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Home , Blood pressure, Enalaprilat

Journal of Human (1997) 11, 177–183  1997 Stockton Press. All rights reserved 0950-9240/97 $12.00

Impact of the -- system on response to intravenous enalaprilat in patients with hypertensive crises

MM Hirschl1, M Binder2, A Bur1, H Herkner1, C Woisetschla¨ger1, C Bieglmayer3 and AN Laggner1 1Department of Emergency , University of Vienna; 2Department of Dermatology, University of Vienna; and 3Institute for Medical and Chemical Laboratory Diagnostics, University of Vienna, Austria

The purpose of the study was to evalute the impact of centrations were significantly higher compared to the renin-angiotensin-aldosterone (RAA) system on patients with mean arterial BP reduction Ͻ25% (BP) response in patients with hyperten- (12.3 ± 6.7 vs 5.6 ± 4.0 pg/ml,P = 0.013). sive emergencies and urgencies treated with intra- These data indicate that PRA and ANG II are the major venous enalaprilat. Thirty-five patients with a systolic determinants for BP response to enalaprilat. This BP (SBP) Ͼ210 mm Hg and/or diastolic BP (DBP) Ͼ110 relation between BP response and RAA system activity mm Hg received 5 mg enalaprilat intravenously. The have important clinical implications for the treatment of extent of systolic and DBP reduction was correlated patients with severe hypertension. Primary therapeutic with pretreatment concentrations of angiotensin II failure indicates that the RAA system contributes very (ANG II) (SBP: r =−0.47; P = 0.006; DBP: r =−0.55; little to the hypertensive status of the patient. Thus, P = 0.001) and (PRA) (SBP: repetitive application on an ACE inhibitor in primary r =−0.49; P = 0.003; DBP: r = 0.48; P = 0.007). Non- responders is clinically unhelpful and may result in an responders to enalaprilat exhibited significant lower unnecessary delay of an effective BP reduction. In con- pretreatment levels of PRA, angiotensin-converting trast, high ANG II concentrations are associated with a enzyme (ACE) and ANG II compared to responders considerable risk for severe after enola- (PRA: 5.5 ± 3.7 vs 1.1 ± 2.2 ng/ml/h, P Ͻ 0.001; ACE: nalaprilat application. Therefore, the status of the RAA 12.8 ± 3.5 vs 8.2 ± 4.8 U/l, P = 0.003; ANG II:8.7 ± 6.2 vs system determines the efficacy as well as the safety of 5.0 ± 3.8 pg/ml, P = 0.04). In patients with severe hypo- ACE inhibitor treatment in patients with severe hyper- tension following application of enalaprilat ANG II con- tension.

