Insulin-like growth factor-I inhibits rat arterial K(ATP) channels through pI 3-kinase

Since, in addition to its growth-promoting actions, insulin-like growth factor-I (IGF-I) has rapid vasoactive actions, we investigated the effects of IGF-I on whole-cell ATP-sensitive K⁺ (K_ATP) currents of rat mesenteric arterial smooth muscle cells. IGF-I (10 or 30 nM) reduced K_ATP currents activated by pinacidil or a membrane permeant cAMP analogue. Inhibition of phospholipase C, protein kinase C, protein kinase A, mitogen-activated protein kinase or mammalian target of rapamycin (mTOR) did not prevent the action of IGF-I. However, inhibition of K_ATP currents by IGF-I was abolished by the tyrosine kinase inhibitor genistein or the phosphoinositide 3-kinase inhibitors, LY 294002 and wortmannin. Intracellular application of either phosphatidylinositol 4,5-bisphosphate (PIP₂) or phosphatidylinositol 3,4,5-trisphosphate (PIP₃) increased the K_ATP current activated by pinacidil and abolished the inhibitory effect of IGF-I. Thus, we show regulation of arterial K_ATP channels by polyphosphoinositides and report for the first time that IGF-I inhibits these channels via a phosphoinositide 3-kinase-dependent pathway.