Regulation of cardiac beta-adrenergic response by nitric oxide.

Abstract

Time for primary review 12 days. 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 α- 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, integrating the more recent evidence implicating the NO pathway from the single myocyte to clinical situations. ### 1.1 β-Adrenergic pathway β-Adrenergic agonists are well known to increase the force and frequency of contraction and increase the rate of relaxation of cardiac muscle. Despite some differences between regions of the heart, in general, the early increase in force of contraction is related directly to an increase in transmembrane flux of calcium, through phosphorylation of the L-type Ca channel, and the subsequent calcium-induced calcium release from the sarcoplasmic reticulum, whereas the sustained inotropic effect during the subsequent beats results from both increased influx and increased mobilization of internal calcium resulting from an increased replenishing of the reservoir of calcium in the sarcoplasmic reticulum [2,3]. A hallmark of the β-adrenergic effect on the heart is to increase the rate of relaxation which has been related to more rapid termination of … * Corresponding author. Tel.: +32-2-764-5349; fax: +32-2-764-9322 balligand{at}mint.ucl.ac.be