(Hypertension. 1995;25:1075-1082.)
© 1995 American Heart Association, Inc.
Articles |
Effects of Bromocriptine on Cardiovascular Regulation in Healthy Humans
From the Human Physiology Laboratory, Medical Clinic IV, Internal Medicine, University of Erlangen-Nürnberg (Germany), and the Franz Volhard Clinic, Rudolf Virchow University Hospitals, Free University of Berlin (F.C.L.) (Germany).
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Abstract Bromocriptine, a dopamine agonist with central nervous system actions, may reduce sympathetic nervous system activity. We tested this hypothesis by measuring arterial blood pressure, central venous pressure, heart rate, muscle sympathetic nerve activity, and forearm blood flow before and after unloading the arterial baroreceptors with sodium nitroprusside (0.5 to 1.5 mcg/kg per minute IV), before and after unloading the cardiopulmonary baroreceptors with incremental lower body negative pressure (0 to -15 mm Hg), and before and after immersion of the hand in ice-cold water for 2 minutes (cold pressor test). After obtaining basal responses to provocative maneuvers, we gave 20 healthy subjects either 5 mg oral bromocriptine (n=10) or placebo (n=10) in a randomized, double-blind fashion. Bromocriptine did not affect resting mean arterial pressure, heart rate, or forearm blood flow. Bromocriptine decreased resting central venous pressure by 1.2 mm Hg (P<.05) and tended to increase total integrated muscle sympathetic nerve activity (from 151±44 to 212±82 U/min, P=NS). The reflex increases in muscle sympathetic nerve activity to nitroprusside infusion and lower body negative pressure were unchanged by bromocriptine; however, vascular responsiveness to both maneuvers was impaired after bromocriptine administration compared with control. Without bromocriptine, the reflex increase in muscle sympathetic nerve activity after nitroprusside-induced hypotension maintained forearm blood flow at a constant level, whereas with bromocriptine the forearm blood flow increased from 1.9±0.3 to 2.8±0.6 mL/min per 100 mL (P<.05). Similarly, the forearm blood flow response to lower body negative pressure at -15 mm Hg was decreased with bromocriptine (+0.0±0.4 mL/min per 100 mL) compared with control values (-0.4±0.3 mL/min per 100 mL, P<.05). Responses to the cold pressor test were not altered by bromocriptine. We conclude that bromocriptine inhibits catecholamine release in peripheral nerves. However, we were unable to substantiate a central effect of bromocriptine on either sympathetic outflow or baroreflex sensitivity.
Key Words: pressoreceptors • receptors, dopamine • nervous system • blood circulation • bromocriptine
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Introduction |
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Recent data suggest that bromocriptine, a dopamine DA2 receptor agonist, lowers the cardiovascular mortality in L-dopa–treated patients with Parkinson's disease.1 The cardioprotective effect of bromocriptine is believed to be due to a reduction in cardiac sympathetic activity, which could diminish the risk of potentially life-threatening ventricular arrhythmias. Data by Falk et al2 support this hypothesis. They showed that in anesthetized dogs, bromocriptine decreased plasma catecholamines and increased the ventricular fibrillation threshold by approximately 50%. Bromocriptine acts on presynaptic dopamine receptors by inhibiting norepinephrine release2 ; however, bromocriptine could also induce a centrally mediated reduction in sympathetic outflow. In humans, bromocriptine decreased plasma norepinephrine not only under resting conditions3 but also in response to hemodynamic maneuvers such as standing or tilt.4 5 6 However, these studies could not clarify whether the decreased plasma norepinephrine levels resulted from reduced central and/or reflex mediated sympathetic nerve firing or from changes in norepinephrine release or reuptake mechanisms at the peripheral sympathetic nerve endings.
