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VOL 72
AUGUST
NO 2
1985
cAln Official Journalof the c.American Heart cjlssociation, Inc.
FEATURES
Dopamine receptors: applications in clinical cardiology
LEON
I.
GOLDBERG, M.D., PH.D.,
AND
SOL
I.
RAJFER, M.D.
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THE DISCOVERY of the renal vasodilating action of
dopamine more than 20 years ago led to extensive
research that demonstrated other unusual actions of
this endogenous catecholamine. 1-' Investigators using
traditional pharmacologic models and modern biochemical techniques have documented the existence of
distinct dopamine receptor subtypes that mediate these
responses. Appreciation of the structure-activity requirements of these receptors has led to the synthesis
of drugs that may have a profound influence on the
management of the patient with heart disease.
Taxonomy of dopamine receptors. Rigid criteria must
be met to prove the existence of a new receptor
by classical pharmacologic methods, including construction of a unique potency series of agonists and
demonstration of specific antagonism.4 5 In contrast,
biochemical techniques are applied to tissue homogenates, and different standards are frequently used to
classify receptors.P 7
After many years of research, two distinct dopamine
receptor subtypes, DA, and DA2, were identified conclusively by classical criteria in physiologic preparations.5 DA receptors are located postsynaptically and
subserve vasodilation in renal, mesenteric, coronary,
and cerebral blood vessels (figure 1). DA,-induced
vasodilation can be observed in other vascular beds,
but the response is less prominent, probably because of
the lower density of dopamine receptors. The molecular structure required for activation of DA, receptors is
very strict.4 Currently, all active compounds have two
hydroxyl groups in positions analogous to the 3- and 4positions on the benzene ring of the dopamine molecule, and a limited distance exists between the hydroxyl groups and the amino group.
From the Committee on Clinical Pharmacology, Departments of
Pharmacological and Physiological Sciences and Medicine, Section of
Cardiology, The University of Chicago.
Address for correspondence: Leon I. Goldberg, M.D., Ph.D., Committee on Clinical Pharmacology, The University of Chicago, 947 E.
58th St., Chicago, IL 60637.
Supported in part by National Institutes of Health grant GM-22220
and HL-00872. Dr. Rajfer is the recipient of a National Institutes of
Health Clinical Investigator award HL-00872.
Vol. 72, No. 2, August 1985
DA2 receptors are located on postganglionic sympathetic nerves and autonomic ganglia, and when these
receptors are activated, norepinephrine release from
sympathetic nerve endings is inhibited (figure 1). DA2
receptors are also located in the emetic center of the
area postrema and in the anterior lobe of the pituitary
gland. Activation of these receptors results in emesis
and inhibition of prolactin release, respectively. The
structural requirements for DA2 agonists are much less
restrictive than those for DA, agonists. Indeed, the
structures of DA2 agonists are so diverse that it is
difficult to determine molecular requirements for activity.4
Major advances have been made in the synthesis of
dopamine agonists, and compounds are now
available with spectra of receptor activity different
from that of dopamine. Of significance, the benzazepine derivative, fenoldopam, proved to be a selective
DA, agonist.' Selective DA2 agonists have been available for several years. Examples include piribedil and
ergot derivatives, which are used for the treatment of
Parkinson's disease, and LY 17155, an ergoline derivative.4
The first dopamine antagonists used to classify dopamine receptors were the neuroleptics, haloperidol
and chlorpromazine.2 Although these agents made it
possible to distinguish dopamine receptors from other
receptors, the dose range in which they are specific
antagonists for dopamine receptors is very narrow.
Furthermore, these antagonists cannot be used to differentiate dopamine receptor subtypes. Recently, selective antagonists that discriminate between DA, and
DA2receptors have been synthesized. An example of a
selective DA, antagonist is the benzazepine, SCH
23390, which is chemically related to fenoldopam.9
Domperidone, a butyrophenone derivative related to
haloperidol, is an example of a selective DA2 antagonist.
Availability of selective dopamine agonists and antagonists has aided in the determination of whether
dopamine subtypes classified on the basis of cardionew
10
245
GOLDBERG and RAJFER
PREJUNCTIONAL
SYMPATHETIC NERVE TERMINAL
POSTJUNCTIONAL
VASCULAR EFFECTOR CELL
DA
(EXOGENOUS)
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FIGURE 1. Location of DA, receptors, a1- and a2-adrenoceptors on postganglionic vascular effector cells, and DA2 receptors
and a2-adrenoceptors on the prejunctional sympathetic nerve terminal. When dopamine is administered, activation of DA1
receptors causes vasodilation and activation of DA2 receptors causes inhibition ( - ) of norepinephrine (NE) release from storage
granules. A larger dose of dopamine activates a1- and a2-adrenoceptors on the postjunctional effector cells to cause vasoconstriction and on a2-adrenoceptors on the prejunctional sympathetic terminal to inhibit release of norepinephrine. Norepinephrine
released from the prejunctional sympathetic terminal also acts on a1- and a2-adrenoceptors.
