enalapril and alacepril

The objectives were to determine the effects of alacepril, an angiotensin-converting enzyme inhibitor, on the expression of adhesion molecules and monocyte adherence to endothelial cells induced by 7-ketocholesterol (7-KC) and tumor necrosis factor (TNF)-alpha. We used human aortic endothelial cells (HAECs) and U937 monocytic cells. Surface expression and mRNA levels of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) were determined by EIA and RT-PCR. Adherence of U937 to HAECs was assessed by adhesion assay. Incubation of HAEC with 7-KC increased the surface expression of protein and mRNA levels of ICAM-1 and VCAM-1 on HAECs and the production of reactive oxygen species (ROS) in HAECs. Pretreatment with alacepril reduced the enhanced expression of these molecules in a dose-dependent manner. The inhibitory effect of alacepril against 7-KC or TNF-alpha-induced CAMs expression was stronger than that of captopril or enalapril. Alacepril inhibited the production of ROS in HAECs stimulated by 7-KC or TNF-alpha. These results suggest that alacepril works as anti-atherogenic agent through inhibiting endothelial-dependent adhesive interactions with monocytes induced by 7-KC and TNF-alpha.

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Cell Adhesion; Dose-Response Relationship, Drug; Enalapril; Endothelium, Vascular; Inflammation; Intercellular Adhesion Molecule-1; Ketocholesterols; Monocytes; Reactive Oxygen Species; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

The effects of angiotensin-converting enzyme (ACE) inhibitors was investigated on the development of cerebral vasospasm and on the endothelium-dependent relaxation in the rat subarachnoid hemorrhage (SAH) model. Alacepril or enalapril was used as an ACE inhibitor with or without a thiol moiety in the structure. SAH rats or sham-operated rats were produced by the injection of homologous blood or artificial cerebrospinal fluid into the cisternal magna, respectively. In the SAH rat, cerebral vasospasm was observed at 24 h after blood injection. Acetylcholine (Ach)-induced relaxation in basilar arteries from SAH rats significantly decreased compared to that from sham-operated rats, although the relaxation induced by 3-morpholinosydnonimine, sodium nitroprusside or papaverine did not decrease. These results suggest that the endothelium cell function of basilar arteries in SAH rats is damaged. Alacepril prevented both the development of cerebral vasospasm and the suppression in the Ach-induced relaxation of basilar artery in SAH rats. However, enalapril did not prevent the suppression of Ach-induced relaxation in SAH rats, despite the tendency to prevent cerebral vasospasm. Therefore, it is suggested that the preventive effect of alacepril on cerebral vasospasm could be based on its protective effect on endothelium-dependent relaxation system.

Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Basilar Artery; Captopril; Disease Models, Animal; Enalapril; In Vitro Techniques; Ischemic Attack, Transient; Male; Muscle Relaxation; Rats; Rats, Sprague-Dawley; Subarachnoid Hemorrhage

One hundred thirteen patients with essential hypertension receiving single or multiple antihypertensive agents were enrolled in the study. All had had mild to severe hypertension before treatment, but their diastolic blood pressure (DBP) at study entry was lower than 90 mm Hg for all measurements. In half of the subjects, non-thiazide diuretics (n = 35) or angiotensin-converting enzyme inhibitors (ACEI, n = 37) were discontinued, and their remaining drugs were maintained throughout the study. The other patients (n = 41) continued all their medications. Forty-one percent of subjects remained normotensive for 12 months after withdrawal of diuretics, and 37% of patients with ACEI discontinuation remained normotensive, although the recurrence of hypertension after withdrawal of ACEI tended to be earlier than its recurrence after withdrawal of diuretics. Serum uric acid and creatinine concentration decreased after diuretic withdrawal, but not after ACEI withdrawal. Diuretic withdrawal resulted in an increase in serum potassium, but ACEI withdrawal induced a decrease in serum potassium. Withdrawal of diuretics or ACEI both significantly reduced plasma renin activity. The present study may be indicative of the ability to withdraw some medications in many patients being treated with multiple antihypertensive agents.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Captopril; Diuretics; Drug Therapy, Combination; Enalapril; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Potassium; Renin; Treatment Outcome; Uric Acid

