RESUMO
Cell therapy repair strategies using adult mesenchymal stromal cells have shown promising evidence to prevent cardiac deterioration in rodents even in the absence of robust differentiation of the cells into cardiomyocytes. We tested whether increasing doses of porcine adipose-tissue derived mesenchymal stem cells (pASCs) increase cardiac tissue perfusion in pigs post-myocardial infarction (MI) receiving angiotensin-converting-enzyme inhibitor (ACE inhibitors) and Beta-blockers similarly to patients. Female pigs were subjected to MI induction by sponge permanent occlusion of left circumflex coronary artery (LCx) generating approximately 10% of injured LV area with minimum hemodynamic impact. We assessed tissue perfusion by real time myocardial perfusion echocardiography (RTMPE) using commercial microbubbles before and following pASCs treatment. Four weeks after the occlusion of the left circumflex artery, we transplanted placebo or pASCs (1, 2 and 4x106 cells/Kg BW) into the myocardium. The highest dose of pASCs increased myocardial vessel number and blood flow in the border (56% and 3.7-fold, respectively) and in the remote area (54% and 3.9-fold, respectively) while the non-perfused scar area decreased (up to 38%). We also found an increase of immature collagen fibers, although the increase in total tissue collagen and types I and III was similar in all groups. Our results provide evidence that pASCs-induced stimulation of tissue perfusion and accumulation of immature collagen fibers attenuates adverse remodeling post-MI beyond the normal beneficial effects associated with ACE inhibition and beta-blockade.
Assuntos
Tecido Adiposo/citologia , Transplante de Células-Tronco Mesenquimais , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Remodelação Ventricular , Animais , Circulação Coronária/efeitos dos fármacos , Enalaprilato/farmacologia , Feminino , Hemodinâmica/efeitos dos fármacos , Metoprolol/farmacologia , Infarto do Miocárdio/fisiopatologia , Suínos , Transplante Homólogo , Remodelação Ventricular/efeitos dos fármacosRESUMO
PURPOSE: Angiotensin-converting enzyme inhibitors (ACEi) may downregulate matrix metalloproteinases (MMPs). We examined whether enalapril affects MMP-2, MMP-8, and MMP-9 levels and activity, and their endogenous inhibitors (tissue inhibitors of MMPs, TIMP-1 and TIMP-2) levels in hypertensive patients. Moreover, we assessed the effects of enalaprilat on MMP-9 and TIMP-1 secretion by human endothelial cells (HUVECs). METHODS: Thirty-eight hypertensive patients received enalapril for 8 weeks and were compared with thirty-eight normotensive controls. Blood samples were collected at baseline and after treatment. Plasma ACE activity was determined by a fluorimetric assay. Plasma MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 were measured by ELISA and gelatin zymography. A fluorogenic peptide cleavage assay was used to measure MMP activity. HUVECs cells were stimulated by phorbol-12-myristate-13-acetate (PMA) and the effects of enalaprilat (10(-10) to 10(-6) M) on MMP-9 and TIMP-1 levels were determined. RESULTS: Enalapril decreased blood pressure and ACE activity in hypertensive patients (P < 0.05), but had no effects on plasma MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 levels, or MMP activity. Enalaprilat had no effects on PMA-induced increases in MMP-9 and TIMP-1 secretion by HUVECs or on MMP activity. CONCLUSIONS: We show consistent evidence, both in vivo and in vitro, that enalapril does not affect MMPs and TIMPs levels in hypertensive patients.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Enalapril/farmacologia , Hipertensão/tratamento farmacológico , Metaloproteinases da Matriz/metabolismo , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Linhagem Celular , Enalapril/uso terapêutico , Enalaprilato/farmacologia , Feminino , Humanos , Masculino , Inibidores Teciduais de Metaloproteinases/metabolismoRESUMO
Gadolinium (Gd) blocks intra- and extracellular ATP hydrolysis. We determined whether Gd affects vascular reactivity to contractile responses to phenylephrine (PHE) by blocking aortic ectonucleoside triphosphate diphosphohydrolase (E-NTPDase). Wistar rats of both sexes (260-300 g, 23 females, 7 males) were used. Experiments were performed before and after incubation of aortic rings with 3 µM Gd. Concentration-response curves to PHE (0.1 nM to 0.1 mM) were obtained in the presence and absence of endothelium, after incubation with 100 µM L-NAME, 10 µM losartan, or 10 µM enalaprilat. Gd significantly increased the maximum response (control: 72.3 ± 3.5; Gd: 101.3 ± 6.4 percent) and sensitivity (control: 6.6 ± 0.1; Gd: 10.5 ± 2.8 percent) to PHE. To investigate the blockade of E-NTDase activity by Gd, we added 1 mM ATP to the bath. ATP reduced smooth muscle tension and Gd increased its relaxing effect (control: -33.5 ± 4.1; Gd: -47.4 ± 4.1 percent). Endothelial damage abolished the effect of Gd on the contractile responses to PHE (control: 132.6 ± 8.6; Gd: 122.4 ± 7.1 percent). L-NAME + Gd in the presence of endothelium reduced PHE contractile responses (control/L-NAME: 151.1 ± 28.8; L-NAME + Gd: 67.9 ± 19 percent AUC). ATP hydrolysis was reduced after Gd administration, which led to ATP accumulation in the nutrient solution and reduced ADP concentration, while adenosine levels remained the same. Incubation with Gd plus losartan and enalaprilat eliminated the pressor effects of Gd. Gd increased vascular reactivity to PHE regardless of the reduction of E-NTPDase activity and adenosine production. Moreover, the increased reactivity to PHE promoted by Gd was endothelium-dependent, reducing NO bioavailability and involving an increased stimulation of angiotensin-converting enzyme and angiotensin II AT1 receptors.
