RESUMO
Surgeries to correct congenital heart diseases are increasing in Brazil and worldwide. However, even with the advances in surgical techniques and perfusion, some cases, especially the more complex ones, can develop heart failure and death. A retrospective study of patients who underwent surgery for correction of congenital heart diseases with cardiopulmonary bypass (CPB) in a university tertiary-care hospital that died, showed infarction in different stages of evolution and scattered microcalcifications in the myocardium, even without coronary obstruction. CPB is a process routinely used during cardiac surgery for congenital heart disease. However, CPB has been related to increased endogenous catecholamines that can lead to major injuries in cardiomyocytes. The mechanisms involved are not completely understood. The aim of this study was to evaluate the alterations induced in the ß-adrenergic receptors and GRK-2 present in atrial cardiomyocytes of infants with congenital heart disease undergoing surgical repair with CPB and correlate the alterations with functional and biochemical markers of ischemia/myocardial injury. The study consisted of right atrial biopsies of infants undergoing surgical correction in HC-FMRPUSP. Thirty-three cases were selected. Atrial biopsies were obtained at the beginning of CPB (group G1) and at the end of CPB (group G2). Real-time PCR, Western blotting, and immunofluorescence analysis were conducted to evaluate the expression of ß1, ß2-adrenergic receptors, and GRK-2 in atrial myocardium. Cardiac function was evaluated by echocardiography and biochemical analysis (N-terminal pro-brain natriuretic peptide (NT-ProBNP), lactate, and cardiac troponin I). We observed an increase in serum lactate, NT-proBNP, and troponin I at the end of CPB indicating tissue hypoxia/ischemia. Even without major clinical consequences in cardiac function, these alterations were followed by a significant increase in gene expression of ß1 and ß2 receptors and GRK-2, suggesting that this is one of the mechanisms responsible for the exacerbated response of cardiomyocytes to circulating catecholamines. These alterations could explain the irreversible myocardial damage and lipid peroxidation of membranes classically attributed to catecholamine excess, observed in some infants who develop heart failure and postoperative death. Although other factors may be involved, this study confirms that CPB acts as a potent inducer of increased gene expression of ß- adrenergic receptors and GRK-2, making the myocardium of these infants more susceptible to the effects of circulating endogenous catecholamines, which may contribute to the development of irreversible myocardial damage and death.
Assuntos
Ponte Cardiopulmonar/efeitos adversos , Quinase 2 de Receptor Acoplado a Proteína G/genética , Átrios do Coração/metabolismo , Cardiopatias Congênitas/cirurgia , Insuficiência Cardíaca/genética , Receptores Adrenérgicos beta/genética , Biomarcadores/análise , Biópsia , Catecolaminas/metabolismo , Feminino , Quinase 2 de Receptor Acoplado a Proteína G/análise , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Expressão Gênica , Átrios do Coração/química , Átrios do Coração/patologia , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Receptores Adrenérgicos beta/análise , Receptores Adrenérgicos beta/metabolismo , Estudos RetrospectivosRESUMO
Atrial myocardium fibrosis and other alterations of fiber continuity and potential circuit reentrancy (disconnections, abrupt turns, crossings, and epicardial reflections) are thought to play an important role in permanent atrial fibrillation. However, few studies have been performed in human beings. Some of them are only descriptive, and controls were usually normal hearts; thus, differences between cases and controls could be related to the underlying disease rather than the arrhythmia. We quantified by histomorphometry the above characteristics in nine samples (three from the left atrium, three from around fat pads, one from the right atrium, one from the cavum-tricuspid isthmus, and one from the ventricular septum) from 13 necropsy hearts of patients with permanent atrial fibrillation and compared the findings with those from 13 control cases with the same diseases but without any atrial arrhythmia. Statistical analysis was performed using generalized estimating equations and a normal linear mixed model for repeated measures, with significance defined as P ≤.05. No differences were found in fibrosis (estimated as collagen/(collagen+myocardium) ratio-0.26 vs. 0.23, P=.35), the presence of disconnections (70.1 vs. 61.5, P=.09), abrupt turns (43.6 vs. 45.3, P=.84), or epicardial reflections (9.4 vs. 14.5, P=.12). The only difference identified was that cases with permanent atrial fibrillation exhibited fewer crossings than those without (79.5 vs. 91.5, P=.02). In conclusion, alterations in myocardial fiber continuity, including fibrosis, seem to reflect a generalized myocardial disorganization of the atria in cardiac disease but are not specifically related to permanent atrial fibrillation.
Assuntos
Fibrilação Atrial/patologia , Miocárdio/patologia , Pericárdio/patologia , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/etiologia , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Colágeno/análise , Feminino , Fibrose , Átrios do Coração/química , Átrios do Coração/patologia , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Miocárdio/química , Pericárdio/química , Fatores de Risco , Coloração e Rotulagem/métodosRESUMO
Chronic stimulation of sympathetic nervous activity contributes to the development and maintenance of hypertension, leading to left ventricular hypertrophy (LVH), arrhythmias and cardiac death. Moxonidine, an imidazoline antihypertensive compound that preferentially activates imidazoline receptors in brainstem rostroventrolateral medulla, suppresses sympathetic activation and reverses LVH. We have identified imidazoline receptors in the heart atria and ventricles, and shown that atrial I1-receptors are up-regulated in spontaneously hypertensive rats (SHR), and ventricular I1-receptors are up-regulated in hamster and human heart failure. Furthermore, cardiac I1-receptor binding decreased after chronic in vivo exposure to moxonidine. These studies implied that cardiac I1-receptors are involved in cardiovascular regulation. The presence of I1-receptors in the heart, the primary site of production of natriuretic peptides, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), cardiac hormones implicated in blood pressure control and cardioprotection, led us to propose that ANP may be involved in the actions of moxonidine. In fact, acute iv administration of moxonidine (50 to 150 microg/rat) dose-dependently decreased blood pressure, stimulated diuresis and natriuresis and increased plasma ANP and its second messenger, cGMP. Chronic SHR treatment with moxonidine (0, 60 and 120 microg kg(-1) h(-1), sc for 4 weeks) dose-dependently decreased blood pressure, resulted in reversal of LVH and decreased ventricular interleukin 1beta concentration after 4 weeks of treatment. These effects were associated with a further increase in already elevated ANP and BNP synthesis and release (after 1 week), and normalization by 4 weeks. In conclusion, cardiac imidazoline receptors and natriuretic peptides may be involved in the acute and chronic effects of moxonidine.
Assuntos
Anti-Hipertensivos/farmacologia , Fator Natriurético Atrial/fisiologia , Imidazóis/farmacologia , Miocárdio/química , Peptídeo Natriurético Encefálico/fisiologia , Receptores de Droga/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Cricetinae , Átrios do Coração/química , Ventrículos do Coração/química , Humanos , Receptores de Imidazolinas , Ratos , Ratos Endogâmicos SHRRESUMO
This work includes results on chronotropic, inotropic and lusitropic changes induced by capsaicin on isolated rat atria. As regards spontaneous frequency, it was stimulated from 10(-9) M up to 7 x 10(-7) M of capsaicin. A simultaneous depression in developed force (F) showed a significant correlation with this positive chronotropic effect up to 7 x 10(-8) M of capsaicin, which is the result of the negative staircase phenomenon in the rat heart. The correlation was lost at 2 and 7 x 10(-7) M of capsaicin since in spite of the sustained increase in atrial rate the decrease in F was reversed and then depressed again at 2 and 7 x 10(-6) M of capsaicin without changes in frequency. A concentration of capsaicin that overcome the negative staircase phenomenon, 5 x 10(-7) M, was tested as unique dose resulting in stimulation of the chronotropic, inotropic and lusitropic states of the atria. Percentual differences with respect to control values were maximal after 1-3 minutes for frequency (10 +/- 3%), F (29 +/- 4%), maximal velocity of force development (+F = 50 +/- 12%) (in all cases +F and -F bold indicates +F and -F, respectively), and maximal velocity of relaxation (-F = 64 +/- 13%); a positive lusitropic effect was significant after 8-10 minutes (+F/-F = 17 +/- 7%). Capsaicin did not affect the rat atria in the presence of 10(-6) M of ruthenium red, a blocker of capsaicin activation of sensory nerves, indicating that the stimulatory effects were entirely mediated by the release of neurotransmitters and that this concentration of capsaicin was not deleterous "per se". Capsaicin elicited similar inotropic responses in electrically driven isolated atria (+F = 41 +/- 9%) but the positive lusitropic effect was lost suggesting that capsaicin-induced increases in -F are limited at a frequency higher than the spontaneous frequency (11 +/- 6 vs. 32 +/- 4%, respectively). 10(-6) M of CGRP8-37, an antagonist of CGRP1 receptors, suppress the stimulatory effects of capsaicin on atrial contraction. In summary, atrial rate as compared to atrial contraction is more sensitive to the neurotransmitter released by capsaicin, which results in mechanical effects expressing the negative staircase phenomenon in the rat at low concentrations of capsaicin. The positive chronotropic, inotropic and lusitropic responses elicited by capsaicin are mediated by the release of neurotransmitters from sensory fibbers and no deletereous effects of capsaicin "per se" became evident when the release of neuropeptides was prevented. Atrial contraction was depressed at higher capsaicin concentrations than the one showing stimulatory effects. Stimulation of atrial contractility is mediated by activation of CGRP receptors.
