Although early studies suggested little role for angiotensin-converting enzyme (ACE) inhibitors in older hypertensive patients, more careful evaluation has confirmed their efficacy and good tolerability. Although the elderly tend to have low plasma renin levels, the fall in blood pressure after ACE inhibitors is at least as great (and in several studies greater) than in younger age groups. Because several ACE inhibitors, including captopril and enalaprilat, are eliminated by the kidneys, there are predictable age-related effects on pharmacokinetics. Reduced renal clearance will contribute, at least in part, to the enhanced intensity and duration of action seen in elderly patients. However, not all the effects of age on the kinetics and dynamics of ACE inhibitors are predictable. Studies with perindopril and benazepril in the elderly confirm the efficacy of this group of drugs but highlight other pharmacokinetic differences. ACE inhibitors are effective in reducing blood pressure and can be considered for wider use in elderly hypertensives.
The antihypertensive effect of enalaprilat (MK-422), an intravenous (IV), nonsulfhydryl converting-enzyme inhibitor, was evaluated in a double-blind study of 14 patients with mild to moderate hypertension. The seven patients in the treatment group initially received IV enalaprilat 1.25 mg q6h for 24 hours. Thereafter, responding patients (diastolic blood pressure [BP] less than or equal to 95 mm Hg) continued receiving this dose q6h for an additional 24 hours, whereas nonresponding patients were increased to IV enalaprilat 5 mg q6h for another 24 hours. Baseline BP for enalaprilat was 161 +/- 5/107 +/- 2 mm Hg (+/- SEM), and for placebo it was 150 +/- 5/103 +/- 2 mm Hg. Within the first 60 minutes, a significant reduction in both systolic and diastolic BP was noted in the enalaprilat group (P less than .05), without significant changes occurring in the placebo group. Although there was a gradual decline in both systolic and diastolic BP throughout the 48-hour study period in the placebo group, systolic and diastolic BP reduction was greater in the enalaprilat group, reaching a maximal decrease of 133 +/- 3/87 +/- 3 mm Hg. Adverse side effects did not occur in any patient.
Early administration of enalaprilat is effective and well tolerated in acute pulmonary edema.
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The aim of this study was to examine whether angiotensin-converting enzyme (ACE) inhibition improves coronary endothelial dysfunction in patients with atherosclerosis and its risk factors and whether this was related to the ACE insertion-deletion (I/D) polymorphism.
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The interaction of angiotensin converting enzyme with six metal-coordinating [(D-3-mercapto-2-methylpropanoyl)-L-Pro (captopril), N-[1(S)-carboxy-3-phenylpropyl]-L-Ala-L-Pro (MK-422), N-(phenylphosphoryl)-L-Phe-L-Phe, N alpha-(3-mercaptopropanoyl)-L-Arg, N alpha-[1(S)-carboxy-3-phenylpropyl]-Ala-L-Lys, and N-[1(S)-carboxy-5-aminopentyl]-L-Phe-Gly] and three dipeptide inhibitors (Gly-L-Trp, L-Phe-L-Arg, and L-Ala-L-Pro) was examined at pH 7.5 in the presence of 300 mM NaCl. Inhibition modes, apparent Ki [Ki(app)] values, and shapes of 1/v vs. [I] plots were found to vary with the substrate employed. All inhibitors except Phe-Arg were competitive with the substrate furanacryloyl (Fa)-Phe-Gly-Gly, while five of seven tested with Fa-Phe-Phe-Arg as substrate produced mixed patterns. Ki-(app) values for N-[1(S)-carboxy-5-aminopentyl]-L-Phe-Gly, N-(phenylphosphoryl)-L-Phe-L-Phe, Gly-Trp, and MK-422 were 8.3-, 5.5-, 4.7-, and 2.6-fold lower, respectively, when Fa-Phe-Gly-Gly was substrate, compared with values measured with Fa-Phe-Phe-Arg. In contrast, Ki(app) values for Phe-Arg and (3-mercaptopropanoyl)-Arg were lower (2.8- and 2.2-fold, respectively) when Fa-Phe-Phe-Arg was the substrate. Plots of 1/v vs. [I] for most of the inhibitors were nonlinear, to an extent which was also substrate dependent.(ABSTRACT TRUNCATED AT 250 WORDS)
