Regulation of cardiac beta-adrenergic response by nitric oxide.

1. Introduction induced calcium release from the sarcoplasmic reticulum, whereas the sustained inotropic effect during the sub-The force and frequency of myocardial contraction are sequent beats results from both increased influx and physiologically regulated by neurotransmitters and hor-increased mobilization of internal calcium resulting from mones. Norepinephrine released by the sympathetic nerves an increased replenishing of the reservoir of calcium in the in the heart and epinephrine released into the circulation by sarcoplasmic reticulum [2,3]. adrenal glands increase myocardial contractility by acting A hallmark of the b-adrenergic effect on the heart is to on both a-and b-adrenergic receptors on heart muscle. increase the rate of relaxation which has been related to Opposed to that is the action of acetylcholine released more rapid termination of calcium influx, increased rate of from parasympathetic nerves which reduces contractility calcium uptake and sequestration into the sarcoplasmic by binding to muscarinic cholinergic receptors. The first reticulum following phospholamban phosphorylation [4,5], demonstration that these two autonomic pathways are increased expulsion of intracellular calcium via sodium / regulated by nitric oxide (NO) produced endogenously calcium exchange [6], and dissociation of calcium from within cardiac muscle cells [1] both completes the troponin after the contraction [7,8]. understanding of the molecular mechanism of action of neurotransmitters in the heart and offers potential new 1.1.1. b-Adrenergic receptors therapeutic approaches for the correction of the altered Even though binding studies with selective ligands have responsiveness of cardiac muscle to autonomic regulation revealed two subtypes of b-adrenergic receptors in the in circumstances such as heart failure. heart (b-1 and b-2), the b-1 subtype usually predominates We will briefly review the molecular pathways leading in the mammalian heart. In the rat heart, the percentage of to the intracellular actions of b-adrenergic and muscarinic b-1 subtype is 85%. The ratio of b-1 and b-2 differs in cholinergic agonists in the cardiac myocyte, integrating the different regions of the human heart, where the percentage more recent evidence implicating the NO pathway from of b-1 is higher in ventricle than in atrium [9]. Recently, the single myocyte to clinical situations. evidence was provided for the expression of b3 adreno-receptors (at the mRNA level) in biopsy specimens from 1.1. b-Adrenergic pathway human ventricles. Functionally, activation of this receptor with specific agonists (in the presence of b1 and b2 b-Adrenergic agonists are well known to increase the blockade) produced a unique negatively inotropic effect on force and frequency of …