Role of Nitric Oxide in Cardiac β-Adrenoceptor–Inotropic Response

Sterin‐Borda, Leonor; Genaro, Ana Marı́a; Leirós, Claudia Pérez; Cremaschi, Graciela; Echagüe, Agustina Vila; Borda, Enri

doi:10.1016/s0898-6568(97)00125-3

Cited by 27 publications

(24 citation statements)

References 19 publications

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“…For example, acetylcholine-mediated inhibition of the ␤-adrenergic-stimulated L-type calcium current in the heart has been shown to involve NO synthesis (41). Also, inhibition of NOS by L-NMMA in rat heart has been shown to potentiate the positive inotropic response to isoproterenol suggesting that NO can dampen the ␤-adrenergic stimulation of the contractile response (7). Similarly, interleukin 1 and LPS, which are present during septic shock, can inhibit ␤-adrenergic-stimulated cardiac contraction through a NO-dependent mechanism (42,43).…”

Section: Discussionmentioning

confidence: 99%

“…Both the calcium-dependent endothelial NOS and the calciumindependent inducible NOS (iNOS or NOS2) have been shown to play an important role in the control of vascular tone in normal and inflammatory conditions (4 -8), respectively. NO can modulate the action of various vasoactive hormones and transmitters (7). In particular, NO-mediated decreases in ␤-adrenergic responsiveness have been described (6,9).…”

Section: Nitric Oxide (No)mentioning

confidence: 99%

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Nitric Oxide Modulates β2-Adrenergic Receptor Palmitoylation and Signaling

Adam¹,

Bouvier²,

Jones³

1999

Journal of Biological Chemistry

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To determine whether nitric oxide (NO) modulates the ␤-adrenergic signaling pathway, we treated cells expressing ␤ 2 -adrenergic receptors (␤ 2 AR) with the NO donors, 3-morpholinosydnonimine (SIN-1) and 1,2,3,4-oxatriazolium,5-amino-3-(3-chloro-2-methylphenyl)-chloride and determined the intracellular production of cAMP after exposure to ␤-adrenergic receptor agonists, cholera toxin and forskolin. NO significantly decreased the potency of the ␤-adrenergic agonist, isoproterenol, to stimulate cAMP production without affecting the stimulatory action of forskolin and cholera toxin, which directly activate adenylyl cyclase and G s , respectively. Treatment with the NO donor increased the guanyl nucleotide-sensitive high affinity constant for the agonist, isoproterenol, thus suggesting that it reduced functional coupling between the receptor and G s . Stimulation of endogenous NO production by lipopolysaccharide in RAW 264.7 macrophages also caused a significant increase in the EC 50 for isoproterenol-stimulated cAMP production. SIN-1 treatment also led to a reduction in both basal and isoproterenol-stimulated incorporation of [ 3 H]palmitate into the ␤ 2 AR. Signaling through the nonpalmitoylated, Gly 341 ␤ 2 AR mutant was unchanged by SIN-1 treatment. Given the link between ␤ 2 AR palmitoylation and its responsiveness to agonist, these results suggest that the primary action of NO was depalmitoylation of the ␤ 2 AR resulting in decreased signaling through the ␤ 2 AR. Nitric oxide (NO)1 is a biologic signal involved in vasodilatation, neurotransmission, and immune defense (1, 2). It is an unstable gas that diffuses across membranes, lacks specific receptors, and is rapidly inactivated by a chemical reaction. Its synthesis by the enzyme NO synthase (NOS) from arginine and oxygen is finely regulated and can be achieved through both calcium-dependent and calcium-independent pathways (3). Both the calcium-dependent endothelial NOS and the calciumindependent inducible NOS (iNOS or NOS2) have been shown to play an important role in the control of vascular tone in normal and inflammatory conditions (4 -8), respectively. NO can modulate the action of various vasoactive hormones and transmitters (7). In particular, NO-mediated decreases in ␤-adrenergic responsiveness have been described (6, 9). However, the biochemical processes underlying this effect remain largely unexplored.At the cellular level, the best characterized effect of NO is the activation of guanylate cyclase by the formation of a heme-NO complex that enhances the catalytic activity of the enzyme and increases cGMP production (10). Although several of the effects of NO have been attributed to cGMP formation, NO also leads to nitrosylation of thiol groups on cysteine residues (3, 11) that may contribute to the diverse physiological actions of this gaseous second messenger. Indeed, nitrosylation has been suggested to modulate protein function as a consequence of conformational changes (3, 11), facilitation of ADP-ribosylation (12), and inhibition of protein palm...

