Effects of d-myo-inositol-1,2,6-trisphosphate on neuropeptide Y-induced potentiation of various vasoconstrictor agents in the rat.

The adrenergic cotransmitter neuropeptide Y (NPY) induces vascular smooth muscle contraction by occupying postsynaptic Y1 receptors and by enhancing the vasoconstriction induced by a series of other pressor agents. In particular, NPY modulates the blood pressure response to alpha-1 adrenergic agonists and angiotensin II. The inositol phosphate derivative, d-myo-inositol-1,2,6-trisphosphate (PP56), is a novel NPY antagonist which within a defined dose range selectively blocks the effects of exogenously administered NPY in vivo. In the pithed animal as well as in the freely moving Sprague-Dawley rat, an i.v. bolus administration of PP56 (2 mg/kg) followed by an infusion (20 mg/kg/hr for 30 min) inhibited the approximate 50% increase in mean arterial blood pressure induced by a continuous infusion of NPY (2 micrograms/kg/min for 10 min). Furthermore, PP56 treatment completely inhibited the enhancement induced by NPY (0.1 microgram/min for 50 min or 2 micrograms/kg/min for 10 min) of the pressor responses to preganglionic sympathetic nerve stimulation (in the pithed rat) and to i.v. bolus injections of noradrenaline (20 ng), the indirect sympathomimetic tyramine (40 micrograms) as well as to angiotensin II (10 ng). These results show that PP56, representing a new class of synthetic nonpeptide drugs, is capable of antagonizing the vascular smooth muscle contractile as well as the potentiating effects of NPY in vivo in the pithed as well as the conscious rat.