vascular responses are similar to those receptors identified in brain and endocrine tissues by biochemical
techniques. In one biochemical method, dopamine receptors are subdivided according to the effects of agonists on the enzyme, adenylate cyclase. Activation of
D, receptors results in stimulation of adenylate cyclase; activation of D2 receptors either results in inhibition of adenylate cyclase or has no effect on that enzyme.6 In a second biochemical method, dopamine
receptors are subdivided according to the pattern of
displacement of radioactive ligands by dopamine
agonists or antagonists.7 The radioligand binding assays have been extremely controversial because of the
many inconsistencies in the dopamine receptor subtypes "identified" by these assays.6' It appears that
many of the early ligand-binding investigations yielded increased numbers of receptor subtypes because the
ligands used were not selective or because strict criteria required to characterize receptors were not fulfilled.4 6 Recent studies conducted with more selective
ligands have identified only two dopamine subtypes
similar to D andD9.6 Comparison of the DA, and DA,
classification with the revised D, and D2 classification
suggests that the same receptors are identified by the
two methods. However, a few significant discrepancies in the potency series of agonists and antagonists
remain, and further studies are needed to determine the
reasons for these differences.'
Pharmacologic actions of dopamine. The activation of
adrenoceptors and dopamine receptors by dopamine is
the basis for its diverse clinical applications.2' 3 Because of extreme individual variations in the infusion
rates of dopamine required to activate the different
246
receptors, patients must be monitored carefully to
achieve the desired hemodynamic profile. DA, and
DA, receptors are activated at the lowest infusion
rates, resulting in a decline in peripheral vascular resistance and modest increments in renal blood flow, urine
volume, and sodium excretion. At these low rates of
infusion (usually 0.5 to 2 gg/kg/min) dopamine may
initiate a diuresis in patients refractory to furosemide. 1 1
As the infusion rate is increased (usually above 2
,ug/kg/min), f,-adrenoceptors are activated and cardiac output begins to increase, typically with little
change in heart rate. This is the hemodynamic response sought in the treatment of heart failure. The
infusion rate may then be gradually increased until
recruitment of a°- and a2-adrenoceptors occurs as
manifested by an increase in vascular resistance or
until excessive 3,-adrenoceptor activity leads to tachycardia or ventricular arrhythmias. Higher infusion
rates can be used if the undesirable vasoconstriction is
eliminated by simultaneous administration of a vasodilating agent.3 With such concurrent administration,
caution must be exercised to avoid excessive reduction
in arterial pressure. Indeed, unmasking of the vasodilating effects of dopamine in the presence of phenoxybenzamine was the first demonstration of its potential
use in the treatment of hypertension.'2 A different
hemodynamic pattern may be achieved by conjoint
administration of dopamine and dobutamine. This
combination provides greater ,/3-adrenoceptor activity, maintenance of the beneficial renal effects of dopamine, and avoidance of a-adrenoceptor-mediated vasoconstriction seen with high doses of dopamine.3
Orally active pro-drugs. Poor oral bioavailability of
CIRCULATION
PERSPECTIVE
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dopamine stimulated the development and investigation of orally active pro-drugs with dopamine activity.
Two oral pro-drugs, levodopa and ibopamine, have
been studied in the treatment of congestive heart
failure.
After oral administration of the biochemical precursor of dopamine, levodopa, dopamine is generated by
the action of aromatic amino acid decarboxylase in the
liver and other tissues. Investigations in patients with
Parkinson's disease demonstrated that oral administration of levodopa in doses of 1 to 1.5 g produces cardiac
and natriuretic effects approximating the responses observed with intravenous infusions of dopamine at rates
of 2 to 4 1tg/kg/min.2 On this basis, levodopa was
studied recently in patients with severe congestive
heart failure. After ingestion of levodopa (1.5 to 2.0
g), significant improvement in cardiac performance
was observed. Furthermore, the beneficial hemodynamic effects were sustained during long-term therapy
for 3 or more months. The lack of tolerance to levodopa is in sharp contrast to the findings of previous
studies conducted with pirbuterol, which was ineffective after sustained therapy. 13 This difference could be
explained by the partial agonist activity of pirbuterol
and the full agonist activity of dopamine. Down-regulation of 8,-adrenoceptors with continuous therapy
should decrease activity of partial agonists to a much
greater extent than that of full agonists. 14
No serious adverse effects were observed in this
initial study with levodopa. However, levodopa can
produce nausea and vomiting unless the dose is gradually increased. Accordingly, the dose was increased
from 250 mg qid to 1.5 to 2.0 g qid over a 5 to 7 day
period. In addition 50 mg of pyridoxine was administered daily, since previous studies have shown that this
vitamin is required for the decarboxylation of levodopa.
