© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Regulation of cardiac β-adrenergic response by nitric oxide
Unit of Pharmacology and Therapeutics, Department of Medicine, University of Louvain Medical School, 53, Avenue E. Mounier, B-1200 Brussels, Belgium
* Corresponding author. Tel.: +32-2-764-5349; fax: +32-2-764-9322 balligand@mint.ucl.ac.be
Received 19 March 1999; accepted 19 April 1999
KEYWORDS Nitric oxide; Adrenergic agonists; Acetylcholine; Heart failure; Contractile function; Experimental studies; Heart; Regulatory mechanisms; Pharmacology; Pathophysiology
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1 Introduction |
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The force and frequency of myocardial contraction are physiologically regulated by neurotransmitters and hormones. Norepinephrine released by the sympathetic nerves in the heart and epinephrine released into the circulation by adrenal glands increase myocardial contractility by acting on both
- and β-adrenergic receptors on heart muscle. Opposed to that is the action of acetylcholine released from parasympathetic nerves which reduces contractility by binding to muscarinic cholinergic receptors. The first demonstration that these two autonomic pathways are regulated by nitric oxide (NO) produced endogenously within cardiac muscle cells [1] both completes the understanding of the molecular mechanism of action of neurotransmitters in the heart and offers potential new therapeutic approaches for the correction of the altered responsiveness of cardiac muscle to autonomic regulation in circumstances such as heart failure.
We will briefly review the molecular pathways leading to the intracellular actions of β-adrenergic and muscarinic cholinergic agonists in the cardiac myocyte,
1.1 β-Adrenergic pathway
1.1.1 β-Adrenergic receptors
1.1.2 Cyclic AMP intracellular pathway
1.1.3 Cyclic AMP phosphodiesterases
1.2 Muscarinic cholinergic pathway
1.2.1 Intracellular effectors for the action of acetylcholine in the heart
1.2.1.1 IK-Ach
1.2.1.2 Inhibition of adenylyl cyclase
1.2.1.3 NO and cyclic GMP
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2 NOS isoforms in heart muscle |
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2.1 nNOS
2.2 eNOS
2.3 iNOS
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3 Regulation of the adrenergic pathway by nNOS |
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4 Modulation of the β-adrenergic response by eNOS |
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4.1 eNOS as a negative feedback for the β-adrenergic inotropic effect
4.2 eNOS and arrhythmia
4.3 Lusitropic effect of eNOS
4.4 Effects of exogenous NO donors on β-adrenergic response
4.5 Mediation by eNOS of the ‘accentuated antagonism’
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5 Modulation of the β-adrenergic response by iNOS |
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5.1 iNOS and the β-adrenergic inotropic effect
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6 Intracellular mechanisms of action of NO in cardiac muscle cells |
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6.1 Cyclic GMP-dependent mechanisms
6.1.1 Enhancement of β-adrenergic response
6.1.2 Decrease in β-adrenergic response
6.2 Cyclic GMP-independent mechanisms
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7 NO-dependent attenuation of β-adrenergic pathway in heart failure |
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