Assuntos
Capsaicina/farmacologia , Átrios do Coração/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/análise , Animais , Capsaicina/análise , Átrios do Coração/química , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/fisiologia , Rutênio Vermelho , Estimulação QuímicaRESUMO
The distribution of prostaglandin-E2 (PGE2) and prostaglandin-F2 alpha (PGF2 alpha) was studied in subcellular fractions isolated from homogenates of human atrial fresh tissue by differential centrifugation. Right and left atrial samples were excised from the same heart of six patients with mitral valve disease at the time of open heart surgery. The atrial fractions investigated were mitochondrial (8,500 g pellet), microsomal (100,000 g pellet) and cytosol soluble (100,000 g supernatant) fractions. After extraction of prostaglandins from the three atrial fractions and separation of PGE from PGF series by chromatography on silicic acid column, these prostaglandins were measured by radioimmunoassay. The results showed that PGE2 and PGF2 alpha were located mainly in the soluble cytosolic fraction of right and left atrial tissue (p < 0.001). Furthermore, the prostaglandins levels were higher in left than in right atria of these patients (p < 0.001). The relation between prostaglandins heart generation in response to elevated work load of mitral valve disease is discussed.
Assuntos
Dinoprosta/metabolismo , Dinoprostona/metabolismo , Insuficiência da Valva Mitral/metabolismo , Estenose da Valva Mitral/metabolismo , Ocitócicos/metabolismo , Adulto , Dinoprosta/análise , Dinoprostona/análise , Feminino , Átrios do Coração/química , Átrios do Coração/metabolismo , Humanos , Masculino , Valva Mitral/química , Ocitócicos/análise , Frações SubcelularesRESUMO
The distribution of prostaglandin-E2 (PGE2) and prostaglandin-F2alpha (PGF2alpha) was studied in subcellular fractions isolated from homogenates of human atrial fresh tissue by differential centrifugation. Right and left atrial samples were excised from the same heart of six patients with mitral valve disease at the time of open heart surgery. The atrial fractions investigated were mitochondrial (8,500 g pellet), microsomal (100,000 g pellet) and cytosol soluble (100,000 g supernatant) fractions. After extraction of prostaglandins from the three atrial fractions and separation of PGE from PGF series by chromatography on silicic acid column, these prostaglandins were measured by radioimmunoassay. The results, showed that PGE2 and PGF2alpha were located mainly in the soluble cytosolic fraction of right and left atrial tissue (p<0.001). Furthermore, the prostaglandins levels were higher in left than in right atria of these patients (p<0.001). The relation between prostaglandins heart generation in response to elevated work load of mitral valve disease is discussed.
