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The survival rate of the gerbils 72 hours after carotid ligation was 65% in control, 62% in losartan, 30% in enalapril, 32% in enalapril + losartan, and 32% in captopril groups. Statistical analysis (log rank test) of the Kaplan-Meier survival curves over 72 hours showed no difference between losartan and controls nor between the various groups treated with ACEI. However survival was significantly lower in the ACEI groups than in the group treated by losartan alone (p < 0.02) or controls (p < 0.02). Intraaortic mean arterial pressure was measured in 6 controls, 6 animals treated with losartan and 6 other treated with enalapril. It was comparable in the losartan and enalapril treated animals (65 +/- 2 mm Hg vs 64 +/- 2) but significantly lower than in the controls (77 +/- 2 mmHg) (p < 0.02).
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Zinc, the catalytically essential metal of angiotensin converting enzyme (ACE), has been replaced by cobalt(II) to give an active, chromophoric enzyme that is spectroscopically responsive to inhibitor binding. Visible absorption spectroscopy and magnetic circular dichroic spectropolarimetry have been used to characterize the catalytic metal binding site in both the cobalt enzyme and in several enzyme-inhibitor complexes. The visible absorption spectrum of cobalt ACE exhibits a single broad maximum (525 nm) of relatively low absorptivity (epsilon = 75 M-1 cm-1). In contrast, the spectra of enzyme-inhibitor complexes display more clearly defined maxima at longer wavelengths (525-637 nm) and of markedly higher absorptivities (130-560 M-1 cm-1). The large spectral response indicates that changes in the cobalt ion coordination sphere occur on inhibitor binding. Magnetic circular dichroic spectropolarimetry has shown that the metal coordination geometry in the inhibitor complexes is tetrahedral and of higher symmetry than in cobalt ACE alone. The presence of sulfur----cobalt charge-transfer bands in both the visible absorption and magnetic circular dichroic spectra of the cobalt ACE-Captopril complex confirm direct ligation of the thiol group of the inhibitor to the active-site metal.
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ACE inhibitors selectively potentiate endothelium dependent relaxations to submaximal concentrations of bradykinin in bovine and human coronary arteries by a local mechanism. This effect on endothelial cells might occur in addition to augmented bradykinin concentrations in the blood and reduced angiotensin II generation.
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In normal rabbits propofol (1.2 mg.kg-1.min-1) reduced mean arterial pressure from awake control by 33(SEM 3)%, cardiac output by 24(4)%, and hindlimb blood flow (HBF) by 10(2)%, but did not change renal blood flow. In rabbits with CHF, although resting mean blood pressure was lower, propofol did not alter blood pressure or hindlimb blood flow, but renal blood flow was reduced by 37(6)%.
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A loading dose of enalaprilat 0.625 mg infused over 1 hr was followed by 5 mg/24 hrs administered continuously for up to 72 hrs.
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The aim of this study was to find predictors to identify patients with hypertension who will not improve after removal of renal artery stenosis (RAS).
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Podocytes play an important role in the pathogenesis and progression of glomerulosclerosis. Various elements of the renin-angiotensin-aldosterone system can induce podocyte apoptosis. However, little is known about the direct effects of renin on podocytes.
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The benefit-risk ratio of combined blocking by the direct renin inhibitor aliskiren and an angiotensin-converting enzyme inhibitor (e.g. enalapril) on the renin-angiotensin-aldosterone system is discussed. No method was available for simultaneous determination of both drugs in urine. A novel sensitive method for simultaneous quantification in undiluted human urine was developed which enables systematic pharmacokinetic investigations, especially in poorly investigated populations like children. Matrix effects were clearly reduced by applying solid-phase extraction followed by a chromatographic separation on Xselect(TM) C18 CSH columns. Mobile phase consisted of methanol and water, both acidified with formic acid. Under gradient conditions and a flow rate of 0.4 mL/min the column effluent was monitored by tandem mass spectrometry with electrospray ionization. Calibration curves were constructed in the range of 9.4-9600 ng/mL regarding aliskiren, 11.6-12000 ng/mL for enalapril and 8.8-9000 ng/mL for enalaprilat. All curves were analyzed utilizing 1/x(2) -weighted quadratic squared regression. Intra-run and inter-run precision were 3.2-5.8% and 6.1-10.3% for aliskiren, 2.4-6.1% and 3.9-7.9% for enalapril as well as 3.1-9.4% and 4.7-12.7% regarding enalaprilat. Selectivity, accuracy and stability results comply with current international bioanalysis guidelines. The fully validated method was successfully applied to a pharmacokinetic investigation in healthy volunteers.
