enalaprilat-anhydrous and Diabetes-Mellitus--Type-2

To examine the acute effects of intravenous metoprolol and enalaprilat on energy expenditure, thermogenesis, blood flow and insulin sensitivity.. Randomized, single-blind, placebo-controlled trial.. Helsinki University Central Hospital, Finland. Seven moderately insulin-resistant nondiabetic subjects.. Each subjects was studied three times at 2-3 week intervals: metoprolol (5 mg), enalaprilat (2 mg) or saline infusions were used.. A 150-min euglycaemic/hyperinsulinaemic clamp combined with indirect calorimetry and blood flow measurements were performed.. Glucose uptake, forearm and skin blood flow, and energy expenditure.. Blood pressure was decreased to the same degree by both drugs. Forearm blood flow (plethysmography) was lower with metoprolol compared to enalaprilat (2.1 +/- 0.2 vs. 2.8 +/- 0.4 mL per 100 mL min-1; P < 0.05). Glucose-plus-insulin-stimulated thermogenesis and total energy expenditures were reduced both by metoprolol (71 and 5.2%; P < 0.05 in both) and enalaprilat (59%, P = 0.06; and 7.6%, P < 0.05) as compared to the control study. Skin blood flow (laser Doppler) increased by 100% (P < 0.01) during the glucose-plus-insulin infusion, but this increment was inhibited by both drug infusions. Forearms and whole-body glucose uptake was not influenced by metoprolol or enalaprilat administration.. (i) Both metoprolol and enalaprilat inhibit glucose-plus-insulin-induced thermogenesis and a rise in skin blood flow. (ii) Metoprolol further reduces forearm blood flow compared to enalaprilat. (iii) Neither drug has any acute effect on insulin sensitivity. (iv) The interference of a physiological response to insulin by ACE inhibitors or beta-blocking agents may have implications both for energy balance and thermoregulation during periods of hyperinsulinaemia in man.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Body Temperature Regulation; Diabetes Mellitus, Type 2; Enalaprilat; Energy Metabolism; Forearm; Humans; Insulin; Metoprolol; Regional Blood Flow; Risk Factors; Skin

Therapies that restore renal cGMP levels are hypothesized to slow the progression of diabetic nephropathy. We investigated the effect of BI 703704, a soluble guanylate cyclase (sGC) activator, on disease progression in obese ZSF1 rats. BI 703704 was administered at doses of 0.3, 1, 3, and 10 mg/kg/d to male ZSF1 rats for 15 weeks, during which mean arterial pressure (MAP), heart rate (HR), and urinary protein excretion (UPE) were determined. Histologic assessment of glomerular and interstitial lesions was also performed. Renal cGMP levels were quantified as an indicator of target modulation. BI 703704 resulted in sGC activation, as evidenced by dose-dependent increases in renal cGMP levels. After 15 weeks of treatment, sGC activation resulted in dose-dependent decreases in UPE (from 463 ± 58 mg/d in vehicle controls to 328 ± 55, 348 ± 23, 283 ± 45, and 108 ± 23 mg/d in BI 703704-treated rats at 0.3, 1, 3, and 10 mg/kg, respectively). These effects were accompanied by a significant reduction in the incidence of glomerulosclerosis and interstitial lesions. Decreases in MAP and increases in HR were only observed at the high dose of BI 703704. These results are the first demonstration of renal protection with sGC activation in a nephropathy model induced by type 2 diabetes. Importantly, beneficial effects were observed at doses that did not significantly alter MAP and HR.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Enalaprilat; Enzyme Activators; Guanylate Cyclase; Male; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase