Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.703
Filtrar
1.
Med Arch ; 73(3): 157-162, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31391706

RESUMO

Introduction: Hypertension is significantly contributing to global mortality and morbidity and has been identified as the most important modifiable risk factor for early development of cardiovascular diseases (CVD). Aim: The aim of this study was to investigate the efficacy of different combinations of antihypertensive therapy on blood pressure, arterial stiffness and peripheral resistance in patients with essential hypertension using the brachial oscillometric ambulatory blood pressure monitor. Methods: This study was designed as an observational, prospective, multi centric study conducted in eight primary care centers of the Health Center of Canton Sarajevo during the period of six months. The study included 655 participants, both genders, aged between 30 and 75, who were diagnosed with hypertension according to the ESC/ESH guidelines. Participants were divided into six treatment groups based on the hypertensive drug therapy they were using; lisinopril, losartan or valsartan alone or in combination with hydrochlorothiazide (A, B and C group respectively) or combination of lisinopril, losartan or valsartan with/without hydrochlorothiazide together with amlodipine (D, E and F respectively). The participants were monitored at baseline, after 3 and 6 months (1st and 2nd follow-up). Brachial oscillometric ambulatory blood pressure monitor was used for measuring systolic (SBP), diastolic (DBP), pulse pressure (PP), pulse wave velocity (PWV) and peripheral resistance (PR). Results: SBP, DPB, PP, and PWV significantly decreased from baseline to 2nd follow-up in all treatment groups. The mean reductions in SBP were from -11.7 (95%CI; 9.3- 14.1) to -23.2 (95%CI; 18.3-28.1) mmHg and DBP reductions varied from -5.5 (95%CI; 3.9- 7.1) to -13.4 (95%CI; 7.7-19.1) mmHg. PWV decreased in all treatment groups (from -3.3% to -8.2%). Treatment regiment was not associated with significant differences in SBP, DBP, PP or PWV reductions or their values measured at 2nd follow-up. Peripheral resistance significantly decreased only in group C (p=0.011), group D (p=0.009) and group F (p=0.027). Conclusion: These data suggest that lisinopril/lisinopril + hydrochlorothiazide, losartan/losartan + hydrochlorothiazide and valsartan/valsartan + hydrochlorothiazide alone or in combination with amlodipine are equally effective and well tolerated for the reduction of both systolic and diastolic blood pressure and improve arterial stiffness in patients with essential hypertension.


Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Rigidez Vascular/efeitos dos fármacos , Idoso , Anlodipino/farmacologia , Anlodipino/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Artérias , Diástole/efeitos dos fármacos , Combinação de Medicamentos , Hipertensão Essencial/tratamento farmacológico , Feminino , Humanos , Hidroclorotiazida/farmacologia , Hidroclorotiazida/uso terapêutico , Lisinopril/farmacologia , Lisinopril/uso terapêutico , Losartan/farmacologia , Losartan/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Onda de Pulso , Sístole/efeitos dos fármacos , Valsartana/farmacologia , Valsartana/uso terapêutico
2.
Eur J Pharmacol ; 860: 172585, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31376367

RESUMO

We previously reported that neonatal blockade of angiotensin II AT1 receptor prevents cardiac changes in 4 weeks rats with neonatal hyperoxia-induced cardiomyopathy, a recognized model of prematurity-related deleterious conditions. Considering the importance of AT1 receptor and the renin angiotensin system (RAS) in normal development, the present study aimed to investigate the adult effects of neonatal AT1 blockade on left ventricle (LV) in rats exposed to neonatal hyperoxia. Sprague-Dawley pups were exposed to 80% O2 or room air from days 3-10. AT1 blocker (losartan) or H2O were given by gavage from day 8-10. LV function (echo and intraventricular pressure), histology and expression of RAS components were examined in 15-16 weeks old adult males. Losartan treatment prevented myocardial fibrosis, LV wall thickening and stroke volume reduction in rats exposed to high O2 in the neonatal period. However, Losartan treatment of O2-exposed pups led to reduced ejection fraction (EF) and fractional shortening (FS), and did not prevent changes in diastolic function. Losartan also did not prevent increased LV AT2 and decreased angiotensin-(1-7) Mas receptors expression observed in high O2-exposed rats. Neonatal Losartan attenuated long-term impact of neonatal hyperoxia but also led to decreased EF and FS. Increased AT2 and decreased Mas receptor expression observed in O2-exposed group were unaffected by Losartan treatment. Our results show that early life Losartan treatment aimed at preventing cardiac consequences of neonatal deleterious conditions may also comprise detrimental effects that require further investigation prior to clinical translation in developing children.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Coração/efeitos dos fármacos , Oxigênio/efeitos adversos , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/metabolismo , Diástole/efeitos dos fármacos , Modelos Animais de Doenças , Fibrose , Coração/fisiopatologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Losartan/farmacologia , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley , Sístole/efeitos dos fármacos , Fatores de Tempo
3.
J Pharmacol Exp Ther ; 370(2): 197-205, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31101682

RESUMO

We have reported that anthracyclines and nonanthracycline chemotherapeutics caused diastolic dysfunction in cancer patients without cardiovascular risk factors. Diastolic dysfunction occurred as early as 1 week after the last chemotherapy cycle and manifested as impaired myocardial relaxation at echocardiography or persistent elevations of B-type natriuretic peptide (BNP) or troponin. The antianginal drug ranolazine shows cardiac relaxant effects that we considered of value to treat early diastolic dysfunction induced by cancer drugs; therefore, 24 low-risk patients with post-chemotherapy diastolic dysfunction were randomized (1:1) to ranolazine or the investigator's choice of common cardiovascular drugs, such as ß-blockers and/or angiotensin-converting enzyme inhibitors or loop diuretics (best standard therapy, BST). After 5 weeks, 12 of 12 patients on ranolazine recovered from diastolic dysfunction, whereas 3 of 12 patients on BST did not improve; however, adverse events (not serious) were apparently more frequent for ranolazine than for BST (4/12 vs. 1/12). Ranolazine did not lower blood pressure, whereas BST reduced systolic pressure and caused a trend toward a reduced diastolic pressure. Most patients at randomization showed tachycardia resulting from chemotherapy-related anemia. Hemoglobin recovery contributed to normalizing heart rate in these patients; however, some patients in the ranolazine arm developed tachycardia through chronotropic effects of high BNP levels and returned to a normal heart rate through the effects of ranolazine on decreasing BNP levels. This minitrial describes the potential effects of ranolazine on relieving chemotherapy-related diastolic dysfunction; however, clinical implications of these findings need to be characterized by studies with an adequate sample size. SIGNIFICANCE STATEMENT: The antianginal drug ranolazine causes cardiac relaxant effects that might relieve diastolic dysfunction. In a clinical pharmacology study, 24 patients were randomized (1:1) to receive ranolazine or common cardiovascular drugs to treat early diastolic dysfunction induced by anthracycline-based or nonanthracycline chemotherapy. Ranolazine relieved diastolic dysfunction in these patients. The safety profile of ranolazine in cancer patients is similar to that of the general population. Compared with common cardiovascular drugs, ranolazine relieved diastolic dysfunction without lowering blood pressure. The sample size of this study was nonetheless too small to permit considerations about the potential clinical value of ranolazine for oncologic patients with early diastolic dysfunction induced by anthracyclines or nonanthracycline chemotherapeutics. This information should be obtained by studies with an adequate sample size.


Assuntos
Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Fármacos Cardiovasculares/farmacologia , Diástole/efeitos dos fármacos , Ranolazina/farmacologia , Adulto , Idoso , Determinação de Ponto Final , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Segurança
4.
Biomed Res Int ; 2019: 6791971, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31139645

RESUMO

The present study aims to investigate whether intravenous dexmedetomidine shows superiority to esmolol for hemodynamic response to tracheal intubation after rapid sequence induction. In the present meta-analysis, PubMed, EMBASE, and the Cochrane Library were searched for trials comparing dexmedetomidine with esmolol for the attenuation of the hemodynamic response to intubation. Ten trials were selected in the present meta-analysis. Compared to esmolol, the use of dexmedetomidine maintains stable heart rates (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) at 1 min, 3 min, and 5 min after tracheal intubation. Dexmedetomidine causes less hemodynamic response to tracheal intubation after rapid sequence induction compared with esmolol.


Assuntos
Dexmedetomidina/administração & dosagem , Dexmedetomidina/farmacologia , Hemodinâmica/efeitos dos fármacos , Intubação Intratraqueal , Propanolaminas/administração & dosagem , Propanolaminas/farmacologia , Administração Intravenosa , Adulto , Pressão Sanguínea/efeitos dos fármacos , Diástole/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Viés de Publicação , Sístole/efeitos dos fármacos , Adulto Jovem
5.
J Endocrinol ; 241(3): 279-292, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31013474

RESUMO

Endogenous glucocorticoid action is important in the structural and functional maturation of the fetal heart. In fetal mice, although glucocorticoid concentrations are extremely low before E14.5, glucocorticoid receptor (GR) is expressed in the heart from E10.5. To investigate whether activation of cardiac GR prior to E14.5 induces precocious fetal heart maturation, we administered dexamethasone in the drinking water of pregnant dams from E12.5 to E15.5. To test the direct effects of glucocorticoids upon the cardiovascular system we used SMGRKO mice, with Sm22-Cre-mediated disruption of GR in cardiomyocytes and vascular smooth muscle. Contrary to expectations, echocardiography showed no advancement of functional maturation of the fetal heart. Moreover, litter size was decreased 2 days following cessation of antenatal glucocorticoid exposure, irrespective of fetal genotype. The myocardial performance index and E/A wave ratio, markers of fetal heart maturation, were not significantly affected by dexamethasone treatment in either genotype. Dexamethasone treatment transiently decreased the myocardial deceleration index (MDI; a marker of diastolic function), in control fetuses at E15.5, with recovery by E17.5, 2 days after cessation of treatment. MDI was lower in SMGRKO than in control fetuses and was unaffected by dexamethasone. The transient decrease in MDI was associated with repression of cardiac GR in control fetuses following dexamethasone treatment. Measurement of glucocorticoid levels in fetal tissue and hypothalamic corticotropin-releasing hormone (Crh) mRNA levels suggest complex and differential effects of dexamethasone treatment upon the hypothalamic-pituitary-adrenal axis between genotypes. These data suggest potentially detrimental and direct effects of antenatal glucocorticoid treatment upon fetal heart function.


