INHIBITORY EFFECT OF NEUROPEPTIDE-Y AND ITS ANALOGS ON INOSITOL 1,4,5-TRISPHOSPHATE LEVEL IN RAT CARDIOMYOCYTES

A negative inotropic effect of neuropeptide Y (NPY) in the mammalian h eart has been reported. The mechanism(s) involved in the action of NPY in the heart is still unclear. Since D-myo-inositol 1,4,5-trisphospha te[Ins(1,4,5)P3] is known to be an important second messenger in the r egulation of cardiac function, we carried out a study to investigate t he status of Ins(1,4,5)P3 levels in response to NPY stimulation in rat cardiomyocytes. We also studied the possible involvement of NPY recep tor subtypes in Ins(1,4,5)P3 formation. [Leu31, Pro-34]NPY,NPY13-36, N PY and peptide YY (PYY) Induced a concentration-dependent decrease in Ins(1,4,5)P3 levels [measured with an Ins(1,4,5)P3 protein binding ass ay kit] in rat cardiomyocytes, which was blocked by NPY antagonists NP Y18-36 or PYX-2. There is no difference in the inhibitory effect of NP Y and PYY on Ins(1,4,5)P3 formation. Furthermore, effects of NPY and i ts analogues were insensitive to pertussis toxin pretreatment. Two new and more specific Y2 receptor agonists, [Ahx5-24]NPY and [Ahx5-24, ga mma-Glu2-epsilon-Lys30]NPY, produced similar effects as NPY13-36 on In s(1,4,5)P3 formation. These observations indicate that Y1 and Y2 subty pes of NPY receptor in rat cardiomyocytes may be associated with Ins(1 ,4,5)P3 formation through a pertussis-toxin-insensitive G(q) protein. The decreased Ins(1,4,5)P3 formation may be implicated in the negative inotropic effect of NPY in the heart.