In addition to the trial of levodopa in congestive
heart failure, the pro-drug has also been used to help
wean patients from long-term intravenous infusion of
dopamine.3
Ibopamine is the diisobutyric ester of N-methyl dopamine (epinine). When ibopamine is absorbed, it is
acted upon by esterases in the plasma to release Nmethyl dopamine (epinine). Epinine resembles dopamine pharmacologically. Several studies in Europe
and the United States have shown that oral ingestion of
100 to 300 mg of ibopamine produces beneficial hemodynamic effects in patients with congestive heart failure.'5'16 Ibopamine has recently been approved for
clinical use in Italy.
New dopamine agonists. The possibility that several
Vol. 72, No. 2, August 1985
receptors may be responsible for the beneficial hemodynamic effects of dopamine, levodopa, and ibopamine is supported by the results of studies which demonstrate that dopamine agonists lacking ,B,-adrenergic
activity elicit beneficial responses in patients with severe congestive heart failure. Propylbutyl dopamine
(an agonist of DA1 and DA2 receptors) was administered intravenously to patients with severe congestive
heart failure."' Cardiac index increased while pulmonary capillary wedge pressure and systemic vascular
resistance were significantly reduced. No change in
heart rate was observed. Mean arterial pressure decreased in a dose-related manner, declining 20 mm Hg
when infused at a rate of 20 gg/kg/min. Vasodilation
caused by activation of DA1 and DA2 receptors by
propylbutyl dopamine appeared to be responsible for
the hemodynamic responses observed. Renal hemodynamics were not measured in these patients, but
studies in normal subjects and hypertensive patients
demonstrated that propylbutyl dopamine produces pronounced increments in renal blood flow.12
Hemodynamic improvement was also observed in
patients with severe congestive heart failure when the
ergot derivative, bromocriptine, was administered
orally in a dose of 2.5 mg.'8 Bromocriptine has been
shown to act as a DA2 agonist in peripheral nerves but
also may decrease sympathetic activity via a central
nervous system mechanism. Heart rate, mean arterial
pressure, left ventricular end-diastolic pressure, and
mean right atrial pressure decreased while stroke volume increased. Cardiac index did not increase, possibly because of the decrease in heart rate. A decline in
plasma norepinephrine concentrations accompanied
these hemodynamic changes.
Hemodynamic actions of the selective DA, agonist,
fenoldopam, were evaluated in a pilot study in patients
with congestive heart failure. 19 Oral administration of
fenoldopam (200 mg) resulted in a decline in pulmonary capillary wedge pressure and systemic vascular
resistance and an increase in cardiac index. Heart rate
did not change. The renal effects of fenoldopam were
not studied in these patients, but increments in renal
blood flow and sodium excretion were observed when
the drug was administered to normal subjects and hypertensive patients.'2 The natriuresis induced by DA,
agonists is unusual for vasodilating agents.
The availability of orally effective dopamine congeners has greatly expanded the potential clinical indications for these agonists. Of particular significance,
fenoldopam, propylbutyl dopamine, and bromocriptine have been found to be effective in lowering blood
pressure in hypertensive patients.'2 Another possible
247
GOLDBERG and RAJFER
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new use for dopamine agonists is in the treatment of
arrhythmias. A study in the anesthetized dog has
shown that bromocriptine is effective in the prevention
of digitalis-induced arrhythmias.20 The mechanism responsible for this antiarrhythmic effect appears to be
decreased sympathetic activity.
In summary, the results of studies with orally effective dopamine agonists have suggested new approaches to the management of patients with cardiovascular disease. The safety and efficacy of these
agents during long-term therapy remains to be established. Athough the results of preliminary investigations are encouraging, only a limited number of patients have been observed for prolonged periods.
Regardless of the results of these studies, future research will undoubtedly lead to the development of
new dopamine agonists with greater bioavailability,
different spectra of receptor activity, and fewer adverse effects. A new and exciting era of dopamine
research has begun.
References
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dopamine in man: augmentation of sodium excretion, glomerular
filtration rate, and renal plasma flow. J Clin Invest 43: 1116, 1964
2. Goldberg LI: Cardiovascular and renal actions of dopamine: potential clinical applications. Pharmacol Rev 24: 1, 1972
3. Goldberg LI, Hsieh YY, Resnekov L: Newer catecholamines for
treatment of heart failure and shock: an update on dopamine and a
first look at dobutamine. Prog Cardiovasc Dis 4: 327, 1977
4. Goldberg LI, Kohli JD: Differentiation of dopamine receptors in
the periphery. In Kaiser C, Kebabian 1W, editors: American
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101-113
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5. Goldberg Ll, Kohli JD: Peripheral pre- and post-synaptic dopamine
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CIRCULATION
Dopamine receptors: applications in clinical cardiology.
L I Goldberg and S I Rajfer
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Circulation. 1985;72:245-248
doi: 10.1161/01.CIR.72.2.245
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1985 American Heart Association, Inc. All rights reserved.
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