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Section: Discussionmentioning

confidence: 99%

Section: Nitric Oxide (No)mentioning

confidence: 99%

Nitric Oxide Modulates β2-Adrenergic Receptor Palmitoylation and Signaling

Adam¹,

Bouvier²,

Jones³

1999

Journal of Biological Chemistry

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“…Balligand et al [14] suggested that an NOmediated mechanism was responsible for limiting the positive inotropic response to bAR agonists in rat ventricular myocytes. Further work by Sterin-Borda et al [110] described how the isoproterenol-mediated positive inotropic response in isolated rat atria is accompanied by a calcium-dependent stimulation of NOS and increased cGMP levels. Inhibition of NOS and sGC enhanced the isoproterenol response, supporting the hypothesis of a parallel negative inotropic regulatory pathway induced by bAR stimulation.…”

Section: Bars No and The Heartmentioning

confidence: 99%

β-Adrenergic receptors and nitric oxide generation in the cardiovascular system

Queen

Ferro

2006

Cell. Mol. Life Sci.

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Nitric oxide plays a crucial role in cardiovascular homeostasis, with important vasodilatory, anti-thrombotic and anti-atherogenic properties. Beta-adrenergic receptors (betaARs), present on a wide variety of cardiovascular cells, including vascular endothelial cells, platelets, cardiac myocytes and leukocytes, have long been established as key players in maintaining cardiovascular homeostatic control. During the last few years a wealth of evidence has emerged which directly links stimulation of these cardiovascular betaARs to nitric oxide (NO) generation, suggesting a new and important mechanism of adrenergic control of cardiovascular function. This review explores the cardiovascular cell systems in which this coupling of betaARs and NO occurs, the intracellular signalling and regulatory mechanisms involved and the abnormalities in betaAR-NO oxide coupling found in cardiovascular disease states.

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“…1 demonstrated an ability of the chagasic antibodies to directly interact with the m2 mAChR. In addition, whereas previous studies have suggested effects of chagasic serum on adrenergic signaling (15)(16)(17)(18)(19), the CHO cells used in this study lack adrenergic receptors, making it unlikely that the observed desensitizing effects of the chagasic antibodies on the mAChR were due to cross-talk arising from effects on signaling pathways downstream of the receptors.…”

Section: Molecular Interaction Of Chagasic Antibodies With Purifiedmentioning

confidence: 70%

“…The paradoxical severe involvement of the heart in the absence of any form of the parasite there has prompted proposals that autoimmune mechanisms participate in the pathogenesis of this cardiac neuromyopathy (12)(13)(14). Chagasic patients have been found to possess circulating antibodies that are able to interact with and modulate the activity of cardiac ␤-adrenergic and mAChRs (15)(16)(17)(18)(19). This report focuses on the molecular events initiated by the interaction of the chagasic antibodies with the mAChRs to begin to understand how the antibodies could ultimately account for the abnormalities of cardiac autonomic function characteristic of the late stages of Chagas' disease.…”

mentioning

confidence: 99%

Desensitization and Sequestration of Human m2 Muscarinic Acetylcholine Receptors by Autoantibodies from Patients with Chagas' Disease

Leirós

Sterin‐Borda

Borda

et al. 1997

Journal of Biological Chemistry

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Chronic Chagas' disease is associated with pathologic changes of the cardiovascular, digestive, and autonomic nervous system, culminating in autonomic denervation and congestive heart failure. Previously, circulating autoantibodies that activate signaling by cardiac muscarinic acetylcholine receptors (mAChRs) have been described. However, it remains unclear whether the chagasic IgGs directly interact with the m2 mAChRs (predominant cardiac subtype), and, if so, whether chronic exposure of the mAChRs to such activating IgGs would result in receptor desensitization. Here we performed studies with purified and reconstituted hm2 mAChRs and demonstrate that IgGs from chagasic serum immunoprecipitated the mAChRs in a manner similar to an anti-m2 mAChR monoclonal antibody tested in parallel. The chagasic antibodies did not directly interact with the ligand binding site, because the binding of radiolabeled antagonist was unchanged by the addition of the chagasic IgG. In intact cells stably expressing the hm2 mAChR, the chagasic IgGs, but not normal IgGs, mimicked the ability of the agonist acetylcholine to induce two effects associated with agonist-induced receptor desensitization: a decrease in affinity for agonist binding to m2 mAChR and sequestration of the hm2 mAChRs from the cell surface. The results demonstrate that the chagasic IgGs can directly interact with and desensitize m2 mAChRs and provide support for the hypothesis of autoimmune mechanisms having a role in the pathogenesis of Chagas' cardioneuromyopathy.

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Role of Nitric Oxide in Cardiac β-Adrenoceptor–Inotropic Response

Cited by 27 publications

References 19 publications

Nitric Oxide Modulates β2-Adrenergic Receptor Palmitoylation and Signaling

Nitric Oxide Modulates β2-Adrenergic Receptor Palmitoylation and Signaling

β-Adrenergic receptors and nitric oxide generation in the cardiovascular system

Desensitization and Sequestration of Human m2 Muscarinic Acetylcholine Receptors by Autoantibodies from Patients with Chagas' Disease

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