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Hemodynamic and renal function in essential hypertension during treatment with enalapril
Hemodynamic and Renal Function in Essential Hypertension during Treatment with Enalapril
JOHN H. BAUER, M.D. GARRY P. REAMS, M.D. Columbia,
Enalapril (at a mean dose of 25 mg), a potent, long-acting angiotensin converting enzyme inhibitor, was prescribed in combination with hydrochlorothiazide (at a mean dose of 64 mg) for 96 weeks in 11 patients with essential hypertension who had pretreatment (placebo) glomerular filtration rates of less than 60 ml/minute/l.73 m2. Blood pressure was well controlled. After 56 weeks of therapy, glomerular filtration rate (assessed by inulin clearance) increased 55 percent and effective renal plasma flow (assessed by para-aminohippurate clearance) increased by 32 percent; these increases were sustained through the 96 weeks of therapy. Furthermore, gains in renal function were sustained without adversely affecting 24-hour urinary protein excretion, sodium excretion, or body fluid composition. These results suggest that enalapril, in combination with hydrochlorothiatide, has the pharmacologic capability to favorably modify a primary pathophysiologic characteristic of essential hy pet-tension by decreasing renal vascular and mesangial tone.
Missouri
We have previously reported that the angiotensin converting enzyme inhibitor enalapril, either alone or in combination with hydrochlorothiazide, is an effective antihypertensive therapy that reverses renal function abnormalities encountered in the hypertensive state; it increases the glomerular filtration rate and the effective renal plasma flow and decreases the renal vascular resistance [I -31. The improvement in glomerular filtration rate after administration of an angiotensin converting enzyme inhibitor may be a unique property of this class of drugs, since no other antihy pertensive agent has been reported to chronically increase the glomerular filtration rate and effective renal plasma flow to levels greater than 30 percent of control values [I]. We have now had the opportunity to serially monitor the long-term effects of enalapril plus hydrochlorothiazide on renal function in 11 patients with essential hypertension and impaired renal function. Our results, obtained over a period of 96 weeks, suggest that long-term treatment with enalapril in combination with hydrochlorothiazide can maintain gains in renal function without adversely affecting 24-hour urinary protein excretion, sodium excretion, or body fluid composition. From the Medical Service, Harry S. Truman Memorial Veterans Hospital, and the Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri. Requests for reprints should be addressed to Dr. John H. Bauer, Department of Medicine, Division of Nephrology, Hypertension Section (Room N-408). University of Missouri School of Medicine, Columbia, Missouri 85212.
10
September
27, 1985
The American
Journal
PATIENTS AND METHODS After giving informed consent, eleven patients with essential hypertension, mean age 54 years (range 32 to 67 years), who maintained a five-minute recumbent
diastolic
pressure
(fifth
phase)
equal
to or greater
than
100 mm
Hg
but less than or equal to 120 mm Hg with placebo therapy and who had a glomerular filtration rate (by inulin clearance) less than or equal to 80 ml/ minute/l .73 m2 were treated with a combination of enalapril (at a mean dose of Medicine
Volume
79 (suppl
3C)
TABLE
I
Effects
of Enalapril
plus Hydrochlorothiazide Parameters
Recumbent Posture (mean Systolic blood pressure Diastolic blood pressure Heart rate (beats/minute) Upright Posture (mean -+ Systolic blood pressure Diastolic blood pressure Heart rate (beats/minute)
lp
co.025 +p <0.005
compared compared
with Week with Week
2 SEM) (mm Hg) (mm Hg) SEM) (mm Hg) (mm Hg)
SYMPOSIUM
ON RENAL FUNCTION
on Blood
Pressure
Week 56
Week 96
153 ? 4 104? 1 a0 -+ 2
120 * 2+ 81 *3+ 74 +- 2*
11ai3+ 80 It 3+ 76 rt 2
155 + 4 106 r 2 64k 3
118?3+ 82~2~ 84 t 5
113 + 2+ 81~2~ 87 ‘: 3
0. 0.