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A model of congestive heart failure (CHF) was produced in rats approximately 76 days following surgical occlusion of the left coronary artery. In rats with healed myocardial infarction (MI size = 45% LV), hemodynamic variables were predictably elevated (LVEDP greater than 20 mm Hg) or depressed LV dP/dtmax (5200 mm Hg/sec). The hemodynamic response (MAP, HR, LVEDP, and dP/dtmax) to intravenous infusion of Mil (54 to 347 micrograms/kg) was measured on two occasions, separated by a 7-12 day period of oral treatment (2 mg/kg/day). Enalaprilat was tested in a similar design with the infusion phase (70 micrograms/kg, total dose) separated by oral enalapril (Enal), 1 mg/kg/day. The hemodynamic response to Mil was also examined in rats treated with the ACE inhibitor. At low doses, Mil modestly elevated HR (+17 beats/min) and dose-dependently increased (P less than 0.05) LV contractility by approximately 25%. Higher doses of Mil reduced preload (LVEDP) and afterload (MAP). Oral Mil produced little hemodynamic improvement except modest elevation (+9%) in LV contractility. There was no evidence of tachyphylaxis to i.v. Mil. In contrast, enalaprilat reduced MAP and preload without altering HR or contractility, effects observed after oral treatment. In the presence of the ACE inhibitor, Mil's hemodynamic actions were not enhanced. These experiments demonstrate that ACE inhibition improves ventricular performance by reducing preload and afterload. In this model, Mil improves performance by a direct inotropic mechanism as well as a reduction in afterload.
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Left ventricular (LV) diastolic function and coronary flow are impaired in hypertrophic obstructive cardiomyopathy (HOCM). This study was designed to evaluate the impact of cardiac and circulatory ACE inhibition on such derangements.
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1. We have estimated potencies of tachykinin receptor agonist and antagonist analogues in order to determine the recognition characteristics of tachykinin receptors mediating phasic contractile responses of the rat isolated urinary bladder in vitro. 2. The NK1-selective synthetic agonists, substance P methyl ester and GR73632, the synthetic NK2-selective agonists [beta-Ala8]-NKA(4-10) and GR64349, and the mammalian tachykinins, neurokinin A and neurokinin B, were assayed relative to substance P and were found to be approximately equipotent. The NK3-selective agonist, senktide, was inactive (10 microM). 3. Potencies of all these agonists were not significantly different (P > 0.05) when experiments were carried out in the presence of the neutral endopeptidase inhibitor, phosphoramidon, and the kininase II inhibitor, enalaprilat (both 1 microM). 4. The NK1-selective antagonist, GR82334, inhibited responses to substance P methyl ester in a competitive manner in the rat urinary bladder and the rat ileum, and also in the guinea-pig ileum. Markedly different pKB estimates were obtained in the rat bladder (6.38) and rat ileum (6.56) compared to the guinea-pig ileum (7.42). GR82334 (3 microM) was inactive against responses of the rat bladder to [beta-Ala8]-NKA(4-10). 5. The NK1-selective antagonist (+/-)-CP-96,345 also inhibited responses of the rat bladder and guinea-pig ileum to substance P methyl ester; however, in the rat bladder at 1 microM, this antagonist reversibly inhibited responses both to the NK2-selective agonist [beta-Ala8]-NKA(4-10) and to the muscarinic agonist carbachol (P < or = 0.01), thus showing evidence of some non-selective depressant actions. 6. The NK2-selective antagonists, MEN10207 and L-659,874, competitively inhibited responses of the rat bladder to the NK2-selective agonist [P-Ala5]-NKA(4-10) giving pKB estimates of 5.75 and 6.68,respectively. Both antagonists (1O microM) were inactive against responses to the NKI-selective agonist substance P methyl ester.7. These results support the proposal of a mixed population of NKI and NK2 receptors mediating contraction of the rat isolated urinary bladder. The NK2 receptor is characterized by a relatively low affinity for the NK2-selective antagonist MEN10207 but a high affinity for L-659,874. The NKImediated responses are inhibited by (+/-)-CP-96,345: this compound however, has non-specific depressant effects in the rat bladder at high concentration (1 microM). In contrast, the NK,-receptor peptide antagonist GR82334, did not have non-specific depressant effects and competitively inhibited NK, responses in the rat bladder and rat ileum with an affinity significantly lower than at the NK,-receptors in the guinea-pigileum.
