Ramipril increases the protein level of skeletal muscle IRS-1 and alters protein tyrosine phosphatase activity in spontaneously hypertensive rats

To investigate mechanisms by which angiotensin converting enzyme (ACE)-inhi bition increases insulin sensitivity, spontaneously hypertensive (SH) rats were treated with or without ramipril (1 mg/kg per day) for 12 weeks. Insul in binding and protein levels of insulin receptor substrate-1 (IRS-1), p85- subunit of phosphatidylinositol 3'-kinase (p85) and Src homology 2 domain-c ontaining phosphatase-2 (SHP2) were then determined in hindlimb muscle and liver. Additionally, protein tyrosine phosphatase (PTPase) activities towar ds immobilized phosphorylated insulin receptor or phosphorylated IRS-1 of m embrane (MF) and cytosolic fractions (CF) of these tissues were measured. R amipril treatment increased IRS-l-protein content in muscle by 31+/-9% (P<0 .05). No effects were observed on IRS-1 content in liver or on insulin bind ing or protein expression of p85 or SHP2 in both tissues. Ramipril treatmen t also increased dephosphorylation of insulin receptor by muscle CF (22.0+/ -1.0%/60 min compared to 16.8+/-1.5%/60 min; P<0.05), and of IRS-1 by liver MF (37.2+/-1.7%/7.5 min compared to 33.8+/-1.7%/7.5 min; P<0.05) and CF (3 6.8+/-1.0%/7.5 min compared to 33.2+/-1.0%/7.5 min; P<0.05). We conclude th at the observed effects of ACE-inhibition by ramipril on the protein expres sion of IRS-1 and on PTPase activity might contribute to its effect on insu lin sensitivity.