RESUMO
Isolated congenital heart block may be associated with Primary Sjögren's Syndrome. In this work we demonstrated that IgG present in the sera of patients with Primary Sjögren's Syndrome (PSS) could bind and activate muscarinic acetylcholine receptors of rat neonatal atria. These antibodies were able to inhibit in a irreversible manner the binding of 3H-QNB to muscarinic cholinergic receptors of purified rat atria membranes. Moreover, IgG from PSS individuals could modify biological effects mediated by muscarinic cholinoceptors activation, i.e. decrease contractility and cAMP and increase phosphoinositide turnover and cGMP. Atropine blocked all of these effects and carbachol mimicked them; confirming muscarinic cholinergic receptors-mediated PSS IgG action. Neither binding nor biological effect were obtained using adult instead of neonatal rat atria. IgG from sera of normal women were not effective in the studied system. The prevalence of cholinergic antibody was 100% in PSS and was independent of Ro/SS-A and La/SS-B antibodies. It could be concluded that antibody against muscarinic cholinergic receptors may be another serum factor to be considered in the pathophysiology of the development of congenital heart block.
Assuntos
Receptores Muscarínicos/imunologia , Síndrome de Sjogren/imunologia , Adulto , Animais , Ligação Competitiva , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Feminino , Humanos , Fosfatidilinositóis/metabolismo , Quinuclidinil Benzilato/metabolismo , RatosRESUMO
In this study we demonstrate that IgG present in the sera of patients with primary Sjögren's syndrome (PSS) could bind and activate muscarinic acetylcholine receptors (mAChRs) of rat parotid gland. These antibodies were able to inhibit in a non-competitive manner the binding of 3H-quinuclidinyl benzilate (QNB) to mAChRs of purified rat parotid gland membranes. Moreover, IgG from PSS could modify biological effects mediated by mAChR activation; i.e. decrease cAMP, increase phosphoinositide turnover without affecting cGMP. Atropine and 4-DAMP blocked all of these effects, and carbachol mimicked them, confirming the M3 subtype mAChRs mediated PSS IgG action. Neither binding nor biological effect were obtained with IgG from sera of normal women. The prevalence of cholinergic antibody was 100% in PSS, and was independent of Ro/SS-A and La/SS-B antibodies. It could be concluded that antibody against mAChRs may be another serum factor to be considered in the pathophysiology of the development of PSS.
Assuntos
Imunoglobulina G/imunologia , Glândula Parótida/imunologia , Fenilcarbamatos , Receptores Muscarínicos/imunologia , Síndrome de Sjogren/imunologia , Adolescente , Agonistas Adrenérgicos beta/farmacologia , Adulto , Animais , Anticorpos Bloqueadores/imunologia , Atropina/farmacologia , Carbacol/farmacologia , Carbamatos/farmacologia , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunoglobulina G/análise , Isoproterenol/farmacologia , Antagonistas Muscarínicos/imunologia , Antagonistas Muscarínicos/farmacologia , Parassimpatolíticos/farmacologia , Fosfatidilinositóis/metabolismo , Piperidinas/farmacologia , Pirenzepina/análogos & derivados , Pirenzepina/farmacologia , Inibidores de Proteases/farmacologia , Quinuclidinil Benzilato/imunologia , Ratos , Ratos Wistar , Síndrome de Sjogren/sangueRESUMO
The negative inotropic effect of carbachol, as well as phosphoinositide hydrolysis, was measured in atria from neonatal and adult rats. Carbachol increased phosphoinositide hydrolysis and decreased dF/dt of both neonatal and adult atria; however, the neonatal atria showed hypereactivity to carbachol as compared with adult atria. Inhibition of phospholipase C reduced the supersensitivity to carbachol upon contractility in neonatal atria producing values similar to those of the adult atria, suggesting that muscarinic acetylcholine receptor (mAchR) stimulation is secondary to receptor-mediated hydrolysis of phosphoinositides. Pharmacological analysis with mAchR antagonists tends to support the idea that m1 and m2 subtypes are the most important mediators of the response to carbachol in neonatal atria. In adult atria, the effect of carbachol is coupled only to mAchR m2 subtypes.
