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THERAPY AND PREVENTION
HYPERTENSION
Immediate and short-term hemodynamic effects of
diltiazem in patients with hypertension
CELSO AMODEO, M.D., ISAAc KOBRIN, M.D., HECTOR 0. VENTURA, M.D.,
FRANZ H. MESSERLI, M.D., AND EDWARD D. FROHLICH, M.D.
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ABSTRACT The immediate effects of intravenous diltiazem effects and short-term (4 weeks) of the
oral drug on systemic and regional hemodynamics, cardiac structure, and humoral responses were
evaluated by previously reported methods in nine patients with mild-to-moderate essential hypertension and in one patient with primary aldosteronism. Diltiazem was first administered in three intravenous doses of 0.06, 0.06, and 0.12 mg/kg, respectively; patients were then treated for 4 weeks with
daily doses ranging from 240 to 360 mg (average 300 mg). Intravenous diltiazem immediately reduced
mean arterial pressure (from 115 + 3 to 96 + 3 mm Hg; p < .01) through a fall in total peripheral
resistance index (from 37 + 3 to 23 + 2 U/M2; p < .01) that was associated with an increase in heart
rate (from 66 + 2 to 77 + 3 beats/min; p < .01) and cardiac index (from 3.3 ± 0.3 to 4.3 ± 0.4
liters/min/m2; p < .01). These changes were not associated with changes in plasma levels of catecholamines or aldosterone or in plasma renin activity. After 4 weeks the significant decrease in mean arterial
pressure persisted (104 ± 3 mm Hg; p < .01) and there were still no changes in the humoral substances
or plasma volume. Renal blood flow index increased (from 368 + 52 to 462 + 57 ml/min/m2; p < .01)
and renal vascular resistance index decreased (from 0.37 + 0.06 to 0.26 + 0.04 U/M2; p < .01), while
splanchnic hemodynamics did not change. Left ventricular mass significantly decreased (from 242 ±
16 to 217 ± 14 g; p < .01). Thus, the fall in arterial pressure produced by diltiazem was associated
with improved renal hemodynamics and reduced left ventricular mass without expansion of intravascular volume or alterations in circulating humoral substances.
Circulation 73, No. 1, 108-113, 1986.
DILTIAZEM is a benzothiazepin derivative calcium
antagonist widely used in the management of angina
pectoris and currently under investigation for patients
with hypertension.1`3 Its antihypertensive effect appears to result from inhibition of calcium entry into
vascular smooth muscle, consequently producing arteriolar dilatation. The precise hemodynamic effects on
systemic and regional blood flow are not totally clear.
The present study was performed to evaluate the immediate and short-term hemodynamic effects of diltiazem in patients with mild-to-moderate hypertension.
Methods
Ten patients (eight men and two women; seven black and
three white) with mild-to-moderate hypertension, including one
white man with primary aldosteronism, were the subjects of this
report. The remainder, therefore, had essential hypertension.
From the Department of Internal Medicine, Section on Hypertensive
Diseases, Ochsner Clinic and Alton Oschsner Medical Foundation,
New Orleans.
Supported in part by Marion Laboratories, Inc., Kansas City, MO.
Address for correspondence: Edward D. Frohlich, M.D., Alton
Ochsner Medical Foundation, 1516 Jefferson Highway, New Orleans,
LA 70121.
Received July 18, 1985; revision accepted Sept. 26, 1985.
108
Their mean age was 47 + 11 (range 34 to 69) years. The
patients had either never received antihypertensive therapy previously or had all antihypertensive medications discontinued at
least 4 weeks before entry into the study.
Clinical evaluation for secondary forms of hypertension had
failed to demonstrate a primary cause of hypertension in all
patients except the one with primary aldosteronism who received spironolactone throughout the study.
Patients were included in the study only if their diastolic
pressures were equal to or higher than 90 mm Hg and less than
120 mm Hg on at least two consecutive outpatient visits during
the 2 weeks before diltiazem therapy was instituted.
After at least 2 weeks without antihypertensive therapy the
patients were given a placebo for another 2 weeks. Informed
written consent, previously approved by our institutional human
study committee, was obtained from the patients after they were
provided with a detailed description of the protocol.
Hemodynamic assessment. At the end of the second week of
the placebo phase, patients were studied in the hemodynamic
laboratory after an overnight fast. By a modified Seldinger
technique, catheters were inserted into a brachial artery and an
antecubital vein and advanced to the shoulder level.4 Continuous recordings of arterial and venous pressures were obtained
simultaneously with the electrocardiogram (lead II). Cardiac
output was determined at least in duplicate, usually in triplicate,
using indocyanine green dye (5 mg each injection). Resting
supine hemodynamic measurements were obtained before and
after sequential intravenous bolus administration of diltiazem at
doses of 0.06, 0.06, and 0.12 mg/kg. In addition, hemodynamic
CIRCULATION
THERAPY AND PREVENTION-HYPERTENSION
upright tilt (48 degrees), isometric exercise (handgrip, 30% of maximum), and Valsalva maneuver were measured before and after the final intravenous dose of diltiazem.
The same hemodynamic measurements were obtained after 4
weeks of diltiazem therapy.
M mode echocardiograms were recorded before and after the
third intravenous injection of diltiazem as well as after 4 weeks
of oral diltiazem therapy. The techniques for left ventricular
visualization have been described previously.5 Posterior and
septal wall thicknesses and systolic and diastolic dimensions
were measured by three independent observers using the same
five consecutive cycles. Left ventricular mass was calculated
according to the formula of Bennett and Evans. 6 Echocardiographic estimates of left ventricular end-systolic and end-diastolic volumes were calculated by the method of Teichholz
et al.7
Renal plasma flow and plasma volume were determined by
the single injection clearance of 131j-paramino hippurate and
RISA-1251, respectively.4 Splanchnic blood flow was obtained
from the plasma clearance of injected indocyanine green dye (50
mg).' Renal and splanchnic vascular resistance were calculated
by dividing mean arterial pressure by the respective regional
blood flows. Glomerular filtration rate was determined from 24
hr creatinine clearance, and filtration fraction was obtained by
dividing glomerular filtration rate by renal blood flow.
Total blood volume and red cell mass were estimated from
plasma volume according to the formula8:
responses to
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TBV
=
PV/1
-
(Hct
x
0.91)
where TBV is total blood volume, PV is plasma volume, Hct is
the peripheral hematocrit, and 0.91 is the correction factor for
total body hematocrit.
Plasma renin activity and catecholamine levels were determined by the methods of Sealey et al.9 and Peuler and Johnson,'0 respectively. Aldosterone was determined by radioimmunoassay technique. l
Treatment. After evaluation of the hemodynamic responses
to intravenous diltiazem, patients were started on diltiazem therapy for 4 weeks and then evaluated again by the same hemodynamic and biochemical methods. The initial diltiazem dose was
two 60 mg capsules twice a day. The dosage was increased to
three capsules twice a day during the third and fourth weeks if
the dosage was considered inadequate to control the patient's
blood pressure. Adequate control of blood pressure was defined
as a fall in resting supine diastolic pressure to below 90 mm Hg
or a reduction of 10 mm Hg or more for those patients whose
pretreatmerit diastolic
pressures were at
least 90 but 100 or less
Hg. The final dose of diltiazem (after 4 weeks) ranged from
240 to 360 mg/day, with an average of 300 mg/day.
Statistical study. One-way analysis of variance with repeated measures was used to compare baseline to immediate and
short-term effects of diltiazem. Subsequent to significance
tests, Dunnett's test was used to make pairwise comparisons
between baseline and treatment values.12
mm
Results
Of the 10 patients, one did not return to undergo
hemodynamic evaluation after 4 weeks of diltiazem
therapy. Important side effects were not observed either immediately after the intravenous dose or during
short-term oral diltiazem therapy.
