SR 120107A ANTAGONIZES NEUROPEPTIDE-Y Y-1 RECEPTOR-MEDIATED SYMPATHETIC VASOCONSTRICTION IN PIGS IN-VIVO

The effects of the neuropeptide Y Y-1 receptor antagonist SR 120107A n aphtylsulfamoyl)-3-phenylpropionamido]3-[4-[N-[4- laminomethyl)-cis-cy clohexylmethyl]amidino]phenyl] propionyl]pyrrolidine, (S,R) stereoisom er) on sympathetic non-adrenergic vasoconstriction in a variety of vas cular beds were studied in reserpinized anesthetized pigs in vivo. The rapid vasoconstrictor response evoked by single impulse stimulation, in hind limb and nasal mucosa, was not affected by SR 120107A (1.5 mg kg(-1) i.v.). Ln contrast, SR 120107A potently inhibited the long-last ing phase of vasoconstriction evoked by high frequency (60 impulses at 20 Hz) sympathetic nerve stimulation, in the main and deep femoral, t he saphenous and the internal maxillary arteries, leaving merely the i nitial rapid peak of vasoconstriction in these vessels. Furthermore, t he vasoconstrictor response was nearly abolished in the kidney and was attenuated in the spleen and main femoral artery, despite maintained neuropeptide Y overflow. The vasoconstrictor response evoked in the ki dney by peptide YY, a neuropeptide Y Y-1 and Y-2 receptor agonist, was also nearly abolished in the presence of SR 120107A. This inhibitory effect on the response to exogenous agonist correlated well with the l ong-lasting inhibition of the response to nerve stimulation in the sam e tissue. The peptide YY-evoked vasoconstriction in the spleen was not altered by SR 120107A, in accordance with the view that the neuropept ide Y receptor population in this organ consists mainly of neuropeptid e Y Y? receptors. SR 120107A did not influence the vasoconstrictor eff ects of alpha,beta-methylene ATP (mATP) or phenylephrine in any of the tissues studied. We conclude that SR 120107A is a potent neuropeptide Y Y-1 receptor antagonist with long duration of action in vivo. Endog enous neuropeptide Y acting on the neuropeptide Y Y-1 receptor is like ly to account for the long-lasting component of the reserpine-resistan t sympathetic vasoconstriction upon high frequency stimulation in hind limb and nasal mucosa. Furthermore, the peak vasoconstriction in kidn ey, and to some extent in spleen, is also neuropeptide Y Y-1 receptor mediated.