Assuntos
Dexametasona/farmacologia , Diástole/efeitos dos fármacos , Coração Fetal/efeitos dos fármacos , Exposição Materna , Animais , Peso Corporal , Feminino , Coração Fetal/diagnóstico por imagem , Genótipo , Glucocorticoides/farmacologia , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Miócitos Cardíacos/metabolismo , Tamanho do Órgão , Sistema Hipófise-Suprarrenal/metabolismo , RNA Mensageiro/metabolismo , Receptores de Glucocorticoides/metabolismo
6.
Int J Mol Sci ; 20(8)2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31010001

RESUMO

Dipeptidyl peptidase IV (DPPIV) inhibitors are antidiabetic agents that exert renoprotective actions independently of glucose lowering. Cardiac dysfunction is one of the main outcomes of chronic kidney disease (CKD); however, the effects of DPPIV inhibition on cardiac impairment during CKD progression remain elusive. This study investigated whether DPPIV inhibition mitigates cardiac dysfunction and remodeling in rats with a 5/6 renal ablation and evaluated if these effects are associated with changes in the cardiac renin-angiotensin system (RAS). To this end, male Wistar rats underwent a 5/6 nephrectomy (Nx) or sham operation, followed by an 8-week treatment period with the DPPIV inhibitor sitagliptin (IDPPIV) or vehicle. Nx rats had lower glomerular filtration rate, overt albuminuria and higher blood pressure compared to sham rats, whereas CKD progression was attenuated in Nx + IDPPIV rats. Additionally, Nx rats exhibited cardiac hypertrophy and fibrosis, which were associated with higher cardiac DPPIV activity and expression. The sitagliptin treatment prevented cardiac fibrosis and mitigated cardiac hypertrophy. The isovolumic relaxation time (IRVT) was higher in Nx than in sham rats, which was suggestive of CKD-associated-diastolic dysfunction. Sitagliptin significantly attenuated the increase in IRVT. Levels of angiotensin II (Ang II) in the heart tissue from Nx rats were higher while those of angiotensin-(1-7) Ang-(1-7) were lower than that in sham rats. This cardiac hormonal imbalance was completely prevented by sitagliptin. Collectively, these results suggest that DPPIV inhibition may delay the onset of cardiovascular impairment in CKD. Furthermore, these findings strengthen the hypothesis that a crosstalk between DPPIV and the renin-angiotensin system plays a role in the pathophysiology of cardiorenal syndromes.


Assuntos
Angiotensina II/metabolismo , Angiotensina I/metabolismo , Cardiotônicos/uso terapêutico , Miocárdio/metabolismo , Fragmentos de Peptídeos/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Fosfato de Sitagliptina/uso terapêutico , Angiotensina I/sangue , Angiotensina II/sangue , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cardiotônicos/farmacologia , Diástole/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Rim/efeitos dos fármacos , Rim/fisiopatologia , Testes de Função Renal , Masculino , Miocárdio/patologia , Fragmentos de Peptídeos/sangue , Peptidil Dipeptidase A/metabolismo , Ratos Wistar , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Fosfato de Sitagliptina/farmacologia , Regulação para Cima/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
7.
Biomed Pharmacother ; 114: 108837, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30965239

RESUMO

BACKGROUND AND PURPOSES: Dexmedetomidine preconditioning (DP) can mimic pharmacological preconditioning and induce cardiac protection. There are controversies on the roles of coronary endothelia in cardioprotection of dexmedetomidine. Herein, we tested the hypothesis that protection of dexmedetomidine is not endothelial dependent in heart against myocardial ischemia/reperfusion (I/R) injury. METHODS: Langendorff-perfused rat hearts were pretreated by 60 mM of potassium to produce endothelial dysfunction (ED), then medicated with dexmedetomidine, and subsequently subjected to 30 min of global ischemia followed by 60 min of reperfusion. To investigate the cardioprotective effect of dexmedetomidine in heart with ED, isolated rat hearts were randomly divided into the following six groups: sham, I/R, DP, ED, ED + I/R, and ED + DP + I/R. Heart rates, left ventricular function, and coronary perfusion pressure were assessed for each heart. Infarct size was evaluated by triphenyltetrazolium chloride staining. High-sensitivity cardiac troponin T (hs-cTNT) of coronary flow perfusion was determined. RESULTS: After the isolated hearts with pretreatment of 60 mM of potassium chloride, diastolic function of coronary endothelia in performance of response to histamine was significantly decreased (P < 0.05). DP attenuated I/R-induced infarct size of the left ventricle (P < 0.05) and decreased hs-cTNT (P < 0.05). Additionally, left ventricular developed pressure, +dp/dtmax, and -dp/dtmax were elevated in rat hearts pretreated with dexmedetomidine. Furthermore, dexmedetomidine-mediated cardiac protection against I/R injury was still remained in isolated hearts with coronary ED. CONCLUSION: Continuous perfusion of 60 mM of potassium for 10 min can produce coronary ED in isolated rat hearts. Dexmedetomidine maintains its protective function against I/R injury in heart with coronary ED. Myocardial protection of dexmedetomidine is non-endothelial function dependent in alleviating I/R injury.