Until recently, it was difficult to assess central nervous system effects of pharmacological agents on sympathetic outflow in humans. However, a microneurographic technique for obtaining direct intraneural recordings of postganglionic sympathetic nerve activity in humans7 now enables a direct assessment of the physiological role of bromocriptine on central and peripheral sympathetic outflow in healthy subjects. We measured efferent muscle sympathetic nerve activity (MSNA) and simultaneously determined forearm blood flow (FBF) before and after short-term bromocriptine administration. To investigate whether impaired catecholamine responses to hemodynamic sympathetic stimulation might be due to a reduction in baroreflex sensitivity, we measured MSNA and FBF not only in the resting state but also during unloading of cardiopulmonary baroreceptors with nonhypotensive lower body negative pressure (LBNP) and during unloading of arterial baroreceptors with a blood pressure–reducing sodium nitroprusside infusion. We also examined responses to the cold pressor test, a non–baroreflex-mediated sympathoexcitatory stimulus, to assess the specificity of the actions of bromocriptine.
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Methods |
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Subjects
Twenty white male volunteers (aged 26±1 years, mean±SEM) recruited from the student population of the university were studied before and after bromocriptine or placebo (n=10 each group) in a double-blind, randomized fashion. Both treatment groups were matched with regard to age, weight, and body mass index. All subjects were normotensive and free of cardiovascular or systemic diseases based on a complete medical history and physical examination. They were receiving no medications and were all studied between the hours of 1 and 5 PM without sedation in the supine, postabsorptive state. Informed written consent was obtained before the study. The protocol was approved by the Human Subjects Review Committee of the University of Erlangen-Nürnberg.
Measurements
A direct-writing, multichannel physiological recorder (Gould
Instruments) was used to simultaneously record arterial and central
venous pressures, heart rate, respiratory activity, FBF, LBNP level,
and MSNA. Systolic and diastolic pressures and mean arterial pressure
(MAP) were measured noninvasively beat-to-beat by a
photoplethysmographic finger device (Finapres, Ohmeda) as described in
detail elsewhere.8 MAP was calculated as 1/3 pulse
pressure+diastolic pressure. Central venous pressure was determined
with an 18.5-gauge polyethylene catheter inserted into a right medial
antecubital vein and advanced to an intrathoracic vein. Heart rate and
rhythm were recorded continuously by electrocardiogram, and respiratory
activity was recorded by a strain-gauge pneumograph. Zero reference
point for all hemodynamic measurements was defined at the phlebostatic
axis in the midaxillary position.
Blood flow of the left forearm was measured by venous occlusion plethysmography with a mercury-in-Silastic Whitney strain gauge as previously described.9 10 Blood flow was measured every 15 seconds and the average value per minute determined. Forearm vascular resistance (FVR) was derived by dividing MAP (millimeters of mercury) by FBF (milliliters per minute per 100 mL of forearm volume) and was expressed as derived arbitrary units.
Microneurographic recordings of MSNA were obtained from a sympathetic nerve fascicle in the peroneal nerve posterior to the fibular head. This technique has been validated and extensively described in numerous studies.11 12 13 14 15 16 In brief, recordings were obtained by percutaneous insertion of tungsten microelectrodes into sympathetic fascicles in the peroneal nerve. The electrodes were connected to a preamplifier, and the nerve signal was fed through a band-pass filter and routed through an amplitude discriminator to a storage oscilloscope and loudspeaker. For recording and analysis, the filtered neurogram was fed through a resistance-capacitance integrating network to obtain a mean voltage display of the neural activity. Standard quality criteria for acceptance of an MSNA recording were achieved in all subjects.11 12 13 14 15 16 Sympathetic bursts were identified by inspection of the mean voltage neurogram, and sympathetic activity was calculated as bursts per minutexmean burst amplitude and was expressed as derived arbitrary units. Prior studies determined an intraobserver variability of 5% and an interobserver variability less than 10% in this calculation of MSNA.13
Procedures
Orthostatic stress was simulated by LBNP using a chamber placed
over the subject's body below the iliac crest.15 16 17 18 19 LBNP
was applied for consecutive sequential 2-minute periods at levels of
-5, -10, and -15 mm Hg, sufficient to reduce cardiac filling
pressures without significantly altering arterial or pulse pressure.