Assuntos
Animais , Feminino , Masculino , Ratos , Aorta/efeitos dos fármacos , Gadolínio/farmacologia , Fenilefrina/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Anti-Hipertensivos/farmacologia , Aorta/fisiologia , Relação Dose-Resposta a Droga , Enalaprilato/farmacologia , Endotélio Vascular/efeitos dos fármacos , Losartan/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Ratos Wistar , Vasoconstrição/fisiologia , Vasodilatação/fisiologiaRESUMO
Gadolinium (Gd) blocks intra- and extracellular ATP hydrolysis. We determined whether Gd affects vascular reactivity to contractile responses to phenylephrine (PHE) by blocking aortic ectonucleoside triphosphate diphosphohydrolase (E-NTPDase). Wistar rats of both sexes (260-300 g, 23 females, 7 males) were used. Experiments were performed before and after incubation of aortic rings with 3 µM Gd. Concentration-response curves to PHE (0.1 nM to 0.1 mM) were obtained in the presence and absence of endothelium, after incubation with 100 µM L-NAME, 10 µM losartan, or 10 µM enalaprilat. Gd significantly increased the maximum response (control: 72.3 ± 3.5; Gd: 101.3 ± 6.4%) and sensitivity (control: 6.6 ± 0.1; Gd: 10.5 ± 2.8%) to PHE. To investigate the blockade of E-NTDase activity by Gd, we added 1 mM ATP to the bath. ATP reduced smooth muscle tension and Gd increased its relaxing effect (control: -33.5 ± 4.1; Gd: -47.4 ± 4.1%). Endothelial damage abolished the effect of Gd on the contractile responses to PHE (control: 132.6 ± 8.6; Gd: 122.4 ± 7.1%). L-NAME + Gd in the presence of endothelium reduced PHE contractile responses (control/L-NAME: 151.1 ± 28.8; L-NAME + Gd: 67.9 ± 19% AUC). ATP hydrolysis was reduced after Gd administration, which led to ATP accumulation in the nutrient solution and reduced ADP concentration, while adenosine levels remained the same. Incubation with Gd plus losartan and enalaprilat eliminated the pressor effects of Gd. Gd increased vascular reactivity to PHE regardless of the reduction of E-NTPDase activity and adenosine production. Moreover, the increased reactivity to PHE promoted by Gd was endothelium-dependent, reducing NO bioavailability and involving an increased stimulation of angiotensin-converting enzyme and angiotensin II AT1 receptors.
Assuntos
Aorta/efeitos dos fármacos , Gadolínio/farmacologia , Fenilefrina/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Anti-Hipertensivos/farmacologia , Aorta/fisiologia , Relação Dose-Resposta a Droga , Enalaprilato/farmacologia , Endotélio Vascular/efeitos dos fármacos , Feminino , Losartan/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Ratos , Ratos Wistar , Vasoconstrição/fisiologia , Vasodilatação/fisiologiaRESUMO
The present study evaluated whether enalaprilat (the active form of enalapril, an angiotensin-converting enzyme inhibitor) activates B(1) receptors. We observed that the levels of B(1) receptor mRNA and protein expression were upregulated in the kidneys of diabetic rats. Bradykinin (BK)-induced renal vasodilation decreased in isolated perfused kidneys of diabetic rats, but des-Arg(9)-BK-induced renal vasodilation increased. Enalaprilat also produced vasodilation in the isolated perfused kidneys of control and diabetic rats. The response to des-Arg(9)-BK or enalaprilat was blocked by Lys-(des-Arg(9), Leu(8))-BK (a B(1) receptor antagonist) and N-nitro-L-arginine methyl ester (an inhibitor of nitric oxide synthase). These results suggest that enalaprilat activates B(1) receptors and stimulates the production of nitric oxide in the kidneys of both control and diabetic rats.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Diabetes Mellitus Experimental/metabolismo , Enalaprilato/farmacologia , Rim/efeitos dos fármacos , Receptor B1 da Bradicinina/metabolismo , Vasodilatação/efeitos dos fármacos , Animais , Western Blotting , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Diabetes Mellitus Experimental/fisiopatologia , Técnicas In Vitro , Rim/irrigação sanguínea , Rim/metabolismo , Masculino , Óxido Nítrico/biossíntese , Ratos , Ratos Wistar , Receptor B1 da Bradicinina/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para CimaRESUMO
UNLABELLED: Enalapril maleate, available on the market in a variety of different pharmaceutical formulations, is commonly used for the control of systemic arterial hypertension. Many therapeutical failures have been reported thus far in clinical practice with respect to switching between different pharmaceutical formulations of the same product during pharmacological therapy. In the present study, plasma concentrations of enalapril and enalaprilate were measured in hypertensive patients undergoing treatment with different pharmaceutical formulations. MATERIALS AND METHODS: Pharmaceutical formulations studied included the reference brand product, a generic formulation, and a third drug product marketed as "similar"; plasma samples were obtained from 30 hypertensive volunteer patients. Drug was extracted from the plasma by solid phase extraction and determined by liquid chromatography-tandem mass spectrometry. The method was validated for the main analytical parameters. RESULTS: The analytical method developed in this study, using liquid chromatography-tandem mass spectrometry, was confirmed as suitable for application in the determination of plasma concentrations in patients and subsequently revealed statistically significant differences in plasma concentrations between the 3 treatment groups. CONCLUSIONS: Such differences reinforce the hypothesis that the bioequivalence tests currently proposed by the regulatory authorities to promote interchangeability between pharmaceutical formulations may not in fact represent a definitive parameter for guaranteeing similar plasma concentrations.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/sangue , Química Farmacêutica/estatística & dados numéricos , Cromatografia Líquida de Alta Pressão/métodos , Enalapril/sangue , Enalaprilato/sangue , Hipertensão/sangue , Espectrometria de Massas em Tandem/métodos , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Calibragem , Enalapril/metabolismo , Enalapril/farmacocinética , Humanos , Hipertensão/tratamento farmacológico , Limite de Detecção , Reprodutibilidade dos Testes , Extração em Fase Sólida , Espectrometria de Massas por Ionização por Electrospray , Equivalência TerapêuticaRESUMO
Enalaprilate (Enal), an active pharmaceutical component, was intercalated into a layered double hydroxide (Mg/Al-LDH) by an ion exchange reaction. The use of a layered double hydroxide (LDH) to release active drugs is limited by the low pH of the stomach (pH approximately 1.2), in whose condition it is readily dissolved. To overcome this limitation, xyloglucan (XG) extracted from Hymenaea courbaril (jatobá) seeds, Brazilian species, was used to protect the LDH and allow the drug to pass through the gastrointestinal tract. All the materials were characterized by X-ray diffraction, Fourier transform infrared spectroscopy, elemental analyses, transmission electronic microscopy, thermal analyses, and a kinetic study of the in vitro release was monitored by ultraviolet spectroscopy. The resulting hybrid system containing HDL-Enal-XG(3) slowly released the Enal. In an 8-h of test, the system protected 40% (w/v) of the drug. The kinetic profile showed that the drug release was a co-effect behavior, involving dissolution of inorganic material and ion exchange between the intercalated anions in the lamella and those of phosphate in the buffer solution. The nanocomposite coated protection with XG was therefore efficient in obtaining a slow release of Enal.
Assuntos
Anti-Hipertensivos/administração & dosagem , Portadores de Fármacos/química , Enalaprilato/administração & dosagem , Glucanos/química , Nanocompostos/química , Xilanos/química , Hidróxido de Alumínio/química , Anti-Hipertensivos/química , Preparações de Ação Retardada , Composição de Medicamentos , Enalaprilato/química , Trato Gastrointestinal/metabolismo , Humanos , Hidróxido de Magnésio/química , Modelos Biológicos , Reologia , Solubilidade , Difração de Raios XRESUMO
We described in mouse inner medullary-collecting duct cells (mIMCD-3) the somatic and the N-domain ACE synthesis and its interaction with the kallikrein-kinin system co-localized in the same cells. We purified two ACE forms from culture medium, M1 (130 kDa) and M2 (N-domain, 60 kDa), and cellular lysate, C1 (130 kDa) and C2 (N-domain, 60 kDa). Captopril and enalaprilat inhibited the purified enzymes. The immunofluorescence studies indicated that ACE is present in the membrane, cytoplasm and in the cell nucleus. Kinin B1 and B2 receptors were detected by immunofluorescence and showed to be activated by BK and DesR9 BK, increasing the acidification rate which was enhanced in the presence of enalaprilat. The presence of secreted and intracellular ACE in mIMCD-3 confirmed the hypothesis previously proposed by our group for a new site of ACE secretion in the collecting duct.
Assuntos
Medula Renal/enzimologia , Túbulos Renais Coletores/enzimologia , Peptidil Dipeptidase A/isolamento & purificação , Receptor B2 da Bradicinina/análise , Animais , Captopril/farmacologia , Células Cultivadas , Enalaprilato/farmacologia , Imunofluorescência , Camundongos , Peptidil Dipeptidase A/análiseRESUMO
Exposure to mercury at nanomolar level affects cardiac function but its effects on vascular reactivity have yet to be investigated. Pressor responses to phenylephrine (PHE) were investigated in perfused rat tail arteries before and after treatment with 6 nM HgCl2 during 1 h, in the presence (E+) and absence (E-) of endothelium, after L-NAME (10(-4) M), indomethacin (10(-5 )M), enalaprilate (1 microM), tempol (1 microM) and deferoxamine (300 microM) treatments. HgCl2 increased sensitivity (pD2) without modifying the maximum response (Emax) to PHE, but the pD2 increase was abolished after endothelial damage. L-NAME treatment increased pD2 and Emax. However, in the presence of HgCl2, this increase was smaller, and it did not modify Emax. After indomethacin treatment, the increase of pD2 induced by HgCl2 was maintained. Enalaprilate, tempol and deferoxamine reversed the increase of pD2 evoked by HgCl2. HgCl2 increased the angiotensin converting enzyme (ACE) activity explaining the result obtained with enalaprilate. Results suggest that at nanomolar concentrations HgCl2 increase the vascular reactivity to PHE. This response is endothelium mediated and involves the reduction of NO bioavailability and the action of reactive oxygen species. The local ACE participates in mercury actions and depends on the angiotensin II generation.
Assuntos
Angiotensinas/metabolismo , Artérias/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Cloreto de Mercúrio/toxicidade , Fenilefrina/farmacologia , Poluentes Químicos da Água/toxicidade , Animais , Artérias/metabolismo , Artérias/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Enalaprilato/farmacologia , Endotélio Vascular/lesões , Endotélio Vascular/fisiopatologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Wistar , Cauda/irrigação sanguíneaRESUMO
1. Pharmacological compounds that release nitric oxide (NO) have been useful tools in the evaluation of the broad role of NO in physiopathology and therapeutics. The present study compared the pharmacokinetics and pharmacodynamics of enalapril and an NO-releasing enalapril molecule (NCX899) in conscious male beagles. The effects of both enalapril and NCX899 in the arterial hypertension and bradycardia induced by acute NO inhibition in anaesthetized dogs were also investigated. 2. Dogs received either NCX899 (4 micromol/kg, i.v.) or enalapril (4 micromol/kg, i.v.), after which plasma concentrations of the analytes and metabolites were quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). 3. In the NCX899 group, the area under the time-course curve (AUC(0-24h)) was 29.18 +/- 4.72, 229.37 +/- 51.32 and 5159.23 +/- 514.88 microg.h/L for the analytes nitro-enalapril, enalapril and enalaprilat, respectively. In the enalapril group, the AUC(0-24h) was 704.53 +/- 158.86 and 4149.27 +/- 847.30 microg.h/L for the analytes enalapril and enalaprilat, respectively. Statistical analysis of data from both groups showed a significant difference for the analyte enalapril, but not for enalaprilat. Moreover, NCX899 and enalapril were equally effective in inhibiting the activity of serum angiotensin-converting enzyme. 4. In anaesthetized dogs, i.v. administration of the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME; 0.1-10 mg/kg) significantly elevated arterial blood pressure, with concomitant bradycardia. The compound NCX899 significantly attenuated both arterial hypertension and bradycardia, whereas enalapril had no significant effect. 5. In conclusion, the present results showed that the NO-releasing derivative of enalapril NCX899 presents a pharmacokinetic/pharmacodynamic relationship similar to its parent compound enalapril. Moreover, NCX899 (but not enalapril) was effective in protecting against the cardiovascular changes induced by acute NOS inhibition.
Assuntos
Enalapril/farmacocinética , Doadores de Óxido Nítrico/farmacocinética , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Animais , Área Sob a Curva , Pressão Sanguínea/efeitos dos fármacos , Cromatografia Líquida , Cães , Relação Dose-Resposta a Droga , Enalapril/administração & dosagem , Enalapril/análogos & derivados , Enalapril/química , Enalaprilato/metabolismo , Inibidores Enzimáticos/farmacologia , Meia-Vida , Frequência Cardíaca/efeitos dos fármacos , Concentração Inibidora 50 , Injeções Intravenosas , Masculino , Estrutura Molecular , NG-Nitroarginina Metil Éster/farmacologia , Doadores de Óxido Nítrico/administração & dosagem , Doadores de Óxido Nítrico/sangue , Espectrometria de Massas em Tandem , Fatores de TempoRESUMO
Objetivo: Avaliar o efeito do enalaprilato, inibidor da enzima conversorade angiotensina, no processo de reversão da hipertrofia, uma vez quea hipertrofia ventricular esquerda é um importante fator fisiológicopreditivo que auxilia na prevenção de doenças cardíacas, pois seusmecanismos indutores estão relacionados ao índice de massa corporal,hipertensão, hipercolesterolemia, tabagismo, diabetes e uso demedicação, que são empregados nos índices para modelos de avaliaçãode risco. Métodos: Um modelo histomorfométrico comparativo foiempregado para analisar os miócitos do ventrículo esquerdo, diafragmae gastrocnêmio. Oitenta ratos Wistar foram divididos em cinco grupos:controle, isoproterenol, enalaprilato, isoproterenol-enalaprilato (ISOE)e isoproterenol-água. O coração, o diafragma e o gastrocnêmioforam submetidos a uma análise histomorfométrica microscópica.Resultados: A proporção da massa tecidual úmida-seca verificouseaumentada entre os grupos controle e isoproterenol. Não houvediferença estatística significativa ou morfológica entre os demaisgrupos experimentais. Conclusão: Sugere-se que há forte evidênciade que a hipertrofia ventricular esquerda seja primariamente induzidapor ativadores neuro-humorais relacionados aos sistemas simpáticoe renina-angiotensina. O enalaprilato aumenta a taxa de regressãohipertrófica no ventrículo esquerdo, mas isto não é observado nodiafragma e gastrocnêmio.
Assuntos
Diafragma , Enalaprilato , Hipertrofia Ventricular Esquerda/induzido quimicamente , Isoproterenol , Miócitos Cardíacos , Músculo EsqueléticoRESUMO
Angiotensin-converting enzyme inhibitors have been shown to improve splanchnic perfusion in distinct shock states. We hypothesized that enalaprilat potentiates the benefits of early fluid resuscitation in severe experimental sepsis, particularly in the splanchnic region. Anesthetized and mechanically ventilated mongrel dogs received an intravenous infusion of live Escherichia coli over a period of 30 min. Thereafter, two interventions were performed: fluid infusion (normal saline, 32 mL/kg over 30 min) and enalaprilat infusion (0.02 mg kg(-1) min(-1) for 60 min) in randomized groups. The following groups were studied: controls (fluid infusion, N = 4), E1 (enalaprilat infusion followed by fluid infusion, N = 5) and E2 (fluid infusion followed by enalaprilat infusion, N = 5). All animals were observed for a 120 min after bacterial infusion. Mean arterial pressure, cardiac output (CO), portal vein blood flow (PVBF), systemic and regional oxygen-derived variables, and lactate levels were measured. Rapid and progressive reductions in CO and PVBF were induced by the infusion of live bacteria, while minor changes were observed in mean arterial pressure. Systemic and regional territories showed a significant increase in oxygen extraction and lactate levels. Widening venous-arterial and portal-arterial pCO2 gradients were also detected. Fluid replacement promoted transient benefits in CO and PVBF. Enalaprilat after fluid resuscitation did not affect systemic or regional hemodynamic variables. We conclude that in this model of normotensive sepsis inhibition of angiotensin-converting enzyme did not interfere with the course of systemic or regional hemodynamic and oxygen-derived variables.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Enalaprilato/farmacologia , Infecções por Escherichia coli , Hidratação , Choque Séptico/terapia , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Animais , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Modelos Animais de Doenças , Cães , Enalaprilato/administração & dosagem , Hidratação/métodos , Infusões Intravenosas , Ácido Láctico/sangue , Masculino , Veia Porta/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Ressuscitação/métodos , Índice de Gravidade de DoençaRESUMO