The effects of the angiotensin-converting enzyme (ACE) inhibitors captopril, enalaprilat and enalapril, and the bioactive peptides angiotensin II (Ang II), [Sar1,Ile8]angiotensin II ([Sar1,Ile8]Ang II), bradykinin and D-Arg[Hyp3,D-Phe7]bradykinin) on mitogen-induced proliferation of T-lymphocytes were evaluated in C57 mouse spleen cells. Captopril (CP) dose-dependently enhanced concanavalin A (Con A)-induced proliferation of T-lymphocytes, with the effective stimulatory concentration range between 0.02-10 mM. The mitogen-induced proliferative response was inhibited at high concentrations (> 10 mM) of CP which affected the number of viable cells. Enalapril dose-dependently inhibited Con A-induced T-lymphocyte proliferation at 0.44-20 mM. This was comparable to the ACE inhibitory peptide, which had a similar range. Enalaprilat, the active parent diacid of enalapril, also showed a weaker inhibitory effect on the Con A-induced proliferative response (4-20 mM). The bioactive peptides had little effect, except at a relatively high concentration. Angiotensin II (Ang II) at 0.05 mM inhibited the Con A-induced proliferative response while [Sar1,Ile8]Ang II, a specific antagonist of Ang II, had no effect. Both bradykinin and its specific antagonist, D-Arg[Hyp3,D-Phe7]bradykinin, had no effect on Con A-induced T-lymphocyte proliferation. The ACE inhibitors and bioactive peptides had little or no cytotoxic effects, except when present at or more than 5 mM. In conclusion, the effects of ACE inhibitors such as captopril and enalapril on Con A-induced T-lymphocyte proliferation were confirmed after a pilot study recently reported. These effects, especially with the stimulatory effect of CP, are unrelated to their ability to inhibit angiotensin-converting enzyme and perturbation of the bioactive peptides such as angiotensin II and bradykinin.
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Administration of enalaprilat and candesartan did not affect the Ppa-Ppao gradient at baseline or during hypoxia. Plasma renin activity and angiotensin II immunoreactivity increased during hypoxia, and subsequent measurements were consistent with effective angiotensin-converting enzyme inhibition after administration of enalaprilat, and with angiotensin receptor blockade after administration of candesartan.
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Angiotensin II maintains extracellular volume homeostasis, in part, by regulating proximal tubule transport. Physiological doses of angiotensin II stimulate volume and solute transport in the proximal tubule independent of changes in the glomerular filtration rate. Stimulation of bicarbonate transport primarily occurs via increasing activity of the sodium/hydrogen exchanger and the sodium/bicarbonate cotransporter. The effects of circulating angiotensin II are mediated by angiotensin II receptors on the basolateral membrane of the proximal tubule. Recently, the proximal tubule was found to synthesize and secrete angiotensin II into the lumen. The luminal membrane contains angiotensin II receptors and luminal angiotensin II levels are 100 to 200-fold higher than that found in plasma. Luminal angiotensin II receptor blockade or luminal inhibition of angiotensin II synthesis both significantly diminish proximal tubule transport, consistent with stimulation of proximal tubule transport by endogenously produced and luminally secreted angiotensin II. These data provide evidence for an autocrine/paracrine role for angiotensin II that functions independent of circulating angiotensin II.
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The acute blood pressure response to an angiotensin converting enzyme inhibitor (enalaprilat) was compared in patients with uncomplicated essential hypertension with that obtained under similar conditions with a calcium entry blocker (nifedipine). The patients were studied after a 3 week washout period. At a 48 h interval, each patient received in randomized order either enalaprilat (5 mg i.v.) or nifedipine (10 mg p.o.). Enalaprilat and nifedipine were equally effective in acutely lowering blood pressure. However, good responders to one agent were not necessarily good responders to the other.