The angiotensin converting enzyme-inhibitor enalapril is the prodrug of enalaprilat and used in the treatment pediatric hypertension and chronic heart failure. Pharmacokinetic data are lacking to provide adequate dosing and for pediatric pharmacotherapeutical trials it is imperative to minimize sample volume. Therefore an HPLC-tandem mass spectrometry (MS) method for the determination of enalapril and enalaprilat in 100 μL of human serum was developed and validated with benazepril as internal standard (IS). After solid-phase extraction, chromatography was performed on a Luna(®) RP-C(18) (2) column with methanol-water-formic acid (65:35:1, v/v/v) as mobile phase and a flow rate of 0.4 mL/min. The MS was set to positive-mode electrospray ionization and multiple reaction monitoring, analyzing the m/z transitions channels 377.3 → 234.2, 349.3 → 206.1 and 425.3 → 351.2 for enalapril, enalaprilat and IS. Calibration curves were linear in the range of 1.61-206 ng/mL (enalapril) and 1.84-236 ng/mL (enalaprilat) with coefficients of determination >0.99. Relative standard deviations of intra- and inter-run precisions were below 7% and relative errors were below 6 ± 7% for both analytes. Also stabilities were acceptable for both analytes. As an application example, concentrations of enalapril and enalaprilat in serum after oral administration of 20 mg enalapril maleat in a healthy volunteer were determined.
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The aim of the present study was to assess the possible differences in hemodynamic and neurohumoral responses to local ACE inhibition in the human forearm of patients with essential hypertension with either quinaprilat or enalaprilat. Forearm vascular responses to infusion of quinaprilat or enalaprilat (0.5 microg/dL/min) into the brachial artery were studied in 12 male patients with essential hypertension. The experiments were performed in a randomized, double-blind, crossover fashion. Before and during ACE inhibition, the vasoconstrictor response to four cumulative doses of angiotensin I (Ang I) was studied. Forearm blood flow was assessed using venous occlusion plethysmography. Local quinaprilat infusion induced a more rapid (even after 15 minutes; median vasodilation quinaprilat 29% vs. enalaprilat --1%, P < 0.02) and longer lasting forearm vasodilation as compared with enalaprilat. After 15 minutes of local ACE inhibition, the vasoconstrictor response to Ang I was completely blocked by both ACE inhibitors. We conclude that in patients with essential hypertension quinaprilat induces a more rapid and longer lasting vasodilatation than enalaprilat. These effects of quinaprilat are possibly related to its higher affinity for vascular ACE. On the other hand, the fact that these effects of quinaprilat were observed despite a similar degree of ACE inhibition as during enalaprilat may suggest that quinaprilat directly stimulates another vasodilatating mechanism.
Severe hypertension is a common clinical problem in the United States, encountered in various clinical settings. Although various terms have been applied to severe hypertension, such as hypertensive crises, emergencies, or urgencies, they are all characterized by acute elevations in BP that may be associated with end-organ damage (hypertensive crisis). The immediate reduction of BP is only required in patients with acute end-organ damage. Hypertension associated with cerebral infarction or intracerebral hemorrhage only rarely requires treatment. While nitroprusside is commonly used to treat severe hypertension, it is an extremely toxic drug that should only be used in rare circumstances. Furthermore, the short-acting calcium channel blocker nifedipine is associated with significant morbidity and should be avoided. Today, a wide range of pharmacologic alternatives are available to the practitioner to control severe hypertension. This article reviews some of the current concepts and common misconceptions in the management of patients with acutely elevated BP.
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A metabolic anomaly mainly affecting the degradation of des-Arg9-BK could be responsible for its accumulation in vivo. Des-Arg9-BK could be responsible, at least in part, for severe hypotensive transfusion reactions.
