Neuropeptide y: neurotransmitter or trophic factor in the heart?

he influence of the sympathetic nervous system on both normal physiology and pathophysiology of the heart extends beyond the beat-to-beat regulation of rate and con-tractile force arising from acute exposure to neurally released norepinephrine (NE). For example, postinfarction arrhythmias have been ascribed to nerve sprouting and excess sympathetic innervation (7). In addition, congenital arrhythmias in a Ger-man shepherd model of sudden death are associated with an abnormal distribution and density of sympathetic innervation as well as excess responsiveness to E 1-adrenergic stimulation (11). These results suggest a long-term influence of innervation to modify the autonomic sensitivity of the heart and/or the ionic channels that are the target of those autonomic agonists. Here we define long-term, or trophic, actions as those appearing only after hours or days of exposure, as opposed to typical neurotransmitter-like (short-term or acute) actions that occur over a period of seconds or minutes. Sympathetic innervation and neuropeptide Y Abundant data support the general concept that innervation influences phenotypic expression of target tissue. Examples include denervation supersensitivity of blood vessels, correlation of cardiac autonomic sensitivity with the time course of innervation, and induction by motor neuron innervation of a Na + channel isoform switch in skeletal muscle. Although there are multiple trophic factor(s) and signaling cascades through which innervation acts, in at least some cases neurally released peptides such as neuropeptide Y (NPY) are involved. Several studies have identified a trophic role for NPY in the nervous (6) and vascular (20) systems and in cardiac hypertro-phy (2, 9). In addition, we and others (16) have provided evidence that a number of developmental changes in cardiac ion channel function and autonomic signaling are dependent on the proper progression of sympathetic innervation. Our results indicate that neurally released NPY serves as the trophic factor in some of these cases. NPY is a 36-amino acid peptide that acts through a family of G protein-coupled receptors and has been associated with numerous physiological processes, including feeding, memory , circadian rhythms, and regulation of blood pressure. NPY is present in, and released from, peripheral sympathetic nerve terminals. Five NPY receptors have been cloned (Y 1 , Y 2 , Y 4 , Y 5 , Y 6) and at least one other (Y 3) has been suggested on the basis of pharmacological evidence. Data indicate the presence of multiple NPY receptors in the heart, including Y 1 , Y 2 , Y 3 …