enalapril and Hyperinsulinism

The effects of a synthetic preparation of an active constituent of garlic, allicin, were studied on blood pressure (BP), triglycerides, and insulin levels in Sprague-Dawley rats in which high fructose feeding elicited hyperinsulinemia, hypertension, and hypertriglyceridemia. Results were compared with those of the antihypertensive drug enalapril. Three groups of male Sprague-Dawley rats were fed a fructose-enriched diet for 5 weeks. During the last 2 weeks 10 animals received only fructose, 10 received allicin, and 10 received enalapril. Blood pressure, insulin level, and triglyceride levels were measured at the beginning of the experiment and after 3 and 5 weeks on the fructose diet, fructose/allicin diet, or fructose/enalapril diet. Allicin lowered BP from the maximal level (after 3 weeks of fructose) of 153.4 +/- 8 mm Hg to 139.7 +/- 12 mm Hg after 2 weeks on allicin; insulin from 11.7 +/- 3.7 ng/mL on fructose diet to 6.92 +/- 3.3 ng/mL on allicin; and triglycerides from 132.8 +/- 18 mg/dL on fructose to 59.6 +/- 27 mg/dL on allicin. The similar effect of allicin and enalapril on BP, insulin, and triglycerides reinforces the trend toward combining the nonpharmacologic approach with drug therapy.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Disulfides; Enalapril; Fructose; Hyperinsulinism; Hyperlipidemias; Hypertension; Hypolipidemic Agents; Insulin; Male; Rats; Rats, Sprague-Dawley; Sulfinic Acids; Triglycerides

The paracrine renin-angiotensin-system (RAS) is increasingly recognized to play an important role in the regulation of both, regional vascular tone and regional glucose metabolism. To date, however, a selective investigation of paracrine RAS effects in an in vivo clinical setting was beyond technical reach. We here set out to selectively study the metabolic effects of paracrine RAS inhibition at different levels in healthy volunteers (n = 8). For this purpose bradykinin, enalaprilate and losartan were administered locally to the interstitial space fluid in skeletal muscle by means of reverse microdialysis and transcapillary glucose transport was measured simultaneously. During reverse microdialysis with bradykinin and enalaprilate a significant decrease in arterial-interstitial-gradient for glucose (AIG(glu)) was observed (from 1.49 +/- 0.08 mM to 0.12 +/- 0.63 mM (p = 0.018) for bradykinin and from 1.5 +/- 0.07 mM to 0.24 +/- 0.67 mM (p = 0.043) for enalaprilate). In contrast, losartan had no effect on AIG(glu). The changes in transcapillary glucose transport during bradykinin and enalaprilate administration were accompanied by significant increases in interstitial lactate levels which was most pronounced for bradykinin (from 0.14 +/- 0.01 mM to 0.40 +/- 0.07 mM, p = 0.018). We conclude that paracrine angiotensin-converting-enzyme (ACE) inhibition but not angiotensin II (AT-II) receptor blockade decreases AIG(glu) and facilitates transcapillary glucose transport due to an increase in interstitial bradykinin concentration. These results support the concept that blood pressure control with ACE-inhibitors but not with AT-II-receptor-antagonists has beneficial long term metabolic consequences in hypertensive, hyperinsulinemic subjects.

Topics: Adult; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biological Transport; Bradykinin; Capillaries; Enalapril; Glucose; Humans; Hyperinsulinism; Losartan; Male; Receptors, Angiotensin

We examined accumulating evidence of the positive contribution of nitric oxide to the pharmacological effects of converting enzyme inhibitors in 36 rats rendered hypertensive, hyperinsulinemic, and hypertriglyceridemic by a fructose-enriched diet. We studied the response of blood pressure, insulin, and triglyceride levels to inhibition of either converting enzyme-kininase II, nitric oxide synthase, or both. Two weeks of the converting enzyme inhibitor enalapril (20 mg/kg) reduced blood pressure from 137 +/- 2 to 105 +/- 7 mm Hg, insulin from 7.6 +/- 2.0 to 2.2 +/- 1.1 pg/mL, and triglycerides from 292 +/- 37 to 163 +/- 37 mg/dL. Treatment with NG-nitro-L-arginine methyl ester (100 mg/kg) raised blood pressure from 144 +/- 7 to 170 +/- 8 mm Hg without affecting the other parameters. Two weeks of concomitant treatment with both agents blunted the hypotensive and beneficial metabolic effects of enalapril; thus, final blood pressure (141 +/- 7 mm Hg), insulin (6.4 +/- 2.4 pg/mL), and triglyceride (231 +/- 51 mg/dL) values were no different from those of untreated fructose-fed rats. These data suggest that persistent synthesis of nitric oxide contributes to the vasodilator and metabolic effects of enalapril in the fructose-fed rat model.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Drug Synergism; Enalapril; Fructose; Hyperinsulinism; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Triglycerides

