a new DIZE-based approach to ameliorate myocardial contractile and electrophysiological dysfunction requires further investigation; however, DIZE may provide the basis for a future beneficial therapy to post-myocardial infarction patients.


Asunto(s)
Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/tratamiento farmacológico , Diminazeno/análogos & derivados , Miocitos Cardíacos/efectos de los fármacos , Animales , Antiarrítmicos/farmacología , Arritmias Cardíacas/fisiopatología , Diminazeno/farmacología , Diminazeno/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/fisiología , Técnicas de Placa-Clamp/métodos , Ratas , Ratas Wistar
3.
Cells Tissues Organs ; 204(3-4): 137-149, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28803236

RESUMEN

It has been reported that carbon nanotubes (CNTs) serve as nucleation sites for the deposition of bone matrix and cell proliferation. Here, we evaluated the effects of multi-walled CNTs (MWCNTs) on bone repair of rat tibiae. Furthermore, because sodium hyaluronate (HY) accelerates bone restoration, we associated CNTs with HY (HY-MWCNTs) in an attempt to boost bone repair. The bone defect was created by a 1.6-mm-diameter drill. After 7 and 14 days, tibiae were processed for histological and morphometric analyses. Immunohistochemistry was used to evaluate the expression of vascular endothelial growth factor (VEGF) in bone defects. Expression of osteocalcin (OCN), bone morphogenetic protein-2 (BMP-2), and collagen I (Col I) was assessed by real-time PCR. Histomorphometric analysis showed a similar increase in the percentage of bone trabeculae in tibia bone defects treated with HY and HY-MWCNTs, and both groups presented more organized and thicker bone trabeculae than nontreated defects. Tibiae treated with MWCNTs or HY- MWCNTs showed a higher expression of VEGF. Treatment with MWCNTs or HY-MWCNTs increased the expression of molecules involved in the bone repair process, such as OCN and BMP-2. Also, HY- and MWCNT-treated tibiae had an increased expression of Col I. Thus, it is tempting to conclude that CNTs associated or not with other materials such as HY emerged as a promising biomaterial for bone tissue engineering.


Asunto(s)
Huesos/metabolismo , Ácido Hialurónico/farmacología , Nanotubos de Carbono/análisis , Factor A de Crecimiento Endotelial Vascular/metabolismo , Cicatrización de Heridas/fisiología , Animales , Ratas , Ratas Wistar
4.
Int J Exp Pathol ; 97(6): 438-446, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-28370591

RESUMEN

Mefenamic acid is a non-steroidal anti-inflammatory drug able to control the symptoms of osteoarthritis (OA), but its effects on protection of cartilage and bone are still unclear. This study aimed to investigate whether the control of inflammation by mefenamic acid translates into decreased joint lesions in experimental OA in rats. OA was induced by injecting 1 mg of monosodium iodoacetate (MIA) into the joints of rats. The animals were treated with mefenamic acid (50 mg/kg, daily, oral gavage) either pre-MIA injection (preventive) or post-MIA injection (therapeutic). Joint swelling and hyperalgesia were evaluated at baseline and 1, 3, 14 and 28 days after induction of OA. Intra-articular lavage and kinetics of cell migration into the synovium were measured 3 and 28 days after OA induction. Histopathological analysis, Osteoarthritis Research Society International (OARSI) score, total synovium cells count, cartilage area and levels of proteoglycans in joints were also evaluated. Mefenamic acid prevented joint oedema and hyperalgesia induced by MIA in the acute phase (3 days) of the disease. In the chronic phase (28 days), preventive and therapeutic regimens decreased the number of mononuclear cells in the joint cavity. In contrast, thickening of the synovium, bone resorption, loss of cartilage and levels of proteoglycans were unaffected by mefenamic acid when it was administered either preventively or therapeutically. Thus, mefenamic acid had anti-inflammatory effects but did not reduce the progression of OA lesions, thereby indicating that it is only effective for symptomatic control of OA.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Inflamación/tratamiento farmacológico , Ácido Mefenámico/uso terapéutico , Osteoartritis/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/farmacología , Huesos/efectos de los fármacos , Huesos/patología , Cartílago/efectos de los fármacos , Cartílago/patología , Modelos Animales de Enfermedad , Inflamación/patología , Articulaciones/efectos de los fármacos , Articulaciones/patología , Masculino , Ácido Mefenámico/farmacología , Osteoartritis/patología , Ratas
5.
Cytokine ; 71(1): 54-9, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25226444