enalapril plus hydrochlorothiazide was associated with significant decreases in serum sodium, potassium, and chloride concentrations (Table II). Effects on Renal Function. In all patients, there were increases in both the glomerular filtration rate (55 percent over the placebo value as assessed by inulin clearance) and the effective renal plasma flow (32 percent over the placebo value) after 56 weeks of treatment with enalapril plus hydrochlorothiazide (Table Ill). These gains were sustained after 96 weeks of combination therapy at which time the glomerular filtration rate was increased by 39 percent over the piacebo value (assessed by inulin clearance) and the effective renal plasma flow was increased by 32 percent over the placebo value. The filtration fraction was significantly increased over the placebo value at Week 56, but was not significantly different from the placebo value at Week 96 of therapy. Long-term therapy with enalapril plus hydrochlorothiazide had no significant effect on 24-hour urinary protein excretion (Table Ill). Indeed, eight of the eleven patients had a decrease in urinary excretion (mean decrease of 65 mg/g creatinine, range between 10 and 170 mg/g creatinine). Three patients had an increase in 24-hour urinary protein excretion of between 40 and 70 mg/g creatinine. Enalapril plus hydrochlorothiazide therapy had no prolonged effect on fractional sodium excretion (Table ill), although this parameter was transiently decreased at Week 56 of therapy. The free water clearance rate, however, was decreased, compared with the placebo value, at both Weeks 56 and 96 of therapy. Effects on Body Fluid Composition. Long-term ther-
RESULTS Effects on Blood P&sure and Heart Rate. All patients showed a good response to long-term therapy with enalapril plus hydrochlorothiazide. Blood pressure was well controlled in both the five-minute recumbent and two-minute upright positions (Table I), without an increase in heart rate or a significant postural change in pressure. Effects on Serum Electrolytes. Long-term therapy with
II
Effects
of Enalapril
plus Hydrochlorothiazide
Electrolytes (Mean 9 SEM) Sodium (meq/liter) Potassium (meq/liter) Chloride (meq/liter) Total carbon dioxide ‘p co.05 compared +p CO.01 compared *p <0.005 compared
and REAMS
and Heart Rate
Week 0
of 25 mg, range 10 to 40 mg) and hydrochlorothiazide (at a mean dose of 64 mg, range 25 to 100 mg) for a period of 95 weeks. Blood pressure was well controlled with the two-drug regimen, and no drug-related side effects were observed. Blood pressure, heart rate, and serum electrolyte levels were measured, and renal function (glomerular filtration rate by creatinine and inulin clearances; effective renal plasma flbw by para-aminohippurate clearance, 24-hour urinary protein excretion, 24-hour urinary sodibm excretion, fractional sodium excretion, and~free water clearance), and body fluid composition (plasma volume by iodinated human serum albumin, extracellirlar fluid by Na235S0,+ and total body water by 3H20) weie assessed as previously described [2-41 after four weeks of placebo therapy and after 56 weeks and 96 weeks of enalapril plus hydroch1orothiazid.e therapy. Prior to the initiation of therapy with enalapril plus hydrochlorothiatide, patients were consuming approximately 4 g of sodium per day, as estimated from 24-hour urinary sodiQm excretion data. During drug therapy, sodium consumption increased to approximately 5.6 g per day at Week 56, and to approximately 5.2 g per day at Week 96. Data were analyzed by a paired Student t test for a withingroup analysis. A difference was considered statistically significant if the p value was less than 0.05.
TABLE
IN HYPERTENSION-BAUER
content
(meq/liter)
on Serum
Electrolyte
Concentrations
Week 0
Week 56
Week 96
1432 1 4.1 % 0.1 102* 1 29 + 1
138 rt 1* 3.8 t 0.2* 96r 1* 28 -t 1
140 + I+ 3.7 k 0.1* 100 k I* -
with Week 0. with Week 0. with Week 0.
