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Single-pass and recirculating rat liver perfusion studies were conducted with [14C]enalapril and [3H]enalaprilat, a precursor-product pair, and the data were modeled according to a physiological model to compare the different biliary clearances for the solely formed metabolite, [14C]enalaprilat, with that of preformed [3H]enalaprilat. With single-pass perfusion, the apparent extraction ratio (or biliary clearance) of formed [14C]enalaprilat was 15-fold the extraction ratio of preformed [3H]enalaprilat, an observation attributed to the presence of a barrier for cellular entry of the metabolite. Upon recirculation of bolus doses of [14C]enalapril and [3H]enalaprilat, the biliary clearance, estimated conventionally as metabolite excretion rate/midtime metabolite concentration, for formed [14C]enalaprilat was again 10- to 15-fold higher than the biliary clearance for preformed [3H]enalaprilat, but this decayed with perfusion time and gradually approached values for preformed [3H]enalaprilat. The decreasing biliary clearance of formed enalaprilat with recirculation was explained by the dual contribution of the circulating and intrahepatic metabolite (formed from circulating drug) to excretion. Physiological modeling predicted (i) an influx barrier (from blood to cell) at the sinusoidal membrane as the rate-limiting process in the overall removal of enalaprilat, (ii) a 15-fold greater extraction ratio or biliary clearance for formed [14C]enalaprilat over [3H]enalaprilat during single-pass perfusion, and (iii) the time-dependent and declining behaviour of the biliary clearance for formed [14C]enalaprilat during recirculation of the medium. In the absence of a direct knowledge of eliminating organs in vivo, this variable pattern for excretory clearance of the formed metabolite within the organ is indicative of a metabolite formation organ.
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The effects of captopril on the response of cytosolic free Ca2+ concentration in cultured vascular smooth muscle cells of aortas from Wistar-Kyoto and spontaneously hypertensive rats to angiotensin II (Ang II) and bradykinin were studied using fura 2. Incubation with captopril for longer than 10 minutes caused a decreased response of cytosolic free Ca2+ to Ang II and bradykinin. Maximal effects of captopril were observed after a 40-minute incubation. The inhibitory effect of captopril was abolished in Ca(2+)-free medium, suggesting that captopril acts by blocking Ca2+ influx. Similar effects were observed with enalaprilat. Isometric contraction of aortic strips induced by Ang II in normotensive rats was reduced from 6.5 +/- 2.5 to 1.8 +/- 0.6 mN by a 40-minute incubation with 1 mumol/L captopril (P = .016). Enalaprilat similarly decreased the Ang II-induced contraction. Besides the inhibition of the angiotensin converting enzyme, direct effects of Ang II converting enzyme inhibitors on vascular contraction and Ca2+ influx in vascular smooth muscle cells may be of therapeutic relevance.
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These results suggest that EN exerts beneficial effects on ischemic intracellular sodium and pH homeostasis via the bradykinin receptor. These effects of EN may provide a mechanism for the beneficial actions of this agent during ischemia.
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To determine the short-term effects of angiotensin-converting enzyme (ACE) inhibition on hemodynamics and circulating levels of norepinephrine, angiotensin, and bradykinin, responses to enalaprilat and perindoprilat were examined at doses of 0.03, 0.3, and 1 mg/kg in permanently instrumented conscious dogs with pacing-induced heart failure (right ventricular pacing, 240-250 beats/min, 3 weeks). All doses of the two inhibitors produced similar decrease in mean aortic pressure and increase in cardiac output. Neither inhibitor affected plasma norepinephrine level. Both compounds induced a similar 60-80% decrease in blood angiotensin II level, a similar two- to eightfold increase in blood angiotensin I level, and a 80-95% decrease in the angiotensin II/angiotensin I ratio. There were also a fourfold to 10-fold increase in blood bradykinin-(1-9) level, a twofold increase in blood bradykinin-(1-7) level, and a 70-85% decrease in bradykinin-(1-7)/bradykinin-(1-9) ratio. In addition, the changes in total peripheral resistance induced by the two ACE inhibitors were weakly but significantly correlated with the changes in blood angiotensin II or blood bradykinin-(1-9). Thus whatever the specificity of enalaprilat and perindoprilat, both inhibitors produced similar acute hemodynamic effects in dogs with heart failure, which was associated with marked decrease in circulating angiotensin II level and increase in bradykinin-(1-9) level. This study, which measures for the first time in heart failure the blood bradykinin level after ACE inhibitors, indicates, in concert with angiotensin II reduction, a role for increased bradykinin-(1-9) level in mediating short-term hemodynamic effects of ACE inhibition in this model of heart failure.
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Twenty-six rats were divided into 4 experimental groups: CsA group, who were treated with CsA (50 mg/kg/d) for 2 days; ATN group, who received clamping of both renal arteries for 45 minutes; vehicle group, who were treated with olive oil (1 mL/kg/d) for 2 days; and sham-operated group, who received the same surgical procedure as ATN group without clamping of renal arteries. The baseline study was performed with 300 microCi of technetium-99m diethylenetriaminepentaacetic acid and enalaprilat scintigraphy with 2 mCi of technetium-99m diethylenetriaminepentaacetic acid 5 minutes after intravenous enalaprilat injection (30 microg/kg). The changes of renogram grade and the renal function indices such as T(max), T(1/2), residual cortical activity, and mean transit time between 2 studies were analyzed. Immediately after renal scintigraphy, blood urea nitrogen and serum creatinine levels were measured and renal tissues stained by periodic acid Schiff reaction were examined in each group.
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Biometric data and time of cross-clamping were not significantly different in the four groups. Changes in the ST segment indicating ischaemia were least common in the enalaprilat group (P < 0.05). Postoperatively, CKMB activity was significantly higher in the clonidine and the control groups. Both new markers of myocardial cell damage increased more after CPB and postoperatively in the control patients (TnT peak: (mean (SD)) 3.99 (0.35) microgram/1; GPBB peak: 82 (15) ng/ml) and the clonidine-treated group (TnT peak: 3.80 (0.3) microgram/1; GPBB peak: 85 (14) ng/ml). Enalaprilat-treated patients showed the smallest overall changes in standard (CKMB) and new serological markers of myocardial ischaemia (TnT peak: 0.71 (0.1) microgram/1; GPBB peak: 44 (14) ng/ml).
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Subcutaneous resistance arteries (250 to 350 microm) were obtained from gluteal biopsies from volunteers and New Zealand White rabbits and mounted on a wire myograph. Contractile ability was tested with high-potassium depolarization and norepinephrine 10 micromol/L and endothelial integrity by relaxation to acetylcholine 3 micromol/L. Cumulative concentration-response curves were constructed for Ang I in the presence of enalaprilat 1 micromol/L, chymostatin 10 micromol/L, or both inhibitors together. In the rabbit, enalaprilat completely inhibited the Ang I response. In human vessels, enalaprilat or chymostatin alone had no effect, but the combination of enalaprilat and chymostatin almost completely inhibited the response to Ang I.
Clinical investigation in a cardiac anaesthesia department of a university hospital.
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In a randomized, cross-over, single-dose study of 19 elderly hypertensive patients (aged 62-84 y, SBP greater than 160 mmHg, DBP greater than 100 mmHg, creatinine clearance 11-93 ml.min-1) we have studied the pharmacokinetics of the angiotensin converting enzyme (ACE) inhibitor enalapril after a single oral dose of either 10 mg enalapril or 10 mg enalapril + 25 mg hydrochlorothiazide. The pharmacokinetics of enalapril were unaffected by hydrochlorothiazide, but there was a significant reduction in renal clearance and a significant increase in AUC(0-24 h) of enalaprilat after hydrochlorothiazide, resulting in higher serum concentrations of the active drug. This was independent of the individual degree of renal impairment and might be due either to an initial reduction of GFR by hydrochlorothiazide or to interference with the tubular secretion of enalaprilat. The relationships between serum enalaprilat and serum ACE activity were similar after both treatments, both consistent with a value for Ki of enalaprilat of about 0.1 nmol.l-1. Thus, serum ACE activity was not affected by hydrochlorothiazide but completely reflected the pharmacokinetics of enalaprilat in both treatments.
This study shows that acute local ACE inhibition restores bradykinin-induced relaxation in smokers to values found in nonsmokers. This observation suggests that increased vascular metabolism of bradykinin exists in veins of smokers and that the vascular renin-angiotensin system may play a key role in smoking-induced endothelial dysfunction.