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The aim of the present study was to investigate whether a pathway for conversion of angiotensin I (ANG I) to angiotensin II (ANG II) other than that via angiotensin-converting enzyme (ACE) is present in the smooth muscle of the human detrusor. Isolated detrusor strips from 11 patients were contracted by ANG I (1 microM) in the absence or presence of enalaprilat (10 microM), soybean trypsin inhibitor (STI, 200 micrograms/ml), or both. The metabolic activity in detrusor membranes from four patients was studied separately using Hip-Gly-Gly or ANG I as a substrate, with or without various protease inhibitors. The contractile response to ANG I (1 microM) was depressed by enalaprilat from 66 +/- 22 (mean +/- SD) to 39 +/- 13% of the K+ (124 mM)-induced response (P < 0.01, n = 11), and the combination of enalaprilat and STI resulted in a further reduction in contractile amplitude to 25 +/- 14% (P < 0.01 vs. K+, and P < 0.05 vs. enalaprilat alone) and a significantly slower developing contraction with a time to peak of 3.7 +/- 1.7 vs. 1.1 +/- 0.3 min for ANG I alone (P < 0.01). In detrusor membranes, a low ACE activity, inhibitable by captopril, was demonstrated by the formation of hippuric acid (0.70 nmol.min-1.mg protein-1) from the synthetic ACE substrate, Hip-Gly-Gly. However, the conversion of ANG I (166 nmol.min-1.mg protein-1) to ANG II was not affected by ACE inhibition, while serine protease inhibitors, e.g., STI and chymostatin, completely prevented ANG II formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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Sodium metabisulfite (MBS) is a food preservative that can trigger bronchoconstriction in asthmatic subjects. Previous studies designed to identify the mechanisms involved in this response have yielded conflicting results. We noted certain similarities between the pharmacology of MBS-induced airway responses and those elicited by bradykinin (BK), another provocating agent in asthmatic subjects. Therefore we used allergic sheep to determine whether MBS-induced bronchoconstriction 1) had a pharmacology similar to that previously seen with BK in this model, including protection by a BK B2-receptor antagonist, NPC-567, and 2) was associated with increased concentrations of immunoreactive kinins in bronchoalveolar lavage. We measured specific lung resistance before and immediately after inhaled buffer and increasing concentrations of MBS (30 breaths of 25, 50, and 100 mg/ml) and calculated the concentration producing 100% increase in specific lung resistance over baseline (PC100). In seven sheep, geometric mean control PC100 was 33.1 mg/ml. Pretreatment with either the anticholinergic agent ipratropium bromide (180 micrograms; PC100 87.1 mg/ml) or the antiasthma drug nedocromil sodium (1 mg/kg aerosol; PC100 97.7 mg/ml) blocked the MBS-induced bronchoconstriction (P less than 0.05), whereas the histamine H1-receptor antagonist chlorpheniramine (2 mg/kg iv) was ineffective. Furthermore the MBS-induced bronchoconstriction was not affected by the neutral endopeptidase inhibitor thiorphan (40 breaths of a 1 mg/ml solution) or the angiotensin-converting enzyme inhibitor enalaprilat (2.5 mg aerosol). In six sheep the MBS-induced bronchoconstriction was completely blocked by NPC-567 (20 breaths, 5 mg/ml aerosol): after treatment with NPC-567 mean PC100 was 100 mg/ml compared with 57.5 mg/ml in the control trial (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
This was a placebo-controlled, randomized, double-blind study performed in 20 congestive heart failure patients (New York Heart Association class III or IV). Systemic and regional hemodynamic parameters, biological parameters, and blood gases were measured before and repeatedly after the onset of infusion. Compared with placebo, enalaprilat decreased pulmonary capillary wedge pressure (-37% versus -10%, P = .001), diastolic and mean systemic blood pressures (-21% versus 0%, P = .009, and -18% versus -1%, P = .026, respectively), diastolic and mean pulmonary blood pressures (-21% versus -8%, P = .040; -18% versus -9%, P = .046), and brachial and renal resistances (-44% versus -14%, P = .017, and -22% versus -2%, P = .014, respectively); increased brachial and renal blood flows (+77% versus +8%, P = .036, and +12% versus 0%, P = .043, respectively), arterial oxygen tension (+2% versus -16%, P = .041), and arterial oxygen saturation (+1% versus -2%, P = .045); and tended to decrease rate-pressure product (-19% versus -7%, P = .076), increase brachial artery diameter (+13% versus 0%, P = .081), and improve intrapulmonary shunt (-18% versus +16%, P = .080). Enalaprilat did not affect cardiac output or carotid or hepatosplanchnic hemodynamics.