Assuntos
Humanos , Masculino , Feminino , Adulto , Dinoprostona/metabolismo , Dinoprosta/metabolismo , Insuficiência da Valva Mitral/metabolismo , Estenose da Valva Mitral/metabolismo , Ocitócicos/metabolismo , Dinoprostona/análise , Dinoprosta/análise , Átrios do Coração/química , Átrios do Coração/metabolismo , Valva Mitral/química , Ocitócicos/análise , Frações SubcelularesRESUMO
This work includes results on chronotropic, inotropic and lusitropic changes induced by capsaicin on isolated rat atria. As regards spontaneous frequency, it was stimulated from 10(-9) M up to 7 x 10(-7) M of capsaicin. A simultaneous depression in developed force (F) showed a signigicant correlation with this positive chronotropic effect up to 7 X 10(-8) M of capsaicin, which is the result of the negative staircase phenomenon in the rat heart. The correlation was lost at 2 and 7 x 10(-7) M of capsaicin since in spite of the sustained increase in atrial rate the decrease in F was reversed and then depressed again at 2 and 7x 10(-6) M of capsaicin without changes in frequency. A concentration of capsaicin that overcome the negative staircase phenomenon, 5 x 10(-7) M, was tested as unique dose resulting in stimulation of the chronotropic, inotropic and lusitropic states of the atria. Percentual differences with respect to control values were maximal after 1-3 minutes for frequency (10+3 per cent), F (29+4 per cent), maximal velocity of force development (+F=50+12 per cent) (in all cases +F and -F,bold indicates +F and -F, respectively) and maximal velocity of relaxation (-F=64+13 per cent); a positive lusitropic effect was significant after 8-10 minutes (+F/-F=-17+7 per cent). Capsaicin did not affect the rat atria in the presence of 10(-6) M of ruthenium red, a blocker of capsaicin activation of sensory nerves, indicating that the stimulatory effects were entirely mediated by the release of neurotransmitters and that this concentration of capsaicin was not deleterous "per se". Capsaicin elicited similar inotropic responses in electrically driven isolated atria (+F=41+9 per cent) but the positive lusitropic effect was lost suggesting that capsaicin-induced increases in -F are limited at a frequency higher than the spontaneous frequency (11+6 vs. 32+4 per cent, respectively). 10(-6) M of CGRP8(-37), an antagonist of CGRP1 receptors, suppress the stimulatory effects of capsaicin on atrial contraction. In summary, atrial rate as compared to atrial contraction is more sensitive to the neurotransmitter released by capsaicin, which results in mechanical effects expressing the negative staircase phenomenon in the rat at low concentrations of capsaicin. The positive chronotropic, inotropic and lusitropic responses elicited by capsaicin are mediated by the reelease of neurotransmitters from sensory fibbers and no deletereous effects...
Assuntos
Animais , Masculino , Ratos , Capsaicina/farmacologia , Átrios do Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/análise , Capsaicina/análise , Átrios do Coração/química , Ratos Sprague-Dawley , Rutênio Vermelho , Estimulação QuímicaRESUMO
This work includes results on chronotropic, inotropic and lusitropic changes induced by capsaicin on isolated rat atria. As regards spontaneous frequency, it was stimulated from 10(-9) M up to 7 x 10(-7) M of capsaicin. A simultaneous depression in developed force (F) showed a signigicant correlation with this positive chronotropic effect up to 7 X 10(-8) M of capsaicin, which is the result of the negative staircase phenomenon in the rat heart. The correlation was lost at 2 and 7 x 10(-7) M of capsaicin since in spite of the sustained increase in atrial rate the decrease in F was reversed and then depressed again at 2 and 7x 10(-6) M of capsaicin without changes in frequency. A concentration of capsaicin that overcome the negative staircase phenomenon, 5 x 10(-7) M, was tested as unique dose resulting in stimulation of the chronotropic, inotropic and lusitropic states of the atria. Percentual differences with respect to control values were maximal after 1-3 minutes for frequency (10+3 per cent), F (29+4 per cent), maximal velocity of force development (+F=50+12 per cent) (in all cases +F and -F,bold indicates +F and -F, respectively) and maximal velocity of relaxation (-F=64+13 per cent); a positive lusitropic effect was significant after 8-10 minutes (+F/-F=-17+7 per cent). Capsaicin did not affect the rat atria in the presence of 10(-6) M of ruthenium red, a blocker of capsaicin activation of sensory nerves, indicating that the stimulatory effects were entirely mediated by the release of neurotransmitters and that this concentration of capsaicin was not deleterous "per se". Capsaicin elicited similar inotropic responses in electrically driven isolated atria (+F=41+9 per cent) but the positive lusitropic effect was lost suggesting that capsaicin-induced increases in -F are limited at a frequency higher than the spontaneous frequency (11+6 vs. 32+4 per cent, respectively). 