Assuntos
Dexmedetomidina/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Diástole/efeitos dos fármacos , Células Endoteliais , Frequência Cardíaca/efeitos dos fármacos , Precondicionamento Isquêmico/métodos , Masculino , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
8.
Biol Pharm Bull ; 42(7): 1102-1111, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30867344

RESUMO

This study aimed to evaluate the effects of combined use of tetrahydrobiopterin (BH4) and nebivolol on cardiac diastolic dysfunction in spontaneously hypertensive rats (SHRs). Twelve-week-old male SHRs were treated with BH4, nebivolol, or a combination of both. Left ventricle function was evaluated, and reactive oxygen species (ROS) production (including dihydroethidium (DHE) and 3-nitrotyrosine (3-NT)), nitric oxide synthase (NOS) activity and the level of NO in myocardial tissue were determined. The expression levels of endothelial NOS (eNOS), phospholamban (PLN), sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), ß3-adrenoceptor, cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG) were assayed. Treatment with BH4, nebivolol, or both reversed the noninvasive indexes of diastolic function, including E/E' and E'/A', and the invasive indexes, including time constant of isovolumic left ventricle (LV) relaxation (tau), -dP/dtmin, -dP/dtmin/LV systolic pressure (LVSP), and LV end-diastolic pressure (LVEDP) in SHRs. mRNA and protein expression levels of eNOS dimer, phosphorylated PLN, SERCA2a, cGMP, and PKG in the myocardium of treated SHRs were significantly up-regulated compared with those in control rats (p < 0.05 or p < 0.01). The expression levels of 3-NT and DHE were reduced in all treated groups (p < 0.05 or p < 0.01). Notably, combined use of BH4 and nebivolol had better cardioprotective effects than monotherapies. BH4 or nebivolol has a protective effect on diastolic dysfunction in SHRs, and BH4 combined with nebivolol may exert a synergistically cardioprotective effect through activation of ß3-adrenoceptor and the NO/cGMP/PKG signaling pathway.


Assuntos
Anti-Hipertensivos/farmacologia , Biopterina/análogos & derivados , Cardiotônicos/farmacologia , Diástole/efeitos dos fármacos , Nebivolol/farmacologia , Animais , Biopterina/farmacologia , GMP Cíclico/metabolismo , Sinergismo Farmacológico , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Miocárdio/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Espécies Reativas de Oxigênio/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos
9.
Drug Discov Ther ; 13(1): 38-46, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30880321

RESUMO

Heart failure with preserved ejection fraction (HFpEF) is a leading cause of morbidity and mortality without an established treatment. Diastolic dysfunction, the hallmark of HFpEF, is associated with altered myocardial bioenergetics. No previous study has examined the effects of coenzyme Q10 (CoQ10) on left ventricle (LV) diastolic function in patients with HFpEF. We investigated whether CoQ10 could improve LV diastolic function in patients with HFpEF. We performed a randomized controlled trial (RCT) using pretest and posttest control groups of 30 patients with HFpEF. The patients received either CoQ10 100 mg three times a day or no CoQ10 in addition to routine treatment for 30 days. Echocardiographic study was performed at baseline and follow-up. LV diastolic function was evaluated by two dimensional and Doppler echocardiography as follows; average E/e׳, septal and lateral e׳velocity, and left atrium volume index (LAVI). A total of 28 patients completed the study. A statistically significant improvement was observed in the CoQ10 treatment group in terms between groups (∆E/e׳ ‒ 3.6 vs. ‒ 2.4; p = 0.28) and (∆LAVI ‒ 5.4 vs. ‒ 4.4; p = 0.83). Short term CoQ10 supplementation provided no additional benefits in improving LV diastolic function in patients with HFpEF.


Assuntos
Diástole/efeitos dos fármacos , Suplementos Nutricionais , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico/efeitos dos fármacos , Ubiquinona/análogos & derivados , Idoso , Diástole/fisiologia , Feminino , Seguimentos , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico/fisiologia , Ubiquinona/administração & dosagem , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologia
10.
Molecules ; 24(3)2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30736394

RESUMO

Background and Aims: Diabetic cardiomyopathy (DCM) is an emerging problem worldwide due to an increase in the incidence of type 2 diabetes. Animal studies have indicated that metformin and pioglitazone can prevent DCM partly by normalizing insulin resistance, and partly by other, pleiotropic mechanisms. One clinical study has evidenced the insulin-senzitizing effect of the drug candidate BGP-15, along with additional animal studies that have confirmed its beneficial effects in models of diabetes, muscular dystrophy and heart failure, with the drug affecting chaperones, contractile proteins and mitochondria. Our aim was to investigate whether the inzulin-senzitizer BGP-15 exert any additive cardiovascular effects compared to metformin or pioglitazone, using Goto-Kakizaki (GotoK) rats. Methods: Rats were divided into five groups: (I) healthy control (Wistar), (II) diseased (GotoK), and GotoK rats treated with: (III) BGP-15, (IV) metformin, and (V) pioglitazone, respectively, for 12 weeks. Metabolic parameters and insulin levels were determined at the endpoint. Doppler echocardiography was carried out to estimate diabetes-associated cardiac dysfunction. Thoracotomy was performed after the vascular status of rats was evaluated using an isolated aortic ring method. Furthermore, western blot assays were carried out to determine expression or phosphorylation levels of selected proteins that take part in myocyte relaxation. Results: BGP-15 restored diastolic parameters (e'/a', E/e', LAP, E and A wave) and improved Tei-index compared to untreated GotoK rats. Vascular status was unaffected by BGP-15. Expression of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) and phosphodiesterase 9A (PDE9A) were unchanged by the treatments, but the phosphorylation level of vasodilator-stimulated phosphoprotein (VASP) and phospholamban (PLB) increased in BGP-15-treated rats, in comparison to GotoK. Conclusions: Even though the BGP-15-treatment did not interfere significantly with glucose homeostasis and vascular status, it considerably enhanced diastolic function, by affecting the SERCA/phospholamban pathway in GotoK rats. Although it requires further investigation, BGP-15 may offer a new therapeutic approach in DCM.