Keywords: plasma renin activity; angiotensin II; enalaprilat

Introduction in patients with are limited. Hodsman et al8 reported about a positive correlation Angiotensin-converting enzyme (ACE) inhibitors are between pretreatment ANG II levels and decrease of well established in the treatment of chronic hyper- blood pressure (BP) in patients with essential hyper- tension, congestive failure and diabetic tension and severe hypertensive dysregulation. nephropathy.1–4 Recently, parenteral enalaprilat has More recently obtained data, however, are rather been recommended for the treatment of patients controversial concerning the relation between the with hypertensive crises.5 However, some earlier renin-angiotensin-aldosterone (RAA) system and the published reports have demonstrated that the oral extent of BP reduction after ACE-inhibitor appli- application of an ACE inhibitor was associated with cation.13,14 Whereas Dipette et al13 demonstrated a a considerable risk for severe hypotension early after 6,7 considerable relation between renin activity and BP drug application. High pretreatment levels of 14 plasma renin and angiotensin II (ANG II), prior reduction, Strauss et al failed to observe any treatment and higher age were identified as relation between pretreatment plasma renin activity risk factors for this first dose hypotension induced (PRA) and response to treatment. by an ACE inhibitor.8,9 These data were obtained We, therefore, conducted a study to: (1) evaluate mainly in patients with congestive or the relation between pretreatment activity of the with of the renal .10–12 Data about RAA system and BP response to enalaprilat in severe hypotension after ACE-inhibitor application patients with hypertensive crises; and (2) assess the clinical impact of this relation on safety and efficacy of ACE inhibitors in the treatment of hypertensive Correspondence: Dr M Hirschl, Department of Emergency Medi- individuals admitted to the emergency room. cine, Wa¨hringer Gu¨rtel 18–20, A-1090 Vienna, Austria Received 26 July 1996; revised 4 December 1996; accepted 12 December 1996 Renin-angiotensin-aldosterone system in hypertension MM Hirschl et al 178 Patients and methods patients through a venous cannula inserted in the forearm not used for administration of the treatment Study design to determine PRA, ACE, ANG II and aldosterone. This was prospectively designed study was perfor- The first 5 ml were discarded and samples for PRA med in the Emergency Department of the New Gen- and ANG II were collected into evacuated glass eral Hospital in Vienna. tubes with EDTA (Becton Dickinson Vacutainer Sys- tems, France) and immediately stored on ice. Patient selection Samples for PRA and ANG II were centrifuged at 3000 g at 4°C for 15 min and plasma specimens of All patients admitted to the emergency department 1 ml were stored in plastic tubes at −70°C. Blood with hypertensive urgency or emergency were prim- samples for ACE and serum aldosterone were col- arily included to the study protocol. Hypertensive lected in silicone coated evacuated glass tubes urgency was defined as an elevation of systolic BP (Becton Dickinson) and stored at room temperature. Ͼ Ͼ (SBP) 210 mm Hg and/or diastolic BP (DBP) 120 All patients gave their written informed consent for mm Hg without evidence of end-organ damage. taking the additional blood samples. was defined as an elevation of SBP Ͼ200 mm Hg and/or DBP Ͼ110 mm Hg with the evidence of end-organ damage, ie, acute conges- Assays tive heart failure, , aortic or All radioimmunoassay incubations were set up in angina pectoris. duplicates. Radioactivity was counted by a 1470 Exclusion criteria were intake of ACE-inhibitors Wizard gamma-counter (Wallac, Finland); the Multi- within the last 72 hours, permanent therapy with calc software from Wallac was used for data , evidence of acute or chronic renal insuf- reduction. ficiency and uni- or bilateral stenosis of renal arteries. Acute renal failure was diagnosed by the PRA: Renin activity was analysed by in vitro pro- following parameters: negative previous history of duced angiotensin I (ANG I), measured with ± renal disease; urine osmolarity 300 20 mosmol/l; radioimmunoassay kits (Sorin Biomedica, France). Ͼ urinary 30 mmol/l; urine/plasma osmo- All procedures were according to the protocol of the = Ͼ ␮ lality 1; serum creatinine 176.8 mol/l (2 mg/dl); manufacturer, including the volumes, addition of Chronic renal failure was evident if a positive his- protease inhibitor and set up of the ANG I radioim- tory of renal disease was combined with elevated munoassay. The interassay precision was monitored serum creatinine (Ͼ176.8 ␮mol/l [2 mg/dl]). After by calculation of coefficients of variation (CV) from the acute event duplexsonography of renal arteries control samples: kit control (CV = 10% at 1.1 angio- was performed in all patients to exclude uni- or tensin l/ml/h) and control materials obtained from bilateral stenosis of the renal arteries. Ciba-Corning, USA. (CV = 9% both at 0.9 ng/ml/h and at 3.5 ng/ml/h). Baseline stabilization period ACE: ACE was analysed by a colorimetric method After diagnosis of all patients (ACEcolor, Fujirebio Inc, Japan) which was run on a were told to rest in a supine position and were Cobas Fara automated analyser (Hoffmann LaRoche, observed for 30 min without any antihypertensive Switzerland). Interassay CV was 2.3% at 11.6 U/l. . During this period, complete , electrocardiograms and laboratory ANG II: ANG II was measured by radioimmunoas- evaluations to determine serum creatinine, blood say (ERIA Diagnostics Pasteur, France) after thawing , creatine-kinase and levels the samples in an ice-water bath, centrifugation in were performed. Heart rates were monitored con- the cold and extraction with phenylsilyl-silica tinuously and BP was measured every 5 min auto- according to Nussberger et al.15 Extraction was per- matically using a non-invasive BP measurement formed on Isolute PH (EC) 100 mg/1 ml minicolums parameter unit (NIBP module; Hewlett Packard from International Sorbent Technology (UK) by Component System, Cincinnati, OH, means of an ASPEC XL solid phase extraction USA). machine. The extraction machine was equipped with a Peltier-cooled sample rack set at 4°C, the Treatment period eluents were cooled during the whole extraction If after this stabilization period the patients still ful- procedure. The minicolumns were activated by sub- filled inclusion criteria, the patients received 5 mg sequent washing with 1 ml methanol and 1 ml dis- enalaprilat. Response to treatment was defined as a tilled water (10 ml/min). Plasma (2 m) was applied reduction of SBP below 180 mm Hg and DBP below and columns were washed with 1 ml distilled water. 95 mm Hg within 75 min after application of enala- ANG II was eluted with 0.5 ml methanol (3 ml/min) prilat. Severe hypotension was defined as reduction into glass tubes. The eluents were dried in a Tur- ° of SBP or DBP Ͼ25% of the pretreatment BP. boVap LV Evaporator (Zymark, USA) at 37 C under nitrogen flow. The residues were dissolved in 0.5 ml assay buffer, centrifuged in the cold and the ANG II Blood sampling and handling radioimmunoassay was performed immediately on Immediately before the start of antihypertensive the supernatants according to manufacturer’s treatment, blood samples were collected from suggestions. By addition of 125I-angiotensin II we Renin-angiotensin-aldosterone system in hypertension MM Hirschl et al 179 observed an average extraction yield of 86 ± 2%, Table 1 Correlation coefficients between PRA, ACE, ANG II and which was used for correction. Repeated analyses of serum ALDO in patients with severe hypertension receiving 5 mg intravenous enalaprilat selected samples in different assays showed devi- ations below 14%. ANG II (pg/ml) ALDO (ng/dl) ACE (U/l)

