Background Angiotensin-converting–enzyme (ACE) inhibitorsnot only decrease the production of angiotensin II but alsodecrease the degradation of bradykinin. In this study, a specificbradykinin-receptor antagonist, icatibant acetate (HOE 140),was used to determine the contribution of bradykinin to theshort-term effects of ACE inhibition on blood pressure and plasmarenin activity in both normotensive and hypertensive subjects.
Methods We compared the hemodynamic, renal, and endocrine effectsof captopril alone (25 mg), captopril plus icatibant (100 µgper kilogram of body weight), the angiotensin II subtype 1–receptorantagonist losartan (75 mg), and placebo in 20 subjects withnormal blood pressure and 7 subjects with hypertension. Thesubjects were studied while they were salt depleted (i.e., inbalance on a diet in which they were allowed 10 mmol of sodiumper day). The drugs were administered on four separate studydays in a single-blind, randomized fashion.
Results The coadministration of icatibant significantly attenuatedthe hypotensive effect of captopril (maximal decrease in mean[±SE] arterial pressure for all subjects combined, 10.5±1.0mm Hg, as compared with 14.0±1.0 mm Hg for captoprilalone; P=0.001), in such a way that the decrease in blood pressureafter the administration of captopril plus icatibant was similarto that after the administration of losartan (maximal decreasein mean arterial pressure, 11.0±1.7 mm Hg). Icatibantdid not alter the renal hemodynamic response to captopril, butit significantly altered the change in plasma renin activityin response to ACE inhibition (–0.4±0.4 ng of angiotensinI per milliliter per hour, as compared with 2.0±0.7 ngper milliliter per hour for captopril alone; P=0.007). The magnitudeof these effects was similar in both the normotensive and thehypertensive subjects, as well as in both the black subjectsand the white subjects.
Conclusions These data confirm that bradykinin contributes tothe short-term effects of ACE inhibition on blood pressure innormotensive and hypertensive persons and suggest that bradykininalso contributes to the short-term effects of ACE inhibitionon the renin–angiotensin system.
Angiotensin-converting enzyme (ACE) catalyzes the formationof angiotensin II from angiotensin I and the breakdown of bradykinininto inactive products.1 ACE inhibitors are widely used in thetreatment of hypertension, congestive heart failure, and diabeticnephropathy, and they decrease blood pressure without increasingthe heart rate.2 Given over the short term, they decrease angiotensinII and aldosterone concentrations and increase plasma reninactivity.2 Under most conditions, ACE inhibitors cause natriuresisand increase renal plasma flow without altering the glomerularfiltration rate.3,4,5
The contribution of bradykinin to the actions of ACE inhibitorshas been the subject of debate. With long-term administration,ACE inhibitors lower blood pressure, even in patients with low-reninhypertension,2 suggesting an effect that is independent of adecrease in angiotensin II. Bradykinin is a potent vasodilator,acting through the release of prostacyclin, nitric oxide, andendothelial-derived hyperpolarizing factor.6 Accurate measurementof bradykinin concentrations is technically difficult, and bradykininconcentrations have been reported to be increased7 or unchanged8after ACE inhibition. ACE inhibition potentiates the hemodynamiceffects of exogenous bradykinin,9 but this observation doesnot address whether endogenous bradykinin plays a part in theactions of ACE inhibitors. Determining the contribution of bradykininto the effects of ACE inhibitors is relevant, given the widespreaduse of these agents and the introduction of specific angiotensinII subtype 1–receptor antagonists.
The availability of a specific bradykinin-receptor antagonist,icatibant acetate (HOE 140),10 has allowed investigators todetermine the contribution of bradykinin to the effects of ACEinhibitors in animals. Administration of icatibant attenuatesthe hypotensive response to ACE inhibition in rats11,12 anddogs.13 Using icatibant, Hornig et al. recently demonstratedthat bradykinin contributes to ACE-inhibitor–induced vasodilatationin the human forearm.14 Our purpose in the present study wasto measure the contribution of bradykinin to the hemodynamic,endocrine, and renal responses to short-term ACE inhibitionby comparing the effects of the ACE inhibitor captopril, captoprilplus icatibant, the angiotensin-receptor antagonist losartan,and placebo in healthy normotensive and hypertensive subjectswho were salt depleted.
Methods
The subjects provided a complete history and underwent physicaland laboratory examinations. Those with diseases other thanhypertension were excluded from the study, as were pregnantwomen. Subjects were considered to have hypertension if theyhad a documented untreated diastolic blood pressure of 90 mmHg or more on at least three occasions or had had hypertensionfor at least six months. Written informed consent was obtainedfrom all the subjects, and the protocol was approved by theinstitutional review board of Vanderbilt University MedicalCenter.
Each subject was provided a daily diet containing 10 mmol ofsodium, 100 mmol of potassium, and 2500 ml of water for a totalof 12 days. The subjects were studied under conditions of saltdepletion because angiotensin and kinin are maximally stimulatedby sodium depletion.15 On days 6, 8, 10, and 12 of the diet,the subjects reported to the Vanderbilt Clinical Research Centerat 7 a.m. after an overnight fast. A catheter was inserted intoeach antecubital vein, one for the infusion of drug and theother for drawing blood. On day 6 of the diet, blood was drawnfor the determination of plasma renin activity after the subjecthad been standing for at least one half-hour. (Subjects withnormal-to-high levels of renin activity were defined as thosewho had plasma renin activity of at least 2.4 ng of angiotensinI per milliliter per hour while in an upright position.16) Thesubjects remained in the supine position and fasted during theremainder of the study and on days 8, 10, and 12. After collectionof a control blood sample, loading doses of aminohippurate (8mg per kilogram of body weight, Merck Sharp and Dohme, WestPoint, Pa.) and inulin (50 mg per kilogram, Iso-Tex Diagnostics,Friendswood, Tex.) were given. Constant infusions were theninitiated at a rate of 12 mg per minute for aminohippurate and30 mg per minute for inulin.16 Plasma samples were obtained90 minutes after the start of the infusion of aminohippurateand inulin and 1, 3, and 4 hours after the administration ofthe study drugs. Renal vascular resistance was calculated asthe ratio of mean arterial pressure to renal plasma flow.
Study drugs were administered in a single-blind fashion on eachof the four study days as follows: 25 mg of oral captopril (Capoten,Bristol-Myers Squibb, Princeton, N.J.) plus intravenous vehicle(normal saline), 25 mg of oral captopril plus 100 µg perkilogram of intravenous icatibant (a gift from Hoechst, Frankfurt,Germany), 75 mg of oral losartan (Cozaar, Merck Sharp and Dohme)plus intravenous vehicle, and oral placebo plus intravenousvehicle. The order in which the subjects received the treatmentswas randomly assigned. Oral medications were given at time 0in opaque, identical-appearing capsules. The 25-mg dose of captoprilwas chosen because maximal renal vasodilation occurs at thisdose,3 with the peak response occurring within one hour afteradministration.17 A dose of approximately 75 mg of losartanhas been shown to block most fully the pressor response to angiotensinII in normal subjects,18 with the peak response occurring threeto four hours after administration.19 Icatibant (100 µgper milliliter) or vehicle was infused for the first hour. Thetotal dose of icatibant (100 µg per kilogram) has beenpreviously shown to inhibit the vasodilator response to bradykininin the forearm without affecting blood pressure or heart ratein normal controls.20 Pilot studies in three normotensive andtwo hypertensive subjects confirmed bradykinin antagonism overthe period of the study and the lack of effect of icatibantalone on blood pressure or heart rate.
Blood was collected for the determination of plasma renin activityand aldosterone concentrations at time 0 and four hours afterthe administration of the oral drugs. Urine was collected attime 0 and two and four hours after oral-drug administrationfor measurement of urine electrolytes and the stable hydrolysisproduct of prostacyclin, 2,3-dinor-6-keto-prostaglandin-F1.
Laboratory Analysis
Blood samples were collected, placed on ice, and spun immediately,and the supernatant was frozen at –70°C until thesamples were assayed. Urinary sodium concentrations were measuredby flame photometry. The concentrations of aminohippurate andinulin were measured by an AutoAnalyzer.16 Plasma renin activitywas measured by radioimmunoassay for angiotensin I at 37°Cand pH 7.4.21 Aldosterone concentrations were measured by radioimmunoassay(Coatacount Products, Los Angeles). 2,3-Dinor-6-keto-prostaglandin-F1was measured by gas chromatography–negative-ion chemical-ionizationmass spectrometry.22
Statistical Analysis
Data are expressed as means ±SE. Missing values (seebelow) were excluded from the calculations of the means. Comparisonsamong drug treatments were made by analysis of variance withrepeated measures in which the within-subject variables weredrug and time. The between-subject variables were race, diseasestatus (hypertension as compared with normotension), and reninstatus (low as compared with normal-to-high activity). Comparisonsbetween drug treatments at a specific time were made with theuse of a paired t-test or, if appropriate, the Wilcoxon signed-ranktest. Comparisons between groups were made with the use of anunpaired t-test or the Mann–Whitney U test. All P valuesare two-sided.
