enalaprilat-anhydrous and Diabetes-Mellitus--Type-1

We postulated that nitric oxide (NO)-mediated endothelial function would be improved by acute and short-term treatment with an angiotensin converting enzyme (ACE) inhibitor in patients with type I diabetes mellitus, in whom endothelial function is depressed. Nine type I diabetic patients and eight healthy subjects underwent forearm blood flow measurement using strain gauge plethysmography during intraarterial infusion of incremental doses of endothelium-dependent (acetylcholine [ACh]) and endothelium-independent (sodium nitroprusside [SNP]) vasodilators. Pretreatment ACh responses were depressed in diabetic patients relative to the normal subjects (P < 0.05). No difference between the groups was evident in response to SNP. Acute ACE inhibition (with intrabrachial enalaprilat) enhanced ACh responses in the diabetic patients (P < 0.005), with a further improvement evident after 1 mo of oral therapy with enalapril (P < 0.001) when ACh responses were normalized. ACE inhibition did not affect SNP responses. We conclude that acute administration of the ACE inhibitor, enalaprilat, enhances NO-mediated endothelial function in type I diabetic patients, with further improvement evident after 4 wk of enalapril therapy.

Topics: Administration, Oral; Adult; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 1; Enalapril; Enalaprilat; Endothelium; Humans; Male; Middle Aged; Nitric Oxide

1. A sustained high glomerular filtration rate in diabetes mellitus is associated with increased proximal reabsorption, suggesting alterations in the tubuloglomerular feedback system. To test this hypothesis, renal function was studied in eight control subjects and 14 recent-onset euglycaemic insulin-dependent diabetic patients before and after infusion of the carbonic anhydrase inhibitor, acetazolamide (5 mg/kg body weight). 2. Acetazolamide induced a dramatic fall in glomerular filtration rate in both diabetic patients and control subjects (from 138 +/- 5 to 114 +/- 4 and from 127 +/- 3 to 113 +/- 2 ml min-1 1.73 m-2, respectively, P less than 0.0001). This fall in glomerular filtration rate was strongly correlated with the acetazolamide-induced decrease in absolute proximal reabsorption calculated by using lithium clearance. 3. To further assess the potential role of angiotensin II in the acetazolamide-induced tubulo-glomerular feedback response, 11 additional diabetic patients were investigated before and after the administration of acetazolamide plus the angiotensin-converting enzyme inhibitor, enalaprilat (1.25 mg intravenously). Despite the effective blockade of angiotensin II formation and a slight decrease in renal vascular resistance, the glomerular filtration rate fell significantly and by a similar magnitude as seen with acetazolamide alone. 4. These results indirectly suggest that there is an altered basal tubulo-glomerular feedback system in diabetic patients but a normal response to the increase in distal delivery. No convincing role for an angiotensin II-mediated effect on the afferent limb of the tubuloglomerular feedback response could be demonstrated.

Topics: Acetazolamide; Adolescent; Adult; Diabetes Mellitus, Type 1; Enalaprilat; Feedback; Glomerular Filtration Rate; Humans; Kidney; Kidney Glomerulus; Kidney Tubules; Lithium; Vascular Resistance

Early antihypertensive treatment with beta1 blockers and diuretics has proved to delay progression in diabetic nephropathy. Application of angiotensin converting enzyme inhibitors (ACE-I) may also be relevant. To elucidate possible differences in acute renal response to ACE-I and beta-blockers, kidney function was investigated before and after enalaprilat (10 mg) and metoprolol (10 mg) i.v. in 8 microalbuminuric insulin-dependent diabetic patients on no antihypertensive therapy (Study A). Glomerular filtration rate (clearance of 125I-iothalamate) was unchanged with both agents. ACE-I gave rise to efferent renal vasodilation: renal resistance and filtration fraction fell, renal plasma flow (RPF; 131I-hippuran) tended to rise (2p = 0.07) and blood pressure and urinary albumin excretion rate (UAE; radioimmunoassay) were reduced. In contrast, metoprolol caused a decline in RPF, an increase in renal resistance and filtration fraction, and no change in blood pressure or UAE. In 10 diabetic, nephropathic patients undergoing treatment with metoprolol and thiazide (Study B), the acute response to enalaprilat corresponded closely to that observed in Study A, including a decrease in UAE and blood pressure. Over 6 months the addition of enalapril (20 mg/d) to metoprolol and thiazide produced a more pronounced UAE-reduction, although no significant decrease in blood pressure was observed. The present findings support that ACE-I may process specific renoprotective effects. A combination therapy with beta1 blockers, ACE-I, and diuretics is suggested.

Topics: Adult; Albuminuria; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Enalaprilat; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension; Kidney; Male; Metoprolol; Middle Aged; Natriuresis; Renal Circulation; Vascular Resistance