Assuntos
Cardiomiopatias Diabéticas/fisiopatologia , Diástole/efeitos dos fármacos , Insuficiência Cardíaca Diastólica/etiologia , Insuficiência Cardíaca Diastólica/fisiopatologia , Oximas/farmacologia , Piperidinas/farmacologia , Animais , Biomarcadores , Cardiomiopatias Diabéticas/diagnóstico , Cardiomiopatias Diabéticas/tratamento farmacológico , Modelos Animais de Doenças , Ecocardiografia/métodos , Insuficiência Cardíaca Diastólica/diagnóstico , Insuficiência Cardíaca Diastólica/tratamento farmacológico , Testes de Função Cardíaca , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Ratos
11.
Mol Cell Biochem ; 456(1-2): 85-93, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30712071

RESUMO

Chymases, a family of serine proteases with chymotryptic activity, play a significant role in cardiac angiotensin II (Ang II) formation from its substrate Ang-(1-12) in both human and rodent models. No studies, to date, have assessed the differences in enzymatic activity among these isoforms in Ang II formation, particularly in the cardiomyocyte (CM). Using PCR and DNA sequencing, we demonstrated that MCP-1, MCP-2, MCP-4, and MCP-5 mRNAs are expressed in the CM of both spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). While rMCP-1 and rMCP-5 gene transcripts were higher than that of other isoforms in both rat strains, WKY CM exhibits higher levels of rMCP-1 and rMCP-5 mRNAs compared to the SHR CM. Ovariectomy (OVX) increased the expression of rMCP-1 and rMCP-5 mRNAs in WKY. In SHR, OVX was associated with a blunted increase in rMCP-1 mRNA compared to OVX normotensive WKY. Chymase activity, measured as Ang II formation from Ang-(1-12), significantly correlated with rMCP-1 and rMCP-5 mRNA expression in both rat strains. Both rMCP-1 and rMCP-5 mRNA expressions were positively correlated with progressive diastolic dysfunction (increasing the ratio of early mitral inflow velocity-to-early mitral annular velocity, E/e') and expanding chamber dimensions or increasing left ventricular internal diameter end diastole. These data show rMCP-1 and rMCP-5 as the Ang II forming chymase isoforms participating in the loss of normal cardiac function due to OVX in rodents.


Assuntos
Quimases/biossíntese , Diástole/efeitos dos fármacos , Estrogênios/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Proteínas Musculares/biossíntese , Miócitos Cardíacos/enzimologia , Animais , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Feminino , Miócitos Cardíacos/citologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
12.
Arch Physiol Biochem ; 125(4): 311-320, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29616829

RESUMO

This study investigated the effects of chronic supraphysiological dose of testosterone propionate administration cardiovascular function in rats from the perspective of haemostatic function including platelet functions, coagulation, and fibrinolysis. Testosterone significantly enhanced cardiac contractility by enhancing LVSP (10%), dp/dtmax (36.7%), dp/dtmin (14.6%) without altering heart rate, diastolic function, and serum lipid profile. While it has no effect on platelets count, thromboxane B2 levels, and platelet aggregation, testosterone significantly enhanced bleeding time and increased circulatory and thoracic aorta mRNA and protein levels of tPA (46.5%, 58.2%, and 74.3%, respectively) and significantly decreased those of PAI-1 (29.3%, 26.4%, and 32.8%, respectively). While there were no significant changes in PT and aPTT, mRNA and protein levels of prothrombin and factor VII were downregulated in the livers of the testosterone-treated rats (57.7% and 64.9%, respectively). Overall, chronic testosterone administration in rats may act as a cardio-protective agent by modulating haemostasis in rats.


Assuntos
Fibrinólise/efeitos dos fármacos , Hemostasia/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Testosterona/administração & dosagem , Testosterona/farmacologia , Animais , Diástole/efeitos dos fármacos , Diástole/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Lipídeos/sangue , Masculino , Agregação Plaquetária/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
13.
Kidney Int ; 95(4): 973-982, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30473139

RESUMO

The safety and efficacy of spironolactone is uncertain in end-stage renal disease. We randomized 129 maintenance hemodialysis patients to placebo (n=51) or spironolactone 12.5 mg (n=27), 25 mg (n=26), or 50 mg (n=25) daily for 36 weeks in a double-blind, placebo-controlled, multiple dosage trial to assess safety, tolerability and feasibility and to explore cardiovascular efficacy. The primary safety endpoints were hyperkalemia (potassium > 6.5 mEq/L) and hypotension requiring emergency department visit or hospitalization. Diastolic function was assessed by Doppler echocardiography. 125 participants (97%) completed dose escalation, with no significant difference in permanent study drug discontinuation between the groups (27.5% in placebo versus 16.7% in the combined spironolactone groups and 28% in the 50 mg group). Hyperkalemia frequency was similar between spironolactone and placebo (0.49 versus 0.50 events per patient-year) but demonstrated a significant linear trend due primarily to an increased event rate at the 50 mg dose (0.89 events per patient-year). The primary hypotension outcome was infrequent and similar with spironolactone and placebo (0.11 versus 0 events per patient-year). Gynecomastia was rare and did not differ significantly between groups. Change in diastolic function was similar with spironolactone and placebo. Spironolactone appears safe in carefully monitored maintenance hemodialysis patients, but did not affect cardiovascular parameters in this small study. Hyperkalemia occurs more frequently as dosage increases to 50 mg daily.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Hiperpotassemia/epidemiologia , Hipotensão/epidemiologia , Falência Renal Crônica/terapia , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Espironolactona/efeitos adversos , Adulto , Idoso , Aldosterona/metabolismo , Doenças Cardiovasculares/diagnóstico por imagem , Diástole/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Ecocardiografia Doppler , Estudos de Viabilidade , Feminino , Ginecomastia/induzido quimicamente , Ginecomastia/epidemiologia , Humanos , Hiperpotassemia/sangue , Hiperpotassemia/induzido quimicamente , Hipotensão/induzido quimicamente , Falência Renal Crônica/complicações , Falência Renal Crônica/metabolismo , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Placebos/administração & dosagem , Placebos/efeitos adversos , Potássio/sangue , Diálise Renal , Espironolactona/administração & dosagem
14.
Nucl Med Commun ; 40(1): 22-29, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30418380

