The newer sympathomimetic amines, dopamine and dobutamine, are now being
investigated for treatment ofcongestive heart failure .
Dopamine, the precursor in the endogenous synthesis of noradrenaline, acts directly
on ß.-adrenergic receptors of the myocardium and indirectly by releasing
noradrenaline from sympathetic nerve endings. Dopamine also acts on a-adrenergic
receptors in arteries and veins. lts effects on ß2-adrenergic receptors are minimal.
Dopamine-induced vasodilation of the renal, mesenteric, coronary, and cerebral
vascular beds is attributed to activation of dopamine vascular receptors (Goldberg,
1972). Because of the multiple actions of dopamine, variable haemodynamic
responses are observed with different concentrations of dopamine. At low infusion
rates, cardiac contractility, cardiac output, and renal blood flow increase with little
change in heart rate and either reduction or no change in total peripheral vascular
resistance (McDonald, Goldberg, McNay & Tuttle, 1964; Goldberg, 1974). The
relati ve lack of incrcase in heart rate appears to be due to an inhibition of
sympathetic nerve ac tivity, possibly by the action of dopamine on presynaptic
dopamine receptors (Langer & Dubocovich, 1979). At higher doses (usually greatcr
) peripheral resistance increases, heart rate may increase, and
renal blood flow decreases (Goldberg, Hsieh & Resnekov, 1977). Therefore, careful
adjustment ofthe dose is necessary to prevent an excessive increase in heart rate and
vascular resistance. Left ventricular filling pressure generally remains unchanged or
is increased with higher doses (Beregovich, Bianchi, Rubler, Lomnitz, Cagin &
Levitt, 1974; Leier, Heban, Hu ss, Bush & Lewis, 1978).
Dopamine increases sodium cxcrction in both normal subjects and patients with
heart failure (McDonald et al., 1964). The diurcsis appears to be secondary to the
incrcase in renal blood flow but other mechanisms ma yaiso be responsible .
184 L. I. GOLDBERG & S. I. RAJFER
The use of a vasodilator drug with dopamine can lead to additive beneficial
haemodynamic effects (Miller, Awan, Joye, Maxwell, DeMaria, Amsterdam &
Mason, 1977; Stemple, Kleiman & Harrison, 1978). This combination can be a very
effective pharmacological measure for restoring cardiac output to adequate levels in
the setting ofsevere pump failure. This is usually accomplished with a simultaneous
reduction in ventricular filling pressure.
) and increased gradually as needed. This dose should be reduced ifthe patient
has been recently treated with monoamine oxidase inhibitors (Goldberg et al., 1972).
this agent (Alexander, Sako & Mikulic, 1975). Nausea and vomiting may be observed
and are more common with high doses (Goldberg, 1972).
Two orally active forms of dopamine have been reported in human studies. The
anti-Parkinson drug, levodopa, is decarboxylated to dopamine. When administered
orally in-doses of 1.0 and 1.5 g, a significant shortening of systolic time intervals
occurs for a duration of30 to 90 min (Whitsett & Goldberg, 1972). The same doses of
levodopa have been shown to increase inulin c1earance, PAH c1earance and sodium
th is tolerance is not known since the cardiac responses to dopamine were unchanged.
It is possible that continuous therapy with levodopa results in decreased activity of
the enzyme required to convert levodopa to dopamine. More recently, a potent orally
and sodium diuresis (DeiCas, Manca, Vansini, Mansour, Bernardini & Visioli, 1980).
The effects ofchronic treatment ofpatients with congestive heart failure by SB 7505
Dobutamine is a synthetic catecholamine that acts directly on ßi-adrenergic
receptors to increase cardiac contractility and heart rate . It does not stimulate the
dopamine receptors (Robie & Goldberg, 1975). At equivalent cardiac inotropic
effects dobutamine exerts a much weaker ß2-adrenergic action than isoprenaline
and a much weaker a receptor activity than noradrenaline. With moderate
infusion rates , augmentation of myocardial contractility is the most prominent
action of dobutamine without major changes in arterial pressure or heart rate
(Sonnenblick, Frishman & LeJemtel, 1979). A decrease in left ventricular filling
pressure usually accompanies the increase in cardiac output (Leier et al., 1978;Jewitt,
Jennings & Jackson, 1978). At very high doses tachycardia and a decrease in vascular
Dobutamine requires continuous intravenous administration. Its serum half-life is
2 min . The drug is metabolized in the liver, and most of its metabolites are excreted
in the urine. The drug is infused at a rate of2.5-1O g lJg kg-1min-1
40 lJg kg-1 mirr" have been used . The most serious adverse effect is the precipitation
ofarrhythmias. Angina has also been reported (Sonnenblick el al., 1979).
An orally active derivative of dobutamine is not available, but other orally active
sympathomimetic amines with predominant ßi-adrenergic activity are under
investigation (Johnsson, Jordö, Lundborg, Rönn, Welin-Fogelberg & Wikstrand,
Other positive inotropic drugs
Po sitive inotropic agents with mechanism s of action d iffer ent from those of cardiac
glyco sides and sym pa thomimetic amines a lso ha ve promise in th e treatment of
congestive heart failure. Phosphodiesterase in hibitors increase cardi ac contractile
force and decrease peripheral vascular resistance. The co mmonly used in hibitor,
aminophylline , has limited oral utility and a narrow th erapeutic range when given
intravenously. However, new inhibitors wh ich ma y have greater application are now
under in vestigation (Je nnings, Jackson , Mon aghan & Jewitt, 1978).