This study examined the role of endogenous kinins in the alteration of renal hemodynamics induced by low-dose converting enzyme inhibition in hydropenic normotensive rats and in the nonclipped kidney of hydropenic two-kidney, one clip hypertensive rats. Infusion of a bradykinin B2 receptor antagonist (D-Arg0,[Hyp3,Thi5,8,D-Phe7]-bradykinin, 1 or 10 micrograms.kg-1.min-1) did not alter renal function of normotensive rats. In a second series of experiments, infusion of enalaprilat at 0.1 mg.kg-1.h-1 increased renal blood flow (P < .01) and decreased renal vascular resistance (P < .01). The superimposition of the kinin antagonist at 1 micrograms.kg.min-1 during the enalaprilat infusion decreased renal blood flow to a value similar to the preenalaprilat baseline and significantly different from the mean of the two enalaprilat periods before and after the addition of the kinin antagonist--the "mean effect of enalaprilat." The decrease in renal blood flow induced by the kinin antagonist was associated with an increase in renal vascular resistance above the mean effect of enalaprilat (P < .025). In two-kidney, one clip hypertensive rats, systemic infusion of enalaprilat augmented the hemodynamics of the nonclipped kidney by a degree similar to that in normotensive rats. In contrast to normotensive rats, superimposition of the kinin antagonist did not alter the enalaprilat-induced change in blood flow or vascular resistance of the nonclipped kidney. The results of this study suggest that endogenous kinins contribute to the increased renal function induced by low-dose converting enzyme inhibition in hydropenic normotensive rats but appear to contribute less to the enalaprilat-induced alterations of renal function in the nonclipped kidney of two-kidney, one clip hypertensive rats.
Somatic ACE (EC 126.96.36.199), a Zn(II) metalloproteinase, is composed of functionally active N and C domains resulting from tandem gene duplication. Despite the high degree of sequence similarity between the two domains, they differ in substrate and inhibitor specificity and in their activation by chloride ions. Because of the critical role of ACE in cardiovascular and renal diseases, both domains are attractive targets for drug design. Putative structural models have been generated for the interactions of ACE inhibitors (lisinopril, captoril, enalaprilat, keto-ACE, ramiprilat, quinaprilat, peridoprilat, fosinoprilat, and RXP 407) with both the ACE_C and the ACE_N domains. Inhibitor-domain selectivity was interpreted in terms of residue alterations observed in the four subsites of the binding grooves of the ACE_C/ACE_N domains (S1: V516/N494, V518/T496, S2: F391/Y369, E403/R381, S1': D377/Q355, E162/D140, V379/S357, V380/T358, and S2': D463/E431, T282/S260). The interactions governing the ligand-receptor recognition process in the ACE_C domain are: a salt bridge between D377, E162, and the NH(2) group (P1' position), a hydrogen bond of the inhibitor with Q281, the presence of bulky hydrophobic groups in the P1 and P2' sites, and a stacking interaction of F391 with a benzyl group in the P2 position. In ACE_N these interactions are: hydrogen bonds of the inhibitor with E431, Y369, and R381, and a salt bridge between the carboxy group in the P2 position of the inhibitor and R500. The calculated complexes were evaluated for their consistency with structure-activity relationships and site-directed mutagenesis data. A comparison between the calculated interaction free energies and the experimentally observed biological activities was also made. Pharmacophore refinement was achieved at an atomic level, and might provide an improved basis for structure-based rational design of second-generation, domain-selective inhibitors.
