Autoinhibitory function of the sympathetic prejunctional neuropeptide Y Y(2) receptor evidenced by BIIE0246.
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.
Malmström
Rickard E
RE
Department of Physiology and Pharmacology, Karolinska Institutet, S-17177, Stockholm, Sweden. rickard.malmstrom@fyfa.ki.se
Lundberg
Jon O N
JO
Weitzberg
Eddie
E
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology*; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D004558:Electric Stimulation; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007668:Kidney / Q000098:blood supply / Q000294:innervation / Q000378:metabolism; D008297:Male; D009478:Neuropeptide Y / Q000187:drug effects / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000502:physiology; D012079:Renal Circulation / Q000187:drug effects; D012110:Reserpine / Q000494:pharmacology; D013154:Spleen / Q000098:blood supply / Q000294:innervation / Q000378:metabolism; D013552:Swine; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology
D001552:Benzazepines; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; D012110:Reserpine; D001120:Arginine; C403256:BIIE 0246