RESUMO

BACKGROUND: Trastuzumab (T) and anthracycline (A)-based chemotherapy is considered the standard of care in human epidermal growth factor receptor-2+ overexpressing breast cancer, but requires monitoring for known cardiotoxicity using left ventricular (LV) ejection fraction (EF) every 3-4 months during treatment. It is not conclusively established whether diastolic dysfunction (DD) precedes LVEF decrease in patients developing trastuzumab-induced cardiotoxicity (TIC). OBJECTIVE: The aim was to elucidate whether DD precedes LVEF decrease in trastuzumab-treated patients being monitored with radionuclide multigated acquisition for TIC. PATIENTS AND METHODS: Patients treated with T±A-based chemotherapy who had undergone multigated acquisition were selected by date range (January 2006-September 2015). Up to four scans were analyzed per patient: (a) pre-A therapy, (b) pre-T therapy, (c) 4 months into T therapy, and (d) at end of T therapy. Baseline referred to the first scan of each patient (i.e. pre-A or pre-T). LV systolic and DD were defined as follows: EF less than 50% or a 10-point decrease from baseline and LV peak filling rate (PFR) less than 2.5 end-diastolic volume/s and time to peak LV filling rates (TPFR) greater than 180 ms, respectively. RESULTS: A total of 202 patients were screened for this study, of whom 153 had received A therapy (5.1±4.1 months duration) before T, 192 had 4 months of follow-up data, and 146 had 4 months of follow-up data and beyond (10.5±5.0 months). LVEF decreased with A and T therapy (P<0.005), but remained stable between 4 months and the final exam (P=0.26). In patients with normal diastolic function at baseline (45.5%), PFR decreased with A and T, and DD preceded SD by 73 days on average. In the remaining patients, with abnormal diastolic function at baseline (54.5%), PFR did not change over the course of treatment (P>0.1), nor did TPFR (P>0.3). CONCLUSION: Patients with normal diastolic function at baseline receiving trastuzumab±anthracycline adjuvant therapy may develop DD before SD, therefore offering an opportunity for early referral to cardiologists to optimize cardiovascular risk factors and manage cardiotoxicity.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/fisiopatologia , Diástole/efeitos dos fármacos , Sístole/efeitos dos fármacos , Trastuzumab/uso terapêutico , Neoplasias da Mama/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Trastuzumab/farmacologia
15.
NMR Biomed ; 32(1): e4022, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30403426

RESUMO

Intracardiac blood flow patterns are affected by the morphology of cardiac structures and are set up to support the heart's pump function. Exercise affects contractility and chamber size as well as pre- and afterload. The aim of this study was to test the feasibility of four-dimensional phase contrast cardiovascular MRI under pharmacological stress and to study left ventricular blood flow under stress. 4D flow data were successfully acquired and analysed in 12 animals. During dobutamine infusion, heart rate and ejection fraction increased (82 ± 5 bpm versus 124 ± 3 bpm/46 ± 9% versus 65 ± 7%; both p < 0.05). A decrease in left ventricular end-diastolic volume (72 ± 14 mL versus 55 ± 8 mL; p < 0.05) and end-systolic volume (40 ± 15 mL versus 19 ± 6 mL; p < 0.05) but no change in stroke volume were observed. Trans-mitral diastolic inflow velocity increased under dobutamine and the trajectory of inflowing blood was directed towards the anterior septum with increased inflow angle (26 ± 5°) when compared with controls (15 ± 2°). In 5/6 animals undergoing stress diastolic vortices developed later, and in 3/6 animals vortices collapsed earlier with significantly smaller cross-sectional area during diastole. The vorticity index was not affected. Under the stress condition direct flow (% ejection within the next heart beat) increased from 43 ± 6% to 53 ± 8%. 4D MRI blood flow acquisition and analysis are feasible in pig hearts under dobutamine-induced stress. Flow patterns characterized by high blood velocity and antero-septally oriented diastolic inflow as well as decreased ventricular volumes are unfavourable conditions for diastolic vortex development under pharmacological stress, and cardiac output is increased by a rise in heart rate and directly ejected left ventricular blood volume.