To elucidate the antihypertensive mechanisms of alacepril (DU-1219), the drug itself and its metabolites, desacetylalacepril (DU-1227) and captopril, were examined both in vitro and in vivo for their effects on the sympathetic nerve which innervates the peripheral vessels. 1. In isolated perfused mesenteric preparations from spontaneously hypertensive rats (SHR, DU-1227 (10(-6)-10(-5) mol/l) attenuated dose-dependently the increases in perfusion pressure and in norepinephrine (NE) overflow which were induced by electrical stimulation of periarterial sympathetic nerves (15 Hz). Captopril (10(-6)-10(-5) mol/l) caused a similar attenuation, though to a lesser degree, of the perfusion pressure but did not inhibit the increase in NE overflow. 2. The sympatho-inhibitory effect of DU-1227 in the above experiment was shown to be caused by DU-1227 per se, since no captopril was detected in either the perfusate or tissues perfused with DU-1227. 3. In pithed SHR, alacepril (3 mg/kg) caused as potent an inhibitory effect as captopril (3 mg/kg) on the pressor response to the electrical sympathetic nerve stimulation (3 Hz) at an oral dose about half as that of captopril on the molar basis. The effect of alacepril tended to last longer than that of captopril. However, at higher oral dose levels, the inhibitory effect of alacepril (30 mg/kg) was of the similar extent to that of captopril (30 mg/kg). 4. In pithed SHR which had received bilateral nephrectomy 2 to 8 h previously, alacepril (30 mg/kg p.o.) significantly attenuated the vasopressor response induced by electrical stimulation (1-30 Hz) 1 and 3 h after administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Captopril; Electric Stimulation; Enalapril; Male; Nephrectomy; Norepinephrine; Rats; Rats, Inbred SHR; Sympathetic Nervous System

The mechanisms underlying drug-induced neutropenia are poorly characterized. We have examined the mechanism of suppression of granulocytopoiesis by captopril and penicillamine using human and canine bone marrow cells in an in vitro culture system. Addition of captopril caused no significant change in granulocyte-macrophage colony formation at concentrations up to 30 micrograms/ml. In the presence of CuSO4 (1-3 micrograms/ml), however, captopril caused significant inhibition of colony growth (p less than 0.05). Penicillamine, another agent associated with neutropenia and, like captopril, having a reactive thiol group, also inhibited colony formation in the presence of copper. Chemical congeners of captopril lacking a reactive thiol group and enalaprilic acid, an alternative angiotensin-converting enzyme (ACE) inhibitor, failed to show inhibition, suggesting that the thiol group and not ACE inhibition was responsible. Analysis of day-7 colonies (98% neutrophilic) and day-21 colonies (37% neutrophilic, 30% macrophagic, 27% eosinophilic, and 6% mixed) showed that neutrophil-containing colonies, but not nonneutrophilic colonies were inhibited by the addition of captopril plus copper. Catalase totally reversed the inhibition of colony formation caused by these agents. Direct measurement of oxygen consumption in the presence of captopril showed marked enhancement with the addition of CuSO4 and a 48% reduction in the presence of added catalase. These data indicate that drugs with a reactive thiol group can interact with copper to generate H2O2, which can be toxic to neutrophilic progenitor cells. We postulate that this may be an important mechanism for drug-associated neutropenia and a general mechanism for drug-induced marrow cell injury.

Topics: Animals; Bone Marrow; Captopril; Catalase; Cells, Cultured; Colony-Forming Units Assay; Dogs; Enalapril; Enalaprilat; Granulocytes; Hematopoiesis; Hematopoietic Stem Cells; Humans; Leukopenia; Oxygen Consumption; Penicillamine; Sulfhydryl Compounds