September 27, 1985
The
American Journal of Medicine
Volume 79 (suppl 3C)
11
SYMPOSIUM
TABLE
ON RENAL FUNCTION
III
IN HYPERTENSION-BAUER
Effects of Enalapril
and REAMS
plus Hydrochlorothiazide
on Renal
Parameter (Mean -e SEM) Plasma creatinine (mg/dl) Creatinine clearance (mllminil.73 lnulin clearance (ml/min/l.73 m’) Para-aminohippurate Filtration
fraction
clearance
mZ)
mZ)
(percent)
of Enalapril
k + t 2
28 8 0.5 1.0
‘= k = 2 2 zk t
1.28 87 86 (n 377 (n 23.9 (n 55 138 2.4 5.0
35* 10) 2.3+ 10) 35 13* 0.2* 0.7+
+ 0.06+ 2 4 c 4* = 10) t 24s = 9) + 0.8 = 9) 2 23 I?r 16* ‘-’ 0.3 k 1 .o*
Angiotensin II may modify glomerular filtration by altering segmental vascular resistance; infusion of angiotensin II increases efferent arteriolar resistance, increasing glomerular capillary hydrostatic pressure [6]. Converting enzyme inhibitors would be expected to decrease efferent arteriolar tone, which would decrease glomerular hydrostatic pressure. A decrease in efferent arteriolar tone would be expected to decrease the filtration fraction, and a decrease in glomerular hydrostatic pressure would be expected to decrease glomerular filtration. Since the filtration fraction was either increased (Week 56) or unchanged (Week 96), and glomerular filtration was increased, an alternative (non-vascular) hypothesis is required to explain the gains in renal function we observed after treatment with enalapril plus hydrochlorothiazide. In addition to the effect of angiotensin II on the efferent arteriolar tone, the hormone also modulates mesangial cell contractility, thereby increasing the glomerular capillary surface area and the ultrafiltration coefficient; infusion of angiotensin II markedly decreases glomerular ultrafiltration [7]. The administration of a converting enzyme inhibitor might be expected to decrease mesangial cell contractility, thereby increasing the glomerular capillary filtration surface area and the ultrafiltration coefficient. Sodium depletion, via diuretic therapy, would be expected to decrease the density of mesangial cell receptors or their affinity for angiotensin II [8,9]. Therefore, the admin-
plus Hydrochlorothiazide
Parameter (Mean * SEM) Plasma volume (liters) Extracellular fluid (liters) Total body water (liters) Weight (kg)
12
366 (n 27.6 (n 85 145 2.0 4.8
Week 96
with Week 0. with Week 0. with Week 0.
Effects
compared compared
1.35 + 0.06 91 *7* 93 -t 6’
74 99 2.9 7.1
creatinine)
These long-term results confirm and extend our prior observations on therapy with enalapril in combination with hydrochlorothiazide in patients with essential hypertension and impaired renal function [l-3]. Blood pressure was well controlled: tolerance to the drugs did not develop. The modest decreases in serum sodium, potassium, and chloride concentrations observed are consistent with the known metabolic effects of diuretic therapy [3,4], but were less severe than metabolic changes previously repotted with diuretic monotherapy [4]. Gains in the glomerular filtration rate as determined by the inulin clearance rate and the effective renal plasma flow were observed at 56 weeks of therapy and maintained at 96 weeks of therapy. Less precise indicators of glomerular filtration-the serum creatinine level and creatinine clearance rate-demonstrated qualitatively similar changes to that observed with the inulin clearance rate. However, the serum creatinine level and creatinine clearance rate are equally poor at predicting the glomerular filtration rate as determined by inulin clearance, especially in patients with mild to moderate renal insufficiency [5].
‘p co.025 +p 10.005
1.39 -c 0.06
21.6 + 0.6
COMMENTS
IV
Week 56
273 k 21
apy with enalapril plus hydrochlorothiazide was associated with a decrease in plasma volume, but there were no significant changes in extracellular fluid, total body water, or body weight (Table IV).
TABLE
Week II 82 2 8 62 f 4
(mVmirA.73
24-Hour urine protein (mg/g creatinine) 24-Hour urinary sodium excretion (meq/g Fractional excretion of sodium (percent) Free water clearance (mVminD.73 m2) *p ~0.05 compared +p co.025 compared *p <0.005 compared
Function
with Week with Week
September 27, 1985
on Body Fluid Composition
Week 0 3.9 18.5 48.5 99.1
t 2 -t r
0.1 0.7 2.0 3.9
Week 56 3.5 17.9 49.3 99.9
k t + f
0.2+ 1.0 1.8 4.1
0. 0.