The pancreat ic hormon e, glucagon, a lso ex hibits a positi ve inotropic effect by an
unusual mechanism . Unfortunately thi s drug has a relatively poor ratio betwe en its
effect ive dose and the dose producin g nausea and vomiting (Glick, Pa rmley,
We chs ler & Sonnenblick, 1969; Will iams, 1969; Siman is & Goldberg, 1971).
Amrinone, a rece ntly syn thesized bipyridine derivative, causes a do se-related
phosphodiesterase activity ar e altered by a mrinone. Na+, K+-ATPase ac tivi ty is not
inhibited (Alousi, Farah, Lesher & Opalka, 1979).
In animal studies amrinone has proven to be a potent, long-act ing po sitive
inotropic agent with a wide therap eutic index . The augmentation in contractile force
occurs without development of arrhyt hmias. Large doses are associated with a
reduction in blood pressure (Alousi et al., 1979).
In pat ients with congest ive heart failure, the haemod ynamic effects of amrinone
are characterized by an inc rease in ca rdiac output accom panied by substantial
reduction s in left ventric ula r filling pressu re and syste m ic vasc ular resistan ce. Left
ventricular ejection fraction increases, wh ile arter ial pr essure is un ch anged or
minimally reduced. Heart rate is not a ltered (Benott i, Grossman, Braunwold,
Davolds & Alousi, 1978 ; LeJ emtel, Keung, Sonnenblick, Ribner, Matsumoto, Da vis,
Schwartz, Alousi & Davolos, 1979; LeJemtel, Keung, Ribner, Davis, We xler,
Blaufox & Sonnenblick , 1980). Thus, the improvement in ventricular performance
appear s to result from increased myocardial contractil ity, possibl y associated with
direct arteria l vasodilation.
The beneficial effects of amrinone occur after oral or intravenous administration.
Aft er an intravenous dose the onse t of ac tio n was noted within 2 min and persi sted
for 60-90 min. With oral ad ministration, haemodynamic effects were first ob served
at 30-120 min and persisted for 4-7 h.
The safety of long-terrn admi nis tratio n of am rino ne remains to be estab lished.
Fo ur cases ofthrombocy topenia have now been rep orted after 4-9 wee ks of trea tme nt
(LcJe mtel et al.. 1980 ; Wynn e, Malacoff, Benotti, C urfma n, Grossm an , Holman,
Smith & Braunwald, 1980). Defin itive Iong-terrn studie s have not been co mpleted.
Arrh ythmias ha ve not been documented .
It is appa rent fro m th is review that th e ino tropic agents pr esently available po ssess
man y deficiencies. The only clinic all y useful oral ino tropic age nts a re the digital is
glycosides, despite th eir narrow th erap eutic ran ge and high inci de nce of toxicity.
Sympathomimetic amines are poten t card iot onic agents but these drugs a lso have th e
po tential to ind uce tac hycardia and arrhythmias . A large number of inot ro pic agents
of different classes have been eva lua ted but have not found clin ical a pplication for
the treatment of heart failure. A recen tly synthesize d co m pound, amrinone, has been
shown in preliminary studies to be effective both ora lly and intrave nously, but its
long-term efficac y rem ains to be established.
186 L. I. GOLDBERG & S. I. RAJFER
An orally effective inotropi c agent, with a wi de therapeutic index, is urgen tl y
This work was sup ported b y NIH grants PHS G M-222 20 a nd G M-07019.
Ake ra. T. & Brod y, T. M. (1977). The role of Na", K+-ATPase in the inotropic act ion ofdigitalis.
Alexander, C. S., Sako, Y. & Mikulic, E. (1975). Pedal gangrene associated with the use of
dopam ine. New Eng. J. Med. , 293, 591.
Allen. D. G & Blinks, J. R.(l978). Calci um transients in aegnoun-injected frog cardiac muscle.
Alousi, A. A., Farah, A. E., Lesher, G. Y. & Opalka, C. J., Jr. (1 979). Cardiotonic activity of
amrinone-WIN 40680 (5-amino-3,4'-bipyridin-6(1H)-one). Circulation Res.. 45, 666-677 .
Beller. G . A.. Smith , T. W.. Abelrnann, W. H., Haber, E. & Hood, W. B., Jr. (1 971 ). Digitalis
intox icatio n. New Eng 1. Med.. 284, 989-997.
Benotti, J. R.. Gross man, W.. Braun wald. E.. Davolds, D. D. & Alousi. A. A. (1 978).
Hemodynam ic assessment ofamrinone. Ne w Eng 1. M ed., 299, 1373-1377.
Beregovich , L Bian chi . c.. Rubler, S.. Lomn itz, E.. Cagin, N. & Levitt. B. (1974). Dose-related
hemodynam ic and renal effects of dopam ine in congestive heart failure. Am. H eart 1.. 87 ,
Braunwald. E. (1 971 ). Contro l ofmyocardial oxygen consum ption. A m . 1. Ca rdiol.. 27, 416-432.
Carl iner . N. H.. Gilbert, C. A.. Pruitt, A. W. & Go ldberg . L. I. (1974). Effects ofmaintenance
digoxin therap y on systolic time intervals and serum digoxi n conce ntrations. Circulation
Chan. V.. Tse. T. F. & Wong, V. (1 978). Transfer of digoxin across the placenta and into breast
milk. Brit. 1. Ob st. Grnee.. 85,607-609.
Effects on myocard ial oxygen consumption. 1. clin. l nvest.. 45,1 535-1542.
ora l ad min istra tion of SB 7505 in man . Arzneim ettel Forschung. Drug Research. 30,
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