Results
Twenty subjects with normal blood pressure (10 blacks and 10whites; 12 men and 8 women) and 7 subjects with hypertension(3 blacks and 4 whites; 3 men and 4 women) completed the study.Two normotensive subjects withdrew after one study day, andone was excluded because of noncompliance with the dietary requirements.Due to technical difficulties, blood samples for aminohippurateand inulin measurements were not obtained from one normotensiveblack subject during treatment with losartan and from two othersubjects at one time during placebo treatment; blood sampleswere not obtained from one hypertensive white subject for thedetermination of renin activity and aldosterone concentrationsduring treatment with losartan.
The mean untreated blood pressure of the hypertensive subjectswhile seated and before sodium depletion was 147±2.9/95.1±2.6mm Hg. As compared with the normotensive subjects, the hypertensivesubjects were significantly older (42.6±4.7 vs. 29.9±1.8years, P=0.005) and heavier (body-mass index [the weight inkilograms divided by the square of the height in meters], 32.4±1.7vs. 25.2±1.0; P=0.002). Seven of the 20 normotensivesubjects (4 of the 10 whites and 3 of the 10 blacks) and 5 ofthe 7 hypertensive subjects (3 of the 4 whites and 2 of the3 blacks) had low renin activity when in an upright position.
The base-line characteristics of the subjects are shown in Table 1.The mean arterial pressure was significantly higher in thehypertensive subjects than in the normotensive subjects (P<0.001for all study days). Renal vascular resistance was significantlyhigher in the hypertensive subjects than in the normotensivesubjects (0.185±0.014 vs. 0.149±0.008 mm Hg permilliliter per minute per 1.73 m2 of body-surface area, P=0.029);it was also higher in the black subjects than in the white subjects(0.177±0.01 vs. 0.141±0.009 mm Hg per milliliterper minute per 1.73 m2, P=0.012). There were no significantdifferences among study days in base-line mean arterial pressure,heart rate, 24-hour urinary sodium excretion, plasma renin activity,aldosterone concentration, renal plasma flow, renal vascularresistance, and glomerular filtration rate. There was no evidenceof a carryover effect of any treatment on these measurements.
Table 1. Base-Line Data and Urinary Sodium Excretion after Each Treatment.
Hemodynamic Effects
Figure 1 and Figure 2 show the change in the mean arterial pressureover time in response to each treatment in the normotensivesubjects and the hypertensive subjects. The mean arterial pressurefor all subjects combined decreased significantly from base-linevalues after the administration of captopril, captopril plusicatibant, and losartan, but not after the administration ofplacebo. The decreases in the mean arterial pressure in responseto captopril (F=42.2, P<0.001 for the comparison with placebo),captopril plus icatibant (F=16.7, P=0.001), and losartan (F=5.6,P=0.03) were significantly greater than the decrease in responseto placebo. The decrease in the mean arterial pressure in responseto short-term captopril administration was significantly greaterthan that in response to losartan (F=7.2, P=0.01). Icatibantsignificantly attenuated the decrease in the mean arterial pressurein response to captopril (F=14.9, P=0.001). This effect wasseen both in the normotensive subjects (F=10.0, P=0.005) (Figure 1)and in the hypertensive subjects (F=8.3, P=0.03) (Figure 2).Thus, for all subjects combined the maximal decrease inthe mean arterial pressure after the administration of captoprilplus icatibant (10.5±1.0 mm Hg) was significantly lessthan that after captopril alone (14.0±1.0 mm Hg, P=0.001)and similar to that after losartan (11.0 ±1.7 mm Hg).
Figure 1. Mean (±SE) Changes in Mean Arterial Pressure after the Administration of Oral Drugs in 20 Normotensive Subjects.
Icatibant or vehicle was administered intravenously from 0 to 60 minutes after the oral drugs. The decreases in mean arterial pressure after the administration of captopril (F=33.3, P<0.001), captopril plus icatibant (F=17.3, P=0.001), and losartan (F=8.5, P=0.01) were significantly greater than that after placebo. The decrease in mean arterial pressure after captopril alone was significantly greater than that after captopril plus icatibant (F=10.0, P=0.005) and losartan (F=5.7, P=0.03).