The American Journal of Medicine
Volume 79 (suppl 3C)
Week 96 3.6 18.1 49.4 100.8
k 2 jI -c
O.l* 0.8 1.5 4.1
SYMPOSIUM
ON RENAL FUNCTION
IN HYPERTENSION-BAIJER
and REAMS
tered from control values during prolonged therapy, suggesting restoration of volume homeostasis. Restoration is supported by the minimal (300 ml) change found in plasma volume and by the absence of significant changes in extracellular fluid, total body water, or body weight after long-term therapy with enalapril plus hydrochlorothiazide. The decrease in the free water clearance rate was an expected result of diuretic therapy [4] and may play a role in the restoration of volume homeostasis. In conclusion, angiotensin converting enzyme inhibition therapy with enalapril, combined with modest doses of hydrochlorothiazide, is an effective antihypertensive therapy. It has the beneficial effect of reversing angiotensin II-mediated decreases in the glomerular filtration rate and effective renal plasma flow. Our long-term results provide strong evidence that the two-drug regimen of enalapril and hydrochlorothiazide has the pharmacologic capability to favorably modify a primary pathophysiologic characteristic of the essential hypertensive state by normalizing the renal vascular tone and mesangial cell contractility. These findings suggest that the potent, long-acting converting enzyme inhibitor enalapril will have an important role in the treatment of patients with essential hypertension.
&ration of a converting enzyme inhibitor, in combination with a diuretic, might be expected to have the greatest potential effect on mesangial cell contractility. Our finding that glomerular filtration increased after administration of enalapril and hydrochlorothiazide, with either an increase or no change in the filtration fraction, is consistent with this latter hypothesis. That renal function in patients with essential hypertension and impaired glomerular filtration rate improves to levels observed in age-matched normotensive controls [lo] is a fundamentally unique observation confined to the angiotensin converting enzyme inhibitor enalapril. Chronic diuretic monotherapy is not associated with significant changes in inulin or para-aminohippurate clearance rates [4,11]. Although the acute administration of teprotide [I 2,131 or captopril [14] has been demonstrated to produce quantitatively similar increments in the glomerular filtration rate and effective renal plasma flow in patients with essential hypertension and impaired renal function, published results of chronic therapy with captopril have not demonstrated sustained improvement in either of these measures [15-181. This difference may be related to the greater potency and longer duration of action of enalapril, in comparison with captopril [19]. Gains in the glomerular filtration rate and effective renal plasma flow were achieved without adverse effect on 24hour urinary protein excretion; indeed, in most patients a decrease in protein excretion was demonstrated. Fractional sodium excretion values were not significantly al-
ACKNOWLEDGMENT
We wish to acknowlege the technical assistance of Richard Lumpkin and Evelyn Monzon; the nursing support of Patricia Gaddy, Alisa Lau, Karla Wilson, and Ann Hamory; and the secretarial skills of Jo Ann Snell.
REFERENCES 1.
2.
3.
4.
5.
6. 7. 8.
9.
10.
Bauer JH: Role of angiotensin converting enzyme inhibitors in essential and renal hypertension. Am J Med 1984; 77 (suppl 2A): 43-51. Bauer JH, Reams G, Gaddy P: Renal function and hemodynamits during treatment with enalapril in primary hypertension. Hypertension (in press). Bauer JH, Gaddy P: Effects of enalapril alone and in combination with hydrochlorothiazide on renin-angiotensin-aldosterohe, renal function, salt and water excretion, and body fluid composition. Am J Kidney Dis (in press). Bauer JH, Jones LB: Comparative studies: enalapril versus hydrochlorothiszide as first-step therapy for the treatment of primary hypertension. Am J Kidney Dis 1984; 4: 55-62. Bauer JH, Brooks CS, Burch RN: Clinical appraisal of creatinine clearance as a measurement of glomerular filtration rate. Am J Kidney Dis 1982; 2: 337-346. Fried TA, Stein JH: Glomerular dynamics. Arch Intern Med 1983; 143: 787-791. Blantz RC, Pelayo JC: In viva actions of angiotensin II on glomerular function. Fed Proc 1983; 42: 307i-3074. Skorecki KL. Ballermana BJ. Reinke HG. Brenner BM: Anaiotensin II receptor regulation in isolated renal glomeruli. Fed Proc 1983; 42: 3064-3070. Bellucci A, Wilkes BM: Mechanism of sodium modulation of glomerular angiotensin receptors in the rat. J Clin Invest 1984; 74: 1593-l 600. Bauer JH, Brooks CS, Burch RN: Renal function and hemodynamic studies in low- and normal-renin essential hypertension. Arch fntern Med 1982; 142: 1317-1323.
September
27, 1985
11.
12.
