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(Hypertension. 1995;26:143-149.)
© 1995 American Heart Association, Inc.
Articles |
Divergent Effects of Dihydropyridine and Phenylalkylamine Calcium Channel Antagonist Classes on Autonomic Function in Human Hypertension
From the Department of Medicine, University of California, and Department of Veterans Affairs Medical Center, San Diego, Calif.
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Abstract |
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Abstract Calcium channel antagonists differ by class in reported frequency of side effects that suggest reflex sympathoadrenal activation. Do such differences result from differential effects on autonomic and baroreflex function? The present study compared acute and chronic effects of two classes of calcium channel antagonists, the dihydropyridine type (felodipine) and the phenylalkylamine type (verapamil), on efferent sympathetic outflow and baroreflex slope in 15 essential hypertensive subjects. Blood pressure, heart rate, hemodynamics, and biochemistries were determined at baseline and after acute (first dose) and chronic (4 weeks) administration of the drugs versus placebo. Acutely, felodipine caused a greater decrease in blood pressure associated with a larger decline in systemic vascular resistance than the corresponding effects produced by verapamil. Chronically, there were similar, significant declines in blood pressure (P=.001) and systemic vascular resistance (P=.001) after each drug. Acutely, increased sympathetic activity after felodipine was suggested by reflex tachycardia (from 69±3 to 74±2 beats per minute, P=.014) and elevation of plasma norepinephrine (from 264±25 to 323±25 pg/mL, P=.037), whereas after verapamil the corresponding changes were closely similar to those after placebo. Chronically, verapamil suppressed sympathetic activity, as evidenced by a decrease in resting heart rate (from 76±2 to 69±3 beats per minute, P=.002), decrease in plasma norepinephrine (from 264±25 to 178±21 pg/mL, P<.001), decrease in chromogranin A (from 33.0±2.4 to 27.8±1.7 ng/mL, P<.001), and lessened response of mean arterial pressure (P=.006) and heart rate (P=.016) to phentolamine
-adrenergic blockade; after
chronic felodipine, all of these variables were unchanged. Neither drug
affected baroreflex slope. We conclude that felodipine and verapamil
have qualitatively different, time-dependent actions on efferent
sympathetic nervous system activity, actions that may in part explain
the disparity in autonomic/hemodynamic side effect profiles of the
dihydropyridine and phenylalkylamine classes of calcium channel
antagonists.
Key Words: catecholamines • hypertension, essential • baroreflex • verapamil • felodipine • autonomic nervous system • sympathetic nervous system • chromogranins
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Introduction |
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Evidence for involvement of the nervous system in essential hypertension includes baroreflex dysfunction1 2 3 as well as the response of hypertension to drugs that act centrally to diminish sympathetic outflow.1 2 4 5 6 The effects of several antihypertensive agents at least in part depend on their ability to restore (that is, augment) the depressed baroreflex slope found in essential hypertension.2 4 5
Calcium channel antagonists have been used increasingly as
first-line therapy in essential hypertension, in part because of their
favorable side effect and metabolic profiles.7 Although
all calcium channel blockers antagonize calcium entry into
cardiovascular cells by binding to the 1-subunit of the
L-type voltage gated (slow) calcium channel,8 the drug
class is heterogenous,8 with subgroups including drugs
with dihydropyridine (eg, felodipine) or phenylalkylamine (eg,
verapamil) structures. Clinically, calcium channel antagonists vary in
frequency of side effects such as palpitations, tachycardia, headache,
and pedal edema. These side effects, most commonly seen with
dihydropyridines,9 suggest that peripheral vasodilation
re-sults in reflexly elevated sympathoadrenal outflow, with
consequent increases in cardiac output and heart rate.
The disparity in autonomic/hemodynamic side effect profiles between classes of calcium channel antagonists may in part be explained by the preferential action of one group (dihydropyridines) on vascular smooth muscle.10 By contrast, verapamil, which also acts prominently on myocardial calcium channels,11 did not cause reflex stimulation of norepinephrine release in clinical hypertension trials.11
To provide systematic and explicit comparisons of the sympathoadrenal actions of dihydropyridines compared with phenylalkylamines, we performed a crossover study in human essential hypertensive subjects, evaluating autonomic/baroreflex function after acute (time of maximal plasma concentration after first dose) and chronic (4 weeks) calcium channel blockade with verapamil (controlled release12 13 ) versus felodipine (extended release10 14 15 ). Our results suggest that these two agents differ markedly in both acute and chronic actions on the autonomic nervous system.
