Autoinhibitory function of the sympathetic prejunctional neuropeptide Y Y 2 receptor evidenced by BIIE0246

Abstract

The significance of neuropeptide Y Y 2 receptors in sympathetic nonadrenergic transmission was investigated using the novel selective antagonist BIIE0246 (( S)- N2-[[1-[2-[4-[( R, S)-5,11-dihydro-6(6 h)-oxodibenz[ b, e]azepin-11-yl]-1-piperazinyl]-2-oxoethyl]cyclopentyl]acetyl]- N-[2-[1,2-dihydro-3,5 (4 H)-dioxo-1,2-diphenyl-3 H-1,2,4-triazol-4-yl]ethyl]-argininamide). In anaesthetized pigs pretreated with reserpine, and after transection of sympathetic nerves (depleted of noradrenaline), electrical stimulation of renal and splanchnic sympathetic nerves evoked vasoconstriction in, and overflow of neuropeptide Y-like immunoreactivity from, kidney and spleen, respectively. In the presence of BIIE0246, the nerve-evoked overflows of neuropeptide Y-like immunoreactivity were markedly increased and the splenic vasoconstrictor response prolonged. In addition, BIIE0246 caused splenic vasodilatation per se in this model where basal levels of circulating neuropeptide Y exceed 40 pM. It is concluded that endogenous neurogenical neuropeptide Y regulates its own release via activation of sympathetic prejunctional inhibitory neuropeptide Y Y 2 receptors in both spleen and kidney in the reserpinized pig. Moreover, when circulating levels of neuropeptide Y are moderately increased, activation of neuropeptide Y Y 2 receptors seems to contribute to basal splenic vascular tone.