alpha-Trinositol: a functional (non-receptor) neuropeptide Y antagonist in vasculature.
Neuropeptide Y is a sympathetic co-neurotransmitter released with noradrenaline upon sympathetic nerve stimulation. This study describes the ability of a synthetic inositol phosphate, alpha-trinositol(D-myo-inositol 1,2,6-triphosphate; PP 56) to antagonize vasoconstrictor responses to neuropeptide Y in-vitro as well as in-vivo. In human and guinea-pig isolated arteries alpha-trinositol potently (10 nM to 1 microM extracellular concentration) suppressed the constriction evoked by neuropeptide Y alone, the potentiation by neuropeptide Y of noradrenaline-evoked constriction, and the neuropeptide Y-induced inhibition of relaxation. Moreover, in the pithed (areflexive) rat, a non-adrenergic portion of the pressor response to preganglionic sympathetic nerve stimulation was sensitive to alpha-trinositol. As studied in the recently cloned human (vascular-type) Y1 receptor, the action of alpha-trinositol does not occur through antagonism at the neuropeptide Y recognition site nor does it induce allosteric changes of this receptor. However, we found alpha-trinositol to inhibit the rise in intracellular Ca2+ as well as inositol triphosphate concentrations induced by neuropeptide Y. It is, therefore, proposed that alpha-trinositol represents a non-receptor, but yet selective antagonist of neuropeptide Y in vasculature, opening up the possibility to investigate involvement of neuropeptide Y in sympathetic blood pressure control and in cardiovascular disorders.
Sun
X
X
Department of Pharmacology, University of Göteborg, Sweden.
You
J
J
Hedner
T
T
Erlinge
D
D
Fellström
B
B
Yoo
H
H
Wahlestedt
C
C
Edvinsson
L
L
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001488:Basilar Artery / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009478:Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000098:blood supply; D009435:Synaptic Transmission / Q000187:drug effects; D014599:Uterus / Q000098:blood supply; D014649:Vas Deferens / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
D000317:Adrenergic alpha-Antagonists; D007295:Inositol Phosphates; D009478:Neuropeptide Y; D010975:Platelet Aggregation Inhibitors; D002118:Calcium; C059368:atrinositol; D009638:Norepinephrine; D011224:Prazosin