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Methods |
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Subjects
We studied the acute and chronic effects of verapamil versus felodipine in 15 uncomplicated essential hypertensive subjects. Before entry into the study, all subjects had seated diastolic blood pressure (DBP) greater than 90 mm Hg on at least three outpatient visits. We excluded secondary causes of hypertension as well as advanced hypertension end-organ damage by history, physical examination, and laboratory tests (chest radiograph, electrocardiogram, hemogram, blood urea nitrogen, serum creatinine and electrolytes, and urinalysis). Subjects were previously untreated for hypertension or discontinued any antihypertensive medications before entry into the study.
All subjects gave informed written consent, and the study was approved by the Human Subjects Committee of the University of California, San Diego. No anesthetics were used.
Table 1 shows the demographic profile of the subjects studied.
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Study Design
Each subject was treated initially with a once-daily oral
placebo for 2 weeks. Subjects were then randomized in single-blind
crossover fashion to receive either verapamil (240 to 480 mg once
daily) for 4 weeks, followed by placebo washout for 2 weeks and then by
felodipine (5 to 10 mg once daily) for 4 weeks (group 1), or felodipine
(5 to 10 mg once daily) for 4 weeks, followed by placebo for 2 weeks
and then by verapamil (240 to 480 mg once daily) for 4 weeks (group
2).
Medication doses were in the customary range required for essential hypertension; the once-daily regimen was chosen because of the sustained-release formulation of the drugs used: controlled-release for verapamil (Verelan, Lederle Laboratories)12 13 and extended-release for felodipine (Plendil, Merck Sharp & Dohme Laboratories).10 14 15 Doses were individually adjusted for blood pressure control (goal DBP, <90 mm Hg). For verapamil, 4 of 15 subjects required 240 mg/d, and 11 of 15 required 480 mg/d. For felodipine, 5 of 15 subjects required 5 mg/d, and 10 of 15 required 10 mg/d. The diet was unrestricted in fluid and salt throughout the study, and no other medications were used.
During both acute and chronic studies, blood pressure (millimeters of mercury) and heart rate (beats per minute [bpm]) were measured in triplicate (each replicate was within 10% of the mean) in seated subjects by the automated Dinamap (Critikon, Inc) electronic device at 1-minute intervals. The automated device was periodically calibrated against a mercury sphygmomanometer. Systolic blood pressure (SBP), DBP, and mean arterial pressure (MAP) were recorded.
Acute Study
Subjects were admitted to a metabolic (clinical research) ward
for acute study just before and after the first dose of each
medication. Hemodynamics were noninvasively monitored for 6 hours with
the Dinamap blood pressure device and an NCCOM-3 impedance cardiograph
(BoMed Medical Manufacturing)16 17 for measurement of
stroke volume (milliliters per beat), heart rate (beats per minute),
cardiac output (liters per minute), and systemic vascular resistance
(MAP/cardiac output; milliliters of mercury/liters per minute). Plasma
chemistries (see below) were obtained after the first dose, after 4
hours for subjects taking felodipine, and after 6 hours for subjects
taking verapamil, in accordance with the pharmacokinetic profiles for
peak plasma concentration of the two drugs.18 19
Chronic Study
The chronic studies were done after the initial placebo period
and after 4 weeks of therapy with each active medication. With the
subject supine, biochemistries (see below) and autonomic and baroreflex
studies were done noninvasively with the NCCOM-3 impedance cardiograph
and the Finapres 2300 blood pressure monitor
(Ohmeda)17 20 21 for continuous hemodynamic monitoring and
analysis of beat-to-beat variations in blood pressure and heart
rate.
