Effects of the neuropeptide Y Y2 receptor antagonist BIIE0246 on sympathetic transmitter release in the pig in vivo.

Abstract

This study investigated the effects of BIIE0246, a novel neuropeptide Y (NPY) Y(2) receptor antagonist, on renal sympathetic nerve-evoked release of noradrenaline and NPY-like immunoreactivity (-LI) in the pig in vivo. Stimulation (5 Hz, 60 s) of renal sympathetic nerves evoked vasoconstriction and overflow of noradrenaline and NPY-LI. Infusion of peptide YY (PYY; 1 microg/kg per min) strongly inhibited the stimulation-evoked overflow of noradrenaline and NPY-LI. BIIE0246 (100 nmol/kg) abolished the inhibitory effect of PYY. BIIE0246 did not however affect the stimulation-evoked overflow of noradrenaline and NPY-LI, or basal cardiovascular parameters, per se. The alpha(2)-adrenoceptor antagonist yohimbine (0.2 mg/kg) significantly elevated both basal plasma levels and the nerve stimulation-evoked overflow of noradrenaline and NPY-LI. Subsequent administration of BIIE0246 did not further alter these effects. However, BIIE0246 caused splenic vasodilatation per se when given after yohimbine. It is concluded that the renal sympathetic nerves in the pig possess NPY Y(2) receptors, which upon activation inhibit transmitter (noradrenaline and NPY) release. Furthermore, when circulating levels of NPY were enhanced after blockade of alpha(2)-adrenoceptors, an involvement of endogenous NPY, acting on the NPY Y(2) receptor, in regulation of basal splenic vascular tone was unveiled.