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Earlier studies in rabbits revealed that in this species, in contrast to most other species studied, water intake was not influenced by injection or infusion of angiotensin II (ANG II). In order to establish whether ANG II has any role in the regulation of water intake of rabbits, a comprehensive study of the effect of converting enzyme inhibition was undertaken. Enalaprilat was given systemically in various doses to sodium- and water-replete, sodium-deplete, and water-deprived rabbits, and the intake and excretion of water and sodium was measured. In replete rabbits systemic injection of enalaprilat, 8 mg/kg and 8 micrograms/kg, but not 0.8 mg/kg, was followed by increased daily water intake. In sodium-deplete rabbits injection of enalaprilat, 80 mg/kg, was followed by water drinking within 1 h, and daily sodium intake was reduced. Systemic administration of ANG II increased, but did not restore to control level the sodium appetite of sodium-deplete rabbits attenuated by 80 mg/kg enalaprilat. Rabbits deprived of water for 24 h, however, drank the same amount of water after injection of vehicle or enalaprilat, 80 and 8 mg/kg. The efficacy of converting enzyme inhibition was also tested by measuring the blood pressure response to ANG I. Blood pressure responses revealed that in replete animals converting enzyme activity was depressed below control levels for 30 h after injection of 80 mg/kg enalaprilat. In sodium-deplete rabbits blood pressure fell following injection of 80 mg/kg enalaprilat and did not return to control level until 48 h after the injection.(ABSTRACT TRUNCATED AT 250 WORDS)
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Experiments were performed to test the hypothesis that tyrosine kinase activity contributes to renal arteriolar contractile responses to angiotensin (Ang) II. Rats were subjected to short-term enalaprilat treatment to decrease endogenous Ang II formation before tissue was harvested for experiments with the in vitro blood-perfused juxtamedullary nephron technique. Acute surgical papillectomy was used to avoid the indirect afferent arteriolar effect of Ang II that arises through increased tubuloglomerular feedback sensitivity. Arteriolar lumen diameter responses to 1 and 10 nmol/L Ang II were monitored by videomicroscopic methods before and during treatment with various tyrphostin compounds: 100 micromol/L AG18 (broad-spectrum tyrosine kinase inhibitor), 100 nmol/L AG1478 (selective epidermal growth factor receptor tyrosine kinase inhibitor), or 100 micromol/L AG9 (inactive analog). Baseline afferent arteriolar lumen diameter averaged 23.5+/-1.2 micrometer and was not influenced by any tyrphostin. Ang II (10 nmol/L) decreased afferent diameter by 11.1+/-1.0 micrometer under untreated conditions, a response that was not altered by AG9 but significantly blunted by AG18 (34+/-9% inhibition) or AG1478 (52+/-8% inhibition). AG18 did not suppress afferent arteriolar contractile responses to membrane depolarization (20 to 55 mmol/L K(+ )bath). Efferent arteriolar baseline diameter averaged 24.1+/-0.8 micrometer and was unaltered by AG18 or AG1478; however, efferent diameter responses to 10 nmol/L Ang II were diminished 52+/-10% by AG18 and 51+/-13% by AG1478. These observations indicate that Ang II signaling in renal afferent and efferent arteriolar vascular smooth muscle is either mediated or modulated by tyrosine kinase activity, including that of the epidermal growth factor receptor tyrosine kinase.
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A sensitive and rapid method based on liquid chromatography/tandem mass spectrometry (LC/MS/MS) combined with rapid solid-phase extraction (SPE) has been developed and validated for the quantitative determination of enalapril and its active metabolite enalaprilat in human plasma. After addition of internal standard to human plasma, samples were extracted by 96-well SPE cartridge. The extracts were analyzed by HPLC with the detection of the analyte in the multiple reaction monitoring (MRM) mode. This method for the simultaneous determination of enalapril and enalaprilat was accurate and reproducible, with respective limits of quantitation of 0.2 and 1.0 ng/mL in plasma. The standard calibration curves for both enalapril and enalaprilat were linear (r(2) = 0.9978 and 0.9998) over the concentration ranges 0.2-200 and 1.0-100 ng/mL in human plasma, respectively. The intra- and inter-day precision over the concentration range for enalapril and enalaprilat were lower than 13.3 and 15.4% (relative standard deviation, %RSD), and accuracy was between 89.2-105.0 and 91.9-104.7%, respectively.