Drugs 35 (Suppl, 5): 62-71 (1988)

0012-6667/88/0500-0062/$5.00/0© ADIS Press LimitedAll rights reserved .

Renal Protective Effect of Long TermAntihypertensive Therapy with Enalapril

John H. Bauer and Garry P. ReamsHypertension Section, Division of Nephrology, Department of Medicine, University ofMissouri School of Medicine, Columbia

Summary This review focuses on recent human studies with the angiotensin-converting enzyme(ACE) inhibitor enalapril, prescribed either alone or in combination with a diuretic, topatients with essential hypertension and to patients with hypertension associated withmoderate to severe renal parenchymal disease. Data suggest that enalapril therapy mayprovide a renal protective effect. In addition to lowering and controlling systemic arterialblood pressure, enalapril therapy is associated with stabilisation of, and/or improvementin effective renal plasma flow, glomerular filtration rate (GFR) and urinary protein ex­cretion. Such renal protective effects are probably mediated by normalisation ofboth thesystemic arterial blood pressure and intraglomerular capillary hydraulic pressure, and byan increase in the glomerular ultrafiltration coefficient. Drug therapy enabling control ofboth systemic and glomerular hypertension may prevent hypertensive renal end-organdamage and attenuate the natural progression of renal parenchymal disease.

For patients with essential hypertension, andpatients with hypertension associated with mod­erate to severe renal parenchymal disease, drugtherapy which can attenuate the effects of angio­tensin II on the systemic and intrarenal vascula­ture (table I) has the potential to normalise bothsystemic arterial pressure and glomerular capillaryhydraulic pressure. Such therapy may improve ef­fective renal plasma flow, lower renal vascular re­sistance, and decrease urinary protein excretion.Furthermore, by attenuating the effects of angio­tensin II on the mesangium, (i.e. by increasing theultrafiltration coefficient), such treatment may sta­bilise or improve the glomerular filtration rate(GFR).

This review focuses on recent human studieswith the angiotensin-converting enzyme (ACE) in-

hibitor enalapril, given as monotherapy or in com­bination with a diuretic to patients with essentialhypertension and to patients with hypertension as­sociated with moderate to severe renal parenchy­mal disease. The data suggestthat enalapril therapymay convey a renal protective effect, since in ad­dition to lowering and controlling systemic arterialblood pressure, renal function is stabilised or im­proved.

We suggestthat this renal protection results fromstrict control of both systemic arterial blood pres­sure and intraglomerular capillary hydraulic pres­sure. It remains to be determined whether the renalprotective effect of enalapril is drug specific andrelated to the high concentration of enalaprilachieved in renal tissue, or whether it is a propertyof all ACE inhibitors.

Renal Protect ive Effect of Enalapril

Table I. Direct actions of angiotensin II within the kidney

63

Vascular endothelium

Preferential constriction of the efferent postglomerular arterioles, which increases the filtration fract ion and results in:proximal tubular sodium and water reabsorptionat low perfusion pressures, regulation (preservation) of glomerular filtration rate

enhanced transglomeru lar passage of albumin

Tubular epithelium

Direct effect on the renal tubular transport of sodium and water resulting in:sodium reabsorption (antinatriuresis)water reabsorpt ion (antidiuresis)

Mesangial cells

Direct effect on the mesangial cells, resulting in:contraction of the mesangium, and reduction, therefore, in the ultrafiltration coefficient, and in the glomerular filtration rate

increased mesangial uptake of macromolecules and disruption of macromolecular clearance; trapping may precipitate mesangialinjury which leads to sclerosis

Juxtaglomerular cells

Direct inhibition of renin release (short-loop, negative feedback mechanism)

Interstitial cells

Direct stimulation and biosynthesis of vasodilatory prostaglandin

1. Renal Protective Effects of Enalapril inEssential Hypertension1.I Study Design

23 patients with essential hypertension were in­cluded in this prospective study, and for 3 yearsserial assessment of renal function during eitherenalapril monotherapy (n = 8) or enalapril-hydro­chlorothiazide therapy (n = 15) was made. Thesepatients were from a group of 39 patients originallyincluded in a study with a double-blind, random­ised protocol designed to compare their blood pres­sure and renal function lresponses to enalaprilmonotherapy, enalapril-hydrochlorothiazide com­bination therapy , or hydrochlorothiazide mono­therapy (Bauer & Jones 1984). After 8 weeks' treat­ment, patients unresponsive to either monotherapywere placed on the combination therapy , and at Iyear 9 patients were on 'enalapril monotherapy(mean dose 22 rug/day), 21 were on combinationtherapy (mean doses;' enalapril 21 rug/day andhydrochlorothiazide 52 rug/day), and 4 were onhydrochlorothiazide monotherapy (mean dose 88mg/day) [Bauer & Gaddy, 1985]. Patients whoseblood pressure was successfully controlled on either

