EFFECTS OF ANGIOTENSIN RECEPTOR ANTAGONIST AND ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR ON INSULIN SENSITIVITY IN FRUCTOSE-FED HYPERTENSIVE RATS AND ESSENTIAL HYPERTENSIVES

This study was designed to investigate the effects of angiotensin II (AII) receptor antagonist and angiotensin converting enzyme (ACE) inhibitor on insulin resistance, and the mechanism by which ACE inhibitor improves insulin-dependent glucose uptake (insulin sensitivity) in an insulin-resistant hypertensive rat model (fructose-fed rats, FFR) and in essential hypertensives (EHT). Male Sprague-Dawley rats were fed on fructose-rich or standard chow for 4 weeks and treated either with 10 mg/kg/day of delapril (n = 8), 1 mg/kg/day of TCV-116 (AII receptor antagonist; n 13), or vehicle (n = 9) for the latter 2 weeks. Steady-state plasma glucose (SSPG) was measured with the subjects in the conscious state; simultaneously, we infused insulin (2.5 mU/kg/min) and glucose (8 mg/kg/min) to determine insulin sensitivity in each group. Thirteen EHT were hospitalized and the 2-h euglycemic hyperinsulinemic glucose clamp (GC) method was performed in a fasting condition before and after 2 weeks' administration of TCV-116 (8 mg/day) in 7 EHT and of delapril (120 mg/day) in 6 EHT. Insulin sensitivity was evaluated as M-value calculated from the infusion rate of glucose. Mean blood pressure (MBP) was higher in FFR (137.7 +/- 73.8 mm Hg, P < .05) compared to controls (120.8 +/- 2.7 mm Hg), and was lower in both the delapril (108.1 +/- 6.3 mm Hg, P < .05) and TCV-116 (112.8 +/- 4.3 mm Hg, P < .05) groups than in FFR. SSPG was higher in FFR (209.3 +/- 7.6 mg/dL, P < .01) compared to controls (136.8 +/- 10.1 mg/dL), and was lower in the delapril (170.8 +/- 4.2 mg/dL, P < .05) and TCV-116 (171.7 +/- 6.8 mg/dL, P < .05) groups. There was no significant difference between the delapril and TCV-116 groups in SSPG levels. In EHT, delapril and TCV-116 decreased MBP. M-value in the control period in EHT was lower than in normal controls in this study. After delapril and TCV-116 treatment, M-value was significantly higher to the same extent as that observed in the control period. Thus, both ACE inhibitor and AII receptor antagonist improved insulin resistance as assessed by SSPG in FFR and by GC in EHT, suggesting that the improvement of insulin resistance by ACE inhibitor might depend on suppression of AII action.