PRA (ng/ml/h) 0.75 0.14 0.52 Aldosterone P Ͻ 0.001 P = 0.42 P Ͻ 0.001 Serum aldosterone (ALDO) was quantified by ANG II (pg/ml) 0.22 0.51 P = 0.19 P Ͻ0.001 radioimmunoassay (Coat-A-Count, Diagnostic Pro- ALDO (ng/dl) −0.06 ducts Corporation, USA). A Probe 1000 pipetting P = 0.69 machine (Packard Instruments, USA) was used for delivery of standards, controls (Lyphocheck, BIO- PRA = plasma renin activity; ACE = angiotensin-converting RAD, USA) and samples. Interassay coefficient CVs enzyme; ANG II = angiotensin II; ALDO = serum aldosterone. were 11% (66 pg/ml), 8% (309 pg/ml) and 5% (692 pg/ml). Table 1 illustrates the correlation between PRA, ACE, ANG II and serum ALDO in hypertensive Units: PRA, ANG II and ALDO results are reported patients. PRA correlates positively with ACE and in conventional units. SI conversions are as follows: ANG II. A significant correlation was also observed × = aldosterone: ng/dl 27.74 pmol/l; ANG II: pg/ml between ANG II and ACE. Correlation coefficients × = × = ␮ 1 ng/l; PRA: ng/ml/h 1 g/l/h between serum ALDO and the other three factors of the RAA system did not exhibit statistical signifi- cance (Table 1). Statistical analysis All data are reported as mean s.d. unless otherwise Overall relation between BP reduction and the indicated. Comparisons of variables between groups activity of the RAA system were performed using unpaired Student’s t-test for continuous data and ␹2 test for categorical data. The Table 2 illustrates the relation between the extent of least square method was used to exploratively exam- SBP or DBP reduction and the pretreatment levels ine for correlation between laboratory values and for of PRA, ACE, ANG II and ALDO. The extent of SBP relation between the extent of BP reduction and pre- as well as DBP reduction was correlated with pre- treatment levels of PRA, ACE, ANG II and ALDO. treatment levels of PRA and ANG II. No significant Receiver–operator analysis (ROC) was used for the correlations were observed between pretreatment determination of the optimal cut-off value of PRA levels of ACE or ALDO and extent of BP reduction. with regard to treatment response after enalapri- lat.16,17 All analyses were calculated on SPSS 6.0 Response to treatment (Figure 1) (SPSS Inc, Cincinnati, OH, USA). A probability level of 5% was considered statistically significant. In 20 (57%) out of 35 patients the treatment goal listed above was reached. Fifteen (43%) patients did not achieve goal of treatment 75 min after appli- Results cation of 5 mg enalaprilat. The average magnitude Patients characteristics of SBP decrease in responders within 75 min was 46.1 ± 3.6 mm Hg, whereas in non-responders SBP Thirty-five patients (23 males, 12 females) with decrease was 17.3 ± 3.4 mm Hg. Average DBP hypertensive urgencies (n = 15; 43%) or emergencies reduction in responders and non-responders was (n = 20; 57%) were enrolled into the study. The 31.8 ± 1.7 mm Hg and 10.6 ± 3.0 mm Hg, respect- mean age was 55 years (range: 34 to 82 years). ively. decreased in Reasons for seeking medical aid included cardio- responders by 36.5 ± 1.8 mm Hg and in non- vascular emergencies (angina pectoris: n = 6; 17%, responders by 12.7 ± 2.5 mm Hg, respectively. congestive heart failure: n = 5; 14%), neurological The observed magnitudes of SBP and DBP emergencies (n = 9; 25%) or hypertensive urgencies decrease were significantly different between (epistaxis: n = 2; 6%; feeling of general illness: n = 7, 20%, palpitations n = 3; 9%, nausea: n = 3; 9%). Twenty-one (60%) patients had a prior history of Table 2 Relation between decrease of systolic or DBP and pre- treatment levels of PRA, ACE, ANG II and ALDO hypertension. SBP DBP General characteristics of the RAA R = P = r = P = Overall PRA ranged from 0.0 to 13.3 ng/ml/h with an average of 3.6 ± 3.9 ng/ml/h. Mean ACE-concen- PRA −0.49 0.003 −0.48 0.007 − − tration was 10.8 ± 4.6 U/l with a range from 2.5 to ACE 0.33 0.06 0.08 0.63 ANG II −0.47 0.006 −0.55 0.001 19.1 U/l. ANG II concentrations ranged from unde- ALDO −0.22 0.22 −0.31 0.07 tectable (below: 0.95) to 22.9 pg/ml with an average ± of 7.1 5.5 pg/ml. Mean serum ALDO concen- PRA = plasma renin activity; ACE = angiotensin-converting trations was 17.3 ± 7.8 ng/dl (range: 2.5–33.1 ng/dl). enzyme; ANG II = angiotensin II; ALDO = serum aldosterone. Renin-angiotensin-aldosterone system in hypertension MM Hirschl et al 180 Table 3 Characteristics of responders and non-responders after application of enalaprilat

