enalapril and isosorbide-5-mononitrate

The effects of renin-angiotensin system blockade on nitric oxide (NO), especially in pathological conditions, are far from being established. The influence of kinins and angiotensin type 2 receptor are largely speculative and based mainly on animal studies. This study was aimed to address these aspects in humans.. Eight IgA nephropathy patients with documented clinical and histological indicators of poor prognosis were given 50 mg of losartan, 10 mg of enalapril, and 40 mg of the NO donor isosorbide 5 mononitrate (as a control of NO generation) in randomized order for 7 days each. Treatment periods were separated by washout periods of 7 days each. Laboratory investigations were performed before and after each study period. Seven healthy controls received losartan and enalapril according to the same study design.. Glomerular filtration rate remained stable while effective renal plasma flow increased with each treatment (P<0.05). Under losartan and enalapril, filtration fraction fell (P=0.02), plasma renin activity increased (P<0.05) and urinary aldosterone concentration decreased (P=0.02). Angiotensin-converting enzyme activity was reduced to the limit of detection under enalapril (P<0.001). Blood NO, detected as nitrosylhaemoglobin by a recently developed technique of spin-trap electron paramagnetic resonance, increased significantly, as expected, during treatment with isosorbide 5 mononitrate (P=0.01), with enalapril (P<0.05), and also with losartan (P<0.05). Unlike losartan, enalapril significantly reduced albuminuria (P=0.01) in this short-term period. In the seven healthy controls, neither enalapril nor losartan were able to increase blood NO levels significantly.. Blood levels of nitrosylhaemoglobin, a surrogate marker of NO, increased under blockade of the renin-angiotensin system in patients with IgA nephropathy, but not in healthy volunteers. This increase could contribute to changes of effective renal plasma flow in renal disease states.

Topics: Adult; Aged; Albuminuria; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Glomerulonephritis, IGA; Hemoglobins; Humans; Isosorbide Dinitrate; Losartan; Male; Middle Aged; Nitric Oxide; Nitric Oxide Donors; Reference Values; Renal Circulation

The aim of the study was to compare hypotensive reaction after treatment with enalapril and enalapril with isosorbide mononitrate in patients with mild and moderate hypertension. Investigations were carried out in 49 patients. In every patient at baseline and after 3 hours from oral administration of enalapril or enalapril and isosorbide mononitrate plasma renin activity, plasma angiotensin converting enzyme activity, plasma aldosterone concentration and blood pressure were estimated. All measurements were repeated after 7 days of treatment. Adding a nitric oxide donor--isosorbide mononitrate--to enalapril does not enhance decrease in blood pressure nor influence plasma renin activity, plasma ACE activity nor plasma aldosterone concentration in patients with mild and moderate hypertension.

Topics: Administration, Oral; Adult; Aged; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Isosorbide Dinitrate; Male; Middle Aged; Nitric Oxide Donors; Renin; Severity of Illness Index; Time Factors; Treatment Outcome

Atrial structural remodeling creates a substrate for atrial fibrillation (AF), but the underlying signal transduction mechanisms are unknown. This study assessed the effects of ACE inhibition on arrhythmogenic atrial remodeling and associated mitogen-activated protein kinase (MAPK) changes in a dog model of congestive heart failure (CHF).. Dogs were subjected to various durations of ventricular tachypacing (VTP, 220 to 240 bpm) in the presence or absence of oral enalapril 2 mg. kg(-1). d(-1). VTP for 5 weeks induced CHF, local atrial conduction slowing, and interstitial fibrosis and prolonged atrial burst pacing-induced AF. Atrial angiotensin II concentrations and MAPK expression were increased by tachypacing, with substantial changes in phosphorylated forms of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38-kinase. Enalapril significantly reduced tachypacing-induced changes in atrial angiotensin II concentrations and ERK expression. Enalapril also attenuated the effects of CHF on atrial conduction (conduction heterogeneity index reduced from 3.1+/-0.4 to 1.9+/-0.2 ms/mm, P<0.05), atrial fibrosis (from 11.9+/-1.1% to 7.5+/-0.4%, P<0.01), and mean AF duration (from 651+/-164 to 218+/-75 seconds, P<0.05). Vasodilator therapy of a separate group of VTP dogs with hydralazine and isosorbide mononitrate did not alter CHF-induced fibrosis or AF promotion.. CHF-induced increases in angiotensin II content and MAPK activation contribute to arrhythmogenic atrial structural remodeling. ACE inhibition interferes with signal transduction leading to the AF substrate in CHF and may represent a useful new component to AF therapy.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Fibrillation; Dogs; Electrophysiology; Enalapril; Endomyocardial Fibrosis; Heart Atria; Heart Failure; Hemodynamics; Hydralazine; Isosorbide Dinitrate; Mitogen-Activated Protein Kinases; Renin-Angiotensin System; Signal Transduction; Tachycardia, Ventricular

1. The hypotensive effects of glyceryl trinitrate (GTN, 0.5 mg kg-1) but not of 3-morpholino-sydnonimine (SIN-1, 0.125 mg kg-1) in anaesthetized rats were attenuated following a seven day (using a q.i.d. dosing schedule) oral treatment with isosorbide-5-mononitrate (IS-5-MN; 5 mg kg-1) indicative of the induction of tolerance to GTN but not to SIN-1. The hypotensive effects of GTN did not decline when the sulphydryl (SH) containing angiotensin converting enzyme inhibitor (ACE-1), captopril (CPT, 5 mg kg-1) or the structurally unrelated SH-containing, N-acetylcysteine (NAC, 10 mg kg-1) but not the non-SH-containing ACE-I, enalaprilat (ENA, 5 mg kg-1) were given together with IS-5-MN for the seven days treatment. 2. The attenuated hypotensive effects of GTN (0.5 mg kg-1) in rats treated with IS-5-MN were also restored when CPT (1 mg kg-1) or NAC (2.5 mg kg-1) but not ENA (1 mg kg-1) was administered intraperitoneally (i.p.) 30 min before GTN. Furthermore, in control rats, CPT or NAC but not ENA given i.p. 30 min before GTN, potentiated its haemodynamic effects. These effects were blocked by methylene blue (10 mg kg-1). At the same doses, CPT or NAC did not affect the hypotensive effects of SIN-1. 3. The reduced ability of cultured tolerant smooth muscle cells (SMC, 24 x 103 cells) or endothelial cells(EC, 40 x 103 cells) to potentiate the anti-platelet effects of GTN (44 microM) was restored by CPT or NAC but not by ENA or glutathione (all at 0.5 mM). Potentiation of the anti-platelet effects of tolerant SMC or EC by CPT or NAC was abolished by co-incubation with oxyhaemoglobin (Oxy-Hb, 10 microM)indicative of nitric oxide (NO) formation.4. When GTN (150-2400 microM) was incubated with CPT, NAC or glutathione but not ENA (all at 0.1 mM) for 30 min in Krebs buffer at 37 degrees C a concentration-dependent increase in nitrite (NO2-)formation was observed. 5. The antiplatelet effects of GTN (5.5-352 microM) were potentiated by co-incubation with CPT or NAC but not with ENA or glutathione (all at 0.5 mM). The concentration of GTN required to inhibit platelet aggregation by 50% (IC50) was 110 +/- 2 microM for GTN alone, 14 +/- 2 microM for GTN in the presence of NAC and 30 +/- 2 microM for GTN in the presence of CPT. The potentiation of the effects of GTN by CPT or NAC was inhibited by co-incubation with Oxy-Hb (10 microM). By themselves, CPT or NAC did not inhibit platelet aggregation.6. The ability of CPT to restore (a) the haemodynamic effects of GTN in toler

Topics: Acetylcysteine; Animals; Captopril; Cattle; Enalapril; Endothelium, Vascular; Glutathione; Humans; In Vitro Techniques; Isosorbide Dinitrate; Male; Muscle, Smooth, Vascular; Nitric Oxide; Nitrites; Nitroglycerin; Platelet Aggregation; Rats; Rats, Wistar; Vasodilator Agents

The hemodynamic response of isosorbide-5-mononitrate (IS-5-MN) to the addition of the widely used therapy of diuretic drugs and the maximally tolerated dose of enalapril for heart failure was assessed in 8 patients with congestive heart failure (CHF) (New York Heart Association class II and III). The diuretic therapy was furosemide, 40 to 80 mg/day, with or without amiloride, 5 to 10 mg/day. The dose of enalapril was 5 to 20 mg/day. Four hours after the administration of the morning dose of enalapril, a Swan-Ganz catheter was positioned in the pulmonary artery. Patients received increasing doses of IS-5-MN to produce a satisfactory decrease in pulmonary capillary wedge pressure. Two of the first 3 patients studied had a large reduction in blood pressure when given 10 mg of IS-5-MN. Subsequent patients were therefore given an initial dose of 5 mg, the total dose being 5 to 20 mg over 2 hours. Results at baseline and 1 hour after the final dose of IS-5-MN are expressed as mean +/- standard deviation. Both pulmonary artery systolic and diastolic pressures decreased significantly (p less than 0.05) by 12.2 +/- 8.9/4.2 +/- 5.2 mm Hg, from 47.2 +/- 16.0/21.6 +/- 6.0 mm Hg to 35.0 +/- 15.2/17.4 +/- 9.3 mm Hg. Pulmonary capillary wedge pressure decreased by 8.6 +/- 4.4 mm Hg, from 22.1 +/- 5.4 to 13.6 +/- 7.5 mm Hg (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Blood Pressure; Cardiac Output; Chronic Disease; Diuretics; Drug Therapy, Combination; Enalapril; Female; Heart Failure; Heart Rate; Humans; Isosorbide Dinitrate; Male; Middle Aged; Pulmonary Wedge Pressure