Effects of Imidapril, an Angiotensin-converting Enzyme Inhibitor, on Insulin Sensitivity and Responsiveness in Streptozotocin-induced Diabetic Rats

Abstract

We have studied the effect of imidapril, an angiotensin-converting enzyme inhibitor, on streptozotocin-induced diabetic rats. A sequential euglycemic hyperinsulinemic clamp procedure was used (insulin infusion rates: 3 and 30 mU/kg BW/min) in 30 diabetic rats. The rats were divided in 6 groups: a control group, a control group with N-monomethyl-L-arginine (L-NMMA, 1 mg/kg/min, a nitric oxide synthase inhibitor) infusion, a streptozotocin-induced diabetic group, a diabetic group with L-NMMA infusion, a diabetic group involving imidapril infusion (5 μg/kg/min), and a diabetic group involving simultaneous imidapril and L-NMMA infusion. Glucose concentrations were maintained around 140 mg/dl during the clamp studies. Plasma insulin levels during the 3 and 30 mU/kg BW/min insulin infusions were 30 and 400 μU/ml, respectively. Glucose infusion rates (GIR) in STZ-induced diabetic rats showed a significant decrease compared to controls. At both insulin infusion rates, imidapril-infused diabetic rats showed an increased GIR, compared with the saline infused ones. There was no significant difference in GIR between L-NMMA and saline infusion in diabetic rats. Simultaneous infusion of imidapril and L-NMMA did not significantly decrease GIR with low-dose insulin infusion, but the increase in GIR induced by imidapril with high-dose insulin infusion was impaired by 100 % by L-NMMA infusion in diabetic rats. These results suggest that imidapril may improve insulin action, in part, via nitric oxide.

Key words

Angiotensin-Converting Enzyme Inhibitor - Euglycemic Clamp Technique - L-NMMA - Streptozotocin

