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1.
Braz J Med Biol Res ; 43(5): 506-14, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20490436

RESUMO

It has been recently shown that calcium channel blockers might have a protective effect on cardiac fibrogenesis induced by aldosterone. The objective of this study was to evaluate the protective effect of felodipine, a dihydropyridine calcium channel blocker, against heart and kidney damage caused by aldosterone-high sodium intake in uninephrectomized rats. Wistar rats were divided into three groups: CNEP (uninephrectomized + 1% NaCl in the drinking water, N = 9); ALDO (same as CNEP group plus continuous infusion of 0.75 microg/h aldosterone, N = 12); ALDOF (same as ALDO group plus 30 mg*kg(-1)*day(-1) felodipine in the drinking water, N = 10). All results were compared with those of age-matched, untreated rats (CTL group, N = 10). After 6 weeks, tail cuff blood pressure was recorded and the rats were killed for histological analysis. Blood pressure (mmHg) was significantly elevated (P < 0.05) in ALDO (180 +/- 20) and ALDOF (168 +/- 13) compared to CTL (123 +/- 12) and CNEP (134 +/- 13). Heart damage (lesion scores - median and interquartile range) was 7.0 (5.5-8.0) in ALDO and was fully prevented in ALDOF (1.5; 1.0-2.0). Also, left ventricular collagen volume fraction (%) in ALDOF (2.9 +/- 0.5) was similar to CTL (2.9 +/- 0.5) and CNEP (3.4 +/- 0.4) and decreased compared to ALDO (5.1 +/- 1.6). Felodipine partially prevented kidney injury since the damage score for ALDOF (2.0; 2.0-3.0) was significantly decreased compared to ALDO (7.5; 4.0-10.5), although higher than CTL (null score). Felodipine has a protective effect on the myocardium and kidney as evidenced by decreased perivascular inflammation, myocardial necrosis and fibrosis.


Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Felodipino/uso terapêutico , Hipertensão/tratamento farmacológico , Rim/patologia , Miocárdio/patologia , Cloreto de Sódio , Aldosterona/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Fibrose/prevenção & controle , Hipertensão/patologia , Necrose/prevenção & controle , Nefrectomia , Ratos , Ratos Wistar
2.
Braz. j. med. biol. res ; 43(5): 506-514, May 2010. tab, ilus
Artigo em Inglês | LILACS | ID: lil-546326

RESUMO

It has been recently shown that calcium channel blockers might have a protective effect on cardiac fibrogenesis induced by aldosterone. The objective of this study was to evaluate the protective effect of felodipine, a dihydropyridine calcium channel blocker, against heart and kidney damage caused by aldosterone-high sodium intake in uninephrectomized rats. Wistar rats were divided into three groups: CNEP (uninephrectomized + 1 percent NaCl in the drinking water, N = 9); ALDO (same as CNEP group plus continuous infusion of 0.75 µg/h aldosterone, N = 12); ALDOF (same as ALDO group plus 30 mg·kg-1·day-1 felodipine in the drinking water, N = 10). All results were compared with those of age-matched, untreated rats (CTL group, N = 10). After 6 weeks, tail cuff blood pressure was recorded and the rats were killed for histological analysis. Blood pressure (mmHg) was significantly elevated (P < 0.05) in ALDO (180 ± 20) and ALDOF (168 ± 13) compared to CTL (123 ± 12) and CNEP (134 ± 13). Heart damage (lesion scores - median and interquartile range) was 7.0 (5.5-8.0) in ALDO and was fully prevented in ALDOF (1.5; 1.0-2.0). Also, left ventricular collagen volume fraction ( percent) in ALDOF (2.9 ± 0.5) was similar to CTL (2.9 ± 0.5) and CNEP (3.4 ± 0.4) and decreased compared to ALDO (5.1 ± 1.6). Felodipine partially prevented kidney injury since the damage score for ALDOF (2.0; 2.0-3.0) was significantly decreased compared to ALDO (7.5; 4.0-10.5), although higher than CTL (null score). Felodipine has a protective effect on the myocardium and kidney as evidenced by decreased perivascular inflammation, myocardial necrosis and fibrosis.


Assuntos
Animais , Ratos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Felodipino/uso terapêutico , Hipertensão/tratamento farmacológico , Rim/patologia , Miocárdio/patologia , Cloreto de Sódio , Aldosterona/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Fibrose/prevenção & controle , Hipertensão/patologia , Nefrectomia , Necrose/prevenção & controle , Ratos Wistar
3.
Med Eng Phys ; 31(10): 1276-82, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19762270

RESUMO

We present single fibre heart activity model (SFHAM) based on the current flow through the five bunches of fibres of the cardiac muscle (CM). The five effective fibres are identified and assigned to the appropriate segments of CM. Analytical functions describing ionic flows along the fibres are derived and proposed. The parameters determining the shapes and amplitudes of the functions proposed are obtained on the basis of standard 12-lead ECG measurements after numerical fitting procedures concentrating on the QRS-waves. As a consequence, five independent courses of partial, transient potentials are obtained representing: anterior, inferior, lateral, posterior walls, and interventricular septum activities, respectively. Moreover, to check our theoretical results we compare the potentials calculated with those from physical measurements performed on the patient's body surface. We expect that SFHAM will permit detection of pathological changes in particular fragments of CM.


