imidapril and Insulin-Resistance

The aim of this study was to evaluate the effects of imidapril and candesartan on fibrinolysis and insulin sensitivity in normoweight hypertensive patients. After a 2-week wash-out period, 61 patients with mild-to-moderate hypertension were randomized to imidapril or candesartan for 12 weeks. Blood pressure (BP), plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) antigen activities were evaluated at baseline and during treatment. The patients underwent a euglycemic-hyperinsulinemic clamp (insulin sensitivity was evaluated as glucose infusion rate during the last 30 min) and a desmopressin test (with desmopressin infusion in the brachial artery) to evaluate endothelial ability to release t-PA. Imidapril and candesartan induced similar systolic/diastolic BP reductions (-16/12.6 and -16.1/12.2 mm Hg, respectively, P<0.001 vs. baseline). Imidapril increased glucose infusion rate (+1.1 mg min(-1) per kg, P<0.02), whereas candesartan did not change it. Both drugs decreased PAI-1 antigen activity after 4 weeks of treatment; subsequently, only the decreasing effect of imidapril was sustained throughout the 12 weeks, whereas candesartan increased PAI-1 activity at week 12 (P<0.05 vs. baseline, P<0.01 vs. imidapril). Activity of t-PA decreased with candesartan (from 0.48±0.16 to 0.43±0.14 IU ml(-1), P<0.05) but not with imidapril. Activity of t-PA in response to desmopressin was increased more by imidapril (+4.45 IU ml(-1)) than by candesartan (+2.73 IU ml(-1), P<0.01 vs. imidapril). These results indicate that in normoweight hypertensive patients, despite similar BP reduction, imidapril but not candesartan improved the fibrinolytic balance, suggesting that mechanisms other than Ang II inhibition, possibly including bradykinin-mediated effects on insulin sensitivity and endothelial function, may be responsible for these different effects.

Topics: Adolescent; Adult; Aged; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Endothelium, Vascular; Female; Fibrinolysis; Humans; Hypertension; Imidazolidines; Insulin Resistance; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Prospective Studies; Signal Transduction; Single-Blind Method; Tetrazoles; Tissue Plasminogen Activator; Treatment Outcome; Young Adult

Angiotensin II and insulin resistance (IR) have clinical implications in the pathophysiology of chronic heart failure (CHF). However, it is still unclear whether the combination of an angiotensin-receptor blocker and angiotensin-converting enzyme inhibitor (ACEI) improves IR in CHF patients who do not receive β-blockers. Thus, the aim of the present study was to evaluate the effects of losartan on glucose metabolism and inflammatory cytokines in CHF patients treated with ACEI but not β-blockers.. The effect of losartan treatment for 16 weeks on IR was analyzed in 16 CHF patients in a randomized crossover trial. Insulin level and homeostasis model IR index (HOMA-IR) decreased significantly (P<0.05), but fasting plasma glucose did not change significantly. Serum tumor necrosis factor (TNF)-α, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1 levels were significantly decreased with losartan (P<0.05). Furthermore, the changes in IL-6 and MCP-1 levels were significantly correlated with the reduction in HOMA-IR (P<0.05), but the change in TNF-α levels was not significantly correlated.. The addition of losartan to ACEI therapy improved IR and decreased inflammatory cytokines in CHF patients who did not receive β-blockers.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Blood Glucose; Chemokine CCL2; Chronic Disease; Cross-Over Studies; Drug Therapy, Combination; Enalapril; Female; Heart Failure; Humans; Imidazolidines; Inflammation Mediators; Insulin; Insulin Resistance; Interleukin-6; Japan; Lisinopril; Losartan; Male; Middle Aged; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Endothelium, Vascular; Fibrinolysis; Humans; Hypertension; Imidazolidines; Insulin Resistance; Plasminogen Activator Inhibitor 1; Tetrazoles; Tissue Plasminogen Activator; Treatment Outcome

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 microg/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 microU/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.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Glucose; Glucose Clamp Technique; Imidazoles; Imidazolidines; Insulin; Insulin Resistance; Male; Nitric Oxide Synthase; omega-N-Methylarginine; Rats; Rats, Wistar

The effect of imidapril, an angiotensin-converting enzyme (ACE) inhibitor, on insulin resistance was studied in high-fructose-fed rats. A sequential hyperinsulinemic euglycemic clamp procedure (insulin infusion rates: 3 and 30 mU/kg BW/min) was employed in 15 high-fructose-fed rats and 10 normal chow-fed rats under the awake condition. Five of the high-fructose-fed and five of the normal chow-fed rats, respectively, were continuously given imidapril (5 mg/kg BW/min) or saline during the two-step euglycemic clamp study. Furthermore, both imidapril and L-NMMA were infused in another 5 high-fructose-fed rats during the low-dose insulin clamp. Glucose infusion rate (GIR) was regarded as an index of the whole-body insulin action. In the low-dose insulin infusion, the high-fructose feeding resulted in a marked decrease in GIR (p<0.05). Imidapril infusion significantly raised the GIRs in the high-fructose-fed rats (p<0.05). There was no significant difference in GIRs between the chow-fed rats and the imidapril-infused rats with high-fructose diet. In the high-fructose-fed rats, L-NMMA abolished the increase in GIR induced by imidapril (p<0.05). Imidapril did not significantly change the GIRs in the chow-fed rats. In the high-dose insulin infusion, no significant difference in GIR was found among the chow-fed rats, the chow-fed rats given imidapril, the high-fructose-fed rats, and the high-fructose-fed rats given imidapril. These results suggest that, in insulin-resistant rats induced by the high-fructose feeding, an ACE inhibitor, such as imidapril, can improve the whole-body insulin-mediated glucose disposal and that this effect of imidapril is essentially linked to increased activation of NO-pathway.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fructose; Glucose; Glucose Clamp Technique; Imidazoles; Imidazolidines; Infusions, Intravenous; Insulin; Insulin Resistance; Male; Nitric Oxide Synthase; omega-N-Methylarginine; Rats; Rats, Wistar