RESUMEN

This study examined the sex differences for physical, morphological, histological, mRNA, and protein expression levels changes for interleukins and natriuretic peptides in left ventricle (LV) of two groups of adult FVB/N mice; males (WM) and females (WF). LV morphological, histological, reverse transcription and quantitative real-time PCR (RT-PCR), and immunohistochemical (IHC) alterations were determined in FVB/N mice at 34-35 weeks on gender basis. Confirming the gender dimorphism, FVB/N males (WM) illustrated a significant reduction in ANP and IL1-A levels as well as significantly increased body weight (BW (gm)), tibia length (TL (mm)), heart weight (HW (mg)), heart weight-to-body weight (HW/BW (mg/gm)) ratio, heart weight-to-tibia length (HW/TL (mg/mm)) ratio, left ventricle weight (LV (mg)), left ventricle-to-body weight (LV/BW (mg/gm)) ratio, and left ventricle-to-tibia length (LV/TL (mg/mm)) ratio, left ventricular (LV) cardiomyocyte diameter, high BNP, NPRA, IL-1B, and IL1R1 expression in comparison with FVB/N females (WF). Gender differences in relation to left ventricle (LV) may be due to differences in the interleukins and natriuretic peptides levels as an outcome of sex related hormones.


Asunto(s)
Factor Natriurético Atrial/metabolismo , Ventrículos Cardíacos/anatomía & histología , Ventrículos Cardíacos/metabolismo , Interleucinas/metabolismo , Animales , Factor Natriurético Atrial/genética , Peso Corporal , Femenino , Ventrículos Cardíacos/citología , Ventrículos Cardíacos/ultraestructura , Interleucinas/genética , Interleucinas/inmunología , Masculino , Ratones , Miocardio , Miocitos Cardíacos/citología , Péptido Natriurético Encefálico/genética , Péptido Natriurético Encefálico/metabolismo , Tamaño de los Órganos , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores del Factor Natriurético Atrial/genética , Receptores del Factor Natriurético Atrial/metabolismo , Receptores Tipo I de Interleucina-1/genética , Caracteres Sexuales , Tibia/anatomía & histología
6.
Europace ; 16(11): 1689-96, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24741027

RESUMEN

AIMS: Diabetic patients present a high level of cardiac arrhythmias and risk of cardiac sudden death. The renin-angiotensin system (RAS) plays a key role in diabetes and cardiac diseases. The present study aimed to evaluate whether an angiotensin-converting enzyme 2 (ACE2) activator, diminazene aceturate (DIZE), could improve the streptozotocin (STZ)-induced electrical changes in ventricular repolarization in hyperglycaemic rats. METHODS AND RESULTS: Hyperglycaemia was induced in Wistar male rats with STZ (60 mg/kg/iv). After 4 weeks of STZ injection, rats were daily treated with saline (control) or DIZE (1 mg/kg/gavage) for four consecutive weeks. The cardiac electrical function was evaluated in vivo by electrocardiogram and in vitro by cardiac action potential records in different pacing frequencies. Treatment with DIZE was not able to reverse hyperglycaemia nor body weight loss. However, DIZE reversed hyperglycaemia-induced cardiac electrical changes in ventricular repolarization. Specifically, animals treated with DIZE showed shorter QT and QTc intervals. In addition, ACE2 activation was capable to shorten the cardiac action potential and also reverse the arrhythmic markers. Diminazene aceturate treatment did not induce arrhythmic events in normal, as well as in hyperglycaemic animals. CONCLUSION: Our data indicate that activation of ACE2 has a beneficial effect in hyperglycaemic rats, improving the cardiac electrical function. Thus, DIZE represents a promising new therapeutic agent to treat hyperglycaemia-induced cardiac electrical changes in ventricular repolarization.


Asunto(s)
Antiarrítmicos/farmacología , Arritmias Cardíacas/prevención & control , Diminazeno/análogos & derivados , Activadores de Enzimas/farmacología , Sistema de Conducción Cardíaco/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Hiperglucemia/tratamiento farmacológico , Peptidil-Dipeptidasa A/metabolismo , Estreptozocina , Potenciales de Acción , Enzima Convertidora de Angiotensina 2 , Animales , Arritmias Cardíacas/sangre , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/enzimología , Arritmias Cardíacas/fisiopatología , Diminazeno/farmacología , Activación Enzimática , Sistema de Conducción Cardíaco/enzimología , Sistema de Conducción Cardíaco/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/enzimología , Ventrículos Cardíacos/fisiopatología , Hiperglucemia/sangre , Hiperglucemia/inducido químicamente , Hiperglucemia/enzimología , Hiperglucemia/fisiopatología , Masculino , Ratas Wistar , Factores de Tiempo
7.
Am J Respir Crit Care Med ; 187(6): 648-57, 2013 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-23370913

RESUMEN

RATIONALE: Studies have demonstrated that angiotensin-converting enzyme 2 (ACE2) plays a protective role against lung diseases, including pulmonary hypertension (PH). Recently, an antitrypanosomal drug, diminazene aceturate (DIZE), was shown to exert an "off-target" effect of enhancing the enzymatic activity of ACE2 in vitro. OBJECTIVES: To evaluate the pharmacological actions of DIZE in experimental models of PH. METHODS: PH was induced in male Sprague Dawley rats by monocrotaline, hypoxia, or bleomycin challenge. Subsets of animals were simultaneously treated with DIZE. In a separate set of experiments, DIZE was administered after 3 weeks of PH induction to determine whether the drug could reverse PH. MEASUREMENTS AND MAIN RESULTS: DIZE treatment significantly prevented the development of PH in all of the animal models studied. The protective effects were associated with an increase in the vasoprotective axis of the lung renin-angiotensin system, decreased inflammatory cytokines, improved pulmonary vasoreactivity, and enhanced cardiac function. These beneficial effects were abolished by C-16, an ACE2 inhibitor. Initiation of DIZE treatment after the induction of PH arrested disease progression. Endothelial dysfunction represents a hallmark of PH pathophysiology, and growing evidence suggests that bone marrow-derived angiogenic progenitor cells contribute to endothelial homeostasis. We observed that angiogenic progenitor cells derived from the bone marrow of monocrotaline-challenged rats were dysfunctional and were repaired by DIZE treatment. Likewise, angiogenic progenitor cells isolated from patients with PH exhibited diminished migratory capacity toward the key chemoattractant stromal-derived factor 1α, which was corrected by in vitro DIZE treatment. CONCLUSIONS: Our results identify a therapeutic potential of DIZE in PH therapy.


Asunto(s)
Diminazeno/análogos & derivados , Hipertensión Pulmonar/prevención & control , Tripanocidas/farmacología , Animales , Ensayos de Migración Celular , Diminazeno/farmacología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Endotelio Vascular/fisiopatología , Hipertensión Pulmonar/fisiopatología , Masculino , Neovascularización Fisiológica/fisiología , Ratas , Ratas Sprague-Dawley , Sistema Renina-Angiotensina , Células Madre/fisiología
8.
J Cell Mol Med ; 17(5): 617-25, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23490190

RESUMEN

Cardiovascular diseases are the number one cause of death globally and are projected to remain the single leading cause of death. Treatment options abounds, although efficacy is limited. Recent studies attribute discrete and ephemeral benefits to adult stem cell therapies, indicating the urge to improve stem cell based-therapy. In this study, we show that priming mesenchymal stem cells (MSC) towards cardiomyogenic lineage enhances their beneficial effects in vivo as treatment option for acute phase myocardial infarction. MSC were primed using cardiomyogenic media for 4 days, after which peak expression of key cardiomyogenic genes are reached and protein expression of Cx-43 and sarcomeric α-actinin are observed. MSC and primed MSC (pMSC) were characterized in vitro and used to treat infarcted rats immediately after left anterior descending (LAD) occlusion. Echocardiography analysis indicated that MSC-treated myocardium presented discrete improvement in function, but it also showed that pMSC treatment lead to superior beneficial results, compared with undifferentiated MSC. Seven days after cell injection, MSC and pMSC could still be detected in the myocardium. Connexin-43 expression was quantified through immunoblotting, and was superior in pMSC, indicating that this could be a possible explanation for the superior performance of pMSC therapy.


Asunto(s)
Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Infarto del Miocardio/terapia , Actinina/metabolismo , Animales , Diferenciación Celular , Separación Celular , Conexina 43/metabolismo , Ecocardiografía , Proteínas Fluorescentes Verdes/metabolismo , Pruebas de Función Cardíaca , Immunoblotting , Células Madre Mesenquimatosas/metabolismo , Infarto del Miocardio/fisiopatología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Ratas , Ratas Endogámicas Lew , Sarcómeros/metabolismo
9.
Clin Sci (Lond) ; 125(9): 449-59, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23718715

RESUMEN

The aim of the present study was to investigate the coronary effects of Ang-(1-7) [angiotensin-(1-7)] in hypertrophic rat hearts. Heart hypertrophy was induced by abdominal aorta CoA (coarctation). Ang-(1-7) and AVE 0991, a non-peptide Mas-receptor agonist, at picomolar concentration, induced a significant vasodilation in hearts from sham-operated rats. These effects were blocked by the Mas receptor antagonist A-779. Pre-treatment with L-NAME (N(G)-nitro-L-arginine methyl ester) or ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinozalin-1-one) [NOS (NO synthase) and soluble guanylate cyclase inhibitors respectively] also abolished the effect of Ang-(1-7) in control hearts. The coronary vasodilation produced by Ang-(1-7) and AVE 0991 was completely blunted in hypertrophic hearts. Chronic oral administration of losartan in CoA rats restored the coronary vasodilation effect of Ang-(1-7). This effect was blocked by A-779 and AT2 receptor (angiotensin II type 2 receptor) antagonist PD123319. Acute pre-incubation with losartan also restored the Ang-(1-7)-induced, but not BK (bradykinin)-induced, coronary vasodilation in hypertrophic hearts. This effect was inhibited by A-779, PD123319 and L-NAME. Chronic treatment with losartan did not change the protein expression of Mas and AT2 receptor and ACE (angiotensin-converting enzyme) and ACE2 in coronary arteries from CoA rats, but induced a slight increase in AT2 receptor in aorta of these animals. Ang-(1-7)-induced relaxation in aortas from sham-operated rats was absent in aortas from CoA rats. In vitro pre-treatment with losartan restored the Ang-(1-7)-induced relaxation in aortic rings of CoA rats, which was blocked by the Mas antagonist A-779 and L-NAME. These data demonstrate that Mas is strongly involved in coronary vasodilation and that AT1 receptor (angiotensin II type 1 receptor) blockade potentiates the vasodilatory effects of Ang-(1-7) in the coronary beds of pressure-overloaded rat hearts through NO-related AT2- and Mas-receptor-dependent mechanisms. These data suggest the association of Ang-(1-7) and AT1 receptor antagonists as a potential therapeutic avenue for coronary artery diseases.


Asunto(s)
Angiotensina I/farmacología , Cardiomegalia/tratamiento farmacológico , Losartán/farmacología , Fragmentos de Péptidos/farmacología , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Animales , Imidazoles/farmacología , Técnicas In Vitro , Masculino , NG-Nitroarginina Metil Éster/farmacología , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/agonistas , Proteínas Proto-Oncogénicas/efectos de los fármacos , Piridinas/farmacología , Ratas , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/efectos de los fármacos , Vasodilatación/efectos de los fármacos
10.
Exp Physiol ; 98(1): 57-66, 2013 01.
Artículo en Inglés | MEDLINE | ID: mdl-22730415

RESUMEN

Previous studies have shown that postweaning protein restriction induces changes in the sympathetic nervous system in rats, leading to alterations in cardiovascular parameters. In addition, the renin-angiotensin system is also affected in these animals. Here, we hypothesized that adjustments in the interaction between the RAS and SNS underlie the cardiovascular adaptations observed in rats fed a low-protein diet. Thus, we evaluated the alterations in the mean arterial pressure (MAP) and heart rate of Fisher rats fed a protein-deficient diet before and after systemic administration of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin II (Ang II) type 1 (AT(1)) receptor antagonist losartan alone or in combination with the α(1)-adrenergic receptor antagonist prazosin. Administration of enalapril or losartan decreased the MAP only of rats under protein restriction. Prazosin injection after the infusion of losartan caused a further decrease in the MAP of malnourished rats. In contrast, only the administration of prazosin elicited a reduction in the MAP of control animals. When the sequence of administration of the antagonists was inverted, infusion of prazosin in animals fed the standard or the low-protein diet induced a reduction in the MAP that was further decreased by the subsequent injection of losartan. Importantly, in both protocols the responses of malnourished animals to losartan were markedly greater when compared with the control group. Moreover, these animals presented lower levels of circulating Ang II and a reduced responsiveness to Ang II. In contrast, the expression of AT(1) receptors in the aorta of malnourished animals was increased. Thus, our data suggest that the renin-angiotensin system is an important factor supporting blood pressure in rats fed a low-protein diet and that the sympathetic nervous system activity in these animals is under strong influence of Ang II acting via AT(1) receptors.


Asunto(s)
Angiotensina II/metabolismo , Presión Arterial/efectos de los fármacos , Receptor de Angiotensina Tipo 1/metabolismo , Antagonistas de Receptores de Angiotensina/farmacología , Animales , Dieta con Restricción de Proteínas , Enalapril/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Losartán/farmacología , Masculino , Prazosina/farmacología , Ratas , Ratas Endogámicas F344 , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Sistema Nervioso Simpático/fisiología
11.
Exp Physiol ; 97(6): 699-709, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22286369

RESUMEN

In this study, we evaluated whether the activation of endogenous angiotensin-converting enzyme 2 (ACE2) would improve the cardiovascular autonomic dysfunction of diabetic rats. Ten days after induction of type 1 diabetes (streptozotocin, 50 mg kg(-1) i.v.), the rats were treated orally with 1-[(2-dimethylamino)ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one (XNT), a newly discovered ACE2 activator (1 mg kg(-1) day(-1)), or saline (equivalent volume) for 30 days. Autonomic cardiovascular parameters were evaluated in conscious animals, and an isolated heart preparation was used to analyse cardiac function. Diabetes induced a significant decrease in the baroreflex bradycardia sensitivity, as well as in the chemoreflex chronotropic response and parasympathetic tone. The XNT treatment improved these parameters by ≈ 76% [0.82 ± 0.09 versus 1.44 ± 0.17 Ratio between changes in pulse interval and changes in mean arterial pressure (ΔPI/ΔmmHg)], ∼85% (-57 ± 9 versus -105 ± 10 beats min(-1)) and ≈ 205% (22 ± 2 versus 66 ± 12 beats min(-1)), respectively. Also, XNT administration enhanced the bradycardia induced by the chemoreflex activation by v 74% in non-diabetic animals (-98 ± 16 versus -170 ± 9 Δbeats min(-1)). No significant changes were observed in the mean arterial pressure, baroreflex tachycardia sensitivity, chemoreflex pressor response and sympathetic tone among any of the groups. Furthermore, chronic XNT treatment ameliorated the cardiac function of diabetic animals. However, the coronary vasoconstriction observed in diabetic rats was unchanged by ACE2 activation. These findings indicate that XNT protects against the autonomic and cardiac dysfunction induced by diabetes. Thus, our results provide evidence for the viability and effectiveness of oral administration of an ACE2 activator for the treatment of the cardiovascular autonomic dysfunction caused by diabetes.


Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Sistema Nervioso Parasimpático/efectos de los fármacos , Sistema Nervioso Parasimpático/fisiopatología , Peptidil-Dipeptidasa A/metabolismo , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología , Enzima Convertidora de Angiotensina 2 , Animales , Enfermedades del Sistema Nervioso Autónomo/tratamiento farmacológico , Enfermedades del Sistema Nervioso Autónomo/metabolismo , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Barorreflejo/efectos de los fármacos , Barorreflejo/fisiología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Bradicardia/tratamiento farmacológico , Bradicardia/fisiopatología , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Células Quimiorreceptoras/efectos de los fármacos , Células Quimiorreceptoras/fisiología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/fisiopatología , Corazón/efectos de los fármacos , Corazón/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/fisiopatología , Masculino , Ratas , Ratas Wistar , Taquicardia/tratamiento farmacológico , Taquicardia/fisiopatología , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacología
12.
Peptides ; 151: 170746, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35033621

RESUMEN

This study aimed to investigate whether the Diminazene Aceturate (DIZE), an angiotensin-converting enzyme 2 (ACE2) activator, can revert cardiac dysfunction in ischemia reperfusion-induced (I/R) injury in animals and examine the mechanism underlying this effect. Wistar rats systemically received DIZE (1 mg/kg) for thirty days. Cardiac function in isolated rat hearts was evaluated using the Langendorff technique. After I/R, ventricular non-I/R and I/R samples were used to evaluate ATP levels. Mitochondrial function was assessed using cardiac permeabilized fibers and isolated cardiac mitochondria. Cardiac cellular electrophysiology was evaluated using the patch clamp technique. DIZE protected the heart after I/R from arrhythmia and cardiac dysfunction by preserving ATP levels, independently of any change in coronary flow and heart rate. DIZE improved mitochondrial function, increasing the capacity for generating ATP and reducing proton leak without changing the specific citrate synthase activity. The activation of the ACE2 remodeled cardiac electrical profiles, shortening the cardiac action potential duration at 90 % repolarization. Additionally, cardiomyocytes from DIZE-treated animals exhibited reduced sensibility to diazoxide (KATP agonist) and a higher KATP current compared to the controls. DIZE was able to improve mitochondrial function and modulate cardiac electrical variables with a cardio-protective profile, resulting in direct myocardial cell protection from I/R injury.


Asunto(s)
Enzima Convertidora de Angiotensina 2 , Daño por Reperfusión , Adenosina Trifosfato , Animales , Arritmias Cardíacas , Diminazeno/análogos & derivados , Miocitos Cardíacos , Peptidil-Dipeptidasa A , Ratas , Ratas Wistar , Reperfusión
13.
Life Sci ; 304: 120693, 2022 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-35688180

RESUMEN

AIMS: Diminazene aceturate, a putative ACE2 activator, is susceptible to cleavage resulting in the formation of p-aminobenzamidine (PAB). This study aimed to investigate the effects of PAB in addressing cardiovascular dysfunctions in spontaneously hypertensive rats (SHR). MAIN METHODS: Acute effects of PAB on mean arterial pressure (MAP), heart rate (HR), and aortic (AVC) and mesenteric vascular conductance (MVC) were evaluated in anesthetized SHR. Isolated aortic rings and the Langendorff technique were used to investigate the acute and chronic effects of PAB in the artery and heart. Chronic treatment with PAB (1 mg/kg, gavage) was carried out for 60 days. During this period, systolic blood pressure (SBP) and HR were measured by tail-cuff plethysmography. After the treatment, the left ventricle was collected for histology analyses, western blotting, and ACE2 activity. KEY FINDINGS: Bolus infusion of PAB acutely reduced MAP and increased both AVC and MVC in SHR. Additionally, PAB induced coronary and aorta vasodilation in isolated organs from Wistar and SHR in an endothelial-dependent manner. The chronic PAB treatment in SHR significantly attenuated the increase of SBP and improved the aorta vasorelaxation induced by acetylcholine and bradykinin-induced coronary vasodilation. In addition, chronic treatment with PAB attenuated the cardiomyocyte hypertrophy and extracellular matrix deposition in hearts from SHR. PAB did not alter the protein expression of the AT1, AT2, Mas, ACE, ACE2, or ACE2 activity. SIGNIFICANCE: PAB induced beneficial effects on cardiovascular dysfunctions induced by hypertension, suggesting that this molecule could be used in the development of new drugs for the treatment of cardiovascular diseases.