Assuntos
Eletrocardiografia/métodos , Coração/fisiologia , Miocárdio/metabolismo , Potenciais de Ação , Mapeamento Potencial de Superfície Corporal , Eletrofisiologia/métodos , Sistema de Condução Cardíaco , Ventrículos do Coração , Humanos , Íons , Modelos Anatômicos , Modelos Teóricos , Contração Miocárdica , Processamento de Sinais Assistido por Computador
4.
Inflamm Res ; 57(5): 241-6, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18465084

RESUMO

OBJECTIVE AND DESIGN: The purpose of this study was to determine the feasibility of adapting peritoneal and pleural mast cell isolation techniques to recover cardiac mast cells that retain their functional response to the secretagogue, compound 48/80. METHODS: Using a novel protocol in rats, viable epicardial mast cells were recovered by aspiration of HBSS injected into the pericardial space. Functionality of these cells was determined by ELISA quantification of histamine release in response to compound 48/80, calcium ionophore A23187 and substance P. Mast cell phenotype was determined based on the presence of chymase and tryptase demonstrated by immunofluorescence, alcian blue-safranin staining, and Western blotting. RESULTS: Mast cells isolated in this manner have low basal rates of histamine release and are highly responsive to these secretagogues. These epicardial mast cells were of the connective tissue type, which is consistent with previous reports characterizing cardiac mast cells isolated from the heart by enzymatic dispersion techniques. CONCLUSIONS: This novel pericardial aspiration technique facilitates the straightforward characterization of isolated epicardial mast cell functionality in a controlled in vitro environment, furthering our understanding of their contribution to myocardial disease.


Assuntos
Separação Celular/métodos , Mastócitos/citologia , Miocárdio/citologia , Animais , Calcimicina/farmacologia , Histamina/metabolismo , Ionóforos/farmacologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/fisiologia , Ratos , Ratos Sprague-Dawley , Substância P/farmacologia , p-Metoxi-N-metilfenetilamina/farmacologia
5.
Inflamm Res ; 55(10): 408-15, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17109067

RESUMO

OBJECTIVE: Cardiac mast cell numbers increase significantly within 12 h following the creation of an aortocaval (AV) fistula in rats and play a central role in mediating adverse left ventricular remodeling. We studied whether this increase was related to maturation of resident immature mast cells. METHODS: We measured percentages of immature and mature cardiac mast cells at 1, 2 and 7 days following AV-fistula or sham surgery and in non-surgical control rats using the alcian-blue safranin reaction. RESULTS: Relative to sham-operated and control rats, there was a significant shift from immature to a greater percentage of mature cardiac mast cells at 1 day and 2 days post-fistula that returned to a normal distribution by 7 days. CONCLUSIONS: We conclude that the acute increase in mast cell density following volume overload is due to a paracrine response in the heart that stimulates the maturation and differentiation of resident immature cardiac mast cells.


Assuntos
Fístula Arteriovenosa , Mastócitos/citologia , Miocárdio/citologia , Animais , Anti-Inflamatórios/farmacologia , Aorta , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Masculino , Nedocromil/farmacologia , Cavidade Peritoneal/citologia , Ratos , Ratos Sprague-Dawley , Veias Cavas
6.
Inflamm Res ; 53(9): 453-7, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15550997

RESUMO

OBJECTIVE: To test the hypothesis that spontaneous release of histamine occurring during an isolation protocol may modify responses of rat cardiac mast cells (connective tissue-type mast cells) to secretagogues. METHODS: We assessed two protocols for enzymatic dispersion utilizing collagenase, hyaluronidase, and deoxyribonuclease; with protease (Protocol 1, n = 8) or without protease (Protocol 2, n = 3). Spontaneous release of histamine was quantified following mechanical and enzymatic dispersion of the whole heart. RESULTS: Total histamine loss (Mean +/- SEM) was 963+/-92 and 833+/-60 ng/g of tissue weight following Protocols 1 and 2. Percentages of histamine release from cell isolates following Protocol 1 were 40+/-5%, 41+/-6%, and 51+/-7% at 0, 30, and 300 microg/mL of compound 48/80. CONCLUSIONS: Enzymatic dispersion of cardiac mast cells affects their response to secretagogues.


Assuntos
Separação Celular/métodos , Liberação de Histamina , Mastócitos/metabolismo , Miocárdio/citologia , Animais , Histamina/análise , Liberação de Histamina/efeitos dos fármacos , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley , p-Metoxi-N-metilfenetilamina/farmacologia
7.
Am J Physiol Heart Circ Physiol ; 280(2): H674-83, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11158966

RESUMO

We previously reported an approximately 50% incidence of rats with symptoms of congestive heart failure (CHF) at 8 wk postinfrarenal aorto-caval fistula. However, it was not clear whether compensatory ventricular remodeling could continue beyond 8 wk or whether the remaining animals would have developed CHF or died. Therefore, the intent of this study was to complete the characterization of this model of sustained volume overload by determining the morbidity and mortality and the temporal response of left ventricular (LV) remodeling and function beyond 8 wk. The findings demonstrate an upper limit to LV hypertrophy and substantial increases in LV volume and compliance, matrix metalloproteinase activity, and collagen volume fraction associated with the development of CHF. There was an 80% incidence of morbidity and mortality following 21 wk of chronic volume overload. These findings indicate that the development of CHF is triggered by marked ventricular dilatation and increased compliance occurring once the myocardial hypertrophic response is exhausted.


Assuntos
Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Remodelação Ventricular/fisiologia , Animais , Fístula Arteriovenosa/mortalidade , Fístula Arteriovenosa/fisiopatologia , Volume Cardíaco/fisiologia , Modelos Animais de Doenças , Insuficiência Cardíaca/mortalidade , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/mortalidade , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/mortalidade , Hipertrofia Ventricular Direita/fisiopatologia , Masculino , Metaloproteinases da Matriz/metabolismo , Miocárdio/enzimologia , Ratos , Ratos Sprague-Dawley , Sístole/fisiologia , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/mortalidade , Disfunção Ventricular Esquerda/fisiopatologia
8.
Am J Physiol Heart Circ Physiol ; 279(4): H1534-9, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11009438

RESUMO

We investigated the influence of myocardial collagen volume fraction (CVF, %) and hydroxyproline concentration (microg/mg) on rat papillary muscle function. Collagen excess was obtained in 10 rats with unilateral renal ischemia for 5 wk followed by 3-wk treatment with ramipril (20 mg. kg(-1). day(-1)) (RHTR rats; CVF = 3.83 +/- 0. 80, hydroxyproline = 3.79 +/- 0.50). Collagen degradation was induced by double infusion of oxidized glutathione (GSSG rats; CVF = 2.45 +/- 0.52, hydroxyproline = 2.85 +/- 0.18). Nine untreated rats were used as controls (CFV = 3.04 +/- 0.58, hydroxyproline = 3.21 +/- 0.30). Active stiffness (AS; g. cm(-2). %L(max)(-1)) and myocyte cross-sectional area (MA; micrometer(2)) were increased in the GSSG rats compared with controls [AS 5.86 vs. 3.96 (P < 0.05); MA 363 +/- 59 vs. 305 +/- 28 (P < 0.05)]. In GSSG and RHTR groups the passive tension-length curves were shifted downwards, indicating decreased passive stiffness, and upwards, indicating increased passive stiffness, respectively. Decreased collagen content induced by GSSG is related to myocyte hypertrophy, decreased passive stiffness, and increased AS, and increased collagen concentration causes myocardial diastolic dysfunction with no effect on systolic function.


Assuntos
Colágeno/metabolismo , Hipertensão Renovascular/fisiopatologia , Miocárdio/metabolismo , Músculos Papilares/fisiopatologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Elasticidade , Dissulfeto de Glutationa/farmacologia , Hidroxiprolina/metabolismo , Técnicas In Vitro , Isquemia/fisiopatologia , Masculino , Contração Miocárdica , Miocárdio/patologia , Ramipril/farmacologia , Ratos , Ratos Wistar , Valores de Referência
9.
Circ Res ; 86(7): 807-15, 2000 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-10764416

