Renal Effects of Diltiazem in

Primary Hypertension
SOBHA SUNDERRAJAN, GARRY REAMS, AND JOHN H. BAUER

SUMMARY Although the calcium channel blocker diltiazem has been shown to be an effective
antihypertensive agent, its effect on renal function, salt and water excretion, and bodyfluidcomposi-
tion has not been well characterized in patients with primary hypertension. Therefore, these param-
eters were prospectively studied in 18 subjects with primary hypertension after placebo and 8 weeks of
diltiazem monotherapy. Diltiazem monotherapy was confirmed to be an effective antihypertensive
agent. Although mean arterial pressure was reduced from 121 to 108 mm Hg, diltiazem had no overall
effect on glomerular filtration rate, renal plasma blood flow, salt and water excretion, or body fluid
composition. Renal vascular resistance,, however, was decreased. In subjects with pretreatment
glomerularfiltrationrates of 80 ml/min/1.73 m2 or less, diltiazem therapy was associated with marked
improvement in glomerular filtration rate (48%) and effective renal plasma flow (36%). Since the
filtration fraction was unchanged, changes in glomerular filtration rate may have been related to the
attenuated intrarenal effects of angiotensin II or norepinephrine, or both.
(Hypertension 8: 238-242, 1986)

KEY WORDS • diltiazem • hypertension • glomerular filtration • renal plasma flow •

calcium antagonists
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T HE calcium channel blocker diltiazem has been

shown to be an effective antihypertensive
agent in patients with primary hyperten-
sion1"4; however, its effect on renal function has not
been well characterized. Short-term studies in animals
have demonstrated diltiazem-induced dose-dependent
increases in glomerular filtration rate (GFR) and effec-
tive renal plasma flow (ERPF).5"8 Studies in patients
with primary or secondary renal disease (with and
without hypertension) have suggested that chronic oral
diltiazem therapy (dose ranges, 30-120 mg/day for 1
week to 3 months) tended to increase GFR and ERPF;
the latter demonstrated the greatest and most consistent
change.9"12 Conversely, short-term oral administration
of diltiazem (30-60 mg) to patients with arteriosclerot-
ic cardiovascular disease or chronic congestive heart
failure (with or without hypertension) has failed to
demonstrate a consistent effect on either GFR or
ERPF. 1314
Although use of diltiazem reportedly has been asso-
ciated with a low incidence of swelling or edema for-
mation,15 its effect on the renal excretion of salt and
From the Department of Medicine, University of Missouri
School of Medicine, Columbia, Missouri.
Address for reprints: John H. Bauer, M.D., Department of Medi-
cine, Division of Nephrology, University of Missouri School of
Medicine, Columbia, MO 65201.
Received April 29, 1985; accepted September 3, 1985.
238
water or on body fluid composition has not been well
characterized. Short-term studies in both animals and
humans have demonstrated that diltiazem administra-
tion produces prompt increases in urinary sodium ex-
cretion and urine flow rate. 5 ' l2 " 14 ' 16 ' l7 Long-term stud-
ies in humans, however, of dosages ranging to 360
mg/day, have failed to demonstrate any diltiazem-in-
duced change in either serum electrolyte levels or fluid
retention, as evidenced by edema or weight gain.18-19
Therefore, the current prospective study attempted to
evaluate the short-term (8 weeks) effects of diltiazem
monotherapy on renal function, salt and water excre-
tion, and body fluid composition in patients with pri-
mary hypertension.
Subjects and Methods
Eighteen hypertensive men (mean age, 54 years;
mean duration of documented hypertension, 9 years)
were selected for the study. To be included in the
protocol all subjects had to have supine diastolic blood
pressures greater than 95 mm Hg on two successive
occasions and subsequently had to maintain a supine
diastolic blood pressure greater than 95 mm Hg while
receiving placebo (2-4 weeks). Informed consent was
obtained from all subjects according to the principles
of the Declaration of Helsinki. All studies were ap-
proved by the Harry S. Truman Memorial Veterans
Hospital and the University of Missouri (joint commit-
tee for research involving human subjects).
A standard mercury sphygmomanometer was used
 RENAL EFFECTS OF DlLTlAZEMJSunderrajan et al.
to record systolic (first phase) and diastolic (fifth
phase) blood pressure. The subjects' blood pressure
and heart rate were recorded after 10 minutes in a
supine position and 5 minutes of standing. Average
recordings of three measurements were then deter-
mined. Mean arterial pressure was calculated as dia-
stolic pressure plus one third pulse pressure.