enalapril monotherapy or enalapril-h ydrochloro­thiazide combination therapy were continued in theprotocol. AI! 9 patients randomised to enalaprilmonotherapy (mean dose 17.7 rug/day), and 20 of21 patients on combination therapy (mean doses,enalapril 20.5 mg/day and hydrochlorothiazide 51mg/day), were assessed for renal function for 2 years(Reams & Bauer 1986a). Eight of the 9 patientsrandomised to enalapril monotherapy (mean dose17.5 mg/day), and 15 of the 21 on combinationtherapy (mean doses, enalapril 20.7 rug/day andhydrochlorothiazide 51.7 mg/day), were assessedfor renal function for 3 years (Bauer et al. 1987a).

1.2 Results

Systolic and diastolic arterial blood pressure(first and fifth phase) were controlled well in boththe recumbent and upright positions (table II).GFR, assessed by serum creatinine concentration,creatinine clearance or inulin clearance, was un­changed throughout the study when compared withthe pretreatment (placebo) assessment (table III).There was a sustained 17% increase in effectiverenal plasma flow. Mean filtration fraction and ur-

Renal Protective Effect of Enalapril

Table II. Response of blood pressure (mean ± SO, n =23) to enalapri l therapy in essential hypertension

Placebo Year 1 Year 2 Year 3

Recumbentsystol ic pressure (mm Hg) 156 ± 14 123 ± 10' 120 ± 10" 127 ± 20"diastolic pressure (mm Hg) 104 ± 4 81 ± 8" 80 ± 8" 83 ± 6"

Upright

systolic pressure (mm Hg) 155 ± 14 120 ± 10" 115 ± 9" 118 ± 16"diasto lic pressure (mm Hg) 106 ± 6 82 ± 6" 80 ± 7" 82 ± 6"

, = P < 0.01, " = P < 0.0005 compared with placebo .

Table III. Response of renal funct ion (mean ± SO, n = 23) to enalapril therapy in essential hypertension

Placebo Year 1 Year 2 Year 3

Scr (mg/dl) 1.38 ± 0.18 1.30 ± 0.20 1.25 ± 0.18" 1.24 ± 0.17"

Ccra 91 ± 23 94 ± 21 93 ± 17 93 ± 20

C inulina 84 ± 30 95 ± 24 95 ± 25 93 ± 26

Cpaha 326' ± 107 388 ± 129" (n = 22) 388 ± 104 (n = 22) 398 ± 73'

Cinulin/Cpah (%) 26.1 ± 6.0 26.3 ± 7.9 (n = 22) 25.4 ± 4.8 (n = 22) 24.6 ± 6.3

U proteinb 0.06 ± 0.06 0.05 ± 0.06 0.04 ± 0.01 (n = 21) 0.08 ± 0.12

64

a ml/min/1.73m2•

b gIg creatin ine.Abbreviations : Scr = serum creatinine ; Ccr = creat inine clearance ; Cinulin = inulin clearance ; Cpah = para-aminohippurate clearance ;

Cinulin/Cpah = filtration fract ion; UpI'D'.in = 24-hour urinary protein excretion. ' = p < 0.01, " = P < 0.001 compared with placebo.

inary protein excretion were also unchanged. 12 ofthe 23 patients had moderately impaired renalfunction (inulin clearance ~ 80 ml/min/1.73m2)

before starting active drug therapy, and after thefirst year a 50% increase in their inulin clearanceand a 39% increase in their effective renal plasmaflow was observed (table IV). After 3 years' treat­ment inulin and para-aminohippurate clearanceswere 33 and 47% higher, respectively, than afterplacebo therapy. The less sensitive markers of renalfunction, serum creatinine concentration and cre­atinine clearance, demonstrated qualitatively sim­ilar mean changes. In these patients, mean filtra­tion fraction and urinary protein excretion wereunchanged. II patients who entered the study withnormal renal function (inulin clearance > 80 milmin/1.73m2) demonstrated no change in their in­dices of renal function (table V).

