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(Circulation. 2003;107:1923.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Vasopeptidase Inhibitor Omapatrilat Induces Profound Insulin Sensitization and Increases Myocardial Glucose Uptake in Zucker Fatty Rats

Studies Comparing a Vasopeptidase Inhibitor, Angiotensin-Converting Enzyme Inhibitor, and Angiotensin II Type I Receptor Blocker

Chao-Hung Wang, MD; Nathalie Leung, MD; Nathalie Lapointe, RN, MSc; Linda Szeto, MSc; Kristine D. Uffelman, MSc; Adria Giacca, MD; Jean L. Rouleau, MD; Gary F. Lewis, MD

From the Department of Medicine, Division of Endocrinology and Metabolism (C.W., N. Leung, L.S., K.D.U., A.G., G.F.L.), and the Department of Medicine, Division of Cardiology (N. Lapointe, J.L.R.), Toronto General Hospital and University Health Network; and the Department of Physiology, University of Toronto (A.G., G.F.L.), Toronto, Ontario, Canada.

Correspondence to Gary F. Lewis, Toronto General Hospital, EN11-229, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4. E-mail gary.lewis{at}uhn.on.ca

Background— ACE inhibitors (ACEIs) improve insulin resistance and prevent type 2 diabetes, possibly mediated by inhibition of bradykinin (BK) degradation. The vasopeptidase inhibitor omapatrilat (OMA) raises BK to a greater extent than ACEIs by dual enzyme inhibition, whereas its insulin-sensitizing effects and mechanisms have not been investigated.

Methods and Results— We compared the insulin-sensitizing effects of OMA, ramipril (an ACEI), losartan (an angiotensin II type 1 receptor blocker), and placebo by 2-step euglycemic hyperinsulinemic clamp in insulin-resistant Zucker fatty rats (n=6 to 7 in each group). OMA resulted in a lower rate of endogenous glucose production than placebo at baseline (35±5 versus 54±4 mmol · kg^-1 · min^-1, P<0.01), greater suppression of endogenous glucose production by low-dose insulin (73±11% versus 27±18%, P<0.05), and greater glucose disposal at high-dose insulin (135±5 versus 92±4 mmol · kg^-1 · min^-1, P<0.01). Ramipril tended to improve insulin sensitivity, but losartan did not. OMA significantly increased 2-deoxyglucose uptake by myocardium, fat, and skeletal muscle. Ramipril increased 2-deoxyglucose uptake only by some skeletal muscles, but losartan did not. The insulin-sensitizing effects of OMA were blocked significantly by HOE-140 (a BK, B₂ receptor antagonist) and N^G-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor) in all tissues except myocardium.

Conclusions— OMA induces profound insulin sensitization and increases myocardial glucose uptake in Zucker fatty rats. This effect is greater than that of ramipril and probably occurs at least in part via stimulation of the B₂ receptor. OMA has the potential for greater type 2 diabetes prevention than ACEI.

Key Words: insulin • bradykinin • glucose • hypertension • diabetes mellitus