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

• Published in: European journal of pharmacology Vol. 439; no. 1-3; pp. 113 - 119
• Main Authors: Malmström, Rickard E, Lundberg, Jon O N, Weitzberg, Eddie
• Format: Journal Article
• Language: English
• Published: Netherlands 29.03.2002
• Subjects: Animals; Arginine - analogs & derivatives; Arginine - pharmacology; Benzazepines - pharmacology; Blood Flow Velocity - drug effects; Blood Pressure - drug effects; Electric Stimulation; Female; Heart Rate - drug effects; Kidney - blood supply; Kidney - innervation; Kidney - metabolism; Male; Medicin och hälsovetenskap; Neuropeptide Y - drug effects; Neuropeptide Y - metabolism; Receptors, Neuropeptide Y - antagonists & inhibitors; Receptors, Neuropeptide Y - physiology; Renal Circulation - drug effects; Reserpine - pharmacology; Spleen - blood supply; Spleen - innervation; Spleen - metabolism; Swine; Sympathetic Nervous System - drug effects; Sympathetic Nervous System - physiology
• ISSN: 0014-2999
• DOI: 10.1016/S0014-2999(02)01371-7

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(6h)-oxodibenz[b,e]azepin-11-yl]-1-piperazinyl]-2-oxoethyl]cyclopentyl]acetyl]-N-[2-[1,2-dihydro-3,5 (4H)-dioxo-1,2-diphenyl-3H-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.