13.
14.
15. 16.
17.
18.
19.
The
Bauer JH, Brooks CS: Comparative effects of ticrynafen and hydrochlorothiazide on blood pressure, renal function, serum uric acid and electrolytes, and body fluid spaces in hypertensive man. Nephron 1979; 23 (suppl 1): 57-63. Williams GH, Hollenberg NK: Accentuated vascular and endocrine response to SQ 20,681 in hypertension. N Eng J Med 1977; 297: 184-168. Hollenberg NK, Swartz SL, Parson DR, Williams GH: Increased glomerular filtration rate after converting enzyme inhibition in essential hypertension. N Eng J Med 1979; 301: 9-l 2. Harrington DP: Sodium intake and renal responses to captopril in normal man and in essential hypertension. Kidney Int 1981; 20: 240-245. Pessina AC, Gatta A, Semplicini A, et al: Hypotensive and renal effects of captopril. Eur J Clin Invest 1961; 1 ‘I: 409-413. Palla R, Marchitiello MI, Sassano P, Salvetti A: Effect of captopril on renal function in patients with essential hypertension. Am J Cardiol 1982; 49: 1577-1579. Aldigier JC, Plouin PF, Guyene lT, Thibonnier M, Corvol P, Menard J: Comparison of the hormonal and renal effects of captopril in severe essential and renovascular hypertension” Am J Cardiol 1982; 49: 1442-1452. Kiowski W, vanBrummelen P, Hulthen L, Amann FW, Buhler FR: Antihypertensive and renal effects of captopril in relation to renin activity and bradykinin-induced vasodilation. Clin Pharmacol Ther 1982; 31: 677-684. Gavras H, Waeber B, Gavras I, Biollaz J, Brunner HR, Davies RO: Antihypertensive effect of the new oral angiotensin converting enzyme inhibitor “MK421,” Lancet 1981; II: 543-547.
American
Journal
of Medicine
Volume
79 (suppl
3C)
13
JOHN H. BAUER, M.D. GARRY P. REAMS, M.D. Columbia,
Enalapril (at a mean dose of 25 mg), a potent, long-acting angiotensin converting enzyme inhibitor, was prescribed in combination with hydrochlorothiazide (at a mean dose of 64 mg) for 96 weeks in 11 patients with essential hypertension who had pretreatment (placebo) glomerular filtration rates of less than 60 ml/minute/l.73 m2. Blood pressure was well controlled. After 56 weeks of therapy, glomerular filtration rate (assessed by inulin clearance) increased 55 percent and effective renal plasma flow (assessed by para-aminohippurate clearance) increased by 32 percent; these increases were sustained through the 96 weeks of therapy. Furthermore, gains in renal function were sustained without adversely affecting 24-hour urinary protein excretion, sodium excretion, or body fluid composition. These results suggest that enalapril, in combination with hydrochlorothiatide, has the pharmacologic capability to favorably modify a primary pathophysiologic characteristic of essential hy pet-tension by decreasing renal vascular and mesangial tone.
Missouri
We have previously reported that the angiotensin converting enzyme inhibitor enalapril, either alone or in combination with hydrochlorothiazide, is an effective antihypertensive therapy that reverses renal function abnormalities encountered in the hypertensive state; it increases the glomerular filtration rate and the effective renal plasma flow and decreases the renal vascular resistance [I -31. The improvement in glomerular filtration rate after administration of an angiotensin converting enzyme inhibitor may be a unique property of this class of drugs, since no other antihy pertensive agent has been reported to chronically increase the glomerular filtration rate and effective renal plasma flow to levels greater than 30 percent of control values [I]. We have now had the opportunity to serially monitor the long-term effects of enalapril plus hydrochlorothiazide on renal function in 11 patients with essential hypertension and impaired renal function. Our results, obtained over a period of 96 weeks, suggest that long-term treatment with enalapril in combination with hydrochlorothiazide can maintain gains in renal function without adversely affecting 24-hour urinary protein excretion, sodium excretion, or body fluid composition. From the Medical Service, Harry S. Truman Memorial Veterans Hospital, and the Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri. Requests for reprints should be addressed to Dr. John H. Bauer, Department of Medicine, Division of Nephrology, Hypertension Section (Room N-408). University of Missouri School of Medicine, Columbia, Missouri 85212.