RESUMO

Angiotensin II (Ang II)-mediated sympathostimulation may worsen the progression of cardiac failure, although the nature and mechanisms of such interactions are largely unknown. We previously demonstrated that Ang II combined with evolving cardiodepression (48-hour tachycardia pacing, 48hP) induces marked chamber stiffening and increases metalloproteinases (MMPs). Here, we test the hypothesis that both abnormalities stem from sympathostimulatory effects of Ang II. Forty-eight dogs were instrumented to serially assess conscious ventricular mechanics, MMP abundance and activity, and myocardial histopathology. 48hP combined with 5 days of Ang II (15+/-5 ng. kg(-1). min(-1) IV) more than doubled chamber stiffness (end-diastolic pressure >25 mm Hg, P<0.001), whereas stiffness was unchanged by Ang II or 48hP alone. In vitro and in situ zymography revealed increased MMP abundance and activity (principally 92-kDa gelatinase) from Ang II+48hP. Both stiffening and MMP changes were prevented by cotreatment with high-dose atenolol (which nearly fully inhibited isoproterenol-induced inotropy) but not partial beta-blockade. Myocellular damage with fibroblast/neutrophil infiltration from Ang II+48hP was also inhibited by high- but not low-dose atenolol, whereas collagen content was not elevated with either dose. These data support a role of sympathostimulation by Ang II in modulating myocardial MMP abundance and activity and diastolic stiffening in evolving heart failure and suggest a novel mechanism by which beta-blockade may limit chamber remodeling and diastolic dysfunction.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Angiotensina II/farmacologia , Atenolol/farmacologia , Coração/fisiologia , Hemodinâmica/efeitos dos fármacos , Isoproterenol/farmacologia , Metaloendopeptidases/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Animais , Diástole/efeitos dos fármacos , Cães , Ativação Enzimática , Feminino , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hemodinâmica/fisiologia , Masculino , Contração Miocárdica/efeitos dos fármacos , Miocárdio/enzimologia , Receptores Adrenérgicos beta/fisiologia , Sístole/efeitos dos fármacos , Taquicardia , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologia
10.
J Mol Cell Cardiol ; 31(10): 1927-36, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10525429

RESUMO

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) upregulation are genetic markers for the chronic hypertrophic phenotype but also have important acute physiologic effects on salt and water balance and blood pressure control. The presence of a dual NP-system led us to hypothesize a differential expression of ANP and BNP in response to an acute hemodynamic stress of volume overload in the left ventricle (LV) and right ventricle (RV). Accordingly, we examined the temporal relationship between the RV and LV expression of ANP and BNP mRNA and NP receptor mRNA levels on days 1, 2, 3, and 7 after induction of aortocaval fistula in the rat. LV end-diastolic pressure was increased 1.5-fold by day 3 and 2.0-fold by day 7 compared to control (P<0.05). LV weight increased by day 7 compared to control (2.34+/-0.04 vs 3.07+/-0.10 mg/g, P<0.05) while RV weight did not change over the 7 days. There was a 7-fold increase of ANP mRNA in LV at day 1, which was sustained through day 7, while LV BNP mRNA levels did not differ from controls over the 7 days. In contrast, RV mRNA transcript levels for ANP and BNP were increased >2-fold by day 2 and this increase was sustained throughout 7 days. NP clearance receptor was decreased by 75% by day 7 in the LV but did not change in the RV. Thus, LV ANP mRNA levels increased before the onset of LV hypertrophy and RV BNP mRNA levels increased in the absence of RV hypertrophy. The disparate response of BNP and the NP clearance receptor transcript levels in the LV and RV may be related to differences in load and/or differential expression of the NP system in the LV and RV in response to acute haemodynamic stress.


Assuntos
Fator Natriurético Atrial/genética , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Regulação da Expressão Gênica , Hemodinâmica , Peptídeo Natriurético Encefálico/genética , Receptores do Fator Natriurético Atrial/genética , Animais , Pressão Sanguínea , Peso Corporal , Cardiomegalia/metabolismo , Masculino , Miocárdio/metabolismo , Tamanho do Órgão , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Transcrição Gênica
11.
Int J Exp Pathol ; 80(2): 97-104, 1999 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10469264

RESUMO

In renovascular hypertensive rats, low doses of angiotensin converting enzyme (ACE) inhibitors have been found to prevent myocardial hypertrophy independent of blood pressure level. This finding would suggest humoral rather than mechanical control of myocyte growth. The aim of this study was to examine the effect of nonantihypertensive doses of ACE inhibitor on myocardial hypertrophy and necrosis in hypertensive rats. Renovascular hypertension (RHT) was induced in four-week-old Wistar rats. Twenty-eight animals were treated for four weeks with three doses of ramipril (0.01, 0.1 or 1. 0 mg/kg/day, which are unable to lower blood pressure. Fourteen animals were not treated (RHT group). A sham operated, age/sex-matched group was used as control (n = 10). Myocardial histology was analysed in 3 microm thick sections of the ventricle stained with either haematoxylin-eosin, reticulin silver stain or Masson's trichrome. There was a significant correlation between systolic blood pressure and left ventricular to body weight ratio in both sets of animals: untreated plus controls and ramipril-treated rats. ACE inhibition prevented myocyte and perivascular necrosis and fibrosis in a dose-dependent manner. We conclude that myocardial hypertrophy in rats with renovascular hypertension is directly related to arterial pressure, and that this relationship is not affected by nonantihypertensive doses of ACE inhibitor. Myocardial necrosis/fibrosis and coronary artery damage induced by angiotensin II are prevented by ACE inhibitor in a dose-dependent manner, despite the presence of arterial hypertension.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Cardiomegalia/prevenção & controle , Hipertensão Renovascular/complicações , Ramipril/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Animais , Pressão Sanguínea/fisiologia , Cardiomegalia/etiologia , Relação Dose-Resposta a Droga , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Masculino , Necrose , Tamanho do Órgão/fisiologia , Ramipril/administração & dosagem , Ratos , Ratos Wistar
12.
Basic Res Cardiol ; 93(3): 173-81, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9689443

