HEMODYNAMIC CHARACTERIZATION OF A NOVEL NEUROPEPTIDE-Y RECEPTOR ANTAGONIST

Defining the roles of the vasoconstrictor peptide neuropeptide Y (NPY) in the cardiovascular system is difficult due to lack of availability of specific NPY receptor antagonists. We report the ill vivo NPY rece ptor blocking actions of a novel nonapeptide dimer, 1229U91 {(IleGluPr oDprTyrArgLeuArgTyr-NH2)(2)}, and describe its hemodynamic effects. Ln anesthetized normotensive rats, 1229U91 produced significant and dose -dependent reductions in NPY-reduced hemodynamic responses. 1229U91 (3 -30 nmol/kg intravenously, i.v.) attenuated the presser response (34 /- 6-84 +/- 1%) and the increases in renal vascular resistance (RVR, 5 6 +/- 9-94 +/- 2%) produced by NPY (1 nmol/kg i.v.). Intravenous norep inephrine (NE)-induced hemodynamic responses were not altered by 1229U 91. 1229U91 also produced dose-dependent inhibition of NPY-induced vas oconstrictor responses in anesthetized dogs and spontaneously hyperten sive rats (SHR). These data demonstrate that 1229U91 is a selective NP Y receptor antagonist. 1229U91 had no effect on resting hemodynamic va riables in these preparations. In conscious SHR, 1229U91 did not produ ce significant changes in blood pressure (BP) or heart rate (HR) over a wide dose-range (15-1,500 nmol/kg i.v.). Lack of effect of the NPY r eceptor antagonist in SHR suggests that NPY does not contribute to the maintenance of BP in this hppertension model.