Angiotensin-converting enzyme inhibitors have been shown to improve splanchnic perfusion in distinct shock states. We hypothesized that enalaprilat potentiates the benefits of early fluid resuscitation in severe experimental sepsis, particularly in the splanchnic region. Anesthetized and mechanically ventilated mongrel dogs received an intravenous infusion of live Escherichia coli over a period of 30 min. Thereafter, two interventions were performed: fluid infusion (normal saline, 32 mL/kg over 30 min) and enalaprilat infusion (0.02 mg kg-1 min-1 for 60 min) in randomized groups. The following groups were studied: controls (fluid infusion, N = 4), E1 (enalaprilat infusion followed by fluid infusion, N = 5) and E2 (fluid infusion followed by enalaprilat infusion, N = 5). All animals were observed for a 120 min after bacterial infusion. Mean arterial pressure, cardiac output (CO), portal vein blood flow (PVBF), systemic and regional oxygen-derived variables, and lactate levels were measured. Rapid and progressive reductions in CO and PVBF were induced by the infusion of live bacteria, while minor changes were observed in mean arterial pressure. Systemic and regional territories showed a significant increase in oxygen extraction and lactate levels. Widening venous-arterial and portal-arterial pCO2 gradients were also detected. Fluid replacement promoted transient benefits in CO and PVBF. Enalaprilat after fluid resuscitation did not affect systemic or regional hemodynamic variables. We conclude that in this model of normotensive sepsis inhibition of angiotensin-converting enzyme did not interfere with the course of systemic or regional hemodynamic and oxygen-derived variables.
Assuntos
Animais , Masculino , Cães , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Infecções por Escherichia coli , Enalaprilato/farmacologia , Choque Séptico/terapia , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Modelos Animais de Doenças , Enalaprilato/administração & dosagem , Hidratação/métodos , Infusões Intravenosas , Ácido Láctico/sangue , Veia Porta/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Ressuscitação/métodos , Índice de Gravidade de DoençaRESUMO
INTRODUCTION: Unilateral ureteral obstruction breaks out events that cause the transitory increase of glomerular permeability to macromolecules, both in the obstructed kidney and in the contralateral kidney, suggesting the presence of some factor, with a systemic action, liberated as a response to the obstruction. We know that the rennin-angiotensin system is activated by acute ureteral obstruction. We have developed an experiment to assess the role of angiotensin II on the glomerular permeability to IgG due to acute ureteral obstruction, using enalaprilat, an angiotensin enzyme conversion inhibitor, to block the effects of the activation of the rennin-angiotensin system. MATERIALS AND METHODS: We have used 45 adult Wistar female rats, distributed into 3 main groups: a control group with 5 animals and 2 experiment groups each one with 10 animals submitted to unilateral ureteral obstruction and nephrectomy at 60 and 120 minutes. Each experiment group had its simulation correspondent (sham). We have studied both kidneys through the direct immunofluorescence method. RESULTS: We have found positive permeation in animals without enalaprilat in both kidneys and negative permeation in those in which the drug was used. CONCLUSION: We have concluded that enalaprilat interferes in this alteration of permeability, suggesting that angiotensin II is involved in the loss of selectivity of the glomerular membrane.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Enalaprilato/farmacologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Imunoglobulina G/metabolismo , Substâncias Macromoleculares/metabolismo , Obstrução Ureteral/metabolismo , Doença Aguda , Animais , Modelos Animais de Doenças , Feminino , Técnica Direta de Fluorescência para Anticorpo , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Wistar , Fatores de TempoRESUMO
INTRODUCTION: Unilateral ureteral obstruction breaks out events that cause the transitory increase of glomerular permeability to macromolecules, both in the obstructed kidney and in the contralateral kidney, suggesting the presence of some factor, with a systemic action, liberated as a response to the obstruction. We know that the rennin-angiotensin system is activated by acute ureteral obstruction. We have developed an experiment to assess the role of angiotensin II on the glomerular permeability to IgG due to acute ureteral obstruction, using enalaprilat, an angiotensin enzyme conversion inhibitor, to block the effects of the activation of the rennin-angiotensin system. MATERIALS AND METHODS: We have used 45 adult Wistar female rats, distributed into 3 main groups: a control group with 5 animals and 2 experiment groups each one with 10 animals submitted to unilateral ureteral obstruction and nephrectomy at 60 and 120 minutes. Each experiment group had its simulation correspondent (sham). We have studied both kidneys through the direct immunofluorescence method. RESULTS: We have found positive permeation in animals without enalaprilat in both kidneys and negative permeation in those in which the drug was used. CONCLUSION: We have concluded that enalaprilat interferes in this alteration of permeability, suggesting that angiotensin II is involved in the loss of selectivity of the glomerular membrane.