10
September
27, 1985
The American
Journal
PATIENTS AND METHODS After giving informed consent, eleven patients with essential hypertension, mean age 54 years (range 32 to 67 years), who maintained a five-minute recumbent
diastolic
pressure
(fifth
phase)
equal
to or greater
than
100 mm
Hg
but less than or equal to 120 mm Hg with placebo therapy and who had a glomerular filtration rate (by inulin clearance) less than or equal to 80 ml/ minute/l .73 m2 were treated with a combination of enalapril (at a mean dose of Medicine
Volume
79 (suppl
3C)
TABLE
I
Effects
of Enalapril
plus Hydrochlorothiazide Parameters
Recumbent Posture (mean Systolic blood pressure Diastolic blood pressure Heart rate (beats/minute) Upright Posture (mean -+ Systolic blood pressure Diastolic blood pressure Heart rate (beats/minute)
lp
co.025 +p <0.005
compared compared
with Week with Week
2 SEM) (mm Hg) (mm Hg) SEM) (mm Hg) (mm Hg)
SYMPOSIUM
ON RENAL FUNCTION
on Blood
Pressure
Week 56
Week 96
153 ? 4 104? 1 a0 -+ 2
120 * 2+ 81 *3+ 74 +- 2*
11ai3+ 80 It 3+ 76 rt 2
155 + 4 106 r 2 64k 3
118?3+ 82~2~ 84 t 5
113 + 2+ 81~2~ 87 ‘: 3
0. 0.
enalapril plus hydrochlorothiazide was associated with significant decreases in serum sodium, potassium, and chloride concentrations (Table II). Effects on Renal Function. In all patients, there were increases in both the glomerular filtration rate (55 percent over the placebo value as assessed by inulin clearance) and the effective renal plasma flow (32 percent over the placebo value) after 56 weeks of treatment with enalapril plus hydrochlorothiazide (Table Ill). These gains were sustained after 96 weeks of combination therapy at which time the glomerular filtration rate was increased by 39 percent over the piacebo value (assessed by inulin clearance) and the effective renal plasma flow was increased by 32 percent over the placebo value. The filtration fraction was significantly increased over the placebo value at Week 56, but was not significantly different from the placebo value at Week 96 of therapy. Long-term therapy with enalapril plus hydrochlorothiazide had no significant effect on 24-hour urinary protein excretion (Table Ill). Indeed, eight of the eleven patients had a decrease in urinary excretion (mean decrease of 65 mg/g creatinine, range between 10 and 170 mg/g creatinine). Three patients had an increase in 24-hour urinary protein excretion of between 40 and 70 mg/g creatinine. Enalapril plus hydrochlorothiazide therapy had no prolonged effect on fractional sodium excretion (Table ill), although this parameter was transiently decreased at Week 56 of therapy. The free water clearance rate, however, was decreased, compared with the placebo value, at both Weeks 56 and 96 of therapy. Effects on Body Fluid Composition. Long-term ther-
RESULTS Effects on Blood P&sure and Heart Rate. All patients showed a good response to long-term therapy with enalapril plus hydrochlorothiazide. Blood pressure was well controlled in both the five-minute recumbent and two-minute upright positions (Table I), without an increase in heart rate or a significant postural change in pressure. Effects on Serum Electrolytes. Long-term therapy with
II
Effects
of Enalapril
plus Hydrochlorothiazide
Electrolytes (Mean 9 SEM) Sodium (meq/liter) Potassium (meq/liter) Chloride (meq/liter) Total carbon dioxide ‘p co.05 compared +p CO.01 compared *p <0.005 compared
and REAMS
and Heart Rate
Week 0
of 25 mg, range 10 to 40 mg) and hydrochlorothiazide (at a mean dose of 64 mg, range 25 to 100 mg) for a period of 95 weeks. Blood pressure was well controlled with the two-drug regimen, and no drug-related side effects were observed. Blood pressure, heart rate, and serum electrolyte levels were measured, and renal function (glomerular filtration rate by creatinine and inulin clearances; effective renal plasma flbw by para-aminohippurate clearance, 24-hour urinary protein excretion, 24-hour urinary sodibm excretion, fractional sodium excretion, and~free water clearance), and body fluid composition (plasma volume by iodinated human serum albumin, extracellirlar fluid by Na235S0,+ and total body water by 3H20) weie assessed as previously described [2-41 after four weeks of placebo therapy and after 56 weeks and 96 weeks of enalapril plus hydroch1orothiazid.e therapy. Prior to the initiation of therapy with enalapril plus hydrochlorothiatide, patients were consuming approximately 4 g of sodium per day, as estimated from 24-hour urinary sodiQm excretion data. During drug therapy, sodium consumption increased to approximately 5.6 g per day at Week 56, and to approximately 5.2 g per day at Week 96. Data were analyzed by a paired Student t test for a withingroup analysis. A difference was considered statistically significant if the p value was less than 0.05.