Assuntos
Animais Recém-Nascidos , Coração/crescimento & desenvolvimento , Miocárdio/metabolismo , Fosfatidilinositóis/metabolismo , Receptores Muscarínicos/metabolismo , Animais , Carbacol/farmacologia , Depressão Química , Inibidores Enzimáticos/farmacologia , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/crescimento & desenvolvimento , Átrios do Coração/metabolismo , Hidrólise , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Contração Miocárdica/efeitos dos fármacos , Pirenzepina/análogos & derivados , Pirenzepina/farmacologia , Ratos , Fosfolipases Tipo C/antagonistas & inibidoresRESUMO
In this work we demonstrated that IgG present in the sera of patients with congenital heart block (CHB) and their mothers could bind and activate beta adrenoceptors and muscarinic cholinergic receptors of neonatal heart. These antibodies were able to inhibit in a noncompetitive manner the binding of [3H]QNB and [3H]CGP to muscarinic cholinergic and beta adrenoceptors of purified neonatal rat myocardial membranes, respectively. Moreover, IgG from children with CHB and their mothers could modify biological effects mediated by these neurotransmitter receptors, i.e., heart contractility and cAMP production. Neither binding nor biological effects were obtained using adult instead of neonatal rat atria. Both reactivities (adrenergic and cholinergic) were independent of Ro/SS-A and La/SS-B antibodies and were absent in the sera of normal women of childbearing age and of normal children. It could be concluded that antibodies against cardiac neurotransmitter receptors may be another serum factor (or factors) to be considered in the pathophysiology of the development of CHB.
Assuntos
Autoanticorpos/sangue , Bloqueio Cardíaco/imunologia , Receptores Adrenérgicos beta/imunologia , Receptores Muscarínicos/imunologia , Adulto , Animais , Feminino , Átrios do Coração/fisiopatologia , Bloqueio Cardíaco/congênito , Humanos , Imunoglobulina G/metabolismo , Técnicas In Vitro , Lactente , Mães , Contração Miocárdica , Miocárdio/metabolismo , RatosRESUMO
To determine whether antibodies against beta adrenergic activity interact with neonatal cardiac cell receptors and alter their physiological behaviour. An "in vitro" experimental model measuring the frequency of contraction, the production of cAMP and binding assay on neonatal and adult rat atria was employed. Sera and IgG fraction from mothers of infants with congenital heart block (CHB) interact with neonatal rat atria increasing the frequency of contraction and cAMP production. These effects were abolished by propranolol, pointing to a beta adrenergic participation. IgG also competed with 3H-CGP to beta adrenergic receptors on neonatal cardiac membranes. Neither the contractile nor the cAMP effects or binding assay were obtained using adult instead of neonatal rat atria. Reactivity against cardiac neurotransmitter receptors may be another serum factor(s) to be considered in the pathophysiology of the development of CHB.