Intravenous diltiazem. Table 1 summarizes the immediate (intravenous) hemodynamic and short-term (oral)
effects of diltiazem. Intravenous doses of 0.06 and
0.12 mg/kg diltiazem produced dose-related reductions in mean arterial pressure (from 115 3 to 101 +
4 and 96 + 3 mm Hg, respectively; p < .01) through a
fall in total peripheral resistance (p < .01) associated
TABLE 1
Immediate (intravenous drug) and short-term (oral drug) hemodynamic effects of diltiazem
Dose of intravenous
Control
drug (mglkg)
Short-term
oral drug
(240-360
mg/day;
mg/day;
0.06
0.06
0.12
average 300)
141 S5A
81 + 3A
101 ±4A
75 4
141 6A
81 4A
134+4A
146-4A
83 + 3A
104-3A
64 + 3
Arterial pressure (mm Hg)
Systolic
Diastolic
Mean
Heart rate (bpm)
Cardiac index (1/min/m2)
Stroke volume index (mi/M2)
Total peripheral resistance index (U/m2)
Ejection time (msec)
Mean rate of left ventricular ejection index
(ml/sec/m2)
Left ventricular stroke work index (U/M2)
161 +5
92 3
115+3
66 + 2
3.3 + 0.3
50 + 5
37 + 3
310 + 6
163 16
105 + 10
3.9 0.3
53 3
27 ± 2A
308 ± 7
173+ 12
98 ± 7
77 2A
9643A
77 3
101 +4A
76 + 3
4.1 + 0.3B
54 3
26 2A
307 7
56 + 4
23 ± 2A
303 ±7
3.2 ± 0.2
51 ± 3
33 ± 2
390 + 7
176 14
99 ± 7
187 18
99 ± 9
164± 12
96 ± 7
4.3±04A
Results are expressed as mean ± SEM for nine patients with essential hypertension and one patient with primary aldosteronism receiving the intravenous medication and eight with essential hypertension and one with primary aldosteronism receiving
short-term treatment. When data were calculated excluding results in the patient with aldosteronism there were no differences by
average or statistics.
Ap < .01; Bp < .05 compared with control.
Vol. 73, No. 1, January 1986
109
AMODEO et al.
TABLE 2
Responses to hemodynamic maneuvers before (baseline) and after intravenous and short-term oral (4 weeks) therapy with diltiazem
Isometric exercise
Intra- Short-term
venous
oral
Baseline
Mean arterial pressure 24+5
Cardiac index
3.0+6
Heart rate
18+6
Total peripheral
resistance
22+6
Results are expressed as mean
.01.
Upright tilt
±
28+6
15+6
16+4
28+4
10+3
19+4
14+6
17 5
Baseline
-
Intravenous
Valsalva maneuver
Short-term
oral
Baseline
Intravenous
7+1
14--2A
3.5+±1
48-8
51
14±2A
10+4
33+44A
1.5+3A
-17±5
17±8
17+5
15+4
26+3
72±8A
27±8
13
Short-term
oral
57--11
26±4
SEM of percent change from supine resting responses as compared with baseline.
Ap <
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with reflex increases in heart rate and cardiac output
(p < .01). Ejection time, stroke volume, left ventricular stroke work, and mean rate of left ventricular ejection did not change (table 1). When these data were
calculated excluding results from the patient with primary aldosteronism, neither the average or statistics
changed significantly. After the intravenous injection
of diltiazem the cardiovascular responses to isometric
exercise and the Valsalva maneuvers were unmodified. However, a different response of cardiac index to
passive upright tilt was observed (- 14 ± 2% decrease
before intravenous diltiazem vs - 33 ± 4% decrease
after intravenous diltiazem; p < .01). Moreover, total
peripheral resistance response to upright tilt was greater after intravenous diltiazem (26 + 3% before vs 72
± 8% after; p < .01) (table 2). The responses of
plasma renin activity and aldosterone and catecholamine levels were unchanged by diltiazem (table 3).
Similarly, cardiac structure and function did not
change (table 4).
Four week treatment. Five patients had their doses of
diltiazem increased from 240 to 360 mg/day in order to
achieve adequate arterial pressure control; at 4 weeks
pressures in all patients were under control. This sigTABLE 3
Hormonal responses to diltiazem
Baseline
drug
Short-term
oral
drug
300 ± 54
44 ± 17
12 1
11 ± 3
293 ± 38
39 ± 7
13 1
8±2
319 ± 39
35 ± 7
17+3
8 1
1.6 ± 0.6
0.7 + 0.2
2.2 + 0.5
Intravenous
Norepinephrine (pg/ml)
Epinephrine (pg/ml)
Dopamine (pg/ml)
Aldosterone (ng/dl)
Plasma renin activity
(ng/ml/h)
TABLE 4
Cardiac structure and function before and after diltiazem
Control
Posterior wall
thickness (cm)
Septal thickness
(cm)
Left ventricular
mass (g)
Left ventricular
internal diastolic
diameter (cm)
Left ventricular
internal systolic
diameter (cm)
Ejection fraction
(%)
Results are expressed as mean ± SEM. Note that in this table we
have excluded the data from one patient with primary aldosteronism
from the averages even though his inclusion did not change the statistical results.
110
nificant reduction in mean arterial pressure was a continuation (104 + 3 mm Hg; p < .01) of the effect
achieved by intravenous diltiazem, although the reduction in total peripheral resistance index was no longer
significant statistically (37 ± 3 vs 33 ± 2 U) and
cardiac index and heart rate returned to baseline levels
(table 1). It was of interest that those patients with
pretreatment plasma renin activity less than 1.2
ng/ml/hr showed persistent reduction in total peripheral resistance, whereas those (three patients) who had
pretreatment plasma renin activity of 1.2 ng/ml/hr or
more demonstrated a return of total peripheral resistance toward pretreatment levels despite continued
control of pressure (table 5). Left ventricular mass
measured by M mode echocardiography was reduced
Fractional fiber
shortening of left
ventricle (%)
Intravenous
drug
Short-term
oral
drug
1.1 ±0.05
1. 1
0. 1
1.1 ± 0.04
1.2+0.07
1.2+0.1
1.2+0.05
242
16
236 29
217 ± 14A
4.7 ± 0.1
4.7 ± 0.1
4.7 ± 0.1
3.2+0.2
3.1±0.4
3.1 ±0.2
62±4
62±7
62±4
33 + 3
34 ± 5
34±4
Results are expressed as mean ± SEM.
Ap < .05 compared with control.
CIRCULATION
THERAPY AND PREVENTION-HYPERTENSION
TABLE 5
Effects of short-term therapy with diltiazem on mean arterial pressure (MAP) and total peripheral resistance (TPR) with reference to
pretreatment levels of plasma renin activity (PRA)
PRA (ng/
MAP (mm Hg)
ml/hr)
before
treatment
n
< 1.2
>1.2
6
3
TPR (U)
Control
After
short-term
therapy
Control
After
short-term
therapy
115 9
114±9
102 ± 8A
108+8
19 ± 2
14±3
16 ± 2B
15±3
Results are expressed as mean + SEM.
Ap < .01 and Bp < .05 compared with control.
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from 242 + 16 to 217 + 14 g (p < .05) (table 4).
Renal blood flow increased from 368 + 52 to 462
57 ml/min/m2 (p < .01) as renal vascular resistance
index decreased (from 0.37 + 0.06 to 0.26 ± 0.04
U/M2; p < .01). There was no significant change in
glomerular filtration rate but the renal filtration fraction decreased (from 29 ± 4% to 21 + 3%; p < .01)
(table 6). Plasma volume and splanchnic blood flow
and resistance did not change (table 6).
As with intravenous diltiazem, 4 weeks of treatment
failed to produce any significant change in plasma
renin activity or aldosterone or catecholamine levels
(table 3).
Discussion
The results of this study demonstrate that after intravenous diltiazem there was an immediate dose-related
reduction in mean arterial pressure produced by a fall
in total peripheral resistance that was most likely associated with a reflex increase in heart rate and cardiac
output, although plasma catecholamine levels did not
change. Previous studies have found similar reSUltS.2' 13 Safar et al.'4 observed that similar reflexive
sympathetic adjustments disappeared 25 min after intravenous diltiazem. They hypothesized that this reflex
cardiac stimulation was dampened either by the action
of diltiazem on baroreceptor function'5 or by a calcium-dependent release of neurotransmitter from postganglionic nerve endings.'6 However, they also noted
that the increased heart rate could have resulted from a
direct effect on larger arteries. Diltiazem seems to have
different effects on small and large arteries, dilating
the arterioles and reducing total peripheral resistance,
but having no effect on large arteries. 14 We also calculated changes in large arterial distensibility by dividing
arterial pulse pressure by stroke volume and confirmed
the earlier report demonstrating that diltiazem had no
immediate effect on large arterial distensibility. We
Vol. 73, No. 1,
January 1986
also extended that observation by demonstrating that
the compound also had no effect on distensibility after
4 weeks of therapy (0.71 ± 0.08; 0.54 + 0.07, and
0.63 ± 0.07, before treatment, after intravenous drug,
and after 4 weeks on oral drug, respectively).
The significant immediate reduction in mean arterial
pressure observed after intravenous diltiazem persisted
throughout the 4 week treatment period, although the
significant fall in total peripheral resistance did not
continue as heart rate and cardiac index returned to
pretreatment levels. Interestingly, those patients who
continued to demonstrate a significant fall in total peripheral resistance all had pretreatment plasma renin
activity of 1.2 ng/ml/hr or less, and those with greater
plasma renin activity failed to demonstrate this response even though their pressures remained controlled.