Of the 7 patients withdrawn from the study dur­ing the second and third years, 5 experienced an

intercurrent illness (ischaemic heart disease re­quiring the addition of a {j-blocker), I died of is­chaemic heart disease, and I was withdrawn be­cause of alcoholism. None of these patients hadexperienced a deterioration in renal function at thetime of their exclusion from the study. All had nor­mal levels of glomerular filtration; the average in­ulin clearancebefore withdrawal from the study was97 ml/min/1.73m2•

1.3 Discussion

The data demonstrate that long term enalaprilmonotherapy or enalapril-hydrochlorothiazidecombination therapy lowered and controlled sys­temic arterial blood pressure and stabilised or im­proved GFR, effective renal plasma flow and ur­inary protein excretion. The level of glomerularfiltration sustained in these patients, with this ther­apeutic modality, is similar to that observed in age-

Renal Protective Effect of Enalapril

matched normotensive controls (Baueret al. 1982a).The maintenance of a relatively high filtration frac­tion, from 24.6 to 26.3%, suggests that the im­provement in GFR was disproportionately greaterthan the respective increase in effective renalplasma flow. A normal filtration fraction in ourlaboratory averages 21 to 22%(Bauer et al. 1982a).

Patients with moderately impaired renal func­tion (inulin clearance ~ 80 ml/min/L'Bm? but ~40 ml/min/1.73m2) demonstrated an initial markedincrease in both inulin and para-aminohippurateclearances. Increases in renal filtration and perfu­sion were generally sustained after 3 years' treat­ment. We suggest that the above improvements in

65

renal function resulted from strict control of bothsystemic arterial blood pressure and intraglome­rular capillary hydraulic pressure. Interruption ofthe intrarenal renin-angiotensin system shouldmitigate the effects of angiotensin II on the glo­merular mesangium (sustaining and/or increasingthe ultrafiltration coefficient),and also mitigate theeffects of angiotensin II on efferent arteriolar re­sistance (decreasing renal vascular resistance andglomerular capillary hydraulic pressure) [Bauer1984; Bauer & Reams 1986].

The natural course of untreated essential hyper­tension is characterised by progressive impairmentof renal function (Lindeman et al. 1984; Moyer et

Table IV. Response of renal function (mean ± SO, n == 12) to enalapriltherapy in patients with initial GFR < 80 ml/min/1 .73m2

Sysl./diasl. BP (mm Hg)

Sc, (mg/dl)Cera

Cinulin

Cpaha

Cinulin/Cpah(%)

Uproteinb

Placebo

154 ± 12/104 ± 41.38 ± 0.2081 ± 2660 ± 14

256 ± 7223.9 ± 3.9

0.08 ± 0.07

Year 1

119 ± 9"""/80 ± 9"""1.35 ± 0.2190 ± 2391 ± 19"""357 ± 100""" (n == 11)

26.7 ± 5.9 (n == 11)

0.07 ± 0.08

Year 2

119 ± 9"""/82 ± 8"""1.27 ± 0.20"

87 ± 1286 ± 13"""363 ± 72""" (n == 11)

25.0 ± 2.5 (n == 11)

0.05 ± 0.025

Year 3

126 ± 19"""/84 ± 6"""1.23 ± 0.20"85 ± 1780 ± 20""376 ± 81"""

21.9 ± 5.6

0.13 ± 0.16

a ml/min/1 .73m2•

b gIg creat inine.Abbreviations: BP == blood pressure (systolic/diastolic in recumbent position); Sc, == serum creat inine; Cc, == creatin ine clearance;

Cinulin == inulin clearance; Cpah == para-aminoh ippurate clearance; Cinulin,Cpah == filtration fraction; Up,olein == 24-hour urinary ·proteinexcretion; GFR == glomerular filtration rate. " == p < 0.02, "" == P < O.Q1 , """ == P < 0.001 compared with placebo .

