J. Krutzfeldt et al., Ramipril increases the protein level of skeletal muscle IRS-1 and alters protein tyrosine phosphatase activity in spontaneously hypertensive rats, N-S ARCH PH, 362(1), 2000, pp. 1-6
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.