Publications

Abstract

CONTROL OF CARDIOVASCULAR SYSTEM: Neuropeptide Y has three major activities which are important in the modulation of blood pressure homeostasis. When released from sympathetic neurons innervating the cardiovascular system, this peptide causes direct long-lasting vasoconstriction, inhibits the release of noradrenaline and other neurotransmitters and potentiates the action of noradrenaline and other pressor agents. RECEPTOR SUBTYPE DIVERSITY: At least two major subtypes of neuropeptide Y receptor have been defined by pharmacological criteria, and the major subtype involved in the control of blood pressure (Y1) has been isolated by molecular cloning. Analysis of the cloned DNA sequence has confirmed that the receptor is a member of the G protein-coupled receptor superfamily and when expressed in various cell lines can couple to both the inhibition of adenylate cyclase and the elevation of intracellular calcium. NEUROPEPTIDE Y ANTAGONISTS: A specific neuropeptide Y antagonist has been developed which significantly lowers the dose-dependent neuropeptide Y-induced pressor response in normal rats. The inhibition is specific for the peptide and also selective for the postsynaptic Y1 receptor-mediated vasoconstrictor activity. Administration of this specific and selective inhibitor significantly reduces resting arterial blood pressure, which remains depressed for up to 4 h in normal and spontaneously hypertensive rats. CONCLUSIONS: Inhibition of endogenous neuropeptide Y activity demonstrates that this peptide makes a significant contribution to the control of blood pressure and indicates the therapeutic potential of neuropeptide Y inhibitors as a new class of antihypertensive agent. The molecular cloning of the neuropeptide Y receptor subtype responsible for both the direct vasoconstrictor activity of the peptide and the potentiation of the action of other pressor agents represents an important advance in our understanding of the molecular basis of neuropeptide Y action and will help in the development of selective neuropeptide Y antagonists.