The arterial blood pressure was decrementally lowered by a continuous,
intravenous infusion of sodium nitroprusside given through a peripheral
intravenous line in the right forearm at rates of 0.5, 1.0, and 1.5
mcg/kg per minute for 5 minutes at each dose. The nitroprusside dose
was individualized for each subject to produce a maximal reduction in
MAP of 10% to 15% below the baseline value. To minimize the influence
of cardiopulmonary receptors on changes of MSNA during nitroprusside
administration, we infused 0.9% NaCl solution to maintain central
venous pressure at control levels.20 Responses to the cold
pressor test were assessed by immersion of the subject's left hand up
to the wrist in ice water for 2 minutes. The subjects were instructed
to avoid isometric contraction, performance of Valsalva's maneuver, or
maintained expiration during the cold pressor test.21 The
order of experimental interventions was varied randomly among subjects
to avoid any effects of order.
Protocol
Studies were initiated after a 20-minute rest period during
which all subjects were familiarized with the experimental techniques.
In all subjects, measurements of hemodynamic parameters and MSNA were
obtained over 3-minute periods in the control state; during 2-minute
periods of LBNP at -5, -10, and -15 mm Hg; and during the cold
pressor test. After a 3-minute control period, nitroprusside was
infused until a steady-state dose was identified that produced a
discernible decrease in MAP and increase in MSNA. All variables were
then measured again during a consecutive 2-minute period of
nitroprusside infusion. Because of baseline systolic pressure values of
less than 110 mm Hg, we did not infuse nitroprusside in 2 of the 10
subjects. There were 5 to 10 minutes of rest between interventions to
permit hemodynamic and MSNA parameters to return to control basal
levels. The average response during each period of control,
intervention, and recovery was determined. After the predrug
interventions, subjects received either an oral dose of 5 mg
bromocriptine (Sandoz Co) or a placebo tablet in a randomized
double-blind design. Beginning 60 minutes after drug administration,
subjects underwent repeat application of LBNP, nitroprusside infusion,
and cold pressor testing.
Statistical Analysis
All statistical analyses were performed in consultation with
institutional biostatisticians. Control hemodynamics and MSNA
parameters before and after drug administration were compared within
each treatment group by paired t test. Hemodynamic and MSNA
responses to LBNP before and after drug were compared by
repeated-measures ANOVA within each treatment group separately.
Intragroup comparisons of responses to nitroprusside infusion and to
the cold pressor test were performed by paired t test.
Intergroup (ie, bromocriptine versus placebo) comparisons were done by
means of two-way ANOVA and two-way ANCOVA. Statistical significance was
accepted at a value of P<.05. Values in text, figures, and
tables are mean±SEM.
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Results |
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Effects of Drug Treatment on Resting Hemodynamics and MSNA
Table 1 summarizes the effects of bromocriptine and placebo on resting hemodynamics and MSNA. Except for a higher baseline value of FBF in the placebo group (2.9±0.4 versus 2.0±0.2 mL/min per 100 mL, P<.05), the two groups did not significantly differ with regard to their baseline values of arterial and central venous pressures, heart rate, and MSNA. Oral administration of bromocriptine resulted in a small but significant decrease in central venous pressure (9.7±0.7 to 8.5±0.9 mm Hg, P<.05), with a concomitant increase in MSNA burst frequency (16±3 to 20±3 bursts per minute, P<.05). The numerical increase in total integrated MSNA (151±44 to 212±82 U/min, P=NS) seen after 5 mg bromocriptine was not statistically significant. MAP, heart rate, FBF, and FVR did not change after bromocriptine administration. Placebo did not significantly alter resting hemodynamics or MSNA. Thus, bromocriptine did not decrease central sympathetic outflow to muscle but rather tended to increase MSNA, perhaps because of a slight but significant decrease in central venous pressure.
