delapril and Insulin-Resistance

To compare the effect of delapril/manidipine vs olmesartan/hydrochlorothiazide (HCTZ) combination on insulin sensitivity and plasma fibrinogen in obese hypertensive patients.. After a 4-week placebo period, 88 obese, hypertensive (DBP >95 and <110 mmHg) outpatients were randomized to delapril 30 mg/manidipine 10 mg combination or to olmesartan 20 mg/HCTZ 12.5 mg combination for 24 weeks according to a prospective, randomized, open-label, blinded endpoint, parallel group design. At the end of the placebo period and treatment period, clinical BP, fasting plasma glucose (FPG), plasma insulin, insulin sensitivity (by euglycemic hyperinsulinemic clamp) and plasma fibrinogen were evaluated. Insulin sensitivity was expressed as the amount of glucose infused during the last 30 minutes (glucose infusion rate, GIR) in mg/Kg/min. The total glucose requirement (TGR) to maintain a steady-state blood glucose level in response to a defined increase in plasma insulin concentration was also evaluated.. Both combinations significantly reduced SBP/DBP values (-22.3/16.4 mmHg and -22.6/17.2 mmHg, respectively, all p <0.001 vs placebo). GIR was significantly increased only by delapril/manidipine (+3.01 mg/min/Kg, p=0.038 vs placebo), the difference between treatments being significant (p <0.05). TGR was significantly increased by delapril/manidipine (+9.7 g, p=0.034), while it was unaffected by olmesartan/HCTZ. Plasma insulin as well as fibrinogen were significantly reduced by delapril/manidipine (-17.8 pmol/l, p=0.047 and -67.5 mg/dl, p=0.021, respectively), but not by olmesartan/HCTZ, the difference between the two treatments being statistically significant (p <0.05).. In obese hypertensive patients the delapril/manidipine combination but not the olmesartan/HCTZ combination significantly decreased insulin resistance and plasma fibrinogen levels, despite the similar BP lowering efficacy.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Drug Combinations; Female; Fibrinogen; Glucose Clamp Technique; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Indans; Insulin Resistance; Male; Middle Aged; Nitrobenzenes; Obesity; Piperazines; Tetrazoles

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Glucose; Blood Pressure; Diet; Fructose; Glucose Clamp Technique; Humans; Hypertension; Indans; Insulin Resistance; Male; Middle Aged; Rats; Rats, Sprague-Dawley; Tetrazoles

To investigate the role of kinins in augmentation of insulin sensitivity by angiotensin converting enzyme inhibitor (ACEI), the effects of ACEI (delapril) on the insulin resistance in fructose-fed rats (FFR) were evaluated with or without the administration of bradykinin receptor antagonist (Hoe 140). Male Sprague-Dawley rats were fed on fructose rich chow (FFR) or standard chow (control) for 4 weeks and treated with 10 mg/kg/day of delapril with or without Hoe 140 (0.5 mg/kg/day) for an additional 2 weeks. Steady state plasma glucose (SSPG) and steady state plasma insulin (SSPI) were determined while the rats were conscious. Insulin (2.5 mU/kg/min) and glucose (8 mg/kg/min) were simultaneously infused to determine insulin sensitivity in each group. Mean blood pressure (MBP), SSPG and SSPI were significantly higher in FFR than in control, and were significantly lower in the FFR+delapril than in FFR+vehicle. There were no difference in MBP, SSPG and SSPI between FFR+delapril+vehicle and FFR+delapril+Hoe 140. We concluded that the main mechanisms of improving the insulin sensitivity by ACEI may not be the enhancement of kinins but the suppression of angiotensin II in FFR.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Bradykinin; Homeostasis; Indans; Insulin; Insulin Resistance; Male; Rats; Rats, Sprague-Dawley

The open trial was designed to evaluate the effects of long-term antihypertensive treatment with the calcium-channel blocker, manidipine and the angiotensin converting enzyme (ACE) inhibitor, delapril on insulin sensitivity in Japanese non-insulin dependent diabetes mellitus (NIDDM) patients with essential hypertension. We measured the insulin sensitivity index (SI) and the glucose-effectiveness (SG) by the use of Bergman's minimal model method in 18 hypertensive NIDDM patients before and after administration of manidipine (group A) or delapril (group B) for 3 months. Manidipine treatment for 3 months significantly improved SI in group A from 3.35 +/- 0.61 (x 10(-4) min-1 microU-1 ml-1) to 4.70 +/- 1.34 (P < 0.05). Delapril treatment for 3 months also significantly improved SI in group B from 3.56 +/- 1.04 to 5.00 +/- 0.87 (P < 0.05). Manidipine significantly improved SG in group A from 1.60 +/- 0.64 (x 10(-2) min) to 2.19 +/- 0.38 (P < 0.05). Delapril treatment also significantly improved SG in the group B from 1.41 +/- 0.56 to 1.91 +/- 0.35 (P < 0.05). Manidipine and delapril did not affect urinary C-peptide excretion for 24 h in the hypertensive NIDDM patients. Treatment with manidipine or delapril significantly reduced systolic and diastolic blood pressures in the hypertensive NIDDM patients. There were no differences between plasma glucose, serum total triglycerides, and cholesterol or lipoprotein cholesterol fractions, heart rate and body weight after 3 months on manidipine or delapril. This study confirmed the improving effects on SI and SG by long-term treatment with manidipine or delapril in the hypertensive NIDDM patients.

Topics: Antihypertensive Agents; Blood Glucose; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Female; Glycated Hemoglobin; Humans; Hypertension; Indans; Insulin Resistance; Male; Middle Aged; Nitrobenzenes; Piperazines

This study evaluated insulin secretion and insulin sensitivity in 17 non-obese hypertensive patients (aged 45.6 +/- 2.2 years, body mass index 24.0 +/- 0.5 kg/m2, mean +/- S.E.M.) with (n = 8) and without glucose intolerance (n = 9) and compared the results with those of 16 age-matched non-obese normotensive subjects with (n = 7) and without glucose intolerance (n = 9). The hypertensive patients without glucose intolerance showed a significantly lower insulin-mediated glucose disposal and a compensating increase in second-phase insulin secretion compared with normotensives without glucose intolerance. In hypertensives with glucose intolerance, insulin-mediated glucose disposal was significantly lower and second-phase insulin secretion was comparable to that in normotensives without glucose intolerance. After 3 months of angiotensin-converting enzyme (ACE) inhibition with oral administration of delapril, blood pressure was significantly reduced in the hypertensives with glucose intolerance (n = 9). The insulin-mediated glucose disposal significantly (P < 0.01) recovered from 6.0 +/- 0.81 to 8.0 +/- 0.71 mg/kg per min. The second-phase insulin secretion tended to be lower (but not significantly) but insulin clearance increased from 15.4 +/- 0.85 to 19.1 +/- 1.42 ml/min (P < 0.05). These data show that in hypertensive patients without glucose intolerance insulin resistance might compensatorily augment second-phase insulin secretion and lead to hyperinsulinemia. In hypertensives with glucose intolerance, insulin resistance might induce postprandial hyperglycemia, which leads to hyperinsulinemia because of second phase insulin secretion at a level similar to that of normotensives.

Topics: Administration, Oral; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Body Mass Index; Female; Glucose Clamp Technique; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypertension; Indans; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged