Renin Status Does Not Predict the Anti-Hypertensive Response to Angiotensin- Converting Enzyme Inhibition in African– Americans

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ORIGINAL ARTICLE Renin status does not predict the anti-hypertensive response to angiotensin- converting enzyme inhibition in African– Americans

MR Weir and E Saunders for the Trandolapril Multicenter Study Group Clinical Research Unit and the Divisions of Nephrology and Hypertension, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

The angiotensin-converting enzyme (ACE) inhibitor trough BP. Reduction in BP did not correlate with trough trandolapril, a non-sulfhydryl prodrug which is hydro- plasma trandolaprilat concentration. Pre-treatment lysed into trandolaprilat, was studied in 322 hyperten- plasma renin activity was not a reliable indicator of anti- sives of African–American descent using a double- hypertensive response, as similar reductions in BP blind, randomised, placebo-controlled, parallel study occurred even in patients with the lowest renin levels. design. Following 6 weeks of double-blind treatment There were no observable differences based on age, with placebo or 0.25 to 16 mg/day trandolapril, an analy- gender or measurements of the renin-angiotensin- sis of drug effect on trough blood pressure (BP) strati- aldosterone axis. In conclusion, neither age, gender or fied by age, gender, weight, pre-treatment plasma renin plasma renin activity influenced anti-hypertensive activity, and trandolaprilat concentration was perfor- response to angiotensin-converting enzyme inhibition med. Two mg was the lowest effective trandolapril dose, in African–Americans. whereas doses above 4 mg did not significantly reduce

Keywords: African–Americans; trandolapril; plasma renin; clinical trial

Introduction issues related to the influence of age, gender and pretreatment plasma renin activity on blood press- Hypertensives of African–American descent mani- ure (BP) response to the nonsulfhydryl angiotensin- fest hypertensive disease earlier and more fre- 15–18 1–4 converting enzyme (ACE) inhibitor trandolapril, quently than their non-black counterparts. They as well as to establish the proper dose response. also tend to have a lower renin, more salt sensitive Additionally, we will describe the influence of drug physiology and a tendency toward subtle volume concentration on anti-hypertensive activity and the expansion, coupled with more systemic and intra- 5–9 influence of age and gender with regards to changes renal vasoconstriction. This pathophysiological in the renin-angiotensin-aldosterone axis in background may explain why African–American response to ACE inhibition. hypertensives tend to be more resistant to lower doses of commonly used anti-hypertensive medications which target the renin-angiotensin system Patients and methods and have a different efficacy response to some anti- Study design hypertensive drugs compared to non-black hypertensives.10–14 This was a randomised, double-blind, parallel- Large clinical trials exploring demographic inter- group, placebo-controlled study in which the actions and pharmacodynamics of anti-hypertensive trandolapril dose-response characteristics were medications in hypertensives of African–American evaluated in a population of African–American descent have not been performed. The purpose of hypertensive patients. Patients who had been newly this manuscript is to report for the first time the diagnosed with, or had previously been treated for results of a large clinical trial in hypertensives of mild-to-moderate hypertension discontinued all African–American descent specifically exploring anti-hypertensive medications, and entered into a single-blind, placebo run-in period of 4 weeks. Only patients of self-described African–American descent with mild-to-moderate hypertension Correspondence: Dr Matthew R Weir, Division of Nephrology, (supine diastolic BP between 95 mm Hg and 114 University of Maryland Hospital, 22 S. Greene Street, Baltimore, MD 21201, USA mm Hg) during both of the final two consecutive Received 14 February 1997; revised 1 October 1997; accepted 17 weeks of the placebo run-in period were randomised October 1997 to receive double-blind medication, including either Trandolapril in African–Americans MR Weir and E Saunders 190 placebo, 0.25, 0.5, 1, 2, 4, 8, 12, or 16 mg trandolap- The mean of three consecutive (2 min apart) BP ril once daily for 6 weeks. measurements were recorded.

Patient population Methodology for assays of renin, aldosterone, ACE activity, trandolapril, trandolaprilat African–American patients could be enrolled if they were over 21 years of age and had non-labile, mild- Plasma renin activity determinations were based on competitive binding principles of radio-immuno- to-moderate hypertension. Patients were not 19 enrolled if they had any other form of hypertension assay as previously described. Serum aldosterone determinations were performed using radioimmu- (eg, malignant or severe); had suffered a cerebrovas- 20 cular accident, convulsion or hypertensive encepha- noassay procedures as described in Chattoraj et al. lopathy within the previous year; experienced a The methodology for spectrophotometric determi- nation of serum ACE activity is as described in Lieb- myocardial infarct within 3 months of the study or 21 had a history of severe cardiac abnormalities (such erman et al. All assays were performed by Smith as CHF, arrhythmias, conduction abnormalities or Kline Beecham Clinical Laboratories (Van Nuys, AV block); been treated with anti-hypertensive CA, USA). medication within 4 weeks or spironolactone within Plasma concentrations of trandolapril and its 6 weeks of starting double-blind treatment; had evi- diacid metabolite, trandolaprilat were measured by dence of renal, hepatic, haematological or other radioimmunoassay. Study drug samples were ana- metabolic abnormalities which could interfere with lysed blindly by Analytical Solutions Inc study drug absorption, metabolism or excretion; had (Sunnyvale, CA, USA). a history of drug abuse or addiction. Patients were excluded if they needed concomitant medications Measures of clinical effectiveness such as antidepressants, antiarrhythmic drugs, monoamine oxidase inhibitors, nonsteroidal anti- The change in supine diastolic and systolic BP from inflammatory drugs, digitalis, or major tranquilizers. baseline to end-point was used as the measure of All patients signed an Institutional Review Board clinical effectiveness. End-point was defined as the approved informed consent. end of the double-blind period or the last visit during which the patient received double-blind medication. Study procedures Patients were monitored on a regular basis over the Premature termination duration of the study. Patients were monitored on a Patients were withdrawn from the study if supine weekly basis during the placebo run-in period and diastolic BP rose above 114 mm Hg at any point dur- during the first 2 weeks of the double-blind treat- ing the study and remained elevated above 114 ment period. All subsequent monitoring was at 2- mm Hg at a follow-up visit within 48 to 72 h, or the week intervals. Patients consumed their usual ad physician investigator felt it was in the patient’s best libitum dietary salt intake. medical interest. Blood pressure was measured and trandolapril was administered once daily between 8.00 am to 10.00 am throughout the study. At each visit, an Statistical and analytical methods interim physical examination was done, vital signs An intent-to-treat analysis was performed using and BP were measured, compliance was evaluated, mean end-point values for supine diastolic and sys- and adverse experiences recorded. Special labora- tolic BPs measured as a change from baseline. Base- tory tests including ACE activity, serum aldosterone line data were the values recorded after 4 weeks of levels and plasma renin activity, were measured at placebo medication. Baseline values for the nine baseline and after 6 weeks of double-blind treat- treatment groups were compared using a one-way ment. Blood samples for these special tests were ANOVA. Post-treatment differences between obtained in the recumbent position after the patient treatments were compared using the same test with was supine for 30–45 min. During the double-blind baseline values as covariates. Graphical displays period, BPs were measured at ‘trough’, just prior to represent unadjusted means. Data are expressed as study drug dosing, and approximately 4–5 h after mean ± s.e.m. administration which coincides with peak plasma trandolaprilat concentrations and peak effect.17 Blood samples were also taken during double-blind Results treatment to measure the trough and peak (4–5 h Demographics after dosing) plasma levels of trandolapril and trandolaprilat. Three-hundred and twenty-two patients with mild- After 10 min in a supine position, BP measure- to-moderate hypertension were enrolled from 12 ments were made using a standard mercury sphyg- study sites. Approximately 80% of all patients had momanometer in the arm determined to have the been previously treated (mean = 10.6 ± 5.1 years) highest BP readings at the screening visit. Systolic for hypertension. BP was recorded at Phase I of the Korotkoff sounds As depicted in Table 1, in each of the nine treat- and diastolic BP at Phase V of the Korotkoff sounds. ment groups, there were similar age, weight, pre- Trandolapril in African–Americans MR Weir and E Saunders 191 Table 1 Demographic and baseline data

Trandolapril dose No. (Male; Female) Age Weight Diastolic BP Systolic BP (Yrs) (lbs) (mm Hg) (mm Hg)