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The pulmonary absorption of nine low-molecular-weight (225-430 Da) drugs (atenolol, budesonide, enalaprilat, enalapril, formoterol, losartan, metoprolol, propranolol and terbutaline) and one high-molecular-weight membrane permeability marker compound (FITC-dextran 10000 Da) was investigated using the isolated, perfused and ventilated rat lung (IPL). The relationships between pulmonary transport characteristics, epithelial permeability of Caco-2 cell monolayers and drug physicochemical properties were evaluated using multivariate data analysis. Finally, an in vitro-in vivo correlation was made using in vivo rat lung absorption data. The absorption half-life of the investigated drugs ranged from 2 to 59 min, and the extent of absorption from 21 to 94% in 2 h in the isolated perfused rat lung model. The apparent first-order absorption rate constant in IPL (ka(lung)) was found to correlate to the apparent permeability (P(app)) of Caco-2 cell monolayers (r = 0.87), cLog D(7.4) (r = 0.70), cLog P, and to the molecular polar surface area (%PSA) (r = -0.79) of the drugs. A Partial Least Squares (PLS)-model for prediction of the absorption rate (log ka(lung)) from the descriptors log P(app), %PSA and cLogD(7.4) was found (Q2 = 0.74, R2 = 0.78). Furthermore, a strong in vitro-in vivo correlation (r = 0.98) was found for the in vitro (IPL) drug absorption half-life and the pulmonary absorption half-life obtained in rats in vivo, based on a sub-set of five compounds.
1. The effects of intravenous captopril and enalaprilic acid on the increase in pulmonary inflation pressure induced by different bronchoconstrictor agents were evaluated in the anaesthetized guinea-pig. 2. Captopril and enalaprilic acid (1.6-200 micrograms kg-1) enhanced dose-dependently the bronchoconstriction (BC) induced by substance P. The threshold effective dose was 1.6 micrograms kg-1 and maximal potentiation over the control response was more than 400% for both agents. Enalaprilic acid was also assayed for serum and lung angiotensin converting enzyme (ACE) inhibition in anaesthetized guinea-pigs. This drug produced a dose-dependent inhibition of ACE in both tissues, with ED50 s of 7.6 and 9.4 micrograms kg-1, respectively: this inhibitory activity was positively correlated to substance P potentiation. 3. Captopril (8-1000 micrograms kg-1) enhanced dose-dependently the BC induced by capsaicin. The threshold effective dose was 40 micrograms kg-1 and maximal potentiation about 90%. 4. Captopril (200-1000 micrograms kg-1) did not affect BC induced by bradykinin. However, this response was markedly enhanced (about 200%) by captopril 200 micrograms kg-1 in propranolol-pretreated animals. 5. Captopril and enalaprilic acid (200-1000 micrograms kg-1) slightly (20-40%) but significantly enhanced the BC induced by 5-hydroxytryptamine. However, this response was potentiated to the same extent by a dose of prazosin, which produced a degree of hypotension similar to that observed after administration of the ACE inhibitors. 6. In conclusion, ACE inhibitors potentiate the BC induced by substance P and, to a minor extent, that induced by capsaicin in the anaesthetized guinea-pig. Potentiation of substance P is well correlated with ACE inhibition in guinea-pig serum and lungs. These experimental results may offer a mechanistic interpretation of cough and bronchial hyperreactivity observed in patients receiving treatment with ACE inhibitors.
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We examined the effect of non-SH-containing angiotensin converting enzyme (ACE) inhibitor imidaprilat on hydroxyl radical (.OH) generation using microdialysis. Salicylic acid in Ringer's solution containing sodium salicylate (0.5 n mol microL-1 min-1) was infused directly through a microdialysis probe to detect the generation of .OH as reflected by the formation of 2,3-dihydroxybenzoic acid (DHBA) in the myocardium of anesthetized rats. We compared the ability of two non-SH-containing ACE inhibitors (imidaprilat and enalaprilat) with an -SH-containing ACE inhibitor (captopril) to scavenge the .OH. When iron (II) was administered to animals pretreated with these three ACE inhibitors, a decrease in 2,3-DHBA of all three compounds was observed, as compared with the iron (II) only-treated group. All three ACE inhibitors were able to scavenge .OH generated by the action of iron (II). However, imidaprilat is a free radical scavenger more potent than enalaprilat. These results suggested that ACE inhibitors are probably not only related to the presence of the SH radical.