title: In vivo characterization of the novel neuropeptide Y Y1 receptor antagonist H 409/22.
abstract: We studied the effects of the novel neuropeptide Y (NPY) Y1 receptor antagonist H 409/22, and its inactive enantiomer H 510/45, on vascular responses evoked by endogenous and exogenous NPY in the pig in vivo. H 409/22 and H 510/45 were given as 30-min infusions, and the antagonistic effects and circulating plasma concentrations were measured. The initial and terminal half-lives of H 409/22 in plasma were approximately 3 and 30 min, respectively. In pigs pretreated with reserpine and transection of sympathetic nerves (depletion of noradrenaline), sympathetic nerve stimulation evoked nonadrenergic vasoconstrictor responses in kidney and hindlimb, mediated by neuronally released NPY. Significant inhibition of these vasoconstrictor responses, as well as of vascular responses to injections of exogenous NPY, were seen during a low-dose infusion of H 409/22 (1.8 nmol/kg/min), when plasma levels of the antagonist reached 77 +/- 8 nM. Greatest inhibitory effects were seen at the highest dose of H 409/22 (180 nmol/kg/min, giving plasma levels of 7.4 +/- 0.6 microM) when all vascular responses evoked by NPY were strongly attenuated or largely abolished. H 510/45 did not affect any of the vascular responses studied. It is concluded that H 409/22 potently and dose-dependently antagonizes vascular responses to exogenous and endogenous NPY in the pig, and thus represents an interesting tool for studies on NPY Y1 receptor-mediated effects in vivo.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden. rickard.malmstrom@fyfa.ki.se
authors.forename: R E
authors.initials: RE
authors.lastname: Malmström
authors.forename: A
authors.initials: A
authors.lastname: Alexandersson
authors.forename: K C
authors.initials: KC
authors.lastname: Balmér
authors.forename: J
authors.initials: J
authors.lastname: Weilitz
mesh_terms: D000577:Amides / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006614:Hindlimb / Q000098:blood supply; D066298:In Vitro Techniques; D008297:Male; D009478:Neuropeptide Y / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D012039:Regional Blood Flow / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D012110:Reserpine / Q000494:pharmacology; D013237:Stereoisomerism; D013552:Swine; D013564:Sympathetic Nervous System / Q000187:drug effects; D013565:Sympatholytics / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000577:Amides; C420032:H 409-22; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; D013565:Sympatholytics; C097212:neuropeptide Y-Y1 receptor; D012110:Reserpine