Assuntos
Animais , Feminino , Ratos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Enalaprilato/farmacologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Imunoglobulina G/metabolismo , Substâncias Macromoleculares/metabolismo , Obstrução Ureteral/metabolismo , Doença Aguda , Modelos Animais de Doenças , Técnica Direta de Fluorescência para Anticorpo , Permeabilidade/efeitos dos fármacos , Ratos Wistar , Fatores de TempoRESUMO
BACKGROUND AND PURPOSE: Mechanical and hormonal factors have been implicated in pneumoperitoneum-induced renal alterations. The aim of this study was to evaluate the effects of enalaprilat (Vasotec) administration on renal function during CO2 pneumoperitoneum, given that this drug, which is an angiotensin-converting enzyme inhibitor, by inhibiting the renin-angiotensin-aldosterone system, alters hormone-induced changes during pneumoperitoneum. MATERIALS AND METHODS: Thirty adult dogs were randomly assigned to one of three groups (N = 10 each): group A (pneumoperitoneum not performed); group B (CO2 + enalaprilat); group C CO2 only. The groups were analyzed with consideration for body weight, hematologic values, hemodynamic parameters, and renal function (plasma renin activity, urinary debt, creatinine clearance, and sodium-excretory fraction). RESULTS: Hemodynamic and acid-basic parameter differences did not influence renal function. Plasma renin activity decreased significantly in group B compared with group C and stayed close to the values in group A. Creatinine clearance remained constant in group B, while in group C, creatinine clearance dropped, and this difference was statistically significant. Urinary debt and sodium-excretory fraction increased in group B during pneumoperitoneum and 60 minutes after this period in comparison with the other groups without reaching statistical significance. CONCLUSION: The decline in urinary debt and in creatinine clearance observed during pneumoperitoneum was less accentuated with administration of enalaprilat.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Dióxido de Carbono/administração & dosagem , Enalaprilato/farmacologia , Rim/efeitos dos fármacos , Pneumoperitônio Artificial , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Creatinina/urina , Cães , Distribuição Aleatória , Renina/sangue , Sódio/urina , UrinaRESUMO
The present study determined the participation of PGI2 in the angiotensin-(1-7) [Ang-(1-7)]/bradykinin (BK) interaction, in the presence and absence of Angiotensin Converting Enzyme (ACE) inhibition, trying to correlate it with tissue levels of both peptides. The isolated mesenteric arteriolar bed of Spontaneously Hypertensive Rats (SHR) was perfused with Krebs or Krebs plus enalaprilat (10 nM), and drugs were injected alone or in association. BK (10 ng)-induced relaxation was potentiated by Ang-(1-7) (2.2 microg) in the presence or absence of enalaprilat. Ang-(1-7) receptor blockade [A-779 (4.8 microg)] did not interfere with the BK effect in preparations perfused with normal Krebs, but reversed the increased BK relaxation observed after ACE inhibition. PGI2 release by mesenteric vessels was not altered by BK or Ang-(1-7) alone, but was increased when both peptides were injected in association, in the absence or in the presence of enalaprilat. ACE inhibition caused a 2-fold increase in the BK tissue levels, and a significant decrease in the Ang-(1-7) values. We conclude that endogenous Ang-(1-7) has an important contribution to the effect of ACE inhibitors participating in the enhancement of BK response. The mechanism of Ang-(1-7) potentiating effect probably involves an increased production of PGI2. Our results suggest that a different enzymatic pathway (non-related to ACE) is involved in the local Ang-(1-7) metabolism.
Assuntos
Angiotensina I/metabolismo , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Anti-Hipertensivos/metabolismo , Arteríolas/metabolismo , Pressão Sanguínea/fisiologia , Bradicinina/metabolismo , Epoprostenol/metabolismo , Fragmentos de Peptídeos/metabolismo , Animais , Enalaprilato/metabolismo , Masculino , Mesentério/irrigação sanguínea , Ratos , Ratos Endogâmicos SHRRESUMO
The effects of 1 nM ouabain (OUA) on the contractile actions of phenylephrine (PHE, 0.001-100 microg) and functional activity of the sodium pump (NKA) in isolated-perfused tail vascular beds from WKY and SHR were investigated. In preparations from SHR, perfusion with OUA in the presence of endothelium (E+) increased the sensitivity (pED50) of PHE (before: 2.14 +/- 0.06 versus after: 2.47 +/- 0.07; P < 0.05) without altering the maximal response (Emax). After endothelial damage, OUA reduced the Emax of PHE in SHR (before: 350 +/- 29 versus after: 293 +/- 25 mm Hg; P < 0.05). In SHR/E+, pretreatment with losartan (10 microM) or enalaprilat (1 microM) prevented the increased sensitivity to PHE induced by OUA. OUA increased NKA activity in SHR/E+ (before: 45 +/- 6 versus after: 58 +/- 5%, P < 0.05). Losartan (10 mg/Kg, i.v.) also abolished the increment in systolic and diastolic blood pressure induced by OUA (0.18 microg/Kg, i.v.) in anesthetized SHR. OUA did not alter the actions of PHE in either anesthetized WKY rats or vascular preparations. Results suggest that 1 nM OUA increased the vascular reactivity to PHE only in SHR/E+. This effect is mediated by OUA-induced activation of endothelial angiotensin converting enzyme that promotes the local formation of angiotensin II, which sensitizes the vascular smooth muscle to the actions of PHE.