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Effects of Bromocriptine Versus Placebo on Responses to Arterial
Baroreceptor Deactivation
The effects of drug treatment on hemodynamic and MSNA responses to
a sustained nitroprusside infusion are shown in Table 2
and Fig 1. Fig 1 demonstrates the effects of
bromocriptine versus placebo on hemodynamic and MSNA responses to
unloading of arterial baroreceptors with nitroprusside infusion. In the
bromocriptine group, during the predrug evaluation, nitroprusside
infusion produced a significant decrease in MAP (101±4 to 92±4
mm Hg, P<.05) that was associated with a significant
increase in heart rate (64±2 to 73±3 beats per minute,
P<.05). Central venous pressure, FBF, and FVR did not
change significantly. Nitroprusside induced arterial hypotension and
evoked marked increases in MSNA as measured by burst frequency (14±3
to 32±7 bursts per minute, P<.05) and total activity
(129±50 to 327±90 U/min, P<.05). After bromocriptine,
nitroprusside infusion produced a similar decrease in MAP (98±6 to
85±7 mm Hg, P<.05) and similar increases in heart rate
(65±2 to 78±3 beats per minute, P<.05) and MSNA (22±3 to
44±6 bursts per minute, P<.05, and 247±101 to
562±201 U/min, P<.05). Central venous pressure again was
not significantly altered.
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However, the responses of FBF and FVR to nitroprusside infusion were significantly influenced by bromocriptine. In the predrug state, the marked increase in MSNA in response to blood pressure reduction with nitroprusside maintained FBF at a constant level and thus compensated for the local vasodilator effect of nitroprusside. In contrast to the results obtained with nitroprusside alone, bromocriptine caused a significant increase in FBF during nitroprusside infusion (1.9±0.3 to 2.8±0.6 mL/min per 100 mL, P<.05) despite increases in MSNA, which tended to be even larger compared with before drug. These data are shown in Table 2 and Figs 1 and 2. Fig 2 illustrates the interaction between changes in MSNA and FBF during nitroprusside infusion before and after bromocriptine administration in a single subject. Although nitroprusside produced similar decreases in MAP and increases in MSNA both before and after bromocriptine, FBF during nitroprusside infusion did not change before the drug but increased after the drug. Similarly, after bromocriptine, FVR during nitroprusside infusion decreased significantly (64.8±11.7 to 42.1±8.3 U, P<.05; Table 2 and Fig 1). The results most likely indicate a peripheral inhibition of norepinephrine release during nitroprusside-induced increase in MSNA after bromocriptine administration. As shown in Table 2 and Fig 1, placebo did not significantly alter hemodynamic and MSNA responses during nitroprusside infusion.
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Effects of Bromocriptine on Responses to Cardiopulmonary
Baroreceptor Deactivation (LBNP)
The hemodynamic and MSNA responses of subjects during application
of incremental LBNP at -5, -10, and -15 mm Hg before and after
administration of 5 mg bromocriptine or placebo are summarized in
Tables 3 and 4 and Fig 3.
Fig 3 compares bromocriptine- and placebo-induced effects on
hemodynamic and MSNA responses to cardiopulmonary baroreceptor
unloading with LBNP. During the predrug evaluation of LBNP in the
bromocriptine group, increasing levels of LBNP resulted in
proportionately decreasing levels of central venous pressure and
increasing levels of MSNA (Table 3, Fig 3). LBNP did not significantly
alter MAP or heart rate. After bromocriptine, graded application of the
same levels of LBNP caused similar reductions in central venous
pressure. MSNA increases tended to be greater after drug compared with
before (Table 3, Fig 3, P=NS), and heart rate increased from
66±2 to 72±4 beats per minute (P<.01, Fig 3) during LBNP
after bromocriptine as MAP decreased from 94±2 to 88±6 mm Hg
(P<.01, Fig 3). Furthermore, in contrast to the tendency
for sympathetic vasoconstrictor responses to increase with
bromocriptine, the overall responses to LBNP of FBF and FVR tended to
be diminished after bromocriptine. Before the administration of active
drug, FBF decreased with increasing levels of LBNP, and FVR increased
(Table 3). On the other hand, after active drug, FBF and FVR did not
change (Fig 3). Compared with baseline, the FBF response at -15 mm Hg
LBNP was significantly different before versus after bromocriptine
(-0.4±0.3 before versus 0.0±0.4 mL/min per 100 mL after
bromocriptine, P<.05, Table 3). These results are again
best explained by a peripheral inhibition of norepinephrine release at
nerve endings.