Placebo 60 (27;33) 53.5 ± 10.0 190.2 ± 31.3 100.6 ± 4.2 155.7 ± 15.5 0.25 mg 23 (12;11) 48.6 ± 12.7 199.1 ± 28.9 101.7 ± 5.3 159.1 ± 13.5 0.5 mg 22 (9;13) 49.4 ± 12.3 187.5 ± 30.0 101.6 ± 4.9 152.1 ± 11.7 1.0 mg 23 (7;16) 52.7 ± 11.1 176.1 ± 32.0 99.7 ± 3.5 150.7 ± 13.1 2.0 mg 22 (10;12) 53.0 ± 10.2 182.0 ± 23.0 99.1 ± 3.2 146.1 ± 11.4 4.0 mg 60 (28;32) 53.6 ± 10.8 183.0 ± 30.2 101.7 ± 4.9 156.2 ± 16.1 8.0 mg 38 (19;19) 55.3 ± 11.9 181.5 ± 28.0 101.4 ± 4.3 158.7 ± 19.3 12.0 mg 38 (19;19) 53.1 ± 13.5 175.3 ± 25.3 100.9 ± 4.1 153.0 ± 12.4 16.0 mg 36 (15;21) 54.4 ± 12.2 179.0 ± 29.2 100.5 ± 3.7 159.5 ± 17.3

treatment diastolic and systolic BP and similar bal- plasma renin activity and BP reduction in African– ance of gender, with the exception of the 1.0 mg American hypertensives when examining the data trandolapril group which had seven males and 16 for all the doses together (r =−0.23) or specifically females. Thirty-two patients (12.2%) receiving tran- for equipotent doses of drug (doses 4–16 mg QD) for dolapril discontinued before the completion of the lowering BP (Figure 1). For all patients, the mean study, as did 12 patients (20%) on placebo treat- baseline plasma renin activity before treatment was ment. In the intent-to-treat analysis, all discontinued 0.7 ng/ml/hr increasing significantly (P Ͻ 0.01) to patients were included except one patient in the 2.1 ng/ml/hr after trandolapril treatment. The 12 mg group who had no efficacy data reported. majority of patients either had low renin levels (n = 179) or normal renin levels (n = 57) with only a minority having high plasma renin activity (n = 18). Efficacy After 6 weeks of therapy, trandolapril lowered dias- ACE activity, plasma renin activity, aldosterone tolic and systolic BP significantly with the 2 mg dose values (Table 2). Beyond the 4 mg dose there was no further reduction in either diastolic or systolic BP. The pla- Analysis of BP response was also performed by cebo effect was −0.7 ± 7.0 mm Hg. plasma renin category: low, normal or high in those Although the number of patients is small, patients who received equipotent doses of trandola- reduction in diastolic BP with trandolapril treat- pril for lowering BP (4–16 mg QD). Urinary sodium ment were not markedly influenced by patient gen- excretions were not measured in these patients. der or age. Males started to have significant diastolic Since plasma renin activities should be categorised BP reduction at the 2 mg dose whereas females relative to 24-h sodium excretion, the assignment of started at the 4 mg dose. Above 4 mg there was no low, normal, and high renin was made using a further BP reduction in either group. While patients nomogram which defines normal as a band that over age 65 years only comprised 19% of the included 95% of the renin-sodium values of 104 patient’s receiving trandolapril, Table 2 illustrates normal subjects, and assumes that the hypertensive that there were no important differences in antihy- patients in these studies were not consuming (and pertensive responses between younger and older excreting) large amounts of sodium.21 A plasma patients. A plateauing of response rate occurred renin activity below 0.7 ng angiotensin I/mL/hr was above 4 mg trandolapril. selected for low renin and above 3.0 ng There was not a correlation with pretreatment angiotensin I/mL/hr for high renin.

Table 2 Correlation of mean (± s.e.) trough supine diastolic blood pressure reduction with dose, gender, and age

Dose No. Systolic No. Diastolic No. (Diastolic mean change)a (mg) mean mean a a change change male female Ͻ65 years у65 years

0.25 23 −2.7 ± 3.0 23 0.6 ± 1.6 12 (1.5 ± 1.8) 11 (−0.6 ± 2.4) 20 (0.3 ± 1.6) 3 (2.7 ± 6.6) 0.5 22 0.7 ± 3.3 22 −1.9 ± 1.7 9 (−4.0 ± 2.1) 13 (−0.3 ± 2.5) 20 (−1.5 ± 1.8) 2 (−5.4 ± 7.0) 1.0 23 −1.0 ± 3.9 23 −0.5 ± 1.8 7 (−3.1 ± 1.7) 16 (1.1 ± 2.7) 19 (−0.3 ± 1.6) 4 (−4.6 ± 7.9) 2.0 22 −3.8 ± 3.1 22 −4.0b ± 2.1 10 (−7.3 ± 3.0) 12 (−1.2 ± 2.9) 20 (−4.5 ± 2.1) 2 (−0.9 ± 9.9) 4.0 60 −6.7b ± 2.1 60 −5.8c ± 1.2 28 (−7.5 ± 1.9) 32 (−4.4 ± 1.6) 49 (−5.5 ± 1.3) 11 (−6.7 ± 2.8) 8.0 38 −4.4 ± 3.6 38 −5.1c ± 1.9 19 (−4.9 ± 2.4) 19 (−5.6 ± 3.0) 28 (−5.0 ± 2.1) 10 (−4.6 ± 5.2) 12.0 37 −5.7b ± 3.3 37 −6.2c ± 2.0 18 (−8.5 ± 3.2) 19 (−4.3 ± 2.7) 27 (−7.4 ± 2.2) 10 (−2.4 ± 5.2) 16.0 36 −7.1b ± 2.8 36 −6.2c ± 1.7 15 (−6.7 ± 2.5) 21 (−5.7 ± 2.3) 29 (6.0 ± 1.9) 7 (−6.5 ± 3.5) aMean change corrected for placebo. Placebo change =−0.7 ± 7.0 (n = 59). Statistical comparisons performed on adjusted means. bP Ͻ 0.05. cP Ͻ 0.01. dLow renin is Ͻ0.7 ng/ml/hr. enormal renin is 0.7–3 ng/ml/hr. Trandolapril in African–Americans MR Weir and E Saunders 192 females and in patients Ͻ65 years of age (Table 3). Although there was a similar reduction in aldosterone in patients у65, it did not achieve statistical signiﬁcance. Increases in plasma renin activity in response to trandolapril therapy was similar in both men and women and in patients Ͻ65 (Table 3). Although there was a signiﬁcant increase in plasma renin activity in patients у65, the increase was of lesser magnitude than in patients Ͻ65.

Adverse events Safety and tolerability was evaluated in all patients receiving the study drug. The most common adverse events reported (not necessarily drug related) were upper respiratory tract infection n = 13 (5.0%), cough n = 10 (3.8%), headache n = 10 (3.8%), oed- ema n = 7 (2.7%), upper respiratory tract congestion n = 6 (2.3%) and fatigue n = 4 (1.5%). There were no signiﬁcant differences between any of the trandolapril treatment groups and placebo in the proportion of patients having adverse reactions. Adverse events necessitating withdrawal from the study occurred in eight patients (3.1%) randomised to trandolapril and three patients (5.0%) randomised to placebo.

Figure 1 Scattergram illustrates individual data points for patients comparing pretreatment plasma renin activity (ng Discussion angiotensin 1/ml/hr) with post-treatment blood pressure reduction (r =−0.23). Total daily dose: (¼) 4 mg, (᭜) 8 mg; (̆) No large clinical trials have explored the demo- 12 mg; (#) 16 mg. graphic interactions and pharmacodynamics of ACE inhibitors in hypertensives of African–American descent. In this study, we evaluated a 64-fold dosing Serum ACE activity was measured at baseline and range of the ACE inhibitor trandolapril in 322 end-point in all patients. Trandolapril significantly African–American hypertensive patients to explore reduced serum ACE activity with all doses evaluated the influence of age, gender, and pretreatment (0.25–16 mg). The percent reduction from baseline plasma renin activity on BP responses. Doses of ranged from 75.8 to 9.10% without significant differ- 4 mg QD or greater provided similar levels of dias- ence in level of reduction for each dose. There was tolic BP reduction. We did not observe any signifi- a statistically significant, and moderately strong cant difference of any of these demographic interac- negative correlation between percent ACE activity tions on subsequent BP reduction with equipotent remaining (r =−0.38, P Ͻ 0.01) and plasma trandola- anti-hypertensive doses of trandolapril (4–16 mg QD). prilat concentration. As depicted in Table 3, one Interestingly, pretreatment plasma renin activity did notes a similar trandolapril-induced reduction in not predict BP responses with trandolapril treat- serum ACE irrespective of gender or age when exam- ment. Low plasma renin activity in hypertensive ining equipotent anti-hypertensive doses of trandol- African–Americans has been suggested as a reason april (4–16 mg QD). for the diminished efficacy of ACE inhibitors this Trandolapril therapy also resulted in a significant group compared to Caucasians. However, our obser- decline in plasma aldosterone in both males and vations in a group of predominately low renin

Table 3 Pharmacodynamic responses by gender and age

No. All patients No. Male No. Female No. Ͻ65 years No. у65 years

DBP-Baseline (mm Hg) 171 101.2 ± 0.3 80 101.5 ± 0.5 91 100.9 ± 0.4 113 101.3 ± 0.4 38 100.7 ± 0.7 DBP-Change (mm Hg) Ϫ6.0 ± 0.6** Ϫ5.8 ± 0.9** Ϫ6.1 ± 0.8** Ϫ5.9 ± 0.6** Ϫ6.4 ± 1.5** ACE-Baseline (U/L) 145 32.3 ± 2.1 68 29.7 ± 2.0 77 34.6 ± 3.5 113 33.6 ± 2.6 32 27.8 ± 2.3 ACE-Change (U/L) Ϫ28.3 ± 2.1** Ϫ25.7 ± 1.9** Ϫ30.6 ± 3.5** Ϫ29.8 ± 2.5** Ϫ22.9 ± 2.3** Aldosterone-Baseline (ng/dL) 148 9.1 ± 0.5 69 8.7 ± 0.6 79 9.5 ± 0.7 115 9.6 ± 0.6 33 74 ± 0.6 Aldosterone-Change (ng/dL) Ϫ1.5 ± 0.5** Ϫ1.4 ± 0.6* Ϫ1.6 ± 0.7* Ϫ1.8 ± 0.6** Ϫ0.5 ± 0.6 Renin-Baseline (ng/mL/hr) 147 0.7 ± 0.1 68 0.7 ± 0.1 79 0.7 ± 0.1 114 0.8 ± 0.1 33 0.4 ± 0.1 Renin-Change (ng/mL/hr) 1.8 ± 0.6** 1.6 ± 0.5** 2.0 ± 0.9* 2.1 ± 0.7** 0.7 ± 0.3*

Mean ± s.e. is shown for patients with data at the 4, 8, 12 or 16 mg trandolapril doses. *P Ͻ 0.05 change from baseline. **P Ͻ 0.01 change from baseline. Trandolapril in African–Americans MR Weir and E Saunders 193 African–American hypertensives does not support Acknowledgements this contention. In largely Caucasian populations, renin profiling is helpful in predicting acute BP We wish to acknowledge the editorial review of responses.22 However, with chronic ACE inhibitor Beverly Novrit and Edward Kirsten, PhD and the treatment, the relationship between BP reduction statistical assistance of Tony McGuire. and pre-treatment plasma renin levels dimin- The Trandolapril Multicenter Study Group ishes.23,24 Thus race does not appear to alter this included: William Applegate, MD, University of relationship. However, our data regarding renin pro- Tennessee, Memphis, Tennessee; James M Gray, filing needs to be viewed carefully since we did not MD, James M Gray and Associates, Houston, Texas; use any provocative or suppressive manoeuvers to Adesh Jain, MD, FG McMahon, MD, Ramon Vargas, alter renin responses. We used only a single deter- MD, Fernando Chirino, MD, Clinical Research mination on an ad libitum salt diet in the supine Center, New Orleans, Louisiana; Patricia Jenkins, position which would tend to lead to suppressed MD, Baltimore, Maryland; P Michael Kaihlanen, levels. A more accurate, yet more difficult to per- MD, Dennis Ruff, MD, San Antonio, Texas; Jon Lev- form assessment of plasma renin activity would be ine, MD, Rosalyn McGuire, RN, Pichard D Pinson, serial measurements throughout the day during MD, Clinical Research Associates, Nashville, Ten- varied postures and salt intake. This would provide nessee; Vasilios Papademetriou, MD, VA Medical a more accurate 24-h peripheral renin activity Center, Washington, DC; C Venkata S Ram, MD, Nor- exposure. However, this effort would be impractical man M Kaplan, MD, Alexander F Khoury, MD, Lena in a large scale clinical trial. Farrell, RN, Diane Veath, LVN, University of Texas, Trandolapril significantly inhibited serum ACE Southwestern Medical Center, Dallas, Texas; Harold activity even with the lowest dose tested (0.25 mg). W Schnaper, MD, EE Eddleman, Jr, MD, Scientific There was a statistically significant but weak nega- Applications Company, Inc, Birmingham, Alabama; tive correlation of end-point ACE activity, change in Russell Simpson, MD, PSL Health Care Center, ACE activity from baseline to end-point, and plasma Denver, Colorado; Matthew R Weir, MD, Elijah trandolaprilat concentration. There was also a mod- Saunders, MD, University of Maryland, Baltimore, erately strong negative correlation between percent Maryland; Scott Younkin, MD, Spartanburg, South ACE activity remaining and plasma trandolaprilat Carolina. concentration. However, there was no overall corre- This study was supported in part by a Research lation between inhibition of ACE activity or trough Grant from Knoll Pharmaceutical Company, Mt plasma trandolaprilat concentration and BP Olive, New Jersey 07828, USA. reduction. These observations suggest that the anti- hypertensive activity of trandolapril is dependent References upon other mechanisms in addition to blocking 1 Final Report of the National Black Health Providers serum ACE. Other studies have suggested ACE Task Force on High Blood Pressure Education and inhibitors may reduce BP through augmenting vaso- Control. US Department of Health and Human Ser- dilatory prostaglandin production.25 However, stud- vices, Washington, DC, 1980. ies in indomethacin-pretreated spontaneously 2 The Fifth Report of the Joint National Committee on hypertensive rats suggest that prostaglandins are not Detection, Education, and Treatment of High Blood involved in the anti-hypertensive response to tran- Pressure. NIH Publication No. 93-1088, January 1993. 3 US Renal Data System. USRDS 1990 Annual Data dolapril.26 A similar lack of a prostaglandin mech- 27 Report: National Institute of Diabetes and Digestive anism has been suggested for captopril. Trandolap- Kidney Diseases, The National Institutes of Health, ril may also function through inhibiting the Bethesda, MD, August 1990. breakdown of vasodilatory kinins. 4 Rostand SG, Kirk KA, Rutsky EA, Pate BA. Racial dif- As with other ACE inhibitors, trandolapril therapy ferences in the incidence of treatment for end-stage consistently reduced plasma aldosterone concen- renal disease. N Engl J Med 1982; 306: 1276–1279. trations.28 This effect may, in part, explain some of 5 Weir MR, Saunders E. Pharmacologic management of the anti-hypertensive properties of the drug since, systemic hypertension in blacks. Am J Cardiol 1988; in a largely low renin, salt sensitive population such 61: 46H–52H. as African–Americans, aldosterone, a hormone 6 Weir MR. Impact of age, race, and obesity on hypertensive mechanisms and therapy. Am J Med 1991; 90: which amplifies renal salt conservation, may play a 3S–14S. critical role in the genesis of volume expansion and 7 Frohlich ED et al. Greater renal vascular involvement hypertension. Further clinical trials will need to in black patients with essential hypertension. Miner explore the clinical significance of this observation. Electrolyte Metab 1984; 10: 173–179. In summary, our results provide data concerning 8 Luft FC et al. Cardiovascular and humoral responses the optimal dose response of trandolapril in to extremes of sodium intake in normal black and African–Americans. We also demonstrate that white men. Circulation 1979; 60: 697–706. neither age, gender nor pre-treatment plasma renin 9 Luft FC, Grim CE, Fineberg NS, Weinberger MC. activity predicts anti-hypertensive response to ACE Effects of volume expansion and contraction in normo- inhibition in African–Americans when evaluating tensive whites, blacks, and subjects of different ages. Circulation 1979; 50: 643–650. equipotent anti-hypertensive doses. The lack of cor- 10 Veterans Administration Cooperative Study Group on relation between BP reduction and inhibition of Antihypertensive Agents. Racial differences in serum ACE activity or trough trandolapril concen- response to low-dose captopriol are abolished by the tration was interesting and suggests that other mech- addition of hydrochlorothiazide. Br J Clin Pharmacol anisms may be operative. 1982; 14: 97S–101S. Trandolapril in African–Americans MR Weir and E Saunders 194 11 Ventura HO et al. Cardiovascular effects and regional (ed). Textbook of Clinical Chemistry. WB Saunders, blood flow distribution association with angiotensin Philadelphia, 1986, pp 1075–1076. converting enzyme inhibition (captopril) in essential 21 Lieberman J. Elevation of serum angiotensin- hypertension. Am J Cardiol 1985; 55: 1023–1026. converting-enzyme (ACE) level in sarcoidosis. Am J 12 Materson BJ et al. Single-drug therapy for hyperten- Med 1975; 59: 365–372. sion in men. A comparison of six antihypertensive 22 Hodsman GP et al. Factors related to first dose hypo- agents with placebo. The Department of Veterans tensive effect of captopril: prediction and treatment. Affairs Cooperative Study Group on Antihypertensive Br Med J 1983; 286: 832–834. Agents. N Engl J Med 1993; 328: 914–921. 23 Case DB et al. Use of first dose response or plasma 13 Weinberger MH. Racial differences in antihypertensive renin activity to predict the long-term effect of captop- therapy: Evidence and implications. Cardiovasc ril: identification of triphasic pattern of blood pressure Drugs & Ther 1990; 4: 379–382. response. J Cardiovasc Pharmacol 1980; 2: 339–346. 14 Gavras A, Riberio AR, Gavras I, Brunner HR. Recipro- 24 Waeber B et al. Prediction of sustained antihyperten- cal relation between renin dependency and sodium sive efficacy of chronic captopril therapy: Relation- dependence in essential hypertension. N Engl J Med ships to immediate blood pressure response and con- 1976; 295: 1278–1283. trol plasma renin activity. Am Heart J 1982; 103: 15 Cesarone MR et al. Effects of trandolapril on 24-H 384–390. ambulatory blood pressure in patients with mild to 25 Zusman RM. Effects of converting enzyme inhibitors moderate essential hypertension. J Cardiovasc Pharm- on the renin-angiotensin-aldosterone, bradykinin, and acol 1994; 23: S65–S72. 16 Duc LCN, Brunner HR. Trandolapril in hypertension: arachidonic acid-prostaglandin systems: Correlation of Overview of a new angiotensin-converting enzyme chemical structure and biologic activity. Am J Kidney inhibitor. Am J Cardiol 1992; 70: 27D–34D. Dis 1987; 10 (Suppl 1): 13–23. 17 Lenfant B et al. Trandolapril: Pharmacokinetics of sin- 26 Brown NL et al. Angiotensin-converting enzyme inhi- gle oral doses in healthy male volunteers. J Cardiovasc bition, anti-hypertensive activity and hemodynamic Pharmacol 1994; 23: S38–S43. profile of trandolapril. Eur J Pharmacol 1988; 148: 18 Weir MR, Gray JM, Paster R, Saunders E. Different 79–91. mechanisms of action of angiotensin converting 27 Quilley J, Duchin KL, Hudes EM, McGiff JC. The anti- enzyme inhibition in white and black hypertensives. hypertensive effect of captopril in essential hyperten- Hypertension 1995; 26: 124–130. sion: relationship to prostaglandins and the kallikrein- 19 Haber E et al. Applications of radioimmunoassay for kinin system. J Hypertens 1987; 5: 121–128. angiotensin I to the physiological measurements of 28 Gavras HP et al. Effect of angiotensin converting plasma renin activity in normal human subjects. J Clin enzyme inhibition on blood pressure, plasma renin Endocrinol Metab 1969; 29: 1349–1355. activity and plasma aldosterone in essential hyperten- 20 Chattoraj SC, Watts NB. Endocrinology. In: Tietz NW sion. J Clin Endocrinol Metab 1978; 46: 220–226.