Impedance Cardiography
To evaluate the reproducibility of impedance
cardiography,16 17 we obtained three repeated impedance
cardiography measurements on 12 subjects (6 normotensive, 6
hypertensive) in the supine position at 30-minute intervals. At each
time point, a minimum of three readings was collected and the mean
values were used for analysis. Results were analyzed by one-way
ANOVA with repeated measures. Mean±SEM values for the variables at the
three time points were as follows: cardiac output, 5.7±0.3, 5.5±0.3,
and 5.8±0.3 L/min (P=.185); stroke volume, 90±7, 87±6,
and 93±7 milliliters per beat (P=.133); and heart rate,
65±3, 65±3, and 64±3 bpm (P=.757). There were
significantly positive interindividual correlations for both cardiac
output (r=.92, P<.0001, n=12) and stroke volume
(r=.95, P<.0001, n=12) measurements from the
first to the third reading. Additionally, we obtained an impedance
cardiography measurement on 10 normotensive subjects in the supine
position and repeated the measurement 6 to 12 months later. Both
cardiac output (5.6±0.5 versus 5.6±0.5 L/min, respectively,
P=.792) and stroke volume (83.9±6 versus 86.6±8 mL,
P=.368) remained unchanged over the two time periods. The
two measurements taken several months apart correlated well for both
cardiac output (r=.88, P=.005, n=10) and stroke
volume (r=.93, P<.0001, n=10). Previous studies
have also shown that impedance cardiography provides valid measurements
of cardiac output and stroke volume in humans.22
Autonomic and Baroreceptor Reflex Function
Baroreceptor reflex sensitivity to reduction in arterial
pressure. Low-pressure baroreflex sensitivity was evaluated by
recording cardiac acceleration in response to amyl nitrite–induced
fall in blood pressure.23 The subject inhaled three times
from a gas-filled ampoule of amyl nitrite (James Alexander Corp) broken
under the nose. Pulse interval (heart period, RR interval) was plotted
as a function of SBP. Baroreflex slope is expressed in milliseconds per
millimeter of mercury.
Baroreceptor reflex sensitivity to elevation in arterial
pressure. This was evaluated by recording cardiac slowing in
response to acute phenylephrine-induced
hypertension.24 Changes in arterial pressure and pulse
interval were recorded continuously after an intravenous bolus of 200
µg of the 1-adrenergic agonist
phenylephrine hydrochloride (Neo-synephrine, Winthrop
Laboratories). Baroreflex slope is expressed in milliseconds per
millimeter of mercury.
1-Adrenergic pressor sensitivity. Pressor
sensitivity to the 200-µg phenylephrine intravenous dose
was recorded in millimeters of mercury for SBP, DBP, and
MAP.24
Phentolamine -adrenergic blockade. Change in MAP after
slow (1 minute) intravenous infusion of 20 mg of the -adrenergic
antagonist phentolamine mesylate (Regitine, CIBA Pharmaceutical Co) is
an index of the participation of -adrenergic mechanisms in
sustaining blood pressure and hence of sympathetic stimulation of
resistance vessels.25 26 27 28 Results are expressed as change
in blood pressure (millimeters of mercury).
Cold pressor test. The cold pressor test measures early hemodynamic responses to a cold stimulus and may be an index of integrity of efferent sympathetic vasomotor function; the response does not require stimulation of baroreflex afferents.29 30 31 The subject immersed one hand into ice water (0°C) for 1 minute during continuous monitoring of blood pressure and heart rate. Results are reported as change in MAP in the contralateral arm (millimeters of mercury) as well as change in heart rate (beats per minute).
Protocol of autonomic and baroreflex testing. The sequence of autonomic tests was as follows: initial (pretest) measurements of blood pressure and heart rate, followed in order by cold pressor test, amyl nitrite inhalation, phenylephrine intravenous bolus, and phentolamine intravenous infusion. Between two successive tests there was an equilibration period of at least 10 minutes to permit blood pressure and heart rate to return to pretest baseline values as judged by continuous monitoring.
Biochemistry
During both acute and chronic studies blood was sampled for
catecholamines (norepinephrine and epinephrine [both picograms per
milliliter]), chromogranin A (nanograms per milliliter), aldosterone
(nanograms per deciliter), and renin activity (nanograms per milliliter
per hour) assays. Twenty minutes after the placement of an indwelling
intravenous catheter, blood samples were drawn, and the plasma was
separated, frozen, and batched for assay.32
Results are converted to Système International (SI) units (refer to Fig 2 and Table 4 legends).