After 2 to 4 weeks of placebo therapy, a 24-hour
urine collection was obtained on the day before the
clinic visit. On the day of the clinic visit, volume
studies were performed with subjects in the recumbent
position from 0800 to 1100. After a light lunch, timed
clearances were performed on the recumbent subjects
from 1230 to 1600. Subjects were then begun on diltia-
zem and the dosage was titrated during biweekly visits.
Dosage initially was 120 mg b.i.d. and was increased
to a maximum of 240 mg b.i.d. to achieve a sustained
reduction in the diastolic pressure to below 90 mm Hg.
After 8 weeks of diltiazem monotherapy, 24-hour
urine collection, volume studies, and timed clearances
were repeated.
Simultaneous volume studies were performed as de-
scribed by Bauer et al .20 Radioactive isotopes and aver-
age dosages used were as follows: erythrocytes labeled
with sodium chromate Cr 51, 10 /i.Ci (for red blood
cell mass); human serum albumin labeled with sodium
iodide I 125, 5 /iCi (for plasma volume); sodium sul-
fate S 35, 75 /iCi (for extracellular fluid); and tritiated
water, 90 fxCi (for total body water). Total blood vol-
ume was calculated by adding red blood cell mass and
Downloaded from http://ahajournals.org by on February 13, 2022
plasma volume. Intracellular fluid volume was calcu-
lated by subtracting extracellular fluid from total body
water. All volumes were expressed in absolute units
(liters) since each subject served as his own control.
Peripheral venous hematocrit readings were deter-
mined by the microhematocrit technique. Cumulative
radiation exposure for each study period was estimated
to be less than 100 mrad.
Renal function studies were performed as previous-
ly described.21 Following hydration (20 ml of tap water
per kilogram of body weight; urine specific gravity <
1.010), priming doses of inulin (10% solution purified
inulin) and /?-aminohippurate (20% solution PAH)
were administered to obtain a plasma inulin concentra-
tion of approximately 20 mg/dl and a plasma PAH
concentration of approximately 2 mg/dl. Subsequent-
ly, a sustaining infusion of inulin (rate depending on
the estimated level of GFR) and PAH (rate depending
on the estimated level of ERPF) was administered to
maintain initial plasma concentrations of inulin and
PAH. Three timed urine collections (spontaneous
voidings) were made at approximately 30- to 40-min-
ute intervals following a 90-minute equilibration peri-
od and evidence of good urine flow (75 ml/min). Plas-
ma was obtained between the first and second and the
second and third urine collections; a steady state con-
centration of both inulin and PAH was indicated by a
concentration difference of less than 10% between
sample collections.
Plasma and urine were assayed for the following:
creatinine, according to the method of Bonsnes and
239
Taussky22; inulin, according to the method of Walser et
al.23; PAH, according to the method of Smith et al.24;
osmolality, by freezing point depression; and sodium,
potassium, chloride, and total CO2 content, by auto-
analyzer techniques.
Clearances of creatinine, inulin, PAH, sodium, po-
tassium, and osmolality were calculated as (urine con-
centration/plasma concentration) x urine flow rate (in
ml/min) and were corrected for body surface area (1.73
m2). Since there were no significant differences in
urine flow rate or clearances from one collection peri-
od to another, all results were expressed as single mean
values of the triplicate determinations for each subject.
Filtration fraction was calculated as inulin clearance/
PAH clearance and was expressed as a percent of
PAH clearance. Renal blood flow was calculated from
PAH clearance by using the peripheral venous hemato-
crit reading and assuming 74% extraction of aminohip-
purate.23 Renal vascular resistance was calculated as
(mean arterial pressure/renal blood flow) x 80,000 (in
dynseccm~ 5 /1.73 m2). Fractional sodium and potas-
sium excretion were calculated as sodium clear-
ance/inulin clearance and potassium clearance/inulin
clearance. Free water clearance was calculated as urine
flow rate minus osmolality clearance. The 24-hour
urine determinations for sodium and potassium were
expressed as milliequivalents per gram of creatinine to
normalize for accuracy of the 24-hour urinary collec-
tion. Data were analyzed by paired Student's t test.
A difference was considered statistically significant
when p was less than 0.05.