References

• 1 Ferrannini E, Buzzigoli G, Bonadonna R, Giorico M A, Oleggini M, Graziadei L, Pedrinelli R, Brandi L, Bevilacqua S. Insulin resistance in essential hypertension.  N Engl J Med. 1987;  317 350-357
• 2 Luzio S D, Dunseath G, Owens D R. Acute effects of valsartan on insulin sensitivity in obese, non-hypertensive subjects with and without type 2 diabetes.  Horm Metab Res. 2002;  34 271-274
• 3 Erdös E. Angiotensin I converting enzyme.  Circ Res. 1975;  36 247-255
• 4 Uehara M, Nishikawa H, Isami S, Kisanuki K, Ohkubo Y, Miyamura N, Miyata T, Yano T, Shichiri M. Effect on insulin sensitivity of angiotensin converting enzyme inhibitors with or without a sulphydryl group: Bradykinin may improve insulin resistance in dogs and humans.  Diabetologia. 1994;  37 300-307
• 5 Nawano M, Anai M, Funaki M, Kobayashi H, Kanda A, Fukushima Y, Inukai K, Ogihara T, Sakoda H, Onishi Y, Kikuchi M, Yazaki Y, Oka Y, Asano T. Imidapril, an angiotensin-converting enzyme inhibitor, improves insulin sensitivity by enhancing signal transduction via insulin receptor substrate proteins and improving vascular resistance in the Zucker fatty rat.  Metabolism. 1999;  48 1248-1255
• 6 Carvalho C RO, Thirone A CP, Gontijo J AR, Velloso L A, Saad M JA. Effect of captopril, losartan, and bradykinin on early steps of insulin action.  Diabetes. 1997;  46 1950-1957
• 7 Miyata T, Taguchi T, Uehara M, Isami S, Kishikawa H, Kaneko K, Araki E, Shirichi M. Bradykinin potentiates insulin-stimulated glucose uptake and enhances insulin signal through the bradykinin B2 receptor in dog skeletal muscle and rat L6 myoblasts.  Eur J Endocrinol. 1998;  138 344-352
• 8 Hendriksen E J, Jacob S. Effects of captopril on glucose transport activity in skeletal muscle of obese Zucker rats.  Metabolism. 1995;  44 267-272
• 9 American Diabetes Association. Treatment of hypertension in adults with diabetes (Position Statement).  Diabetes Care. 2002;  25 (S1) S71-S73
• 10 Fujiwara T, Yuasa H, Ogiku N, Kawai Y. Histopathological investigation on salt-loaded stroke-prone spontaneously hypertensive rats, whose biochemical parameters of renal dysfunction were ameliorated by administration of imidapril.  Jpn J Pharmacol. 1994;  66 231-240
• 11 Kadowaki T, Kasuga M, Akanuma Y, Ezaki O, Takaku F. Decreased autophosphorylation of the insulin receptor-kinase in streptozotocin-diabetic rats.  J Biol Chem. 1984;  259 14 208-14 216
• 12 Mitchell D, Tyml K. Nitric oxide release in rat skeletal muscle capillary.  Am J Physiol. 1996;  270 H1696-H1703
• 13 Higaki Y, Hirshman M F, Fujii N, Goodyear L J. Nitric oxide increases glucose uptake through a mechanism that is distinct from the insulin and contraction pathways in rat skeletal muscle.  Diabetes. 2001;  50 241-247
• 14 Roy D, Perreault M, Marette A. Insulin stimulation of glucose uptake in skeletal muscles and adipose tissues in vivo is NO dependent.  Am J Physiol. 1998;  274 E692-E699
• 15 Oshida Y, Tachi Y, Morishita Y, Kitakoshi K, Fuku N, Han Y Q, Ohsawa I. Nitric oxide decreases insulin resistance induced by high-fructose feeding.  Horm Metab Res. 2000;  32 339-342
• 16 Li L, Oshida Y, Kusunoki M, Yamanouchi K, Johansson B L, Wahren J, Sato Y. Rat C peptide I and II stimulate glucose utilization in STZ-induced diabetic rats.  Diabetologia. 1999;  42 958-964
• 17 Oshida Y, Kako M, Nakai N, Shimomura Y, Li L, Sato J, Ohsawa I, Sato Y. Troglitazone improves insulin-stimulated glucose utilization associated with an increased muscle glycogen content in obese Zucker rats.  Endocr J. 1999;  46 723-730
• 18 Kawashima H, Igarashi T, Nakajima Y, Akiyama Y, Usuki K, Ohta S. Chronic hypertension induced by streptozotocin rats.  Naunyn Schmiedebergs Arch Pharmacol. 1978;  305 123-126
• 19 Hartmann J F, Szemplinski M, Hayes N S, Keegan M E, Slater E E. Effects of the angiotensin converting enzyme inhibitor, lisinopril, on normal and diabetic rats.  J Hypertens. 1988;  6 677-683
• 20 Jacob S, Hendriksen E J, Fogt D L, Dietze G J. Effects of trandolapril and verapamil on glucose transport in insulin-resistant rat skeletal muscle.  Metabolism. 1996;  45 535-541
• 21 Jauch K W, Hartl W, Günther B, Wicklmayr M, Rett K, Dietze G. Captopril enhances insulin responsiveness of forearm muscle tissue in non-insulin dependent diabetes mellitus.  Eur J Clin Invest. 1987;  17 448-454
• 22 Kahn C R. Insulin resistance, insulin insensitivity, and insulin unresponsiveness: a necessary distinction.  Metabolism. 1978;  27 1893-1902
• 23 Olefsky J M, Kolterman O G, Scarlett J A. Insulin action and resistance in obesity and noninsulin-dependent type II diabetes mellitus.  Am J Physiol. 1982;  243 E15-30
• 24 Balon T W, Nadler J L. Nitric oxide is present from incubated skeletal muscle.  J Appl Physiol. 1994;  77 2519-2521