Neuropeptide Y accounts for sympathetic vasoconstriction in guinea-pig vena cava: evidence using BIBP 3226 and 3435.
The ability of the novel, non-peptide, neuropeptide Y Y1 receptor antagonist, BIBP 3226 ((R)-N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-argininami de), to antagonize neuropeptide Y- and sympathetic-mediated vasoconstriction was examined in isolated segments of the thoracic vena cava of guinea-pigs. Increasing concentrations (10(-9) - 10(-6) M) of BIBP 3226 caused a parallel and rightward shift in the neuropeptide Y dose-response curve but did not significantly change the effect of noradrenaline. The calculated pA2 value for BIBP 3226 was 8.0 +/- 0.08, a value fully compatible with the reported affinity at rodent and human neuronal Y1 receptors. BIBP 3226 (10(-6) M) also readily reversed the established vasocontraction induced by neuropeptide Y. BIBP 3226 (10(-6) M) markedly inhibited the slow long-lasting contraction evoked by high frequency electrical field stimulation, leaving a rapid component which was abolished by phentolamine. Its enantiomer, BIBP 3435 ((S)-N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-argininami de), which exerts a much weaker action on neuropeptide Y Y1 receptors, had no such inhibitory effect. In propranolol-pretreated vessels, the vasoconstriction evoked by nerve stimulation was enhanced; then BIBP 3226 inhibited the peak response by 44%, and the integrated contractile effect by 90%. We conclude that BIBP 3226 is a potent and competitive antagonist of neuropeptide Y Y1 receptor-mediated vasoconstriction in guinea-pig vena cava and that endogenous neuropeptide Y acting on the neuropeptide Y Y1 receptor is likely to account for the long-lasting component of the sympathetic vasoconstriction in response to high-frequency stimulation in this vessel.
Malmstrom
R E
RE
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Lundberg
J M
JM
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009478:Neuropeptide Y / Q000494:pharmacology*; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013564:Sympathetic Nervous System / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects*; D014684:Venae Cavae / Q000187:drug effects / Q000502:physiology
C092926:BIBP 3226; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; D001120:Arginine