α-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, α-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 α-trinositol potently (10 nM to 1 μM 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 presser response to preganglionic sympathetic nerve stimulation was sensitive to α-trinositol. As studied in the recently cloned human (vascular-type) Y1 receptor, the action of α-trinositol does not occur through antagonism at the neuropeptide Y recognition site nor does it induce allosteric changes of this receptor. However, we found α-trinositol to inhibit the rise in intracellular Ca²⁺ as well as inositol triphosphate concentrations induced by neuropeptide Y. It is, therefore, proposed that α-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.