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indicates before drug; 
, after drug.Placebo did not affect the responses to LBNP as shown in Table 4 and Fig 3. Graded application of LBNP resulted in similar decreases in central venous pressure before and after placebo administration. MAP and heart rate did not change significantly during incremental levels of LBNP before and after placebo. The overall responses of MSNA, FBF, and FVR were not significantly affected by placebo.
Effects of Drug Administration on Responses to Cold Pressor
Stimulus
To assess the specific effects of bromocriptine on
baroreflex-mediated mechanisms, we examined responses to the cold
pressor stimulus before and after drug administration. As shown in
Table 5, neither bromocriptine nor placebo altered the
responses of arterial pressure, central venous pressure, or heart rate
to the cold pressor stimulus. There was no significant difference
between the effects of bromocriptine and placebo on the MSNA response
to the cold pressor test. These results are also shown in Fig 4, which compares the effects of bromocriptine versus
placebo on the MSNA responses to the cold pressor test.
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Discussion |
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We used direct recordings of efferent sympathetic nerve activity to skeletal muscle (MSNA) and demonstrated that short-term administration of the dopamine receptor agonist bromocriptine did not inhibit resting central sympathetic outflow. Bromocriptine also had no inhibitory effect on reflex increases in MSNA in healthy, awake humans. If anything, resting sympathetic activity and reflex responses tended to increase after bromocriptine. Despite this effect, the responsiveness of sympathetically mediated changes in FBF during unloading of arterial baroreceptors with nitroprusside infusion and during unloading of cardiopulmonary baroreceptors with LBNP was diminished after bromocriptine administration. These results are consistent with a peripheral inhibition of norepinephrine release by bromocriptine. They confirm and extend earlier observations by Mohanty et al,6 who showed that bromocriptine blunted the plasma norepinephrine responses to LBNP and tilt in healthy volunteers. They are also in agreement with recent data from experimental animals, which showed that bromocriptine decreased plasma norepinephrine values without inhibiting postganglionic sympathetic nerve activity.22
Bromocriptine has been found to decrease blood pressure in patients with essential hypertension and may cause orthostatic hypotension in normotensive subjects.23 24 Furthermore, pharmacological evidence has been presented that stimulation of presynaptic dopamine receptors inhibits norepinephrine release.25 26 These findings have encouraged a series of investigations to elucidate the effects of bromocriptine on the sympathetic nervous system. Van Loon and colleagues3 showed that a single oral dose of 2.5 mg bromocriptine decreased resting catecholamine levels; however, it remained unclear in their study to what extent peripheral and/or central mechanisms were involved. Mannelli et al4 evaluated the effects of short-term bromocriptine administration on plasma catecholamines, blood pressure, and heart rate in six healthy subjects in the supine and upright positions. Since peripheral dopamine receptor blockade with domperidone did not counteract all the bromocriptine effects during standing, they postulated that part of bromocriptine-induced sympathoinhibition was centrally mediated. The finding that bromocriptine lowered both plasma and cerebrospinal fluid levels of norepinephrine in normotensive subjects27 also argued in favor of the view that bromocriptine inhibits sympathetic discharge of norepinephrine through peripheral and central mechanisms. Mohanty et al6 also concluded that the effects of bromocriptine were likely to be peripheral and central. In contrast, Starke et al,28 who used the norepinephrine "spillover" technique to assess the effects of bromocriptine on the sympathetic nervous system, substantiated a peripheral mode of action. Furthermore, the observations that reflex-induced increases in norepinephrine concentrations during upright posture29 and during LBNP and tilting6 were blunted by bromocriptine raised the possibility that the drug might depress baroreflex-mediated control of sympathetic activity.
It is difficult to evaluate the contribution of central versus peripheral effects of adrenergic drugs in humans. The measurement of plasma norepinephrine, for example, does not permit evaluation of central versus peripheral actions, as either action would be expected to decrease norepinephrine release. Thus, the unique feature of our study was the direct, intraneural recording of MSNA with the use of microneurography. This technique enabled not only an assessment of the effects of bromocriptine on central sympathetic outflow under resting conditions but also permitted observations during perturbation of baroreceptor activity. We were able to combine both the direct assessment of efferent sympathetic nerve activity and the indirect measurement of FBF to evaluate the sympathetic outflow to muscle in our study.