These results are in agreement with previous reports
demonstrating greater effectiveness of calcium entry-blocking drugs in patients with lower plasma renin
activity.'7' 18 In this regard it was of interest that the
patient with the greatest reduction in arterial pressure
in our study had primary aldosteronism; he demonstrated a 20% fall in mean arterial pressure and a 15%
reduction in total peripheral resistance. Guthrie et al. 19
and Millar et al.20 have described impairment of adrenal steroidogenesis after calcium channel-blocker therapy in normal subjects. Such an effect could explain
the greater blood pressure reduction in our patient with
primary aldosteronism. However, his plasma aldosterone levels increased from 72 to 120 and 104 ng/dl after
intravenous drug and 4 weeks of oral therapy, respecTABLE 6
Short-term (4 weeks) effects of diltiazem on fluid volume and regional hemodynamics
Index
Total blood volume (ml)
Red cell mass (ml)
Plasma volume (ml/cm)
Renal blood flow index
Control
After
short-term
therapy
4864 + 355
1823 + 160
18 ± 1
5612 ± 295
2100 ± 126
20 ± 1
368 ±52
(ml/minlm2)
Splanchnic blood flow index
362 43
(ml/min/m2)
Renal vascular resistance index
0.37 ±0.06
(U/M2)
Splanchnic vascular resistance
index (U/M2)
0.35 ±0.04
Filtration fraction (%)
29 ± 4
Glomerular filtration rate (ml/min) 122 ± 11
462 + 57A
416± 46
0.26 ± 0.04A
0.27 ± 0.03
21 ± 3A
116 + 11
Results are expressed as mean ± SEM.
Ap < .01 compared with control.
111
AMODEO et al.
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tively. Perhaps this lack of reduction in aldosterone
levels reflects the fact that our patient did not have
normal aldosterone production before treatment due to
his adrenal tumor. Alternatively, his persistent elevated level of aldosterone could have resulted from additional spironolactone stimulation.
Despite unchanged cardiac output from pretreatment levels after 4 weeks of therapy, renal blood flow
increased and renal vascular resistance decreased,
whereas splachnic blood flow and vascular resistance
did not change. These findings underscore the difference between diltiazem and other agents with more
uniform vascular effects and potential differences
among those agents within the calcium antagonist
"group." Nevertheless, this observation confirms earlier studies21 22 demonstrating increased renal blood
flow after diltiazem in normotensive man and extends
the findings to patients with hypertension.
Pseudotolerance due to expanded intravascular volume associated with pressure reduction was not observed with diltiazem since plasma volume remained
unchanged after 4 weeks of treatment, confirming previous reports with another calcium antagonist and with
diltiazem.23'24 This failure to expand plasma volume
may be explained, in part, by a natriuretic action of
calcium-channel antagonists, but may also have been
produced by diltiazem's renal hemodynamic action.23' 25 These findings provide further credibility for
the use of calcium antagonists as monotherapeutic
agents in the treatment of hypertension.
Left ventricular mass decreased after 4 weeks of
therapy. In this regard, a previous report from our
laboratory26 and others27 demonstrated that other calcium-channel blockers reduced left ventricular mass in
spontaneously hypertensive rats. This reduction could
result from either reduced ventricular afterload, which
plays an important part in the development and progression of ventricular hypertrophy,25 or from reduction in the number of intracellular calcium ions, which
are necessary for protein synthesis.j6 29 Several other
agents previously reported to induce regression of ventricular hypertrophy in animals26'30 and man31' 32 and
that inhibit adrenergic cardiac input by angiotensin
converting-enzyme activity also may reduce calcium
entry and perhaps protein synthesis.26' 29
In summary, diltiazem appeared to be a useful antihypertensive agent in patients with mild-to-moderate
hypertension. The agent was well tolerated and, in this
study, was without side effects. In addition, left ventricular mass decreased within 1 month and renal blood
flow increased. For these reasons, calcium antagonists, and more specifically diltiazem, may be an alter112
native means of initial therapy. This latter concept is
strengthened by the failure of intravascular volume to
expand after pressure reduction.
We thank Ms. Kirsten Sundgaard-Riise for her statistical
support and Mr. Norbert Joseph, Jr., for his technical assistance. Thanks are also due to the Medical Editing Department
for typing this paper.
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Vol. 73, No. 1, January 1986
113
Immediate and short-term hemodynamic effects of diltiazem in patients with
hypertension.
C Amodeo, I Kobrin, H O Ventura, F H Messerli and E D Frohlich
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Circulation. 1986;73:108-113
doi: 10.1161/01.CIR.73.1.108
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