Twelve patients with PTE and 12 renal transplant patients without PTE were studied. Erythroid burst-forming units (BFU-E) were isolated from peripheral blood using standard methods. Ep sensitivity was determined for four patients with PTE and three control patients, using 0-3 U/ml Ep. AII dose response was studied in four patients with PTE and five control patients, using AII concentrations of 0-1000 nM. The effect of enalaprilat was studied in eight patients with PTE and eight control patients, using drug concentrations of 0-10 ng/ml. ACE gene insertion/deletion polymorphism was determined by polymerase chain reaction.
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Prolonged intraoperative renal ischemia requires modalities to reduce the incidence of acute tubular necrosis, but there exists no definitive prophylactic regimen. We studied the effects of enalaprilat, an angiotensin-converting enzyme inhibitor, in an attempt to identify such a protective drug. Thirty-four mongrel dogs underwent 90 min of bilateral renal pedicle clamping. Group I was a control of 6 animals. Group II comprised 10 animals who received 12.5 g iv mannitol 15 min prior to clamping and 1 mg/kg iv furosemide immediately after clamp removal. Group III also comprised 10 animals who received enalaprilat 1 mg/kg iv enalaprilat each 15 min prior to clamp placement. Group IV consisted of 8 dogs, each of which received 12.5 g mannitol and 1 mg/kg iv enalaprilat 15 min prior to clamping and 1 mg/kg iv furosemide immediately upon removal of the clamps. Serum blood urea nitrogen (BUN) and creatinine levels were drawn preoperatively and at 12, 24, 48, and 72 hr postoperatively in each animal. The serum BUN levels in group III were significantly lower than those in group I at all times postoperatively (P < 0.05) and were not significantly different from those of group II at any time postoperatively. Similarly, the serum creatinine levels in group III were significantly lower than those of group I (P < 0.05) and were not significantly different from those in group II at any time postoperatively. Neither the serum BUN nor the serum creatinine levels in group IV were different from those of group I at any time postoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)
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Twelve normal volunteers were given 10 mg enalapril maleate by single and 2 weeks multiple dose administration, and blood samples were collected for the determination of enalaprilat concentration and angiotensin converting enzyme (ACE) activity. The mean terminal elimination half-life following a single administration of 10 mg enalapril, was 27 hours. The inhibition of ACE activity paralleled enalaprilat concentrations following both single and multiple dosing and the time of maximum inhibition of ACE activity was associated on both occasions with maximum concentration of enalaprilat. Emax modelling of enalaprilat concentration and ACE activity gave comparable values of Emax for both methods of administration. An accumulation factor of 1.7 was calculated from the area under the concentration time curve (AUC) of enalaprilat within a dosing interval at steady-state and the total AUC following single administration of enalapril. There were no significant differences between males and females in the accumulation factor, half-life and AUCinf.
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The purpose of this investigation was to study the effect of an angiotensin converting enzyme inhibitor (enalaprilat) on the morphologic manifestations of experimentally induced necrotizing tracheobronchitis (NTB). Twenty piglets were anesthetized before saline lung lavage. High frequency flow interrupter (HFFI) ventilation was used with a strategy known to produce NTB. Animals were randomly assigned to receive IV enalaprilat 0.1 mg/kg (ENP-Hi), enalaprilat 0.01 mg/kg (ENP-Lo), or saline (C). After 8 hours of ventilation, the piglets were sacrificed. Total airway injury scores (mean +/- S.D.) were 1.2 +/- 0.7 for ENP-Hi, 0.2 +/- 0.2 for ENP-Lo, and 21.3 +/- 16 for group C. Enalaprilat minimizes NTB lesions in neonatal piglets exposed to high frequency oscillatory ventilation. Although the origin of NTB is multifactorial, airway mucosa ischemia may play an important role. Enalaprilat may compensate for the reduction of mucosal blood flow by limiting formation of angiotensin II and/or preventing degradation of bradykinin.
We compared the effects of enalaprilat (0.3 mg/kg per min for 5 min bolus, 1 mg/kg per h infusion), losartan (DuP753; 4 mg/kg bolus, 2 mg/kg per h infusion) and vehicle administration on the MAP response to infusions of phenylephrine that were increased incrementally (2.5, 5 and 10 micrograms/kg per min).