1. The present study was undertaken to examine the effect of the angiotensin converting enzyme (ACE) inhibitor, enalapril, on blood pressure and spontaneous blood glucose levels in two rat models: our new diabetic hypertensive rat in which genetic hypertension and diabetes develop following cross-breeding of Cohen diabetic rat (CDR) and spontaneous hypertensive rats (SHR); and a rat in which hypertension, hyperinsulinaemia and hyperlipidaemia were induced by fructose diet. 2. The new strain of animal was fed the usual copper-poor sucrose diet, and for 4 weeks received enalapril. The fructose-induced hyperinsulinaemic animals were fed a fructose-enriched diet for 3 weeks, and enalapril 20 mg per kg per day was added to the drinking water for 2 more weeks. 3. The new strain of diabetic-hypertensive rats that received enalapril showed a significant decrease in blood pressure level. The fructose-fed animals showed a fall in insulin and blood pressure following the introduction of enalapril to their diet. 4. The present study confirms the advantage of the ACE inhibitor enalapril in improving the metabolic parameters of hypertensive diabetic rats, including insulin sensitivity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Copper; Diabetes Mellitus; Diet; Enalapril; Female; Fructose; Hyperinsulinism; Hyperlipidemias; Hypertension; Male; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley

Hypertension in obese patients is associated with hyperinsulinemia and salt sensitivity. Very low salt diets may exacerbate hyperinsulinemia, perhaps by activating the renin-angiotensin system. Therefore, the effects of a low salt diet alone and with enalapril on blood pressure and the insulin response to an oral glucose tolerance test were studied in 9 obese (body mass index 35 +/- 2 kg/m2) men with mild hypertension. Measurements were first obtained after a 2-week high-salt (20 mEq/day sodium diet+eleven 1 g salt tablets per day) baseline period. The same measurements were repeated after 2 weeks on a low salt diet (20 mEq/day) and after 2 weeks on low salt diet with enalapril in random sequence. The insulin area under the curve increased from 12.8 +/- 3.0 mU-min/dl during high salt to 16.6 +/- 3.2 mU-min/dl (p < 0.001). Plasma renin activity also increased with salt restriction from 1.4 +/- 0.2 to 3.0 +/- 0.5 ng/ml/hour, p = 0.01. With addition of enalapril to the low sodium chloride diet, the insulin area under the curve (14.5 +/- 2.6 mU-min/dl) was not significantly different from that during the high sodium chloride phase. Mean blood pressure in the laboratory was 105 +/- 1 mm Hg with high salt versus 99 +/- 1 mm Hg with low salt, p < 0.05. Addition of enalapril to the low-salt diet reduced mean blood pressure to 87 +/- 1 mm Hg (p < 0.01 vs low salt), largely by reducing total systemic resistance (p < 0.05). Salt restriction decreases laboratory BP while raising insulin levels in obese men with mild hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Diet, Sodium-Restricted; Enalapril; Humans; Hyperinsulinism; Hypertension; Insulin; Male; Obesity; Renin; Sodium, Dietary

Acute hyperinsulinaemia, achieving insulin levels within the physiological range, induces sodium retention. At the same time an activation of the renin-angiotensin system occurs, with a rise in plasma renin activity (PRA) and angiotensin-II level but no change in plasma aldosterone. After administration of higher, pharmacological doses of insulin an increase in systolic blood pressure and heart rate can also be observed, while further increases in PRA and angiotensin-II are noted. To determine whether angiotensin-II is involved in observed insulin actions, we studied the renal and cardiovascular effects of three dosages of insulin (50 (Ins I), 300 (Ins II) and 500 (Ins III) mU kg-1 h-1) in healthy subjects after one week of treatment with the angiotensin-I converting enzyme inhibitor enalapril (10 mg twice a day), using the euglycaemic clamp technique. Control data were obtained from two previously conducted experiments in the same subjects, one with infusion of insulin and one with the insulin solvent only. The effect of insulin on fractional sodium excretion, blood pressure and heart rate was unaffected by enalapril, which precludes any involvement of the renin-angiotensin system with regard to these aspects of insulin action. Insulin sensitivity increased significantly during treatment with enalapril (with enalapril: Ins I: 11.3 +/- 3.0, Ins II: 20.0 +/- 3.4 and Ins III: 20.6 +/- 3.9 mg kg-1 min-1 glucose (mean +/- SD); without enalapril: Ins I: 8.7 +/- 2.3, Ins II: 13.7 +/- 3.0 and Ins III: 15.5 +/- 3.1 mg kg-1 min-1 glucose; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Pressure; Cardiovascular System; Drug Interactions; Enalapril; Heart Rate; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Kidney; Male; Natriuresis; Renin-Angiotensin System