Asunto(s)
Enzima Convertidora de Angiotensina 2 , Hipertensión , Animales , Benzamidinas , Presión Sanguínea , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Vasodilatación
14.
Exp Physiol ; 96(3): 287-94, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21148624

RESUMEN

Our previous studies have indicated that chronic treatment with 1-[(2-dimethylamino) ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one (XNT), an angiotensin-converting enzyme 2 (ACE2) activator, reverses hypertension-induced cardiac and renal fibrosis in spontaneously hypertensive rats (SHRs). Furthermore, XNT prevented pulmonary vascular remodelling and right ventricular hypertrophy and fibrosis in a rat model of monocrotaline-induced pulmonary hypertension. The aim of this study was to determine the mechanisms underlying the protective effects of XNT against cardiac fibrosis. Hydroxyproline assay was used to measure cardiac collagen content in control and XNT-treated (200 ng kg(-1) min(-1) for 28 days) SHRs. Cardiac ACE2 activity and protein levels were determined using the fluorogenic peptide assay and Western blot analysis, respectively. Extracellular signal-regulated kinases (ERKs; p44 and p42) and angiotensin II type 1 (AT(1)) receptor levels were quantified by Western blotting. Cardiac ACE2 protein levels were ∼15% lower in SHRs compared with Wistar-Kyoto control animals (ACE2/glyceraldehyde 3-phosphate dehydrogenase ratio: Wistar-Kyoto, 1.00 ± 0.02 versus SHR, 0.87 ± 0.01). However, treatment of SHRs with XNT completely restored the decreased cardiac ACE2 levels. Also, chronic infusion of XNT significantly increased cardiac ACE2 activity in SHRs. This increase in ACE2 activity was associated with decreased cardiac collagen content. Furthermore, the antifibrotic effect of XNT correlated with increased cardiac angiotensin-(1-7) immunostaining, though no change in cardiac AT(1) protein levels was observed. The beneficial effects of XNT were also accompanied by a reduction in ERK phosphorylation (phospho-ERK/total ERK ratio: Wistar-Kyoto, 1.00 ± 0.04; control SHR, 1.46 ± 0.25; treated SHR, 0.86 ± 0.02). Our observations demonstrate that XNT activates cardiac ACE2 and inhibits fibrosis. These effects are associated with increases in angiotensin-(1-7) and inhibition of cardiac ERK signalling.


Asunto(s)
Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hipertensión/fisiopatología , Miocardio/patología , Peptidil-Dipeptidasa A/metabolismo , Angiotensina I/biosíntesis , Angiotensina I/genética , Angiotensina I/metabolismo , Enzima Convertidora de Angiotensina 2 , Animales , Técnicas de Cultivo de Célula , Colágeno/metabolismo , Activación Enzimática/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Fibroblastos/metabolismo , Fibrosis/metabolismo , Corazón/efectos de los fármacos , Hipertensión/enzimología , Masculino , Miocardio/enzimología , Miocardio/metabolismo , Fragmentos de Péptidos/biosíntesis , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Peptidil-Dipeptidasa A/biosíntesis , Peptidil-Dipeptidasa A/genética , Fosforilación/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptor de Angiotensina Tipo 1/metabolismo , Transducción de Señal/efectos de los fármacos , Xantonas/farmacología
15.
Am J Respir Crit Care Med ; 182(8): 1065-72, 2010 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-20581171

RESUMEN

RATIONALE: An activated vasoconstrictive, proliferative, and fibrotic axis of the renin angiotensin system (angiotensin-converting enzyme [ACE]/angiotensin [Ang]II/AngII type 1 receptor) has been implicated in the pathophysiology of pulmonary fibrosis (PF) and pulmonary hypertension (PH). The recent discovery of a counterregulatory axis of the renin angiotensin system composed of ACE2/Ang-(1-7)/Mas has led us to examine the role of this vasoprotective axis on such disorders. OBJECTIVES: We hypothesized that Ang-(1-7) treatment would exert protective effects against PF and PH. METHODS: Lentiviral packaged Ang-(1-7) fusion gene or ACE2 cDNA was intratracheally administered into the lungs of male Sprague Dawley rats. Two weeks after gene transfer, animals received bleomycin (2.5 mg/kg). In a subsequent study, animals were administered monocrotaline (MCT, 50 mg/kg). MEASUREMENTS AND MAIN RESULTS: In the PF study, bleomycin administration resulted in a significant increase in right ventricular systolic pressure, which was associated with the development of right ventricular hypertrophy. The lungs of these animals also exhibited excessive collagen deposition, decreased expression of ACE and ACE2, increased mRNA levels for transforming growth factor ß and other proinflammatory cytokines, and increased protein levels of the AT1R. Overexpression of Ang-(1-7) significantly prevented all the above-mentioned pathophysiological conditions. Similar protective effects were also obtained with ACE2 overexpression. In the PH study, rats injected with MCT developed elevated right ventricular systolic pressure, right ventricular hypertrophy, right ventricular fibrosis, and pulmonary vascular remodeling, all of which were attenuated by Ang-(1-7) overexpression. Blockade of the Mas receptor abolished the beneficial effects of Ang-(1-7) against MCT-induced PH. CONCLUSIONS: Our observations demonstrate a cardiopulmonary protective role for the ACE2/Ang-(1-7)/Mas axis in the treatment of lung disorders.


Asunto(s)
Angiotensina I/genética , Terapia Genética , Hipertensión Pulmonar/prevención & control , Fragmentos de Péptidos/genética , Fibrosis Pulmonar/prevención & control , Sistema Renina-Angiotensina , Angiotensina I/metabolismo , Enzima Convertidora de Angiotensina 2 , Animales , Bleomicina , Hipertensión Pulmonar/patología , Masculino , Fragmentos de Péptidos/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/metabolismo , Fibrosis Pulmonar/patología , Ratas , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas G/metabolismo , Transducción Genética
16.
J Biomed Mater Res A ; 109(3): 336-345, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32490596

RESUMEN

A benzamidine derivative from diminazene was tested for a novel activity: treatment of primary open-angle glaucoma. This drug was incorporated into mucoadhesive polymeric inserts prepared using chitosan (Chs) and chondroitin sulfate (CS). Of current interest is the mucoadhesion, which increases the contact time with the ocular surface, resulting in improved bioavailability; also, the inserts are made to act as a prolonged release system. In the present work the inserts were prepared by the solvent casting method using different polymeric proportions (30:70, 50:50, 75:25% w/w Chs:CS and 100% Chs). Thermal analysis and infrared spectroscopy both demonstrated physical dispersion of the active drug. The most promising was the 50:50% Chs:CS which demonstrated that it was not fragile and has an in vitro release profile of up to 180 minutes. In addition, it presented greater adhesion strength in relation to the other formulations. These physicochemical results corroborate the in vivo tests performed. In this sense, we also demonstrated that the treatment with the 50:50% insert can control the intraocular pressure (IOP) for at least 3 weeks and prevents damage to the retinal ganglion cells (RGCs) compared to the placebo insert. Thus, this indicates thus that the new drug is quite viable and promising in glaucoma treatment.


Asunto(s)
Agentes Antiglaucoma/administración & dosificación , Agentes Antiglaucoma/química , Preparaciones de Acción Retardada/química , Diminazeno/análogos & derivados , Diminazeno/administración & dosificación , Glaucoma de Ángulo Abierto/tratamiento farmacológico , Animales , Agentes Antiglaucoma/farmacocinética , Agentes Antiglaucoma/uso terapéutico , Quitosano/química , Sulfatos de Condroitina/química , Diminazeno/farmacocinética , Diminazeno/uso terapéutico , Liberación de Fármacos , Glaucoma de Ángulo Abierto/patología , Masculino , Ratas , Ratas Wistar
17.
Bone ; 145: 115842, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33422700

RESUMEN

OBJECTIVES: This study aimed to evaluate the involvement of Angiotensin II (Ang II) in joint lesions associated with osteoarthritis (OA) in vitro and in vivo. METHODS: Chondrocyte cultures were obtained from knee joints of neonatal rats and stimulated with Ang II/MIA/ACE inhibitors. In vivo, rats treated or not with the ACE inhibitor captopril, received daily injections of Ang II or sodium monoiodoacetate (MIA) in knee joints for evaluation of cartilage, bone, and synovial lesions. RESULTS: Cultured chondrocytes expressed the mRNA for Ace, Agtr1, Agtr2, and Mas1. Stimulating cells with Ang II reduced chondrocyte viability and metabolism. Accordingly, in vivo Ang II injection into the knees of rats triggered hyperalgesia, joint edema, increased the number of leukocytes in the joint cavity, and induced cartilage lesions associated with OA alterations. In further experiments, Ang II synthesis was prevented with the ACE inhibitor Captopril in the context of MIA-induced OA. Ang II inhibition with captopril improved the OARSI score, induced chondroprotection, and reduced the leukocyte recruitment from synovium after MIA. Additionally, captopril prevented MIA-induced bone resorption, by decreasing the number of osteoclasts and increasing the expression of IL-10 in the bone. In vitro, inhibiting Ang II synthesis decreased MIA-induced chondrocyte death and increased Col2a1 transcription. CONCLUSION: Ang II induces chondrocyte death and joint tissue damages associated with OA and its modulation can be a therapeutic strategy in osteoarthritis.


