NEUROPEPTIDE-Y AND REGULATION OF THE CARDIOVASCULAR-SYSTEM

Control of cardiovascular system: Neuropeptide Y has three major activ ities which are important in the modulation of blood pressure homeosta sis. When released from sympathetic neurons innervating the cardiovasc ular system, this peptide causes direct long-lasting vasoconstriction, inhibits the release of noradrenaline and other neurotransmitters and potentiates the action of noradrenaline and other presser agents. Rec eptor 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 (Y-1) has been isol ated by molecular cloning. Analysis of the cloned DNA sequence has con firmed that the receptor is a member of the G protein-coupled receptor superfamily and when expressed in various cell lines can couple to bo th the inhibition of adenylate cyclase and the elevation of intracellu lar calcium. Neuropeptide Y antagonists: A specific neuropeptide Y ant agonist has been developed which significantly lowers the dose-depende nt neuropeptide Y-induced presser response in normal rats. The inhibit ion is specific for the peptide and also selective for the postsynapti c Y-1 receptor-mediated vasoconstrictor activity. Administration of th is specific and selective inhibitor significantly reduces resting arte rial blood pressure, which remains depressed for up to 4h in normal an d spontaneously hypertensive rats. Conclusions: Inhibition of endogeno us neuropeptide Y activity demonstrates that this peptide makes a sign ificant contribution to the control of blood pressure and indicates th e therapeutic potential of neuropeptide Y inhibitors as a new class of antihypertensive agent. The molecular cloning of the neuropeptide Y r eceptor subtype responsible for both the direct vasoconstrictor activi ty of the peptide and the potentiation of the action of other presser agents represents an important advance in our understanding of the mol ecular basis of neuropeptide Y action and will help in the development of selective neuropeptide Y antagonists.