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Statistics
Results are expressed as mean±1 SEM. Results (first placebo
period versus each of the two drugs) were analyzed by one-way or
two-factor ANOVA. Post hoc tests were accomplished by the Bonferroni
correction. Correlations were done by linear least-squares regression
analysis. Statistical analyses were performed with the
SYSTAT program (Systat, Inc). A power
analysis33 for continuous variables indicated that
from our essential hypertensive population (heart rate SD, 9 bpm), 15
crossover subjects were required to show a treatment difference on
heart rate of 10 bpm, with 80% power, using a one-sided test of
=.05.
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Results |
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Hemodynamics
Acute Effects
Fig 1 illustrates the hemodynamic effects of placebo and each calcium channel antagonist for 6 hours after the first dose.
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SBP declined significantly after felodipine compared with placebo or verapamil. Two-factor ANOVA revealed significant effects for both drug (F=3.718, P=.037) and time (F=6.577, P<.001) and a trend for a drug-time interaction (F=1.667, P=.078). The greatest decrement in SBP was 15±3 mm Hg (9.4%, P<.001) 2 hours after felodipine.
Felodipine similarly affected DBP. Again, two-factor ANOVA revealed significant effects for drug (F=7.636, P=.002) and time (F=5.463, P<.001) and a drug-time interaction (F=2.893, P=.001). DBP declined maximally by 10±1 mm Hg (10.5%, P<.001) 2 hours after felodipine.
MAP declined similarly after felodipine. There were significant effects for drug (F=5.912, P=.007), time (F=6.94, P<.001), and drug-time interaction (F=2.595, P=.003). One-way ANOVA comparing the effects of each drug over time showed that felodipine decreased MAP significantly (F=10.42, P<.001, for time effect); for verapamil, there was a trend toward an acute decrease (F=1.877, P=.094) but little apparent difference (Fig 1) from the unchanged values after placebo (F=0.941, P=.47). The greatest drop in MAP was 12±2 mm Hg (10%, P<.001) 2 hours after felodipine.
Acute felodipine caused significant tachycardia, with peak heart rate response 4 hours after drug administration, in contrast to an unchanged heart rate after placebo or verapamil (two-factor ANOVA results: F=4.986, P=.014 for drug effect; F=3.332, P=.005 for time effect; and F=1.511, P=.124 for drug-time interaction). Heart rate increased maximally by 6±2 bpm (8%, P=.014) 4 hours after felodipine.
Tachycardia after felodipine was accompanied by an immediate and sustained increase in cardiac output of 0.64±0.2 L/min (12.7%, P=.008), also peaking 4 hours after drug (F=2.797, P=.079 for drug effect; F=2.531, P=.027 for time effect; and F=1.403, P=.169 for drug-time interaction, by two-factor ANOVA). There was a statistically insignificant but delayed rise in cardiac output after verapamil, the magnitude of which was the same as after felodipine; placebo caused no consistent change in cardiac output.
The hemodynamic mechanism of the decline in blood pressure after felodipine or verapamil was a fall in systemic vascular resistance; in contrast, placebo did not affect systemic resistance. Two-way ANOVA factoring for drug and time revealed significant effects for drug (F=7.414, P=.003), time (F=4.818, P<.001), and drug-time interaction (F=1.815, P=.049). The maximal decline in systemic resistance after felodipine (at 4 hours after the drug, by 4±1 mm Hg/[L/min] or 6.5%; P<.001) was significantly greater than that after verapamil (Fig 1).
Neither drug produced a consistent change in stroke volume.
Chronic Effects
Both verapamil and felodipine decreased SBP, DBP, and MAP after
chronic treatment (Table 2). SBP fell from 157±3 mm Hg
after placebo to 148±2 after verapamil and 151±3 after felodipine
(P=.017). DBP decreased from 99±2 mm Hg after placebo to
91±2 after verapamil and 92±2 after felodipine (P<.005).
MAP also declined from 118±2 mm Hg after placebo to 110±2 after
verapamil and 112±2 after felodipine (P=.001). Chronic
blood pressure responses did not differ between the two calcium
antagonists.
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Heart rate declined (P=.002) from 76±2 bpm after placebo to 69±3 after verapamil but remained unchanged at 79±3 after felodipine. The chronic antihypertensive hemodynamic mechanism of each drug was a decrease in systemic vascular resistance. Systemic resistance declined from 24.3±2 mm Hg/(L/min) after placebo to 20.6±1 after verapamil and 20.1±1 after felodipine (P=.001). Cardiac output tended to increase (P=.08) after both verapamil (by 0.6 L/min) and felodipine (by 1.2 L/min) compared with after placebo. Overall, there was no significant change in stroke volume after placebo or either calcium channel antagonist (P=.524).