Non- Responders P- responder value

n 15 (43%) 20 (57%) — Age (years) 53.8 ± 14.5 55.9 ± 0.5 0.62 Sex (m/f) 11/4 12/8 0.41 SBP on admission 210 ± 20 208.2 ± 8.1 0.74 DBP on admission 114 ± 8 115.5 ± 4.3 0.51 Urgencies/emergencies 6/9 9/11 0.76 Serum (mmol/l) 4.23 ± 0.27 4.41 ± 0.31 0.08 Serum sodium (mmol/l) 139.7 ± 2.4 140.5 ± 3.07 0.41 Serum creatinine (␮mol/l) 83.1 ± 12.4 85.7 ± 8.8 0.54

1.1 ± 2.2 ng/ml h. The observed difference of renin activity between responders and non-responders was statistically significant at a P-value of Ͻ0.001 (Figure 2). A cut-off value of 2.2 ng/ml/h was found to discriminate best between responders and non- responders (Figure 3). This value represented a sen- sitivity and specificity of 0.86, respectively (Table 4).

ACE: In responders ACE ranged fom 7.0 to 19.1 U/l, the mean was 12.8 ± 3.5 U/l. In non- responders ACE ranged from 2.5 to 15.0 U/l, the mean was 8.2 ± 4.8 U/l. The observed difference of serum ACE concentration between responders and non-responders was statistically significant at at P- value of 0.003.

ANG II: In responders ANG II ranged from 1.0 to 22.9 pg/ml, the mean was 8.7 ± 6.2 pg/ml. In non- responders serum ANG II ranged from undetectable (Ͻ0.95) to 13.3 pg/ml, the mean was 5.0 ± 3.8 pg/ml. Differences of ANG II concentrations between responders and non-responders were at the limit of the chosen significance (P = 0.04).

Serum ALDO: In responders serum ALDO ranged from 2.5 to 28 ng/dl, the mean was 15.5 ± 7.34 ng/dl. Figure 1 Line graphs show treatment response of (a) systolic and (b) diastolic BP within 75 min after initiation of treatment with 5 mg of enalaprilat. After 15 min a significant difference (P Ͻ 0.05) is observed between the two groups throughout the observation period. Values are given as mean s.e.m. („) denote non-responders, (࡯) denote responders.

responders and non-responders (P Ͻ 0.001 for SBP and P Ͻ 0.001 for DBP, respectively.

Characteristics of non-responders and responders General characteristics: Table 3 illustrates general clinical characteristics of non-responders and responders. The groups were well balanced with regard to age, gender, BP on admission, presenting clinical symptom, serum and serum cre- atinine.