Assuntos
Angiotensina II/metabolismo , Endotélio Vascular/metabolismo , Ouabaína/farmacocinética , Cauda/citologia , Angiotensina II/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Sinergismo Farmacológico , Quimioterapia Combinada , Enalaprilato/farmacologia , Glucose/administração & dosagem , Glucose/química , Hexametônio/farmacologia , Injeções Intravenosas , Losartan/antagonistas & inibidores , Losartan/farmacologia , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Ouabaína/administração & dosagem , Perfusão , Fenilefrina/farmacologia , Cloreto de Potássio/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , ATPase Trocadora de Sódio-Potássio/fisiologia , Cauda/irrigação sanguínea , Cauda/metabolismo , Fatores de Tempo , Trometamina/administração & dosagem , Trometamina/química , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
BACKGROUND/AIMS: We previously reported that bradykinin augments liver regeneration in rats. The angiotensin-converting enzyme is also a powerful bradykinin-degrading enzyme. METHODOLOGY: Adult rats received lisinopril, captopril, enalaprilat, or saline solution, intraperitoneally, for 5 days before 70% partial hepatectomy, and daily after surgery. They received also losartan and bradykinin. Rats were sacrificed at 12, 24, 36, 48, 72, and 120 hours after hepatectomy. Liver regeneration was evaluated in terms of the restoration of liver weight in proportion to body weight, liver DNA content and immunostaining for proliferating cell nuclear antigen. RESULTS: The proliferating cell nuclear antigen labeling index was higher in the lisinopril-treated group than in the control group at all time points after hepatectomy, except 120 hours. The remnant liver dry weight was higher in lisinopril-treated rats than in control rats at early time points after surgery. The liver DNA content was higher in three angiotensin-converting enzyme inhibitor-treated groups than in the control group at 36 hours after hepatectomy. The bradykinin-induced regenerative response was similar to the lisinopril-induced response, and losartan induced a lower hepatocyte labeling index in comparison to the control group at 36 hours after hepatectomy. CONCLUSIONS: The present results provide evidence that angiotensin-converting enzyme inhibitors remarkably enhance liver regeneration.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Lisinopril/farmacologia , Regeneração Hepática/efeitos dos fármacos , Animais , Captopril/farmacologia , Enalaprilato/farmacologia , Losartan/farmacologia , Masculino , Tamanho do Órgão , Antígeno Nuclear de Célula em Proliferação/análise , Ratos , Ratos WistarRESUMO
Arterial compliance is determined by structural factors, such as collagen and elastin, and functional factors, such as vasoactive neurohormones. To determine whether angiotensin II contributes to decreased arterial compliance in patients with heart failure, this study tested the hypothesis that administration of an angiotensin-converting enzyme inhibitor improves arterial compliance. Arterial compliance and stiffness were determined by measuring carotid artery diameter, using high-resolution duplex ultrasonography, and blood pressure in 23 patients with heart failure secondary to idiopathic dilated cardiomyopathy. Measurements were made before and after intravenous administration of enalaprilat (1 mg) or vehicle. Arterial compliance was inversely related to both baseline plasma angiotensin II (r = -0.52; P = 0.015) and angiotensin-converting enzyme concentrations (r = -0.45; P = 0.041). During isobaric conditions, enalaprilat increased carotid artery compliance from 3.0 +/- 0.4 to 5.0 +/- 0.4 x 10(-10) N(-1). m(4) (P = 0.001) and decreased the carotid artery stiffness index from 17.5 +/- 1.8 to 10.1 +/- 0.6 units (P = 0.001), whereas the vehicle had no effect. Thus angiotensin II is associated with reduced carotid arterial compliance in patients with congestive heart failure, and angiotensin-converting enzyme inhibition improves arterial elastic properties. This favorable effect on the pulsatile component of afterload may contribute to the improvement in left ventricular performance that occurs in patients with heart failure treated with angiotensin-converting enzyme inhibitors.