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To examine the manner in which changes in diastolic performance can contribute to the effect of vasodilation in patients with left ventricular (LV) systolic dysfunction, we examined the effect of acute inhibition of angiotensin converting enzyme with intravenous enalaprilat on early LV diastolic filling. We studied 43 patients with congestive heart failure and depressed LV systolic function (mean ejection fraction +/- SD, 0.24 +/- 0.06), performing radionuclide ventriculography before and after administration of 1.25 mg intravenous enalaprilat. We measured the effect of enalaprilat on the maximum rate of early LV diastolic filling normalized in four different ways and related these changes to both LV and right ventricular (RV) volumes. Enalaprilat induced a small but statistically significant reduction in LV end-systolic volume and increase in LV ejection fraction. For the entire patient group, there was no significant change in LV peak filling rate after enalaprilat administration. For individual patients, however, the effect of enalaprilat on peak filling rate was related to resting RV end-diastolic and end-systolic volumes. In patients with enlarged RV end-diastolic volumes (greater than or equal to 120 ml/m2), mean peak filling rate increased from 1.38 +/- 0.6 to 1.71 +/- 0.6 end-diastolic volumes (EDV)/sec and from 244 +/- 131 to 297 +/- 162 ml/sec/m2 after enalaprilat administration, whereas no change in mean peak filling rate was observed in patients with nondilated RVs. These observations were present regardless of the method of normalizing peak filling rate. Thus, the response of LV peak filling rate to enalaprilat is influenced by the presence of RV dilatation.(ABSTRACT TRUNCATED AT 250 WORDS)
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A bioequivalence study of two oral formulations of 20/12.5 mg tablets of enalapril/hydrochlorothiazide was carried out in 20 healthy male volunteers according to a single dose, two-sequence, crossover randomized design. One washout period of nine days was observed between the two periods. Multiple samples were collected over 96 hours post-dosing. Bioavailability was evaluated on the basis of plasma concentrations of enalapril and its main active metabolite, enalaprilat and hydrochlorothiazide. Plasma samples were assayed for enalapril, enalaprilat and hydrochlorothiazide using a selective and sensitive high-performance liquid chromatography method with mass spectrometry detection (LC-MS). The pharmacokinetic parameter values of Cmax and tmax were obtained directly from plasma data, k(e) was estimated by log-linear regression, and AUC was calculated by trapezoidal rule. Different statistical tests were performed on the basis of untransformed and log-transformed data and the overall residual variance from ANOVA. Assuming the accepted tolerance intervals, a beta-error of 20% and 90% confidence intervals (alpha = 0.10), all the generally accepted tests (Schuirmann test and Wilcoxon-Tukey and Hauschke nonparametric tests) showed that the formulations can be considered as bioequivalent with respect to the extent of absorption, given by the AUC(0-infinity) and with respect to rate of absorption as assessed by Cmax and tmax.
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Nitric oxide and angiotensin II have been shown to attenuate cardiac beta-adrenergic inotropism.
Carbonic anhydrase inhibition with benzolamide reduces proximal reabsorption and activates tubuloglomerular feedback (TGF). In rats, TGF activation for 30 to 60 minutes locally suppresses renin secretion and resets TGF rightward to accommodate increased late proximal flow. After 24 hours of TGF activation, there is upward resetting of GFR and increased activity of macula densa nitric oxide synthase I (NOS I).
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Endogenous AVP and the renin-angiotensin system play important roles in maintaining blood pressure after epidural anesthesia in healthy subjects.