TABLE
IN HYPERTENSION-BAUER
content
(meq/liter)
on Serum
Electrolyte
Concentrations
Week 0
Week 56
Week 96
1432 1 4.1 % 0.1 102* 1 29 + 1
138 rt 1* 3.8 t 0.2* 96r 1* 28 -t 1
140 + I+ 3.7 k 0.1* 100 k I* -
with Week 0. with Week 0. with Week 0.
September 27, 1985
The
American Journal of Medicine
Volume 79 (suppl 3C)
11
SYMPOSIUM
TABLE
ON RENAL FUNCTION
III
IN HYPERTENSION-BAUER
Effects of Enalapril
and REAMS
plus Hydrochlorothiazide
on Renal
Parameter (Mean -e SEM) Plasma creatinine (mg/dl) Creatinine clearance (mllminil.73 lnulin clearance (ml/min/l.73 m’) Para-aminohippurate Filtration
fraction
clearance
mZ)
mZ)
(percent)
of Enalapril
k + t 2
28 8 0.5 1.0
‘= k = 2 2 zk t
1.28 87 86 (n 377 (n 23.9 (n 55 138 2.4 5.0
35* 10) 2.3+ 10) 35 13* 0.2* 0.7+
+ 0.06+ 2 4 c 4* = 10) t 24s = 9) + 0.8 = 9) 2 23 I?r 16* ‘-’ 0.3 k 1 .o*
Angiotensin II may modify glomerular filtration by altering segmental vascular resistance; infusion of angiotensin II increases efferent arteriolar resistance, increasing glomerular capillary hydrostatic pressure [6]. Converting enzyme inhibitors would be expected to decrease efferent arteriolar tone, which would decrease glomerular hydrostatic pressure. A decrease in efferent arteriolar tone would be expected to decrease the filtration fraction, and a decrease in glomerular hydrostatic pressure would be expected to decrease glomerular filtration. Since the filtration fraction was either increased (Week 56) or unchanged (Week 96), and glomerular filtration was increased, an alternative (non-vascular) hypothesis is required to explain the gains in renal function we observed after treatment with enalapril plus hydrochlorothiazide. In addition to the effect of angiotensin II on the efferent arteriolar tone, the hormone also modulates mesangial cell contractility, thereby increasing the glomerular capillary surface area and the ultrafiltration coefficient; infusion of angiotensin II markedly decreases glomerular ultrafiltration [7]. The administration of a converting enzyme inhibitor might be expected to decrease mesangial cell contractility, thereby increasing the glomerular capillary filtration surface area and the ultrafiltration coefficient. Sodium depletion, via diuretic therapy, would be expected to decrease the density of mesangial cell receptors or their affinity for angiotensin II [8,9]. Therefore, the admin-
plus Hydrochlorothiazide
Parameter (Mean * SEM) Plasma volume (liters) Extracellular fluid (liters) Total body water (liters) Weight (kg)
12
366 (n 27.6 (n 85 145 2.0 4.8
Week 96
with Week 0. with Week 0. with Week 0.
Effects
compared compared
1.35 + 0.06 91 *7* 93 -t 6’
74 99 2.9 7.1
creatinine)
These long-term results confirm and extend our prior observations on therapy with enalapril in combination with hydrochlorothiazide in patients with essential hypertension and impaired renal function [l-3]. Blood pressure was well controlled: tolerance to the drugs did not develop. The modest decreases in serum sodium, potassium, and chloride concentrations observed are consistent with the known metabolic effects of diuretic therapy [3,4], but were less severe than metabolic changes previously repotted with diuretic monotherapy [4]. Gains in the glomerular filtration rate as determined by the inulin clearance rate and the effective renal plasma flow were observed at 56 weeks of therapy and maintained at 96 weeks of therapy. Less precise indicators of glomerular filtration-the serum creatinine level and creatinine clearance rate-demonstrated qualitatively similar changes to that observed with the inulin clearance rate. However, the serum creatinine level and creatinine clearance rate are equally poor at predicting the glomerular filtration rate as determined by inulin clearance, especially in patients with mild to moderate renal insufficiency [5].
‘p co.025 +p 10.005
1.39 -c 0.06
21.6 + 0.6
COMMENTS
IV
Week 56
273 k 21
apy with enalapril plus hydrochlorothiazide was associated with a decrease in plasma volume, but there were no significant changes in extracellular fluid, total body water, or body weight (Table IV).
TABLE
Week II 82 2 8 62 f 4
(mVmirA.73
24-Hour urine protein (mg/g creatinine) 24-Hour urinary sodium excretion (meq/g Fractional excretion of sodium (percent) Free water clearance (mVminD.73 m2) *p ~0.05 compared +p co.025 compared *p <0.005 compared
Function
with Week with Week
September 27, 1985
on Body Fluid Composition
Week 0 3.9 18.5 48.5 99.1
t 2 -t r
0.1 0.7 2.0 3.9
Week 56 3.5 17.9 49.3 99.9
k t + f
0.2+ 1.0 1.8 4.1
0. 0.
The American Journal of Medicine
Volume 79 (suppl 3C)
Week 96 3.6 18.1 49.4 100.8
k 2 jI -c
O.l* 0.8 1.5 4.1
SYMPOSIUM
ON RENAL FUNCTION
IN HYPERTENSION-BAIJER
and REAMS
tered from control values during prolonged therapy, suggesting restoration of volume homeostasis. Restoration is supported by the minimal (300 ml) change found in plasma volume and by the absence of significant changes in extracellular fluid, total body water, or body weight after long-term therapy with enalapril plus hydrochlorothiazide. The decrease in the free water clearance rate was an expected result of diuretic therapy [4] and may play a role in the restoration of volume homeostasis. In conclusion, angiotensin converting enzyme inhibition therapy with enalapril, combined with modest doses of hydrochlorothiazide, is an effective antihypertensive therapy. It has the beneficial effect of reversing angiotensin II-mediated decreases in the glomerular filtration rate and effective renal plasma flow. Our long-term results provide strong evidence that the two-drug regimen of enalapril and hydrochlorothiazide has the pharmacologic capability to favorably modify a primary pathophysiologic characteristic of the essential hypertensive state by normalizing the renal vascular tone and mesangial cell contractility. These findings suggest that the potent, long-acting converting enzyme inhibitor enalapril will have an important role in the treatment of patients with essential hypertension.
&ration of a converting enzyme inhibitor, in combination with a diuretic, might be expected to have the greatest potential effect on mesangial cell contractility. Our finding that glomerular filtration increased after administration of enalapril and hydrochlorothiazide, with either an increase or no change in the filtration fraction, is consistent with this latter hypothesis. That renal function in patients with essential hypertension and impaired glomerular filtration rate improves to levels observed in age-matched normotensive controls [lo] is a fundamentally unique observation confined to the angiotensin converting enzyme inhibitor enalapril. Chronic diuretic monotherapy is not associated with significant changes in inulin or para-aminohippurate clearance rates [4,11]. Although the acute administration of teprotide [I 2,131 or captopril [14] has been demonstrated to produce quantitatively similar increments in the glomerular filtration rate and effective renal plasma flow in patients with essential hypertension and impaired renal function, published results of chronic therapy with captopril have not demonstrated sustained improvement in either of these measures [15-181. This difference may be related to the greater potency and longer duration of action of enalapril, in comparison with captopril [19]. Gains in the glomerular filtration rate and effective renal plasma flow were achieved without adverse effect on 24hour urinary protein excretion; indeed, in most patients a decrease in protein excretion was demonstrated. Fractional sodium excretion values were not significantly al-
ACKNOWLEDGMENT
We wish to acknowlege the technical assistance of Richard Lumpkin and Evelyn Monzon; the nursing support of Patricia Gaddy, Alisa Lau, Karla Wilson, and Ann Hamory; and the secretarial skills of Jo Ann Snell.
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American
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79 (suppl
3C)
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