Results
Short-term diltiazem monotherapy significantly re-
duced both recumbent and upright systolic and diastol-
ic blood pressure in 16 of the 18 hypertensive subjects
(Table 1). Seven subjects required 120 mg of diltia-
zem, twice daily to achieve blood pressure control;
four required 180 mg twice daily, and five required
240 mg twice daily. Two subjects failed to achieve a
diastolic pressure below 90 mm Hg on the maximum
dosage allowed (240 mg b.i.d.). Heart rate was re-
duced significantly from 78 to 71 beats/min only when
the subjects were in the recumbent position.
TABLE 1. Effects of Diltiazem on Blood Pressure and Heart Rate
in 18 Hypertensive Subjects
Placebo Diltiazem
Position (4 wk) (8 wk)
Recumbent
Systolic blood pressure (mm Hg) 163 ±6 149 ±7*
Diastolic blood pressure (mm Hg) 101 + 1 88±2t
78±3 71±2t
Heart rate (beats/min)
Upright
Systolic blood pressure (mm Hg) 157±6 138 + 7*
Diastolic blood pressure (mm Hg) 99±2 85±2t
Heart rate (beats/min) 83±3 79±3
Values are means ± SEM.
*p < 0.005, tp < 0.0005, ip < 0.025, compared with placebo
values.
 240 HYPERTENSION VOL 8, No 3, MARCH 1986

Diltiazem monotherapy had no significant effect on TABLE 3. Differential Effects of Diltiazem on Renal Function,
serum electrolyte levels. Mean ( ± SEM) serum sodi- Hemodynamics, and Fractional Sodium Excretion in Eight Hyper-
um level was 141 ± 1 mEq/L before and 142 ± 1 tensive Subjects with Low Inulin Clearance and 10 with Normal
Inulin Clearance
mEq/L after therapy. Serum potassium level was 4.0
± 0 . 1 mEq/L before and after therapy. Serum chloride Placebo Diltiazem
Variable (4 wk) (8 wk)
level was 104 ± 1 mEq/L before and 103 ± 1 mEq/L
after therapy. Total CO2 content was 27 ± 1 mEq/L Low clearance group*
before and 29 ± 1 mEq/L after therapy. Diltiazem MAP (mm Hg) U9±2 105+ 3t
monotherapy was not associated with a significant ef- CCT (ml/min/1.73 m )2
76±4 92 + 5t
fect on either 24-hour urinary sodium excretion (114 C ^ (ml/min/1.73 m2) 60 + 6 89 + 6t
± 8 mEq/g creatinine during placebo treatment vs 98
CPAH (ml/min/1.73 m2) 250±31 339±21§
± 12 mEq/g creatinine during drug therapy) or 24-
hour urinary potassium excretion (38 ± 4 mEq/g cre- Filtration fraction (%) 25.0±1.9 26.8±2.2
atinine during placebo treatment vs 39 ± 4 mEq/g FENl (%) 2.3±0.5 1.5+0.4$
creatinine during drug therapy). Normal clearance group||
Although diltiazem monotherapy reduced mean ar- MAP (mm Hg) 124 + 4 lll+5t
terial pressure from 121 to 108 mm Hg in the 18 hyper- CCT (ml/min/1.73 m )2
95 ±7 94±7
tensive subjects, it had no overall effect on creatinine
CIN (ml/min/1.73 m2) 116±5 93 + 7§
clearance, inulin clearance, ERPF, or renal blood flow
(Table 2). Filtration fraction was unchanged, while CPAH (mymin/1.73 m2) 405 ±34 350 ±39
renal vascular resistance was reduced significantly. Filtration fraction (%) 29.7 ±1.7 26.0±2.9
In subjects whose GFR (by inulin clearance) was 80 FEN. (%) 1.1 ±0.2 1.1+0.2
ml/min/1.73 m2 or less during placebo therapy, diltia- Values are means ± SEM. Filtration fraction = (CIN/CPAH) x
zem significantly increased GFR, as assessed by both 100.
creatinine and inulin clearance, and ERPF without sig- CCT = creatinine clearance; C ^ = inulin clearance (glomerular
nificantly altering the filtration fraction (Table 3). In- filtration rate); CPAH = p-aminohippurate clearance (effective renal
plasma flow); FENo = fractional excretion of sodium ( [ C ^ C ^ ]
dividual data on GFR and ERPF for the eight subjects x 1).
with impaired renal function are shown in Figure 1. • Initial glomerular filtration rate (GFR) =s 80 ml/min/1.73m2;
In subjects whose GFR was greater than 80 ml/ || initial GFR > 80 ml/min/1.73 m2.
min/1.73 m2 during placebo therapy, diltiazem had no tp < 0.005, t p < 0.05,§ p < 0.01, compared with placebo
Downloaded from http://ahajournals.org by on February 13, 2022

significant effect on the creatinine clearance, ERPF, or values.

the filtration fraction (Table 3). Inulin clearance, how-
ever, was decreased from 116 to 93 ml/ min/1.73 m2. Fractional sodium excretion was decreased from 1.6
to 1.2% only in those subjects whose renal function
was initially impaired (see Tables 2 and 3). Diltiazem
monotherapy had no effect on the fractional excretion
TABLE 2. Effects of Diltiazem on Renal Function, Renal Hemo- of potassium, urine flow rate, free water clearance,
dynamics, and Salt and Water Excretion in 18 Hypertensive body weight, plasma volume, red blood cell mass,
Subjects
total blood volume, extracellular fluid space, intracel-
Placebo Diltiazem lular fluid space, or total body water (Table 4).
Variable (4 wk) (8 wk)
MAP (mm Hg) 121 ± 2 108 ± 3 * Discussion
Clearance (ml/min/1.73 m2) Diltiazem monotherapy, in dosages ranging from
Creatinine 87 + 5 93 ± 4 240 to 480 mg/day for 8 weeks, effectively reduced
Inulint 91 ± 8 91 ± 4 both systolic and diastolic blood pressures in 16 of 18
subjects with primary hypertension. Although mean
PAH* 336 + 29 362 ±23
arterial pressure decreased from 121 to 108 mm Hg,
Free water 8.6±1.3 8.8+1.0 renal function and hemodynamics were not altered sig-
Filtration fraction (%) 27.6± 1.4 26.4+1.9 nificantly, except for a 22% decrease in renal vascular
RBF (ml/min/1.73 m2) 840±71 870 ±54 resistance. Eight subjects with pretreatment (placebo)
RVR(dynseccm" 5 /1.73 m2 x 103) 13.5±1.6 10.5±0.6§ inulin clearance of 80 ml/min/1.73 m2 or less exhibited
marked increases in ERPF (36%) and GFR, as as-
FE Nl (%) 1.6 + 0.3 1.2±0.2§
sessed by both inulin clearance (48%) and creatinine
FEK(%) 12.7+1.7 13.3±1.3 clearance (21%).
Urine flow rate (ml/min) 11.2±1.5 11.2±1.0 At least two pharmacological mechanisms potential-
Values are means ± SEM. ly could account for the observed increase in GFR and
MAP = mean arterial pressure; PAH = p-aminohippurate; RBF ERPF following diltiazem therapy: 1) reversal of an-
= renal blood flow; RVR = renal vascular resistance; FE N , = giotensin II-induced vasoconstriction (mesangium and/
fractional excretion of sodium; FEK = fractional excretion of potas-
sium. or efferent arteriolar tone) and 2) reversal of norepi-
*p < 0.0005, § p < 0.05, compared with placebo values. nephrine-induced vasoconstriction (mesangium and/or
tGlomerular filtration rate; ^effective renal plasma flow. afferent arteriolar tone). The ability of calcium entry
 RENAL EFFECTS OF DKTIAZEM/Sunderrajan et al.
• • MMdwIMa
^ ^ H««t1 VataN (N • I)
* p.O.OW * p«0.01
WkO Wkt WkO WkS
(Pttetbo) (DlltluMn) (Photo) (DfNuwn)
FIGURE 1. Effect of diltiazem on the glomerular filtration
rate, assessed by inulin clearance (Cw), and effective renal
plasma flow assessed by p-aminohippurate clearance (CPAH), in
eight subjects with initially impaired renal function (inulin
clearance ^80 mllminll.73 m2).
blockers to prevent an increase in cytosol-ionized cal-
cium would be expected to decrease the sensitivity of
the renal vasculature and the mesangium to both angio-
tensin II and norepinephrine. Indeed, several investi-
gators have reported that diltiazem or verapamil, or
both drugs attenuate the intrarenal effects of both ex-
ogenously administered angiotensin II5' '• '• M and nor-
epinephrine.27"30 Additionally, both of these drugs may
differentially effect a-adrenergic receptors; both drugs
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have been reported to preferentially antagonize post-
synaptic (voltage-dependent calcium channel) Oj-
adrenergic receptor-mediated vasoconstriction.31"33
Selective interference with the vasoconstrictor action
of norepinephrine on the afferent arteriole (suggesting
greater density of a2-adrenergic receptors), while leav-
ing intact its action on the efferent arteriole (suggesting
a greater density of a,-adrenergic receptors), would be
expected to increase GFR.