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The parent diacid (N-[(S)-1-carboxy-3-phenylpropyl]-L-Ala-L-Pro of MK-421 inhibited hog plasma angiotensin converting enzyme (ACE) by 50% (I50) at a concentration of 1.2 nM and was 17 times more potent than captopril. In vitro the I50 for MK-421, an ethyl ester, was 1200 nM because de-esterification did not occur. Similarly in the guinea-pig ileum, the diacid inhibitor and MK-421 potentiated the contractile effects of bradykinin at an AC50 of 77 pM and 18 nM, respectively. Inhibition of the pressor effects of angiotensin I by the diacid ACE inhibitor occurred at an ID50 of 8.2 micrograms/kg i.v. in rats and 6.4 micrograms/kg i.v. in dogs. Thus, the diacid was approximately 12 times more potent than captopril. The ID50 for MK-421 was 14 and 278 micrograms/kg i.v. in rats and dogs, respectively, because of differences in the rates of de-esterification. Oral ACE inhibitory activity was determined by blockade of the pressor effects of angiotensin I in conscious rats and dogs. In rats, but not in dogs, the diacid inhibitor was poorly absorbed, whereas MK-421 was well absorbed in both species. MK-421 inhibited the pressor effects of angiotensin I at 0.1 to 3.0 mg/kg p.o. for at least 6 hr in rats and dogs, and compared to captopril was 8.6 times more potent in rats and 4.6 times more potent in dogs. These data demonstrate that MK-421 and its parent diacid are potent, long-lasting orally active inhibitors of ACE. In addition, the low activity of MK-421 in vitro contrasts with its substantial in vivo activity, and supports the hypothesis that MK-421 is a prodrug that first must be de-esterified to permit full expression of its significant in vivo pharmacological activity.
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Angiotensin converting enzyme (ACE) inhibitors have been demonstrated to possess proinflammatory properties. Persistent cough and increased broncho-obstruction have been reported frequently in hypertensive subjects on ACE inhibitor therapy. We have studied the effect of an alpha-2 adrenoceptor agonist, clonidine, on MK 422 (active parent diacid of enalapril)-induced hypotension and potentiated inflammatory skin responses in ovalbumin-sensitized guinea pigs. Clonidine was found to abolish dose-dependently MK 422-potentiated ovalbumin-evoked inflammatory dermal responses and it possesses additive hypotensive effects when combined with the ACE inhibitor. It would therefore be interesting to evaluate further alpha-2 adrenoceptor agonists and ACE inhibitors in a combination therapy in humans when single drug antihypertensive therapy of the drugs is insufficient.
Maximakinin (MK), an amphibian peptide possessing the C-terminal sequence of bradykinin (BK), is a BK B2 receptor (B2R) agonist eliciting prolonged signaling. We reinvestigated this 19-mer for species-specific pharmacologic profile, in vivo confirmation of resistance to inactivation by angiotensin converting enzyme (ACE), value as a module for the design of fusion proteins that bind to the B2R in mammalian species and potential activity as a histamine releaser. Competition of the binding of [(3)H]BK to recombinant human myc-B2Rs in cells that express these receptors revealed that MK possessed a tenuous fraction (<0.1%) of the affinity of BK, despite being only ∼20-fold less potent than BK in a contractility assay based on the human isolated umbilical vein. These findings are reconciled by the generation of C-terminal fragments, like Lys-Gly-Pro-BK and Gly-Pro-BK, when the latent MK is incubated with human venous tissue (LC-MS), supporting activation via hydrolysis upstream of the BK sequence. At the rat recombinant myc-B2R, MK had a lesser affinity than that of BK, but with a narrower margin (6.2-fold, radioligand binding competition). Accordingly, MK (10 nM) stimulated calcium transients in cells that expressed the rat receptors, but not the human B2R. Recombinant MRGPRX2, a receptor that mediates cationic peptide-induced mast cell secretion, minimally responded by increased [Ca(+2)]i to MK at 10 µM. Enhanced green fluorescent protein fused to MK (EGFP-MK) labeled cells that expressed rat, but not human B2Rs. Intravenous MK induced dose-dependent hypotensive, vasodilator and tachycardic responses in anesthetized rats and the effects were antagonized by pretreatment with icatibant but not modified by pyrilamine or enalaprilat. Strong species-specific responses to the toxin-derived peptide MK and its prodrug status in the isolated human vein were evidenced. Accordingly, MK in the EGFP-MK fusion protein is a pharmacophore module that confers affinity for the rat B2R, but not for the human form of the B2R. MK is unlikely to be an efficient mast cell activator, but its resistance to inactivation by ACE was confirmed in vivo.