During the second placebo period (between calcium channel blockers), SBP returned to baseline (first placebo period) value, from 157±3 to 157±4 mm Hg (P=.781). However, DBP and MAP did not quite return to baseline values. Baseline (first placebo) DBP and MAP values were 99±2 and 118±2 mm Hg, respectively, falling to 94±2 (P=.01) and 115±3 mm Hg (P=.068), respectively, after the second placebo phase.
Autonomic Function
Baroreflex sensitivity to hypertensive phenylephrine
stimulus was unaffected (P=.308) when the three treatments
were compared by ANOVA (Table 3).
1-Adrenergic pressor sensitivity to
phenylephrine did not differ (P=.414 to.641)
among the three treatments for SBP, DBP, and MAP. Baroreflex
sensitivity in response to pressure reduction with an amyl nitrite
stimulus (Table 3) was unaffected (P=.626) by either drug
treatment (from 4.6±1 ms/mm Hg after placebo to 4.2±1 after
verapamil and 3.9±1 after felodipine). The blood pressure response to
the -antagonist phentolamine was significantly (P=.006)
reduced after verapamil (24±3 mm Hg) compared with placebo (32±4) or
felodipine (30±3). The heart rate response to phentolamine (Table 3)
was also significantly (P=.003) different for verapamil
(16±2 bpm) compared with placebo (21±3) and felodipine (25±2).
The cold stimulus elicited substantial increases in heart rate after
placebo and each drug. Change in heart rate was significantly
(P=.011) different among the three treatments, although
felodipine (6±1 bpm) and verapamil (7±1) did not differ
(P=.262). Blood pressure increments after cold stress were
comparable (P=.657) after all three treatments (Table 3).
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Biochemistry
Table 4 and Fig 2 show biochemical
indexes. Acute felodipine (but not verapamil) significantly
(P=.037) increased plasma norepinephrine (from 264±25 pg/mL
after placebo to 323±25 after felodipine and 279±26 after verapamil);
during chronic treatment, verapamil (but not felodipine) significantly
(P<.001) decreased plasma norepinephrine (from 264±25
pg/mL after placebo to 178±21 after verapamil and 275±21 after
felodipine). Plasma epinephrine was unchanged at either time point
after either drug.
Plasma chromogranin A declined significantly (P<.001) after chronic verapamil (but not felodipine) therapy (from a baseline value of 33.0±2.4 ng/mL to 27.8±1.7 after chronic verapamil and 33.5±2.5 after chronic felodipine). Acute treatment with either drug did not significantly alter plasma chromogranin A (Table 4).
Acute treatment with either calcium channel antagonist decreased plasma aldosterone significantly (P<.001), from 11.3±1.3 ng/dL to 6.4±0.8 after acute verapamil and 6.2±0.8 after acute felodipine. The acute decrease in plasma aldosterone was not apparent after chronic treatment with either drug.
Neither acute nor chronic treatment with verapamil or felodipine significantly altered plasma renin activity (Table 4).
Side Effects
Minor symptomatic side effects were constipation in 2 of 15
subjects on verapamil, pedal edema in 1 of 15 subjects on felodipine,
and headache and fatigue in 2 of 15 subjects on felodipine. None of
these symptoms required discontinuation of drug.
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Discussion |
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Side effects (such as tachycardia) suggesting reflex sympathetic activation after blood pressure reduction are more frequent after calcium channel blockade with dihydropyridines (such as felodipine) than phenylalkylamines (such as verapamil).10 34 35 36 37 38 39 40 Indeed, phenylalkylamines may have a number of specific properties that limit efferent sympathetic outflow of catecholamines, including depletion of catecholamine vesicular stores,34 41 depression of norepinephrine release,42 43 and attenuation of reflex tachycardia.44 Whether such catecholamine release and baroreflex mechanisms differ after antihypertensive treatment with phenylalkylamines versus dihydropyridines in humans has not so far been directly tested. The observation that verapamil penetrates the blood-brain barrier and is found in cerebrospinal fluid45 also suggests that it might be capable of central actions to influence sympathetic outflow. We therefore studied autonomic control of the circulation after verapamil versus felodipine, measuring both biochemical and physiological/pharmacologic indexes of autonomic function.