Plasma renin activity: In responders, renin activity ranged from 0.0 to 13.3 ng/ml/h, the mean was Figure 2 Box-Whisker plot shows differences of plasma renin ± activity between responders and non-responders. The difference 5.5 3.7 ng/ml/h. In non-responders renin activity between groups was highly significant (P Ͻ 0.001). Boxes denote ranged from 0.0 to 8.4 ng/ml/h, the mean was s.e.m., whiskers denote s.d. and („) denote the individual values. Renin-angiotensin-aldosterone system in hypertension MM Hirschl et al 181 Discussion Our study demonstrates that the extent of BP reduction after enalaprilat application is positively correlated to pretreatment levels of plasma renin and ANG II in patients with hypertensive crises. Hodsman et al8 reported similar correlation coef- ficients between PRA or ANG II and percentage change in mean arterial BP after first dose of captop- ril. An even higher correlation coefficient (r = 0.83) was noted by Brown et al,18 who demonstrated a sig- nificant relation between -induced BP reduction and pretreatment ANG II concentrations. According to our own and previously published data the most pronounced fall in BP is observed in patients with the highest activity of the RAA sys- tem.19 Removal of the vasoconstrictor effect of ANG II is one of the major factors in the reduction of BP in the first hours after ACE inhibition. In contrast, low PRA and ANG II concentrations are associated Figure 3 Line graph shows receiver operator characteristics curve with no or only little blood response to ACE inhi- (ROC) to evaluate the optimal cut-off value for plasma renin bition. activity to discriminate best between responders and non- responders. A plasma renin activity of 2.2 ng/ml/h exhibits a sen- However, most of these data have been obtained sitivity and specificity of 0.86 and 0.86, respectively. in patients with clinical renovascular hypertension. The relation between RAA system and fall of BP after enalaprilat is more controversially discussed in patients with essential hypertension.13,14 Moreover, Table 4 Responders and non-responders to treatment according as intravenous enalaprilat has been recommended to the evaluated cut-off value of 2.2 ng/ml/h PRA for the treatment of hypertensive crises,5 our data have important clinical implications for the use of Renin activity Row totals intravenous enalaprilat in this clinical setting. About 40% of all patients with hypertensive р2.2 ng/ml/h Ͼ2.2 ng/ml/h urgencies or emergencies did not respond to intra- venous enalaprilat. In these patients low concen- Non-responders 12 3 15 trations of renin and ANG II were noted. It is in line Responders 2 18 20 with earlier published data demonstrating that ACE All groups 14 21 35 Sensitivity 0.86 inhibition in binephrectomized patients, monkeys Specificity 0.86 or rats did not influence BP, as no circulatory renin was evident in these patients.20–23 We therefore assume that the circulatory RAA system did not con- tribute to the hypertensive status in about 40% of all patients with hypertensive crises. These findings have important clinical impli- In non-responders serum ALDO ranged from 7.7 to cations for the treatment of patients with hyperten- 33.1 ng/dl, the mean was 19.68 ± 8.03 ng/dl. Differ- sive urgencies and emergencies. As primary non- ences of serum ALDO concentrations between response to enalaprilat indicates a low activity of the responders and non-responders did not exhibit stat- RAA system, repetitive application of enalaprilat or istical significance (P = 0.12). increase of dosage is ineffective and may result in an unnecessary delay of an effective therapy. Our Characteristics of patients with severe results are in line with previously published data hypotension demonstrating that increase of dosage did not alter the percentage of responders to enalaprilat.24 Nine patients exhibited a BP lowering Ͼ25% of the In patients with hypertensive crises a 20–25% pretreatment levels. In patients with severe hypoten- reduction in arterial BP over 60–90 min is a reason- sion the percentage of cardiovascular events was sig- able therapeutic goal.25,26 A more rapid and pro- nificantly higher compared to patients with normal nounced lowering of BP may increase the risk for BP response (7 vs 2; P = 0.007). In contrast, the num- further organ damage. ber of urgencies was significantly higher in patients Analysing the group of responders according to with normal BP response compared to those with this therapeutic guideline we observed a more than severe hypotension (8 vs 1; P = 0.006). In these 25% reduction of arterial BP in 13 (37%) patients. patients ANG II concentration was significantly Pretreatment concentration of ANG II was signifi- higher compared to patients with a less pronounced cantly higher in these patients. We therefore assume reduction (Ͻ25%) of mean arterial BP (Table 5). All that in the group of responders the risk for an excess- other factors of the RAA system did not exhibit sig- ive BP reduction increases with higher activity of nificant differences. the RAA system. As 37% of all patients exhibit a Renin-angiotensin-aldosterone system in hypertension MM Hirschl et al 182 Table 5 Characteristics of the RAA system in responders according to the reduction of mean arterial BP

Diff(map)-reduction р25% Diff(map)-reduction Ͼ25% P-value

n 11 (55%) 9 (45%) PRA (ng/ml/h) 4.5 ± 2.9 6.8 ± 4.5 0.19 ACE (U/l) 11.8 ± 2.6 14.0 ± 4.3 0.17 ANG II (pg/ml) 5.6 ± 3.96 12.3 ± 6.7 0.013 ALDO (ng/dl) 14.6 ± 8.11 17.28 ± 6.29 0.34

Variables are given as mean values and standard deviation. = = = Diff(map) difference between mean arterial BP on admission and 75 min after treatment; PRA plasma renin activity; ACE angiotensin- converting enzyme; ANG II = angiotensin II; ALDO = serum aldosterone.

reduction of BP Ͼ25%, a considerable number of capacity trials evaluating in chronic conges- patients with severe hypertension are at risk to tive heart failure. Am J Cardiol 1996; 77: 1191–1196. develop hypotensive episodes after application of 2 Lawson DH et al. European postmarketing surveillance enalaprilat. Analysing factors associated with severe of ramipril in hypertension. 1. Feasibility and study hypotension patients with acute congesive failure cohort. Eur J Clin Pharmacol 1995; 49: 73–79. 3 Ravid M, Lang R, Rachmani R, Lishner M. Long-term carried the highest risk for first dose hypotension. renoprotective effect of angiotensin-converting Similar results have been obtained in patients with enzyme inhibition in non-insulin-dependent congestive heart failure NYHA class III and IV. In mellitus. A 7-year follow-up study. Arch Intern Med these patients a significant relation between the 1996; 156: 239–240. RAA system and BP reduction was noted. The most 4 Inserra F et al. Decrease of -induced micro- pronounced hypotension was observed in patients albuminuria in patients with type 1 diabetes by means with the highest pretreatment levels of plasma of an angiotensin-converting enzyme inhibitor. Am J renin.27,28 Therefore, enalaprilat should be used very Dis 1996; 27: 26–33. cautiously in patients with acute left ventricular fail- 5 Joint National Committee: The fifth report of the Joint ure due to severe hypertension. National Committee on detection, evaluation and treat- Overall, in patients with evidence of high activity ment of high blood pressure. Arch Intern Med 1993; 153: 154–183. of the RAA system, ie patients with diuretic therapy, 6 Cleland JG et al. Severe hypertension after first dose congestive heart failure, renal insufficiency or hypo- of in heart failure. Br Med J 1985; 291: volemia, ACE-inhibition cannot be recommended, 1309–1312. as an excessive BP reduction may occur leading to 7 Reid JL. Angiotensin converting enzyme inhibitors in further organ damage. the elderly. Br Med J 1987; 295: 943–944. Some limitations of our study have to emphas- 8 Hodsman GP et al. Factors related to first dose hypo- ized. First, we did not determine local factors, eg, tensive effect of : prediction and treatment. Br or prostaglandins, which may also con- Med J 1983; 286: 832–834. tribute to the hypotensive effect of enalaprilat.29–32 9 Navis GJ et al. Blood pressure response to enalaprilic However, our study did not address the issue acid in essential hypertension: dose-response and whether local or systemic factors are mainly respon- effect of pretreatment with furosemide. Eur J Clin sible for BP response enalaprilat. The primary aim of Pharmacol 1985; 29: 9–15. 10 Reid JL, MacFayden J, Squire IB, Lees KR. Angioten- our study was to evaluate the influence of the RAA sin-converting enzyme inhibitors in heart failure: system on BP in patients with hypertensive crises, blood pressure changes after the first dose. Am Heart and to identify clinically relevant factors of the RAA J 1993; 126: 794–797. system, which determine the BP reduction to ACE 11 Hodsman GP et al. Enalapril in treatment of hyperten- inhibition. Second, the use of intravenous agents in sion with renal stenosis. Changes in blood press- patients with hypertensive urgencies is contro- ure, renin, angiotensin I and II, renal function, and versially discussed.33 There are some concerns that body composition. Am J Med 1984; 77: 52–60. rapid lowering of BP may result in organ damage or 12 Hodsman et al. Enalapril in the treatment of hyperten- even death of the patient.34,35 In contrast, recently sion with . 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