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 in vivo NPY receptor blocking actions of a novel nonapeptide dimer, 1229U91 {(IleGluProDprTyrArgLeuArgTyrNH(2)(2)}, and describe its hemodynamic effects. In 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 pressor response (34 +/- 6-84 +/- 1%) and the increases in renal vascular resistance (RVR, 56 +/- 9-94 +/- 2%) produced by NPY (1 nmol/kg i.v.). Intravenous norepinephrine (NE)-induced hemodynamic responses were not altered by 1229U91. 1229U91 also produced dose-dependent inhibition of NPYinduced vasoconstrictor responses in anesthetized dogs and spontaneously hypertensive rats (SHR). These data demonstrate that 1229U91 is a selective NPY receptor antagonist. 1229U91 had no effect on resting hemodynamic variables in these preparations. In conscious SHR, 1229U91 did not produce 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 receptor antagonist in SHR suggests that NPY does not contribute to the maintenance of BP in this hypertension model.
Tadepalli
A S
AS
Department of Pharmacology, Glaxo Wellcome, Research Triangle Park, North Carolina, USA.
Harrington
W W
WW
Hashim
M A
MA
Matthews
J
J
Leban
J J
JJ
Spaltenstein
A
A
Daniels
A J
AJ
D000758:Anesthesia; D000818:Animals; D003538:Cystamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000503:physiopathology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*
C097287:1229U91; D010456:Peptides, Cyclic; D017476:Receptors, Neuropeptide Y; C029998:benextramine; D003538:Cystamine