Asunto(s)
Cartílago Articular , Osteoartritis de la Rodilla , Osteoartritis , Angiotensina II , Animales , Condrocitos , Articulación de la Rodilla , Osteoartritis/tratamiento farmacológico , Osteoartritis de la Rodilla/tratamiento farmacológico , Proto-Oncogenes Mas , Ratas
18.
Toxicol Res ; 37(3): 311-321, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34295795

RESUMEN

Methylmercury (MeHg) intoxication is associated with hypertension, hypercholesterolemia, and atherosclerosis by mechanisms that are not yet fully understood. We investigated the effects of MeHg intoxication in atherosclerosis-prone (ApoE-KO) and resistant C57BL/6 mice. Mice were submitted to carotid stenosis surgery (to induce atherosclerosis faster) and received water or MeHg solution (20 mg/L) for 15 days. Tail plethysmography was performed before and after MeHg exposure. Food and MeHg solution intakes were monitored weekly. On the 15th day, mice were submitted to intravital fluorescence microscopy of mesenteric vasculature to observe in vivo leukocyte rolling and adhesion. Results showed that despite the high hair and liver Hg concentrations in the MeHg group, food and water (or MeHg solution) consumption and liver function marker levels were similar to those in controls. MeHg exposure increased total cholesterol, the atherogenic (non-HDL) fraction and systolic and diastolic blood pressure. MeHg exposure also induced inflammation, as seen by the increased rolling and adhered leukocytes in the mesenteric vasculature. Atherosclerosis lesions were more extensive in the aorta and carotid sites of MeHg-ApoE knockout mice. Surprisingly, MeHg exposure also induced atherosclerosis lesions in C57BL/6 mice, which are resistant to atherosclerosis formation. We concluded that MeHg intoxication might represent a risk for cardiovascular diseases since it accelerates atherogenesis by exacerbating several independent risk factors.

19.
Mol Med ; 16(5-6): 210-5, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20111697

RESUMEN

The aim of the present study was to test the hypothesis that the activation of the angiotensin-converting enzyme (ACE)2/angiotensin-(1-7)/Mas receptor axis by use of a novel ACE2 activator (XNT) would protect against thrombosis. Thrombi were induced in the vena cava of spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats, and ACE2 and ACE activity in the thrombus was determined. Real-time thrombus formation was viewed through intravital microscopy of vessels in nude mice. Thrombus weight was 40% greater in the SHR (4.99 +/- 0.39 versus 7.04 +/- 0.66 mg). This weight increase was associated with a 20% decrease in ACE2 activity in the thrombus. In contrast, there were no differences between the WKY and SHR in ACE2 protein and ACE activity in the thrombi. ACE2 inhibition (DX600; 0.1 micromol/L/kg) increased thrombus weight by 30% and XNT treatment (10 mg/kg) resulted in a 30% attenuation of thrombus formation in the SHR. Moreover, XNT reduced platelet attachment to injured vessels, reduced thrombus size, and prolonged the time for complete vessel occlusion in mice. Thus, a decrease in thrombus ACE2 activity is associated with increased thrombus formation in SHR. Furthermore, ACE2 activation attenuates thrombus formation and reduces platelet attachment to vessels. These results suggest that ACE2 could be a novel target for the treatment of thrombogenic diseases.


Asunto(s)
Peptidil-Dipeptidasa A/metabolismo , Trombosis/metabolismo , Análisis de Varianza , Enzima Convertidora de Angiotensina 2 , Animales , Masculino , Ratones , Ratones Desnudos , Peptidil-Dipeptidasa A/genética , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Trombosis/patología , Xantonas/farmacología
20.
Biol Chem ; 391(4): 435-41, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20180641

RESUMEN

Tonin is a serine proteinase of the kallikrein family that can produce angiotensin II directly from angiotensinogen. To clarify the importance of this enzyme for central nervous control of the cardiovascular system, we generated transgenic mice, TGM(rTon), that express rat tonin in astrocytes. These mice present high levels of tonin mRNA and activity specifically in the brain. As a consequence, TGM(rTon) develop increased blood pressure and water intake. Lisinopril, an ACE inhibitor, is less hypotensive for transgenic mice than for control animals. The AT(1) receptor antagonist candesartan equally lowers blood pressure in transgenic and in control mice. Plasma angiotensin II, but not angiotensin I, is increased in TGM(rTon) compared to the wild type, suggesting release of the peptide from the brain into the circulation. However, AT(1) receptors are desensitized in this transgenic model, as demonstrated by a blunted pressor response to intravenous application of angiotensin II. In conclusion, tonin in the brain may represent an alternative pathway for angiotensin II generation with effects on the cardiovascular system.


Asunto(s)
Presión Sanguínea/genética , Encéfalo/metabolismo , Ingestión de Líquidos/genética , Calicreínas de Tejido/genética , Angiotensina II/metabolismo , Animales , Expresión Génica , Riñón/fisiología , Ratones , Ratones Transgénicos , Ratas , Receptor de Angiotensina Tipo 1/metabolismo , Sistema Renina-Angiotensina/genética
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