10(-6) M of CGRP8(-37), an antagonist of CGRP1 receptors, suppress the stimulatory effects of capsaicin on atrial contraction. In summary, atrial rate as compared to atrial contraction is more sensitive to the neurotransmitter released by capsaicin, which results in mechanical effects expressing the negative staircase phenomenon in the rat at low concentrations of capsaicin. The positive chronotropic, inotropic and lusitropic responses elicited by capsaicin are mediated by the reelease of neurotransmitters from sensory fibbers and no deletereous effects...(AU)
Assuntos
Animais , Masculino , RESEARCH SUPPORT, NON-U.S. GOVT , Ratos , Capsaicina/farmacologia , Átrios do Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/análise , Estimulação Química , Rutênio Vermelho , Ratos Sprague-Dawley , Capsaicina/análise , Átrios do Coração/químicaRESUMO
Expression and distribution of atrial natriuretic peptide (ANP) were studied immunohistochemically in the conducting system and internodal atrial myocardium of 5 adult human hearts. Myocytes from the sinus node and compact atrioventricular node were usually ANP-negative; only a very few cells exhibited ANP immunoreactivity. These ANP-positive myocytes were small and did not appear to be trapped working atrial myocytes which are larger than nodal cells. The transitional cell zones of the sinus node and the atrioventricular node were composed of bundles of ANP-positive myocytes, intermingled with non-reactive myocytes. The internodal atrial myocardium exhibited a comparable intensity of myocyte staining in each case examined. Thus, morphologically distinct connecting pathways between the sinus node and the atrioventricular node with regard to myocyte ANP immunoreactivity could not be demonstrated, reinforcing the notion that they actually do not exist. The penetrating bundle, branching bundle and bundle branches were usually composed of ANP-negative myocytes although some ANP-positive myocytes were observed in the branching bundle and bundle branches in 4 cases. Myocytes from the ventricular conducting tissue presenting ANP immunoreactivity have been designated Purkinje fibers and have been found in several mammalian species.
Assuntos
Fator Natriurético Atrial/química , Sistema de Condução Cardíaco/química , Miocárdio/química , Miocárdio/citologia , Adulto , Idoso , Nó Atrioventricular/química , Nó Atrioventricular/citologia , Nó Atrioventricular/imunologia , Feminino , Átrios do Coração/química , Átrios do Coração/citologia , Átrios do Coração/imunologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Miocárdio/imunologia , Nó Sinoatrial/química , Nó Sinoatrial/citologia , Nó Sinoatrial/imunologiaRESUMO
We determined whether ANP (atrial natriuretic peptide) concentrations, measured by radioimmunoassay, in the ANPergic cerebral regions involved in regulation of sodium intake and excretion and pituitary glad correlated with differences in sodium preference among 40 Wistar male rats (180-220 g). Sodium preference was measured as mean spontaneous ingestion of 1.5% NaCl solution during a test period of 12 days. The relevant tissues included the olfactory bulb (OB), the posterior and anterior lobes of the pituitary gland (PP and AP, respectively), the median eminence (ME), the medial basal hypothalamus (MBH), and the region anteroventral to the third ventricle (AV3V). We also measured ANP content in the right (RA) and left atrium (LA) and plasma. The concentrations of ANP in the OB and the AP were correlated with sodium ingestion during the preceding 24 h, since an increase of ANP in these structures was associated with a reduced ingestion and vice-versa (OB: r = -0.3649, P < 0.05; AP: r = -0.3291, P < 0.05). Moreover, the AP exhibited a correlation between ANP concentration and mean NaCl intake (r = -0.4165, P < 0.05), but this was not the case for the OB (r = 0.2422). This suggests that differences in sodium preference among individual male rats can be related to variations of AP ANP level. Earlier studies indicated that the OB is involved in the control of NaCl ingestion. Our data suggests that the OB ANP level may play a role mainly in day-to-day variations of sodium ingestion in the individual rat.