We found that the short-term administration of bromocriptine did not reduce central sympathetic outflow and arterial blood pressure in healthy men under supine, resting conditions. Resting MSNA actually tended to increase with bromocriptine; however, this response may be explained by a slight but significant reduction in central venous pressure after the drug. We also observed that bromocriptine did not alter arterial or cardiopulmonary baroreflex control of sympathetic activity, nor did it alter non–baroreflex-mediated sympathetic responsiveness during the cold pressor test. Finally, we found that the responsiveness of sympathetically mediated reflex decreases in FBF during baroreceptor deactivation was decreased by bromocriptine. Thus, the orthostatic hypotension occasionally observed in normotensive subjects after bromocriptine intake is probably not due to a reduction in baroreflex sensitivity or to a central sympatholytic effect of the drug. Instead, we suggest that the sympathoinhibitory effect of bromocriptine is solely due to peripheral inhibition of norepinephrine release.
Such a peripheral decrease in sympathetic activity could also in part explain the cardioprotective potential of bromocriptine in patients with Parkinson's disease.1 In fact, bromocriptine increased the threshold to induced ventricular arrhythmias in experimental animals.2 Since increased sympathetic activity is associated with ventricular arrhythmias,30 the effect may indeed be clinically relevant. Moreover, a reduction in dopaminergic sympathoinhibitory mechanisms may be a factor in the pathogenesis and maintenance of essential hypertension.31 Our findings could be important in elucidating the effects of bromocriptine in hypertensive patients. The observation that bromocriptine lowers supine basal blood pressure in patients with essential hypertension but not in normotensive subjects supports this view.32
We are aware of several potential limitations in the design and interpretation of our studies. First, these observations were short-term in nature and do not necessarily predict long-term effects of bromocriptine on blood pressure and sympathetic activity in healthy humans. However, studies that compared the effects of one dose and of more than one dose of bromocriptine on supine and standing levels of plasma catecholamines and/or blood pressure in normotensive and hypertensive subjects3 31 did not show any significant differences between the short- and long-term responses to bromocriptine. Second, the studies were performed in healthy human subjects. Caution must be exercised in applying these observations to patients with clinical disorders in whom bromocriptine may be applied therapeutically. Third, we have attempted to examine the arterial and cardiopulmonary baroreflex during maneuvers that deactivated these mechanoreceptors. It is possible that other effects of bromocriptine would be observed under conditions of activation (loading) of such receptors. However, we believe that the current studies are physiologically important because we examined efferent sympathetic responses over an extended and physiologically relevant range of arterial blood pressure and cardiac filling pressures. Finally, we have used direct recordings of efferent sympathetic nerve activity from only one site, the peroneal nerve. It is known that there are important differences in the control of sympathetic nerve activity to various tissues and vascular beds.12 33 In our studies, all MSNA responses were compared with a stable control recording of sympathetic nerve activity. Each subject served as his own control for effects of both provocative interventions and drug. Thus, although we cannot generalize to other organ-specific sympathetic neural responses, the intraindividual comparisons of peroneal MSNA responses remain valid.
In conclusion, the present study indicates that short-term bromocriptine administration does not inhibit resting central sympathetic outflow or baroreflex sympathetic control in healthy humans. The decreased responsiveness of reflex changes in FBF during deactivation of both arterial and cardiopulmonary mechanoreceptors suggests a peripheral inhibition of neurotransmitter release.
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Acknowledgments |
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These studies were supported by a grant-in-aid to H.P.S. from the Deutsche Forschungsgemeinschaft as well as by a grant from the Sandoz Co.
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Footnotes |
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Reprint requests to Hans P. Schobel, MD, 4 Med Klinik, Breslauerstr 201, 90471 Nürnberg, FRG.
Received August 25, 1994; first decision November 10, 1994; accepted January 3, 1995.
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