RESUMO

Recent studies have indicated that chronic inhibition of nitric oxide synthase induces arterial hypertension without myocardial hypertrophy. We investigated the mechanisms of left ventricular (LV) adaptation to this condition. Also, we analyzed the effect of the angiotensin-converting enzyme inhibitor (ACEI), lisinopril, in this experimental model of ventricular pressure overload. Fifty-eight Wistar rats received eight weeks of treatment with either NW-nitro-L-arginine-methyl ester (L-NAME group, n = 19), lisinopril (LISINOPRIL group, n = 19) or the combination of both drugs (LNAMELIS group, n = 20). All results were compared to age and sex matched untreated rats (CONTROL group, n = 18). Tail-cuff blood pressure rose significantly in L-NAME treated rats (195 +/- 29 mm Hg) compared to the CONTROL (141 +/- 12 mm Hg), LISINOPRIL (97 +/- 13 mm Hg), and LNAMELIS (113 +/- 16 mm Hg) groups. There was no myocardial hypertrophy in the chronically hypertensive rats. The ventricular unstressed volume was significantly reduced in the L-NAME group (0.119 +/- 0.027 mL) compared to the CONTROL (0.158 +/- 0.026 mL) indicating a disproportional reduction in ventricular volume related to the myocardial mass. The chamber size modification resulted in a systolic stress which was comparable to the CONTROL even though the isovolumetric systolic pressure was higher. The systolic functional data indicated preserved myocardial contractility in L-NAME. LV compliance was increased in the LISINOPRIL group and myocardial passive stiffness was lower in all treated rats compared to CONTROL. We conclude that LV. adaptation to chronic pressure overload without hypertrophy involves changes in chamber geometry and myocardial diastolic mechanical properties. Also, ACEI fully prevents L-NAME induced hypertension, reduces myocyte cross-sectional area, and myocardial passive stiffness. The combination of L-NAME plus lisinopril decreases the load independent index of myocardial contractility.


Assuntos
Adaptação Fisiológica/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/toxicidade , Ventrículos do Coração/fisiopatologia , Hipertensão/fisiopatologia , Óxido Nítrico Sintase/antagonistas & inibidores , Animais , Pressão Sanguínea/efeitos dos fármacos , Seguimentos , Ventrículos do Coração/patologia , Hipertensão/induzido quimicamente , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Lisinopril/toxicidade , Masculino , Contração Miocárdica/efeitos dos fármacos , NG-Nitroarginina Metil Éster/toxicidade , Tamanho do Órgão , Distribuição Aleatória , Ratos , Ratos Wistar , Pressão Ventricular/efeitos dos fármacos
13.
Am J Physiol ; 275(2): H534-41, 1998 08.
Artigo em Inglês | MEDLINE | ID: mdl-9683442

RESUMO

The objectives of this study were 1) to determine whether ANG II-induced myocardial damage (ANG Dam) is mediated via the beta1-adrenergic receptor, 2) to elucidate whether adrenal medulla or cardiac sympathetic neuron catecholamines are responsible for ANG Dam, and 3) to determine whether the lack of damage after 3 days of elevated ANG II levels is due to beta1-receptor downregulation. To this end, ANG II was administered to rats 1) that were treated with a beta-receptor blocker, 2) after adrenal medullectomy and/or cardiac sympathectomy, and 3) for 3 or 8 days. ANG II caused both myocyte necrosis and coronary vascular damage after adrenal medullectomy but not after cardiac sympathectomy. There was a 38 and 55% decrease in beta-receptor density after 3 and 8 days, respectively, of ANG II infusion, and an upregulation to control levels 5 days after a 3-day ANG II infusion was stopped. We conclude that cardiac sympathetic neuron catecholamines are responsible for ANG Dam and that the acute nature of this damage is associated with a downregulation of beta1-adrenergic receptors.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Angiotensina II/sangue , Angiotensina II/toxicidade , Atenolol/farmacologia , Coração/fisiologia , Miocárdio/patologia , Neurônios/fisiologia , Receptores Adrenérgicos beta 1/biossíntese , Sistema Nervoso Simpático/fisiologia , Medula Suprarrenal/fisiologia , Animais , Catecolaminas/metabolismo , Regulação para Baixo , Coração/efeitos dos fármacos , Coração/inervação , Infusões Intravenosas , Masculino , Miocárdio/metabolismo , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Simpatectomia , Sistema Nervoso Simpático/efeitos dos fármacos , Fatores de Tempo
14.
Circ Res ; 82(4): 503-12, 1998 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-9506711

