The neuropeptide Y (NPY) Y1 receptor antagonist BIBP 3226: effects on vascular responses to exogenous and endogenous NPY in the pig in vivo

Authors


1Division of Pharmacology, Department of Physiology and Pharmacology, Karolinska Institute, S-17177 Stockholm, Sweden.

Abstract

  • The antagonistic effects of the neuropeptide Y (NPY) Y1 receptor antagonist BIBP 3226 on equally prominent vascular responses evoked by sympathetic nerve stimulation and exogenous NPY were compared during different intravenous (i.v.) infusions of the antagonist (0.19–190 nmol kg−1 min−1, for 30 min).

  • High frequency sympathetic nerve stimulation in reserpine-treated pigs in vivo evoked non-adrenergic vasoconstrictor responses in kidney and hind limb, in the latter followed by a long-lasting phase of decreased blood flow. The vascular response in the kidney and the long-lasting phase in hind limb resembled the effects of exogenous NPY administered i.v. (kidney) and intraarterially (i.a.) (in the hind limb, which only responded to higher NPY doses).

  • Plasma levels of BIBP 3226 reached a plateau within 20 min and the inhibitory effects on vascular responses were studied during the last ten minutes of infusion. The elimination of BIBP 3226 from plasma was found to fit a two-compartment model with an α-phase of 2.0±0.2 min and a β-phase of 20.1±0.9 min.

  • Significant inhibition of presumably Y1 receptor-mediated vascular responses evoked by both endogenous and exogenous NPY in kidney and hind limb was seen even during low-dose infusion of BIBP 3226 (1.9 nmol kg−1 min−1), when plasma levels of the antagonist reached 59±8 nM. The maximum inhibitory effects of BIBP 3226 were seen during the highest-dose infusion (190 nmol kg−1 min−1), when the long-lasting vasoconstrictor responses in hind limb to sympathetic nerve stimulation and exogenous NPY administration (i.a.) were abolished. Simultaneously, the vascular responses in kidney to exogenous NPY were inhibited by 89% and to sympathetic nerve stimulation by 60%.

  • It is concluded that BIBP 3226 has a short half-life in plasma and should preferably be given by i.v. infusions to maintain blockade and avoid non-specific effects. Furthermore, BIBP 3226 dose-dependently and with similar potency antagonizes vascular responses to exogenous and endogenous NPY both in the kidney and hind limb of the reserpine-treated pig in vivo. Thus, inhibition of vascular responses to exogenous NPY may be a good indicator of the dose of this antagonist needed to inhibit sympathetic Y1 receptor-transmission.

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