Assuntos
Autoanticorpos/fisiologia , Bloqueio Cardíaco/congênito , Receptores Adrenérgicos beta/imunologia , Animais , Distribuição de Qui-Quadrado , AMP Cíclico/biossíntese , Feminino , Coração/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Bloqueio Cardíaco/imunologia , Humanos , Imunoglobulina G/fisiologia , Técnicas In Vitro , Recém-Nascido , Mães , Contração Miocárdica/efeitos dos fármacos , Propranolol/farmacologia , RatosRESUMO
En este trabajo se empleó un modelo experimental "in vitro" en el cual se midió la frecuencia de las contracciones, la producción de AMPc y la la unión de ligandos específicos al receptor ß adrenérgicos en las aurículas de ratas neonatales y adultas; a fin de, determinar si anticuerpos con actividad ß adrenérgica interactuaban con receptores ß adrenérgicos cardíacos y alteraban su compartimiento fisiológico. Los sueros y la fracción IgG de madres de infantes con bloqueo cardíaco neonatal congénito incrementaron la frecuencia de las contracciones y la producciín de AMPc en el miocardio auricular neonato. Este efecto fue inhibido por propranolol, puntalizando una participación ß adrenérgica. La IgG también compitió con el radiologando específico por los receptores ß adrenérgicos (3H-CGP) en las membranas purificadas de miocardio neonatal. Ni los efectos biológicos ni los ensayos de unión específica fueron modificados cuando se usó miocardio de rata adulta. La reactividad contra adrenoreceptores cardíacos por parte de anticuerpos provenientes de madres de niños con bloqueo neonatal congénito, podría ser otro factor sérico que debería considerarse en la patofisiología del desarrollo del bloqueo neonatal congénito
Assuntos
Humanos , Animais , Feminino , Recém-Nascido , Ratos , Autoanticorpos/fisiologia , Bloqueio Cardíaco/congênito , Receptores Adrenérgicos beta/imunologia , AMP Cíclico/biossíntese , Bloqueio Cardíaco/imunologia , Distribuição de Qui-Quadrado , Cromatografia DEAE-Celulose , Contração Miocárdica , Átrios do Coração/fisiopatologia , Imunoglobulina G/fisiologia , Mães , Propranolol/farmacologiaRESUMO
En este trabajo se empleó un modelo experimental "in vitro" en el cual se midió la frecuencia de las contracciones, la producción de AMPc y la la unión de ligandos específicos al receptor ß adrenérgicos en las aurículas de ratas neonatales y adultas; a fin de, determinar si anticuerpos con actividad ß adrenérgica interactuaban con receptores ß adrenérgicos cardíacos y alteraban su compartimiento fisiológico. Los sueros y la fracción IgG de madres de infantes con bloqueo cardíaco neonatal congénito incrementaron la frecuencia de las contracciones y la producciín de AMPc en el miocardio auricular neonato. Este efecto fue inhibido por propranolol, puntalizando una participación ß adrenérgica. La IgG también compitió con el radiologando específico por los receptores ß adrenérgicos (3H-CGP) en las membranas purificadas de miocardio neonatal. Ni los efectos biológicos ni los ensayos de unión específica fueron modificados cuando se usó miocardio de rata adulta. La reactividad contra adrenoreceptores cardíacos por parte de anticuerpos provenientes de madres de niños con bloqueo neonatal congénito, podría ser otro factor sérico que debería considerarse en la patofisiología del desarrollo del bloqueo neonatal congénito (AU)
Assuntos
Humanos , Animais , Feminino , Estudo Comparativo , Recém-Nascido , Ratos , Receptores Adrenérgicos beta/imunologia , Autoanticorpos/fisiologia , Bloqueio Cardíaco/congênito , Bloqueio Cardíaco/imunologia , AMP Cíclico/biossíntese , Propranolol/farmacologia , Imunoglobulina G/fisiologia , Contração Miocárdica/efeitos dos fármacos , Átrios do Coração/fisiopatologia , Cromatografia DEAE-Celulose , Mães , Distribuição de Qui-QuadradoRESUMO
To determine whether antibodies against beta adrenergic activity interact with neonatal cardiac cell receptors and alter their physiological behaviour. An [quot ]in vitro[quot ] experimental model measuring the frequency of contraction, the production of cAMP and binding assay on neonatal and adult rat atria was employed. Sera and IgG fraction from mothers of infants with congenital heart block (CHB) interact with neonatal rat atria increasing the frequency of contraction and cAMP production. These effects were abolished by propranolol, pointing to a beta adrenergic participation. IgG also competed with 3H-CGP to beta adrenergic receptors on neonatal cardiac membranes. Neither the contractile nor the cAMP effects or binding assay were obtained using adult instead of neonatal rat atria. Reactivity against cardiac neurotransmitter receptors may be another serum factor(s) to be considered in the pathophysiology of the development of CHB.