Assuntos
Circulação Coronária/efeitos dos fármacos , Dobutamina/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Descanso , Estresse Fisiológico/efeitos dos fármacos , Animais , Diástole/efeitos dos fármacos , Imagem Tridimensional , Valva Mitral/efeitos dos fármacos , Valva Mitral/fisiologia , Suínos
16.
Exp Anim ; 68(1): 91-102, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30333366

RESUMO

The present study was conducted to clarify multiple cardiohemodynamic and electrophysiological properties including inotropic/lusitropic effects of nifekalant, a class III antiarrhythmic drug, in an isoflurane-anesthetized monkey. Nifekalant was administered intravenously at the therapeutic dose of 0.3 mg/kg over 10 min to male cynomolgus monkeys (n=4), followed by higher dose of 1 (n=3) or 3 mg/kg (n=1) that was limited due to arrythmogenicity. Left ventricular (LV) pressure-volume (PV) analysis revealed that the 0.3 mg/kg dose of nifekalant induced a negative lusitropic effect, recognized as a decrease in maximal rate of reduction in LV pressure and a prolonged isovolumic relaxation time. Nifekalant also decreased heart rate and increased LV end-diastolic pressure, but had no effects on the other cardiohemodynamic parameters examined. Electrophysiological analysis showed nifekalant at 0.3 mg/kg prolonged QT/QTc intervals with no evidence of arrhythmia. Higher doses of nifekalant induced ventricular arrhythmia in 3 out of 4 animals, in which both the short-term and long-term variability of the QT interval increased just before the occurrence of arrhythmia. In conclusion, a therapeutic dose of nifekalant had no effect on inotropic activity or cardiac compliance, whereas it showed negative lusitropic properties and QT/QTc prolongation in isoflurane-anesthetized monkeys. In addition, higher doses of nifekalant showed remarkable QT/QTc prolongation leading to arrhythmogenicity, which showed good accordance with clinical findings. Caution should be paid to negative lusitropic properties as well as arrhythmogenisity for the safe use of nifekalant.


Assuntos
Anestesia , Antiarrítmicos/efeitos adversos , Antiarrítmicos/farmacologia , Volume Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Pirimidinonas/administração & dosagem , Pirimidinonas/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Pressão Ventricular/efeitos dos fármacos , Animais , Antiarrítmicos/administração & dosagem , Arritmias Cardíacas/induzido quimicamente , Depressão Química , Diástole/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eletrocardiografia/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Infusões Intravenosas , Macaca fascicularis , Masculino , Contração Miocárdica/efeitos dos fármacos , Pirimidinonas/efeitos adversos
17.
Cardiovasc Diabetol ; 17(1): 160, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30591063

RESUMO

BACKGROUND: There are increasing evidence that left ventricle diastolic dysfunction is the initial functional alteration in the diabetic myocardium. In this study, we hypothesized that alogliptin prevents diastolic dysfunction and preserves left ventricular mitochondrial function and structure in diabetic rabbits. METHODS: A total of 30 rabbits were randomized into control group (CON, n = 10), alloxan-induced diabetic group (DM, n = 10) and alogliptin-treated (12.5 mg/kd/day for 12 weeks) diabetic group (DM-A, n = 10). Echocardiographic and hemodynamic studies were performed in vivo. Mitochondrial morphology, respiratory function, membrane potential and reactive oxygen species (ROS) generation rate of left ventricular tissue were assessed. The serum concentrations of glucagon-like peptide-1, insulin, inflammatory and oxidative stress markers were measured. Protein expression of TGF-ß1, NF-κB p65 and mitochondrial biogenesis related proteins were determined by Western blotting. RESULTS: DM rabbits exhibited left ventricular hypertrophy, left atrial dilation, increased E/e' ratio and normal left ventricular ejection fraction. Elevated left ventricular end diastolic pressure combined with decreased maximal decreasing rate of left intraventricular pressure (- dp/dtmax) were observed. Alogliptin alleviated ventricular hypertrophy, interstitial fibrosis and diastolic dysfunction in diabetic rabbits. These changes were associated with decreased mitochondrial ROS production rate, prevented mitochondrial membrane depolarization and improved mitochondrial swelling. It also improved mitochondrial biogenesis by PGC-1α/NRF1/Tfam signaling pathway. CONCLUSIONS: The DPP-4 inhibitor alogliptin prevents cardiac diastolic dysfunction by inhibiting ventricular remodeling, explicable by improved mitochondrial function and increased mitochondrial biogenesis.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Inibidores da Dipeptidil Peptidase IV/farmacologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Piperidinas/farmacologia , Uracila/análogos & derivados , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Diástole/efeitos dos fármacos , Fibrose , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Fator 1 Nuclear Respiratório/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coelhos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Uracila/farmacologia , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Pressão Ventricular/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
18.
J Am Heart Assoc ; 7(21): e009769, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30571375

RESUMO

Background Left ventricular ( LV ) diastolic dysfunction often precedes heart failure with preserved ejection fraction, the dominant form of heart failure in postmenopausal women. The objective of this study was to determine the effect of oral estradiol treatment initiated early after ovariectomy on LV function and myocardial gene expression in female cynomolgus macaques. Methods and Results Monkeys were ovariectomized and randomized to receive placebo (control) or oral estradiol at a human-equivalent dose of 1 mg/day for 8 months. Monkeys then underwent conventional and tissue Doppler imaging to assess cardiac function, followed by transcriptomic and histomorphometric analyses of LV myocardium. Age, body weight, blood pressure, and heart rate were similar between groups. Echocardiographic mitral early and late inflow velocities, mitral annular velocities, and mitral E deceleration slope were higher in estradiol monkeys (all P<0.05), despite similar estimated LV filling pressure. MCP1 (monocyte chemoattractant protein 1) and LV collagen staining were lower in estradiol animals ( P<0.05). Microarray analysis revealed differential myocardial expression of 40 genes (>1.2-fold change; false discovery rate, P<0.05) in estradiol animals relative to controls, which implicated pathways associated with better calcium ion homeostasis and muscle contraction and lower extracellular matrix deposition ( P<0.05). Conclusions Estradiol treatment initiated soon after ovariectomy resulted in enhanced LV diastolic function, and altered myocardial gene expression towards decreased extracellular matrix deposition, improved myocardial contraction, and calcium homeostasis, suggesting that estradiol directly or indirectly modulates the myocardial transcriptome to preserve cardiovascular function.