Our observation that GFR increased in hypertensive
subjects with initially impaired filtration, without an
associated increase in the filtration fraction supports a
differential effect of norepinephrine on the renal vas-
culature. However, we cannot exclude the possibility
of a reversal of the direct effect of angiotensin II or
norepinephrine on the glomerulus (mesangium). Re-
versal of angiotensin II-mediated efferent arteriolar
vasoconstriction would be expected to enhance ERPF
disproportionately, decreasing the filtration fraction;
this effect was not observed. The pathophysiology of
the observed decrease in inulin clearance in hyperten-
sive subjects with pretreatment normal renal function
is unclear. Both creatinine clearance and ERPF, how-
ever, were unchanged.
The acute intravenous administration of nifedipine
has been reported to markedly increase GFR and renal
blood flow in patients with primary hypertension,
whereas these same parameters were not altered sig-
nificantly in normotensive subjects and patients with
chronic glomerulonephritis. 3433 Similar findings have
been reported following 1 week of oral nicardipine
241
TABLE 4. Effects of Diltiazem on Body Fluid Composition in 15
Hypertensive Subjects
Placebo Diltiazem
Variable (4 wk) (8 wk)
Red blood cell mass (L) 2.0±0.1 2.1 ±0.1
Plasma volume (L) 3.5 + 0.1 3.4±0.1
Total blood volume (L) 5.5±0.2 5.5±0.2
Extracellular fluid volume (L) 17.4±0.8 17.9±0.6
Intracellular fluid volume (L) 28.2±0.8 28.6±1.2
Total body water (L) 45.4± 1.3 46.6±1.7
Weight (kg) 89.4±3.2 89.0±3.0
Values are means ± SEM; n = 17.
therapy: creatinine clearance increased markedly in
hypertensive patients, whereas it was not significantly
altered in normotensive subjects.36 These observa-
tions, in addition to ours, suggest that patients who
have primary hypertension with mild to moderate renal
impairment have reversible alterations in renal vascu-
lar or mesangial tone that is modulated, in part, by
changes in intracellular calcium concentration.
Although diltiazem has been observed to induce an
acute natriuresis and diuresis,12"14''7 it has not been
reported to have a clinically important sustained effect
on salt and water excretion, as evidenced by edema or
weight gain. 1819 Although we found that fractional
sodium excretion decreased,' this decrease was restrict-
ed to subjects with initially impaired renal function and
may simply reflect down-regulation of sodium homeo-
static mechanisms resulting from the associated in-
crease in GFR. The fact that we found no alteration in
serum and urine electrolyte levels, potassium excre-
tion, urine flow rate, free water clearance, body
weight, or body fluid composition supports clinical
observations that diltiazem monotherapy has no net
effect on sodium homeostasis. However, anecdotal
case reports do attest to the potential for diltiazem to
produce edema.15 Of 18 subjects who entered our
study, one experienced severe bilateral pitting leg ede-
ma and had to be withdrawn from the study. This
subject showed a 1.2-kg net weight gain; although his
plasma volume was unchanged (3.4 L before and after
therapy), his extracellular fluid volume increased from
13.1 to 16.3 L. The frequency of and mechanisms for
this potential side effect are unclear.
We conclude that diltiazem is an effective antihy-
pertensive drug when given as monotherapy for the
treatment of mild to moderate hypertension. Since
renal function is either unchanged or improved, and
sodium and volume expansion does not usually occur,
diltiazem can be expected to assume a permanent role
as first-step therapy in the treatment of hypertensive
diseases.
Acknowledgments
The authors express their appreciation for the technical assistance
of Richard Lumpkin and Evelyn Monzon; the nursing support of
Alisa Lau, Karla Wilson, and Ann Hamory; and the secretarial
skills of Jo Ann Snell.
 242 HYPERTENSION
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