D-MYO-INOSITOL-1,2,6-TRISPHOSPHATE IS A SELECTIVE ANTAGONIST OF NEUROPEPTIDE Y-INDUCED PRESSOR-RESPONSES IN THE PITHED RAT

The antagonistic effects of a new inositol phosphate derivative, D-myoinositol-1.2,6-trisphosphate (PP56), on pressor responses to preganglionic sympathetic nerve stimulation and exogenously administered phenylephrine or neuropeptide Y (NPY) were investigated in vivo in the pithed rat. In this model an intravenous (i.v.) bolus administration of PP56 (1-50 mg/kg) dose dependently inhibited the increase in mean arterial blood pressure (MAP) induced by a continuous infusion of NPY (2-mu-g/kg per min for 10 min). PP56 in a dose of 5 mg/kg i.v. bolus reduced the entire NPY dose-response curve (0.4-8-mu-g/kg per min 10 min infusion) without any shift to the right indicating a non-competitive interaction. Furthermore, PP56 (10-50 mg/kg i.v.) was found to inhibit the pressor response to preganglionic sympathetic nerve stimulation and i. v' bolus injection of the alpha-1-adrenoceptor agonist, phenylephrine. The dose-response curves for increasing doses of phenylephrine and incremental preganglionic sympathetic nerve stimulation were not significantly altered by a lower dose of PP56 (5 mg/kg i.v. bolus). We conclude that PP56, representing a new class of synthetic drugs, can antagonize the actions of exogenous and endogenous NPY in vivo, an action which is specific for NPY within a limited dose range.