Both verapamil and felodipine lowered blood pressure during chronic use (Table 2). Acute felodipine significantly decreased MAP, whereas for verapamil there was only an insignificant trend toward an acute decrease. Consistent with previous studies,46 felodipine caused tachycardia after acute administration, an effect that disappeared after chronic use (Fig 1, Table 2). That the tachycardia after acute felodipine was reflex in nature is supported by the accompanying significant decrease in systemic vascular resistance (Fig 1) and increase in plasma norepinephrine (Table 4, Fig 2). Verapamil did not acutely alter heart rate (Fig 1) but after 4 weeks caused a significant decrease in heart rate (Table 2), plasma norepinephrine, and chromogranin A (Table 4, Fig 2).
These hemodynamic and biochemical findings suggest that felodipine activated sympathetic activity acutely, but this was not sustained chronically. With verapamil, acute effects were small, but chronically, sympathetic activity was depressed.
It should be noted that plasma catecholamines are an imperfect index of overall efferent sympathetic outflow, and such estimations as the rate of catecholamine spillover from synaptic clefts into plasma may be superior to simple catecholamine concentrations.47 However, plasma norepinephrine and chromogranin A, a protein coreleased with norepinephrine by exocytosis from storage vesicles,32 declined in parallel after chronic verapamil (Table 2), suggesting a decline in exocytotic sympathetic activity.32 This conclusion is reinforced by the finding that plasma norepinephrine parallels norepinephrine spillover rate.48 In addition, the increase in cardiac output after acute felodipine (Fig 1) might be expected to increase norepinephrine clearance from plasma,47 suggesting that the degree of sympathetic activation after felodipine could be even greater than that indicated by the increase of plasma norepinephrine (Table 2).
Since aldosterone release from adrenal glomerulosa cells is mediated by changes in cytosolic calcium,49 50 it might be anticipated that calcium channel blockade would decrease plasma aldosterone. Although both drugs decreased plasma aldosterone acutely, this effect was not sustained (Table 4).
We also found differential effects of these compounds on
pharmacological indexes of autonomic function. Smaller changes in blood
pressure and heart rate during phentolamine -adrenergic blockade
after chronic verapamil (Table 3) suggest that verapamil
decreased sympathetic participation (-adrenergic tone) in long-term
blood pressure maintenance. We found little evidence of differential
effects on 1-adrenergic pressor sensitivity (Table 3)
between the two drugs.
Our findings are consistent with previous observations on
dihydropyridine-induced acute tachycardia, accompanied by catecholamine
release.46 51 By contrast, verapamil had only modest
acute antihypertensive effects and consequently did not produce reflex
changes in heart rate, cardiac output, or catecholamines. Both the
verapamil12 13 and felodipine10 14 15
oral preparations used in this study were formulated for extended
release; hence, it is conceivable that differences in the acute effects
of these compounds represent pharmacokinetic rather than
pharmacodynamic variations. After chronic verapamil (Tables 2 and 4, Fig 2), significant decreases in plasma norepinephrine and
chromogranin A, along with a significant decline in heart rate and
blood pressure response to -blockade, suggest that verapamil
exerts a suppressive effect on the sympathetic outflow as an
antihypertensive mechanism.
In conclusion, the present study demonstrated that two classes of calcium channel antagonists, phenylalkylamine and dihydropyridine, affect autonomic function in strikingly, even qualitatively, different ways in a time-dependent fashion. Such differences may contribute to the marked disparity in reflex side effects seen after antihypertensive therapy with these drug classes.
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Acknowledgments |
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This work was supported by the Department of Veterans Affairs, the American Heart Association, the National Institutes of Health, and Lederle Laboratories. Esther Carlton (Nichols Institute, San Juan Capistrano, Calif) assisted in the measurement of plasma chromogranin A.
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Footnotes |
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Reprint requests to Daniel T. O'Connor, MD, Department of Medicine (9111H), University of California, San Diego, 3350 La Jolla Village Drive, San Diego, CA 92161. E-mail doconnor@ucsd.edu.
Received September 20, 1994; first decision November 7, 1994; accepted February 21, 1995.
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