RESUMO

Synergistic interaction between angiotensin II (Ang II) and evolving cardiodepression may play an important role in worsening chamber function, particularly in diastole. To test this hypothesis, Ang II was infused at 10 or 17 ng.kg(-1).min(-1) in 18 conscious dogs 4 days before and during induction of subacute cardiodepression by 48-hour tachypacing. The lower dose yielded negligible systemic pressure changes. Twelve additional animals served as paced-only controls. Pressure-dimension relations were recorded, and serial endocardial biopsies were obtained to assess histological and metalloproteinase (MMP) changes. Forty-eight-hour pacing alone depressed systolic function but had little effect on diastolic stiffness. Ang II alone only modestly raised diastolic stiffness at both doses and enhanced contractility at the higher dose. These changes recovered toward baseline after a 7-day infusion. However, Ang II (at either dose) combined with 48-hour pacing markedly increased ventricular stiffness (110+/-26% over baseline) and end-diastolic pressure (22+/-1.7 mm Hg). In contrast, pacing-induced inotropic and relaxation abnormalities were not exacerbated by Ang II. Zymography revealed MMP activation (72- and 92-kD gelatinases and 52-kDa caseinase) after a 4-day Ang II infusion (at both doses), which persisted during pacing. Tachypacing initiated 24 hours after cessation of a 7-day Ang II infusion also resulted in diastolic stiffening and corresponded with MMP reactivation. Ang II also induced myocyte necrosis, inflammation, and subsequent interstitial fibrosis, but these changes correlated less with chamber mechanics. Thus, Ang II amplifies and accelerates diastolic dysfunction when combined with evolving cardiodepression. This phenomenon may also underlie Ang II influences in late-stage cardiomyopathy, when chamber distensibility declines.


Assuntos
Angiotensina II/farmacologia , Diástole/efeitos dos fármacos , Taquicardia/fisiopatologia , Angiotensina I/sangue , Angiotensina II/sangue , Animais , Cães , Ativação Enzimática/efeitos dos fármacos , Feminino , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Masculino , Metaloendopeptidases/metabolismo , Contração Miocárdica/efeitos dos fármacos , Fatores de Tempo
15.
Technol Health Care ; 5(1-2): 95-113, 1997 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9134622

RESUMO

The extracellular collagen matrix of the myocardium plays an important role in maintaining muscle fiber and cardiac alignment and ventricular shape and size. It also influences tissue and ventricle stiffness. This network consists of an organized hierarchy of collagen that is intimately associated with individual and groups of myocyte and muscle fibers, as well as the coronary vasculature. In renovascular and genetic hypertension, the hypertrophic response of the myocardium includes an increase in collagen concentration, thickening of existing fibrillar collagen, and addition of newly synthesized collagen to all of the matrix components. The consequences of this remodeling are a stiffer myocardium and left ventricular diastolic dysfunction. With removal of less than half of the normal amount of collagen the opposite occurs. That is, the ventricle dilates and there is an increase in ventricular compliance. Thus an abnormal accumulation of collagen is a major distinguishing factor between physiologic and pathologic hypertrophy while an abrupt decrease in collagen concentration results in a ventricular remodeling similar to that of a heart in failure.


Assuntos
Colágeno/fisiologia , Colágeno/ultraestrutura , Ventrículos do Coração/anatomia & histologia , Miocárdio/ultraestrutura , Miofibrilas/fisiologia , Miofibrilas/ultraestrutura , Função Ventricular , Animais , Colágeno/química , Colagenases/fisiologia , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Coelhos , Ratos
16.
J Cell Biochem ; 63(2): 185-98, 1996 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-8913870

RESUMO

Extracellular matrix metalloproteinases (MMPs) are activated in dilated cardiomyopathic (DCM) hearts [Tyagi et al. (1996): Mol Cell Biochem 155:13-21]. To examine whether the MMP activation is occurring at the gene expression level, we performed differential display mRNA analysis on tissue from six dilated cardiomyopathy (DCM) explanted and five normal human hearts. Specifically, we identified three genes to be induced and several other genes to be repressed following DCM. Southern blot analysis of isolated cDNA using a collagenase cDNA probe indicated that one of the genes induced during DCM was interstitial collagenase (MMP-1). Northern blot analysis using MMP-1 cDNA probe indicated that MMP-1 was induced three- to fourfold in the DCM heart as compared to normal tissue. To analyze posttranslational expression of MMP and tissue inhibitor of matrix metalloproteinase (TIMP) we performed immunoblot, immunoassay, and substrate zymographic assays. TIMP-1 and MMP-1 levels were 37 +/- 8 ng/mg and 9 +/- 2 ng/mg in normal tissue specimens (P < 0.01) and 2 +/- 1 ng/mg and 45 +/- 11 ng/mg in DCM tissue (P < 0.01), respectively. Zymographic analysis demonstrated lytic bands at 66 kDa and 54 kDa in DCM tissue as compared to one band at 66 kDa in normal tissue. Incubation of zymographic gel with metal chelator (phenanthroline) abolished both bands suggesting activation of neutral MMP in DCM heart tissue. TIMP-1 was repressed approximately twentyfold in DCM hearts when compared with normal heart tissue. In situ immunolabeling of MMP-1 indicated phenotypic differences in the fibroblast cells isolated from the DCM heart as compared to normal heart. These results suggest disruption in the balance of myopathic-fibroblast cell ECM-proteinase and antiproteinase in ECM remodeling which is followed by dilated cardiomyopathy.


Assuntos
Cardiomiopatia Dilatada/genética , Colagenases/genética , Proteínas da Matriz Extracelular/genética , Regulação Enzimológica da Expressão Gênica , Glicoproteínas/genética , Northern Blotting , Southern Blotting , Cardiomiopatia Dilatada/metabolismo , Colagenases/metabolismo , Ensaio de Imunoadsorção Enzimática , Proteínas da Matriz Extracelular/metabolismo , Glicoproteínas/metabolismo , Humanos , Metaloproteinase 1 da Matriz , Miocárdio/enzimologia , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Inibidores Teciduais de Metaloproteinases
17.
Am J Physiol ; 271(5 Pt 2): H2071-8, 1996 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8945927

RESUMO

The left ventricle (LV) significantly dilates and hypertrophies in response to chronic volume overload. However, the temporal responses in LV mass, volume, and systolic/diastolic function secondary to chronic volume overload induced by an infrarenal arteriovenous (A-V) fistula in rats have not been well characterized. To this end, LV end-diastolic pressure, size, and function (i.e., isovolumetric pressure-volume relationships in the blood-perfused isolated heart) were assessed at 1, 2, 3, 5, and 8 wk post-A-V fistula and compared with age-matched control animals. Progressive hypertrophy (192% at 8 wk), ventricular dilatation (172% at 8 wk), and a decrease in ventricular stiffness (257% at 8 wk) occurred in the fistula groups. LV end-diastolic pressure increased from a control value of 4.2 +/- 3.1 mmHg to a peak value of 15.7 +/- 3.6 mmHg after 3 wk of volume overload. A subsequent decline in LVEDP to 11.0 +/- 6.0 mmHg together with further LV dilation (169%) corresponded to a significant decrease in LV stiffness (222%) at 5 wk post-A-V fistula. Myocardial contractility, as assessed by the isovolumetric pressure-volume relationship, was significantly reduced in all A-V fistula groups; however, the compensatory remodeling induced by 8 wk of chronic biventricular volume overload tended to preserve systolic function.


Assuntos
Hiperemia/fisiopatologia , Função Ventricular Esquerda , Animais , Aorta Abdominal/cirurgia , Derivação Arteriovenosa Cirúrgica , Doença Crônica , Diástole , Masculino , Ratos , Ratos Sprague-Dawley , Sístole , Fatores de Tempo , Veias Cavas/cirurgia
18.
J Cell Physiol ; 167(1): 137-47, 1996 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-8698831

RESUMO

Following myocardial infarction, extracellular matrix (ECM) is disrupted, which leads to the generation of collagen- and elastin-derived peptides (CDPs and EDPs, respectively). To investigate whether ECM-derived peptides (i.e., CDPs and EDPs) induce extracellular proteinases in human heart fibroblast (HHF) cells, we isolated CDP and EDP using gelfiltration and antibody affinity column chromatography. The CDP and EDP were characterized by their intrinsic fluorescence due to crosslink structure (pyridinoline and desmosine, respectively) and by immunoblot analysis using anti-desmosine antibody. Neutrophil elastase and cathepsin G were identified using selective chromogenic substrates and by their specific inhibition with alpha1-proteinase inhibitor and alpha1-antichymotrypsin, respectively. Elastase and cathepsin G were elevated in the infarcted tissue. Selective inhibition of matrix metalloproteinase (MMP) by a higher concentration of tetracycline or doxycycline in zymographic gels elicited an inhibition constant (IC50) of 278 +/- 10 microM and indicated that majority of MMP in the infarcted tissue is from fibroblast cells. The HHF proliferation was measured using an acid-phosphatase assay. The EDP and CDP induce HHF cell proliferation. After EDP treatment phenotypic (formation of pseudopodia) changes were observed in HHF cells. To measure whether phenotypic changes by EDP or CDP are associated with MMP and tissue inhibitor of metalloproteinase (TIMP) expression in HHF cells, we measured MMP and TIMP expression by zymographic and Northern blot (mRNA) analyses. The expression of MMP and TIMP were upregulated at both the protein and gene transcription levels. These results suggested that during ischemic cardiomyopathy, initially neutrophil proteinase activates latent myocardial MMP which can degrade ECM, which continuously degrades if not controlled by TIMP, leading to ventricular dilatation and dysfunction.