Figure 2. Mean (±SE) Changes in Mean Arterial Pressure after the Administration of Oral Drugs in Seven Hypertensive Subjects.
Icatibant or vehicle was administered intravenously from 0 to 60 minutes after the oral drugs. The decrease in mean arterial pressure after the administration of captopril was significantly greater than those after placebo (F=13.5, P=0.01), captopril plus icatibant (F=8.3, P=0.03), and losartan (F=9.0, P=0.024).
There was no significant effect of race, renin status, or diseasestatus on the change in mean arterial pressure in response toany treatment. The degree to which icatibant attenuated theresponse of blood pressure to captopril tended to be greaterin the subjects with normal-to-high plasma renin activity thanin those with low plasma renin activity, but this differencewas not significant (decrease in response, 66±17 percentvs. 36±16 percent; P=0.19).
The heart rate decreased significantly in response to captopril(F=2.6, P=0.046); in response to losartan it decreased significantlyin the normotensive subjects but not in the hypertensive subjects(F=5.0, P=0.04). However, there were no significant differencesamong treatments in the heart-rate response. There was no significanteffect of race, renin status, or disease status on the heart-rateresponse to any drug.
Renal Effects
Table 1 shows urinary sodium excretion four hours after theoral administration of the study drugs. Urinary sodium excretionwas significantly higher after the administration of losartan(P<0.001 for the comparison with placebo), captopril (P=0.04),and captopril plus icatibant (P=0.02). Urinary sodium excretionafter the administration of losartan was also significantlyhigher than that after either captopril (P=0.004) or captoprilplus icatibant (P=0.003). Although there was no significanteffect of race on urinary sodium excretion after the administrationof any of the study drugs, it tended to be lower in the blacksubjects than in the white subjects after captopril and captoprilplus icatibant (captopril, 12.1±2.1 mmol and 15.8±3.0mmol; captopril plus icatibant, 14.0±2.5 mmol and 15.2±2.2mmol; placebo, 11.4±2.4 mmol and 12.4±2.5 mmol).Thus, urinary sodium excretion after the administration of captopriland captopril plus icatibant was not significantly increasedas compared with that after the administration of placebo inthe black subjects.
Urinary sodium excretion was significantly greater after theadministration of losartan (19.3±3.4 mmol in the blacksubjects and 19.3±2.3 mmol in the white subjects) thanafter placebo in both blacks and whites. There was no significanteffect of renin status or disease status on urinary sodium excretionin response to any drug. There were no significant differencesamong treatments in urine volume or creatinine excretion. Theurinary excretion of 2,3-dinor-6-keto-prostaglandin-F1 did notincrease after the administration of either captopril or losartan(data not shown).
Renal plasma flow increased in response to captopril, captoprilplus icatibant, and losartan but not placebo (data not shown).Because the mean-arterial-pressure response (and therefore therenal perfusion pressure) was different during the various treatments,renal vascular resistance was used to compare treatments (Figure 3).The decreases in renal vascular resistance after the administrationof captopril (F=19.0, P<0.001 for the comparison with placebo),captopril plus icatibant (F=9.1, P=0.007), and losartan (F=6.2,P=0.024) were significantly greater than that after placebo.The addition of icatibant to captopril did not significantlyattenuate the decrease in renal vascular resistance observedwith captopril alone (F=2.1, P=0.16; difference in mean changein renal vascular resistance between captopril and captoprilplus icatibant, 0.0087 mm Hg per milliliter per minute per 1.73m2 [95 percent confidence interval, –0.0014 to 0.0187]).Despite the observed effects of race and disease status on base-linerenal vascular resistance, there was no effect of race, diseasestatus, or renin status on the change in renal vascular resistanceafter the administration of any drug (P>0.3 for each variablefor all drugs). There were no significant differences amongtreatments in the glomerular filtration rate (data not shown),and there was no effect of race, disease status, or renin statuson the glomerular filtration rate in response to any drug.
Figure 3. Mean (±SE) Changes in Renal Vascular Resistance after the Administration of Oral Drugs in All 27 Subjects.
The decreases in renal vascular resistance after the administration of captopril (F=19, P<0.001), captopril plus icatibant (F=9.1, P=0.007), and losartan (F=6.2, P=0.024) were significantly greater than that after placebo.
Renin–Angiotensin System
Plasma renin activity increased in response to both captopril(mean change, 2.0±0.7 ng of angiotensin I per milliliterper hour, as compared with –0.2±0.2 ng of angiotensinI per milliliter per hour with placebo; P=0.007) and losartan(1.2±0.6 ng of angiotensin I per milliliter per hour,P=0.04 for the comparison with placebo), but not in responseto captopril plus icatibant (–0.4±0.4 ng of angiotensinI per milliliter per hour, P=0.7). Concurrent administrationof icatibant eliminated the increase in plasma renin activitythat occurred after the administration of captopril alone (P=0.007).Although there was no effect of either race or disease status,base-line renin status had a dramatic effect on the responseof plasma renin to the study drugs. Plasma renin activity increasedin response to captopril in the subjects with normal-to-highlevels of renin activity but not in those with low renin activity(3.7±1.1 vs. –0.01±0.2 ng of angiotensinI per milliliter per hour, P=0.005) (Figure 4). The plasma reninresponse to losartan did not differ significantly between thesubjects with normal-to-high renin activity and those with lowrenin activity.
Figure 4. Mean (±SE) Changes in Plasma Renin Activity from Base Line to Four Hours after the Administration of Oral Drugs in 15 Subjects with Normal-to-High Renin Activity and 12 Subjects with Low Renin Activity.
Aldosterone concentrations decreased significantly after theadministration of captopril (from 17.5±1.3 to 8.6±1.0ng per deciliter [485.4±36.1 to 238.6±27.7 pmolper liter], P<0.001), captopril plus icatibant (from 19.7±2.0to 9.1±1.3 ng per deciliter [546.5 ±55.5 to 252.4±36.1pmol per liter], P<0.001), losartan (from 17.7±1.6to 6.4±0.7 ng per deciliter [491.0±44.4 to 177.5±19.4pmol per liter], P< 0.001), and placebo (from 22.1±2.8to 12.9±1.8 ng per deciliter [613.1±77.7 to 357.8±49.9pmol per liter], P<0.001). There were no significant differencesamong treatments in the decrease in aldosterone, nor was thereany effect of race, disease status, or renin status on the responseof aldosterone concentrations to treatment.
Discussion
This study provides evidence that bradykinin contributes substantiallyto the hypotensive effects of ACE inhibition. Coadministrationof the bradykinin-receptor antagonist icatibant decreased theaverage response of blood pressure to captopril by 53 percent(95 percent confidence interval, 29 to 76 percent), and thedecrease in blood pressure after the administration of an ACEinhibitor and bradykinin-receptor antagonist combined was similarto that after the administration of the angiotensin-receptorantagonist losartan. This effect was observed in subjects withmild hypertension as well as in normotensive subjects and inboth black subjects and white subjects.
These data confirm observations made in studies in animals thatbradykinin plays a part in the hemodynamic effects of short-termACE inhibition. For example, in 1981 Carretero et al.23 reportedthat pretreatment with antikinin globulins blocked the hypotensiveeffect of ACE inhibition in two-kidney, one-clip rats. Morerecent studies of icatibant have shown that this specific receptorantagonist attenuates the hypotensive response to ACE inhibitionin aortic-banded rats,11 spontaneously hypertensive rats,12and dogs with congestive heart failure.13
Previous studies have demonstrated a blunted hypotensive responseto both ACE inhibition24 and angiotensin-receptor antagonism25in blacks as compared with whites and a blunted acute responseto ACE inhibition in patients with low-renin essential hypertensionas compared with those with normal-to-high-renin26 essentialhypertension. The lack of an effect of either race or reninstatus on the hypotensive response to captopril or losartanin our study probably results from the fact that subjects werestudied while they were salt depleted. Sodium depletion resultingfrom the administration of a diuretic drug has been shown toeliminate differences due to race in the hypotensive responseto ACE inhibition.27
Because the kallikrein–kinin system, like the renin–angiotensinsystem, is activated under conditions of salt depletion,15 thedesign of our study may have obscured an effect of race or reninstatus on the contribution of bradykinin to the hypotensiveeffects of ACE inhibitors. Indeed, data that urinary kallikreinexcretion is decreased in blacks28 and in hypertensive patientswith low renin levels29 and that the level of urinary kallikreinexcretion predicts the hypotensive response to ACE inhibition26suggest that both race and renin status should affect the contributionof bradykinin to the antihypertensive effects of ACE inhibitors.Studies in hypertensive patients whose salt intake is normalare needed to test this hypothesis further.
The short-term renal hemodynamic effects of ACE inhibitors andangiotensin-receptor antagonists have been studied in predominantlywhite populations. ACE inhibitors decrease renal vascular resistance,usually without altering glomerular filtration.3,4,5 However,under conditions of decreased perfusion, glomerular filtrationmay fall during ACE inhibition.30 Data from studies in ratssuggest that this decrease in glomerular filtration may be mediatedthrough selective efferent arteriolar vasodilation by bradykinin.31Losartan also decreased renal vascular resistance without affectingglomerular filtration in most studies,32 although Doig et al.observed a decrease in creatinine clearance in salt-depletedsubjects.33
In our study, the short-term renal effects of an ACE inhibitorand an angiotensin-receptor antagonist were studied in bothblack subjects and white subjects. Strikingly, base-line renalvascular resistance was higher in the black subjects than inthe white subjects. Increased renal vascular resistance hasbeen reported previously in blacks with hypertension,28 andour study extends this observation to normotensive subjects.In both racial groups, renal vascular resistance decreased toa similar extent after the administration of captopril alone,captopril plus icatibant, or losartan. The glomerular filtrationrate did not change significantly from the base-line value duringany treatment.
As observed in previous studies, both captopril3,4,5 and losartan32,33caused natriuresis. However, losartan caused significantly greaternatriuresis than captopril, particularly in the black subjects.The reason for this differential effect of captopril and losartanon sodium excretion, in the face of similar changes in renalvascular resistance, is not clear. Nevertheless, the administrationof both icatibant and captopril did not alter urinary sodiumexcretion significantly from that observed after captopril alone.Taken together, these data suggest that bradykinin does notcontribute importantly to the renal effects of ACE inhibitionin normotensive or hypertensive subjects, regardless of race.This hypothesis is consistent with data from a recent clinicaltrial that showed no difference in the rates of renal insufficiencybetween elderly patients with congestive heart failure who wererandomly assigned to receive an ACE inhibitor and those assignedto receive an angiotensin-receptor antagonist.34
Numerous investigators have demonstrated that short-term ACEinhibition or administration of an angiotensin-receptor antagonistcauses an increase in plasma renin activity.2,35 As in our study,Abe et al.36 reported an increase in renin activity after theadministration of captopril in subjects with normal-to-highlevels of renin activity but not in subjects with low levels.The renin response to ACE inhibition and angiotensin-receptorantagonism has been attributed to decreased feedback inhibitionby angiotensin II.37 However, our findings suggest that increasedbradykinin also plays a part in the renin response to the short-termadministration of captopril. Thus, the administration of bothicatibant and captopril eliminated the increase in plasma reninactivity observed after captopril alone.
The finding of Azizi et al. that the addition of captopril enhancesthe plasma-renin-activity response to losartan also suggestsan effect of bradykinin on renin.38 The mechanism by which bradykininincreases renin activity is not clear. Bradykinin stimulatesthe production of prostacyclin,9 a potent stimulus to reninrelease.39 The coadministration of a cyclooxygenase inhibitorblunts the renin response to short-term ACE inhibition.36 However,urinary excretion of the prostacyclin metabolite 2,3-dinor-6-keto-prostaglandin-F1was not increased after short-term administration of captoprilin our study, suggesting that the effects of captopril-inducedchanges in bradykinin on renin activity were not mediated byprostaglandins. Beierwaltes has reported a prostaglandin-independenteffect of bradykinin on renin activity in isolated rat glomeruli.40
In summary, our study demonstrates that bradykinin contributesto the hypotensive and endocrine effects of short-term ACE inhibitionwith captopril in normotensive and hypertensive subjects whilethey are salt depleted. The role of bradykinin during long-termACE inhibition requires study. Investigators have demonstratedthat angiotensin II concentrations increase toward base-linevalues during long-term ACE inhibition.41 Conversely, the antihypertensiveeffect of angiotensin-receptor antagonists appears to increasegradually with long-term administration.42 Thus, the resultsof our study should not be extrapolated to the long-term treatmentof hypertensive patients whose salt intake is normal with ACEinhibitors or angiotensin-receptor antagonists.
Supported by grants (GM07569, RR00095, HL56963, GM15431, GM42056,and DK48831) from the National Institutes of Health and by aMedical School Grant from Merck Research Laboratories.
Source Information
From the Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville.
Address reprint requests to Dr. Brown at the Division of Clinical Pharmacology, 560 MRB-1, Vanderbilt University Medical Center, Nashville, TN 37232-6602.
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