Table V. Response of renal function (mean ± SO, n == 11) to enalapriltherapy in patients with initial GFR > 80 ml/min/1.73m2

Placebo Year 1 Year 2 Year 3

SySI./diasl. BP (mm Hg) 158 ± 15/105 ± 4 128 ± 11""/83 ± 6"" 120 ± 10""/79 ± 8"" 128 ± 21"/81 ± 2""

Sc, (mg/dl) 1.38 ± 0.15 1.25 ± 0.18" 1.23 ± 0.16" 1.25 ± 0.15

Cc,a 102 ± 12 99 ± 18 99 ± 19 103 ± 20

C inulina 111 ± 17 100 ± 28 105 ± 31 106 ± 26

Cpaha 402 ± 85 420 ± 151 413 ± 127 388 ± 66

Cinulin,Cpah(%) 28.6 ± 7.1 25.6 ± 9.9 26.1 ± 6.4 27.4 ± 6.0

Uproteinb 0.04 ± 0.03 0.03 ± 0.02 0.03 ± 0.01 0.03 ± 0.03

a ml/min/1.73m2•

b gIg creatinine .Abbreviations: BP == blood pressure (systolic/diastolic in recumbent position) ; Sc, == serum creat inine; Cc, == creatinine clearance;

Cinulin == inulin clearance ; Cpah == para-amino hippurate clearance; Cinulin/Cpah == filtration fraction ; Up,otein == 24-hour urinary proteinexcretion; GFR == glomerular filtration rate. " == p < 0.01, "" == P < 0.001 compared with placebo.

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Renal Protective Effect of Enalapril

al. 1958). Effective, long term antihypertensivetherapy may oppose this tendency . The renal ef­fects of most classes of antihypertensive drugs cur­rently prescribed for the treatment of essentialhypertension are shown in table VI. It is clear fromthese studies that pharmacological control of sys­temic arterial blood pressure does not adversely af­fect renal function , with the potential exceptionsbeing {1-adrenergic antagonism, central £¥radren­ergic agonism , and triple drug therapy with me­tolazone, a {1-blocker and minoxidil. Usually , GFRand effective renal plasma flow are sustained atlevels recorded after a placebo run-in period. How­ever, with the exception ofcalcium antagonists andthe ACE inhibitors, none of these drug classes pro­duced and sustained a clinically significant in­crease in GFR and effective renal plasma flow. Onlythe ACE inhibitors and the calcium antagonists(which also attenuate the intrarenal effects ofangiotensin II) appear to reverse renal function andhaemodynamic abnormalities found in patientswith essential hypertension.

Of some concern may be the decrease in GFRpreviously observed in patients with essentialhypertension and a normal GFR (inulin clearance~ 80 ml/min/1.73m2) who were prescribed eitheran ACE inhibitor or a calcium antagonist (tableVI). This could result from a reduction in intra­glomerular capillary hydraulic pressure caused byreducing efferent arteriolar vascular resistance inthe absence of a compensatory increase in the glo­merular ultrafiltration coefficient. Since renal vas­cular abnormalities precede changes in the GFR inpatients with essential hypertension and producethe characteristic rise in the filtration fraction(Bauer et al. 1982a), it is not surprising that thepredominant effect of ACE inhibitor therapy inpatients with normal glomerular function is on therenal vasculature, and not on the glomerular mes­angium. Importantly, GFR is usually not reducedto abnormal levels (inulin clearance < 80 ml/min/1.73m2), and the addition of hydrochlorothiazideattenuates this effect. The observed changes in in­ulin clearance are generally not detectable by theless sensitive creatinine clearance methodologies(Bauer et al. 1982b).

68

2. Renal Protective Effects of Enalapril inHypertension Associated with Moderate toSevere Renal Parenchymal Disease2.1 Study Design

The short term renal response to enalapriltherapy was assessed in 9 patients with hyperten­sion associated with moderate to severe renal pa­renchymal disease (Reams & Bauer 1986a). Fourpatients had hypertensive nephrosclerosis, and 1each had polycystic kidney disease, focal glome­rulosclerosis , hereditary nephritis, glomerulo­nephritis of unknown cause, and diabetic nephro­pathy. Baseline studies were performed after a briefplacebo run-in period (1 to 3 days), and after 2months of enalapril therapy (mean dose 30.5 mg/day). Three patients required the addition of fru­semide (mean dose 66.6 mg/day) to achieve bloodpressure control. Five of the 9 patients were againstudied after an additional 6 months of enalapriltherapy.

2.2 Results

Systolic and diastolic blood pressure (first andfifth phase) were well controlled in both the re­cumbent and upright positions (table VII). GFR,assessed by serum creatinine concentration, cre­atinine clearance or inulin clearance, was main­tained throughout the study compared with theplacebo run-in assessment (table VIII). However,there was a sustained 22%increase in effective renalplasma flow, which resulted in a sustained decreasein the filtration fraction . Urinary protection excre­tion was decreased markedly (-45%). Similar re­sults have been reported by Opsahl et al. (1987).

2.3 Discussion

We suggest that the preservation of glomerularfiltration, the increase in renal perfusion, and thedecrease in urinary protein excretion resulted fromstrict control of both systemic arterial blood pres­sure and intraglomerular capillary hydraulic pres­sure. Interruption of the intrarenal renin-angioten­sin system should . attenuate the effects of

Renal Protective Effect of Enalapril

Table VII. Response of blood pressure (mean ± SEM) to en-

alapril therapy in renal parenchymal disease

Placebo 2 months 6 months

n=9 n=9 n = 5

(n = 5) (n = 5)

Recumbent

Systolic 154 ± 8 137 ± 9"

(mmHg) (141 ± 8) (131 ± 8) 130 ± 8'

Diastolic 97 ± 2 86 ± 3'"

(mmHg) (93 ± 2) (85 ± 1') 81 ± 3'

Upright

Systolic 151 ± 8 130 ± 8'"

(mmHg) (144 ± 9) (128 ± 13') 129 ± 10'

Diastolic 95 ± 3 83 ± 2"

(mmHg) (91 ± 3) (83 ± 3) 84 ± 4'

, = p < 0.05; " = P < 0.015, '" = P < 0.01 compared with

placebo.

angiotensin II on the glomerular mesangium (andthus sustain the ultrafiltration coefficient), andshould also attenuate the effects of angiotensin IIon efferent arteriolar resistance (and decrease glo­merular capillary hydraulic pressure). The decreasein the filtration fraction , which results from effer­ent arteriolar dilatation, should decrease the con-

69

centration of plasma protein along the length of theglomerular capillary, and decrease the transglom­erular passage of protein because of the lower con­centration gradient for diffusion and the lower con­centration of protein in the convected fluid (Bohreret al. 1977). Inhibition of intrarenal angiotensin IIshould also decrease the mesangial uptake ofmacromolecules, reducing the transglomerular pas­sage of albumin (Eisenbach et al. 1975; Keane &Raij 1985; Raij & Keane 1985; Stein et al. 1983).

The natural course of untreated hypertension inrenal parenchymal disease is characterised by pro­gressive impairment of renal function to end-stagedisease (Branca et al. 1983; Lindeman et al. 1984;Moyer et al. 1958). The transmission of systemicpressure to the vasodilated glomerular capillarynetwork may be the most important mechanism inthe progression of renal disease in patients withhypertension. Effective long term antihypertensivetherapy may oppose this tendency, although recentexperimental evidence suggests that reduction ofsystemic arterial blood pressure alone does notprotect the impaired kidney; glomerular capillaryhydraulic pressure must also be reduced to protectthe glomeruli at risk of glomerular sclerosis (An­derson et al. 1985, 1986).

Traditional antihypertensive treatment of

Table VIII. Response of renal function (mean ± SEM) to enalapril therapy in renal parenchymal disease

Placebo 2 months 6 monthsn = 9 (n = 5) n = 9 (n = 5) n = 5

s; 3.2 ± 0.5 3.3 ± 0.6

(mg/dl) (4.1 ± 0.7) (4.3 ± 0.9) 4.4 ± 1.1c; 35 ± 4 37 ± 6

(ml/min/l.73m2) (27 ± 4) (28 ± 6) 28 ± 9

Cinulin 27 ± 5 29 ± 6(ml/min/l .73m2) (17 ± 3) (18 ± 4) 18 + 5

C pah 105 ± 12 128 ± 13"

(ml/min/l.73m2) (82 ± 14) (106 ± 17) 106 ± 30

Cinulin/Cpah 25.7 ± 2.9 21.8 ± 3.3'(%) (22.1 ± 3.3) (16.9 ± 2.1') 17.7 ± 2.3

Uprote in 1.07 ± 0.44 0.59 ± 0.30'"(g/g creatinine) (0.92 ± 0.36) (0.41 ± 0.19') 0.38 ± 0.17"

Abbreviations: So< = serum creatinine; C cr = creatinine clearance; Cinulin = inulin clearance; C pah = para-aminohippurate clearance;

Cinu lin/Cpah = filtration fraction ; Uprotein = 24-hour urinary protein excretion.

, = p < 0.05, " = P < 0.02, '" = P < 0.0015 compared with placebo.

Renal Protective Effect of Enalapril

patients with renal disease has focused on the vol­ume and renin components of the blood pressureequation (Ulvila et al. 1972; Vertes et al. 1969).Because of abnormalities in sodium homeostasis,salt restriction and diuretics are frequently selectedas first-step therapy. Since most patients with renaldisease have an increase in their plasma volume,exchangeable sodium , and/or extracellular fluidspace (Beretta-Piccoli et al. 1976; Tarazi et al. 1970),and most classes of antihypertensive agents do notwork well in the presence of volume expansion(Finnerty et al. 1970), salt restriction and diuretictherapy have been logical and effective ways ofcontrolling systemic hypertension.

In addition, the treatment of patients with renaldisease has largely adhered to the concept ofstepped-care therapy, which usually mimics triple­drug therapy (i.e. diuretic, (j-blocker and vasodi­lator) for the more resistant forms of systemichypertension (Zacest et al. 1972). This approachhas been extremely effective; bilateral nephrec­tomy for the control of resistant-refractory sys­temic hypertension is no longer used. However, theeffect of these therapies on the progression of renaldisease has not been well defined. In spite of theability to control systemic hypertension in patientswith renal disease, these patients may ultimatelydie or require dialysis or transplantation. This sit­uation has generated a number of dietary inter­vention trials to assess the effect of a restriction ofprotein and/or phosphate on the progression ofrenal disease.

Given our present knowledge, the use of di­uretics and vasodilators as sole therapy for thetreatment of hypertension associated with renaldisease is questionable , since both stimulate therenin-angiotensin system. Drug mediated elevationof intrarenal angiotensin II has the potential tovasoconstrict the efferent pressures even thoughsystemic arterial blood pressure is reduced. Indeed,it has been demonstrated experimentally thattriple-drug therapy, with a diuretic, reserpine andhydralazine, does not reduce glomerular capillaryhydraulic pressure even though it produces a sig­nificant drop in systemic blood pressure (Andersonet al. 1986). The net clinical result is that glomer-

70

ular injury and proteinuria are not reduced. Drugmediated elevation of angiotensin II also has thepotential to compromise salt and water homeosta­sis, glomerular filtration, and the transglomerularpassage of albumin.

3. Conclusions

The future approach toward antihypertensivetherapy in patients with renal disease should be di­rected not only at lowering systemic arterial bloodpressure, but also at lowering intraglomerular pres­sure. This appears to require pharmacological in­terruption of the renal renin-angiotensin system.ACE inhibitors may be the drugs to achieve thisgoal. Because these drugs are renally excreted, theybecome more cost effective (i.e. a lower dosage re­quired) as renal function deteriorates, and their lowside effect profile (especially those with a non­sultbydryl structure) makes them particularly at­tractive. However, the use of {j-blockers (withoutintrinsic sympathomimetic activity) and/or cal­cium antagonists may also prove beneficial.

It is important to stress that the renal tissue re­sponses to ACE inhibitor therapy may be drug, notclass, specific. Several recent reports suggest thatthe angiotensin-converting enzyme concentrationin regional tissue beds undergoes differential re­sponses to ACE inhibitors, compared with theirrelatively uniform effect on circulating (serum)angiotensin-converting enzyme (Cohen & Kurz1982;Unger et al. 1982, 1984, 1985). Furthermore,renal tissue angiotensin-converting enzyme, ratherthan its serum counterpart, may be the crucial de­terminant in the long term renal vasculature and/or mesangial response to ACE inhibitor therapy.The ester prodrug enalapril has a high affinity forrenal tissue and undergoes intrarenal de-esterifi­cation (hydrolysis) to its active diacid compound,enalaprilic acid. Enalaprilic acid is a particularlypotent renal ACE inhibitor with a prolonged dur­ation of activity. Clearly, clinical trials are now re­quired to determine the long term clinical import­ance and drug specificity of the renal protectiveeffect exhibited by the ACE inhibitors .

Renal Protective Effect of Enalapril

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Author's address: Dr JohnH. Bauer, Hypertension Section - N403,University of Missouri Health Sciences Center, One HospitalDrive, Columbia, MO 65212 (USA).