Assuntos
Cálcio/fisiologia , Diástole/efeitos dos fármacos , Diástole/fisiologia , Estradiol/farmacologia , Matriz Extracelular/fisiologia , Expressão Gênica/efeitos dos fármacos , Coração/efeitos dos fármacos , Homeostase/fisiologia , Ovariectomia , Animais , Feminino , Macaca fascicularis , Miocárdio , Período Pós-Operatório , Distribuição Aleatória , Fatores de Tempo
19.
Cell Mol Biol (Noisy-le-grand) ; 64(14): 47-52, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30511620

RESUMO

The aim of the present study is to investigate if the melatonin has any protective effect on diabetic cardiomyopathy and antioxidant enzymes via phosphorylation of vascular endothelial growth factor-A (VEGF-A). A total of 40 male Wistar rats were enrolled in the study. Rats were divided into four groups: group 1 (control, n=10), group 2 (DM, n=10), group 3 (melatonin, n=10), and group 4 (melatonin+DM, n=10). Melatonin was injected intraperitoneally at a dose of 50 mg/kg/day for 56 days to group 3 and group 4. We investigated expression and phosphorylation of the VEGF-A in coronary vessels of all groups. Staining intensities, biochemical, immunohistochemistry analysis, and transthoracic echocardiography were performed. In comparison to the group 1, DM induced a decrease in p-VEGF-A in coronary vessels of group 2. The lower constitutive phosphorylation of VEGF-A in the group 2 was also increased in coronary vessels after melatonin treatment (p<0.05). Diabetic rats developed myocardial hypertrophy with preserved cardiac function (p<0.05). Cardio-protective effect of melatonin may reduce the damages of diabetes mellitus on the heart muscle fibers and coronary vessels via the phosphorylation of VEGF-A. Melatonin-dependent phosphorylation of VEGF-A in coronary angiogenesis may be associated with the physiological as well as with the pathological cardiac hypertrophy.


Assuntos
Cardiotônicos/uso terapêutico , Cardiomiopatias Diabéticas/tratamento farmacológico , Melatonina/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Antioxidantes/metabolismo , Glicemia/metabolismo , Cardiotônicos/farmacologia , Vasos Coronários/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Diástole/efeitos dos fármacos , Hiperglicemia/sangue , Hiperglicemia/patologia , Masculino , Malondialdeído/metabolismo , Melatonina/farmacologia , Fosforilação/efeitos dos fármacos , Ratos Wistar , Estreptozocina , Sístole/efeitos dos fármacos
20.
J Transl Med ; 16(1): 352, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30541573

RESUMO

BACKGROUND: To date the TGF-ß1 activation mediated by integrin ανß5 during fibrosis is well-known. This process has been shown also in the heart, where cardiac fibroblasts (CF) differentiate into α-smooth muscle actin (α-SMA)-positive myofibroblasts (MyoFB). Here, we studied the effects on CF, isolated by spontaneously hypertensive rats (SHR), of integrin ανß5 inhibition in MyoFB differentiation. METHODS: Staining and immunohistochemistry were performed on rat cardiac tissue. CF were isolated by enzymatic digestion from SHR (SHR-CF) and normotensive WKY (WKY-CF) rat hearts and then treated for in vitro evaluation. RESULTS: SHR heart tissues revealed a higher TGF-ß1 expression vs. WKY samples. SHR-CF showed an enhanced SMAD2/3 activation and an up-regulated expression of α-SMA, a typical MyoFB marker, especially after TGF-ß1 treatment. Immunostaining on cardiac tissues revealed a higher expression of integrin ανß5 in SHR vs. WKY rat hearts. In vitro results confirmed the up-regulation of integrin ανß5 expression in SHR-CF at basal condition and after TGF-ß1 treatment, in comparison with WKY-CF. Inhibition of integrin ανß5 by cilengitide treatment led a decreased expression of ανß5, collagen I, and α-SMA in SHR-CF vs. WKY-CF, resulting in a diminished differentiation of CF into MyoFB. Taking together, results suggested that SHR-CF are more susceptible to TGF-ß1, showing an up-regulated activation of SMAD2/3 signaling, and an increased ανß5, α-SMA, and collagen I expression. Hypertension stimulus promoted an up-regulation of integrin ανß5 on SHR cardiac tissue and its in vitro inhibition reverted pro-fibrotic events of SHR-CF. CONCLUSION: Inhibition of integrin ανß5 exerted by cilengitide strongly diminished SHR-CF differentiation into detrimental MyoFB. So, integrin ανß5 might be considered a novel therapeutic target and cilengitide an effective pharmacological tool to limit the progression of hypertension-induced cardiac fibrosis.


Assuntos
Fibroblastos/metabolismo , Fibroblastos/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Receptores de Vitronectina/antagonistas & inibidores , Actinas/metabolismo , Animais , Biomarcadores/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Diástole/efeitos dos fármacos , Masculino , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores de Vitronectina/genética , Receptores de Vitronectina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Venenos de Serpentes/farmacologia , Sístole/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA