EFFECT OF CAPTOPRIL, LOSARTAN, AND BRADYKININ ON EARLY STEPS OF INSULIN ACTION

Insulin initiates its metabolic and growth-promoting effects by bindin g to the a subunit of its receptor, thereby activating the kinase in t he beta subunit. This event leads to tyrosyl phosphorylation of its cy tosolic substrate, insulin receptor substrate 1 (IRS-1), which in turn associates with and activates phosphatidylinositol (PI) 3-kinase. The clinical use of ACE inhibitors has been associated with increased ins ulin sensitivity. However, the exact molecular mechanism is unknown. I n the present study, we examined the phosphorylation status of the ins ulin receptor and IBS-I, as well as the association between IRS-1 and PI 3-kinase in the liver and muscle of 20-month-old rats treated acute ly with captopril, using immunoprecipitation with antipeptide antibodi es to the insulin receptor and IRS-1, and immunoblotting with antiphos photyrosine and anti-PI 3-kinase antibodies. Insulin stimulation incre ased receptor autophosphorylation to 462 +/- 253% (P < 0.05) in the li ver and 697 +/- 78% (P < 0.001) in the muscle of ACE inhibitor-treated rats. There were also increases to 250 +/- 17% (P < 0.001) and 280 +/ - 50% (P < 0.05) in the insulin-stimulated IRS-1 phosphorylation level s in the liver and muscle, respectively, of animals treated with capto pril. The insulin-stimulated IRS-1 association with PI 3-kinase rose t o 305 +/- 20% (P < 0.001) in Liver and 267 +/- 48% (P < 0.05) in muscl e. Losartan, an ANG receptor blocker, had no significant effect on ins ulin-stimulated IRS-1 phosphorylation in both tissues. The acute admin istration of bradykinin increased insulin-stimulated tyrosine phosphor ylation of the insulin receptor and IRS-1 in the liver and muscle. The se data demonstrate that ACE inhibitors modulate the early steps of in sulin signaling, and that this effect may be simulated by the administ ration of bradykinin.