Assuntos
Proteínas da Matriz Extracelular/metabolismo , Metaloendopeptidases/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Inibidores Enzimáticos/metabolismo , Fibroblastos/metabolismo , Humanos , Metaloendopeptidases/antagonistas & inibidores , Miocárdio/citologia
19.
Am J Physiol ; 269(5 Pt 2): H1564-9, 1995 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-7503249

RESUMO

Acute elevations in circulating angiotensin II (ANG II) are known to increase circulating norepinephrine (NE) levels. However, the time course of catecholamine release relative to chronic ANG II infusion is not known. Furthermore, it is unknown if this ANG II-induced catecholamine release is ANG II type 1 (AT1) receptor mediated or whether the increase in serum catecholamines is responsible for the myocyte and coronary vascular damage seen within the first 3 days of chronic ANG II infusion. Therefore, we examined the influence of chronic ANG II stimulation on serum catecholamine levels with and without AT1 blockade and the effect of beta-blockade on ANG II-induced myocyte and coronary vascular damage. The results indicate that NE release is AT1 mediated, but NE is not significantly elevated until day 4 of ANG II infusion after which it remains elevated. beta-Blockade prevented most ANG II-related myocyte necrosis and coronary vascular damage. Therefore, myocyte and coronary vascular damage do not appear to be related to increased serum NE levels, but instead may be due to the release of neural catecholamines within the heart.


Assuntos
Angiotensina II/farmacologia , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Coração/efeitos dos fármacos , Miocárdio/patologia , Norepinefrina/sangue , Antagonistas Adrenérgicos beta/farmacologia , Angiotensina II/antagonistas & inibidores , Antagonistas de Receptores de Angiotensina , Animais , Infusões Intravenosas , Masculino , Necrose , Ratos , Ratos Sprague-Dawley , Receptores de Angiotensina/fisiologia , Fatores de Tempo
20.
J Lab Clin Med ; 126(3): 307-15, 1995 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-7665980

RESUMO

Elevations in plasma angiotensin II (AngII) are associated with evidence of vascular hyperpermeability expressed as efflux of plasma macromolecules into the perivascular and interstitial space. This exudative response is followed by a series of fibrogenic events that lead to a perivascular fibrosis of involved vessels. Mediators of hyperpermeability and fibrogenesis are unknown. In dogs receiving intravenous AngII, hemodynamic factors (i.e., arterial hypertension or coronary venoconstriction) were discounted as being responsible for the rise in cardiac lymph-to-plasma protein ratio. Accordingly, we investigated the relationship between AngII-induced coronary hyperpermeability and the release of prostaglandin E2 (PGE2) and activation of the basement membrane degrading matrix metalloproteinase, gelatinase/type IV collagenase. In dogs, cardiac lymph was monitored over the course of a 90-minute intravenous infusion of either AngII (0.2 to 0.3 micrograms/kg/min; n = 8) or saline solution (n = 6). Lymph was examined at 30-minute intervals for the following: total protein (Lowry's method), albumin (sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)), plasma fibronectin (SDS-PAGE and enzyme-linked immunosorbent assay); PGE2 (radioimmunoassay) and gelatinase/type IV collagenase (zymography). In comparison with baseline we found a consistent rise in lymph flow (p = 0.02), total protein (p = 0.02), albumin, fibronectin, PGE2 (p = 0.03), and gelatinase/type IV collagenase (p = 0.019), which began after 30 minutes of AngII infusion. Similar trends were not observed in dogs receiving saline solution alone. We therefore conclude that AngII-induced coronary vascular hyperpermeability is associated with an early release of PGE2 and gelatinase.


Assuntos
Angiotensina II/sangue , Permeabilidade Capilar , Doença das Coronárias/etiologia , Vasos Coronários/fisiopatologia , Angiotensina II/farmacologia , Animais , Doença das Coronárias/patologia , Vasos Coronários/patologia , Dinoprostona/metabolismo , Cães , Fibronectinas/metabolismo , Fibrose , Gelatinases/metabolismo , Cinética , Linfa/metabolismo , Masculino , Miocárdio/metabolismo , Proteínas/metabolismo , Albumina Sérica/metabolismo
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