Pharmacodynamic application of l -dopa in cardiogenic shock

Experimental and laboratory

Pharmacodynamic in cardiogenic

reports

application

of L-dopa

shock

Jose R. Lozano, M.D.* Eliot Corday, M.D.** Hugo A. Carrasco, M.D.* Tzu- Wang Lang, M.D.*** Samuel Meerbaum, Ph.D.**** Los Angeles, Calif.

T

he application of L-dopa to the management of extrapyramidal disorders, especially Parkinson’s syndrome, has led to the increased pharmacologic study of this interesting agent.’ L-dopa, the levorotatory isomer of dopa, is a precursor of dopamine, norepinephrine, and epinephrine, and preliminary observations indicate that L-dopa shares some of the cardiovascular effects of these metabolically related amines. It has been demonstrated that administration of L-dopa will increase the coronary flow in conscious, intact dogs.3 Various alterations in blood pressure levels have been noted during L-dopa treatment of patients with Parkinson’s disease.4*5 L-dopa has been shown to produce adrenergic stimulation in experimental animals and occasionally in clinical trials.’ Because the adrenergic effects of the metabolites, dopamine and norepinephrine, appear to be useful for the

treatment of shock states,6-10 this study was designed to determine whether L-dopa provides hemodynamic benefits in cardiogenie shock.

Methods

and procedures

Group I. Twenty mongrel dogs, unselected by sex or age, weighing from 20 to 30 kilograms, were anesthetized with intravenous sodium pentobarbital (25 mg. per kilogram of body weight). An intratracheal cannula was inserted and ventilation was carried out by means of a Harvard respirator. The heart was exposed by a transthoracic incision. A median laparotomy was performed and the left renal and superior mesenteric arteries were dissected. Pulsed field electromagnetic flow probes were placed around the ascending aorta, left anterior descending coronary, superior mesenteric, and left renal arteries. Pressure

From

the Cedars-Sinai Medical Center, Institute for Medical Research, 47.51 Fountain Ave.. Los Angeles, Calif.. and the Department of Medicine, University of California School of Medicine, Los Angeles, Calif. This study was supported in part by National Institute of Health contract PH 43-68-1333 from the National Heart and Lung Institute. United States Public Health Service grant RR 05468, by a grant from the John A. Hartford Foundation. Inc.. and by research grants from Mr. and Mrs. Edward Mitchell, Mrs. Anna Bing Arnold. Mr. Harry Kunin, and the Jules Stein Foundation. Received for publication May 13, 1971. Reprint requests to: Dr. Eliot Corday. 4751 Fountain Ave.. Los Angeles. Calif. 90029. *Research Fellow, Cedars-Sinai Medical Center, Los Angeles, Calif. **Clinical Professor of Medicine, UCLA School of Medicine, Los Angeles. Calif. ***Senior Research Scientist, Cedars-Sinai Medical Center, Los Angeles, Calif. ***NIH Special Fellowship 5703 GM 39602.

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March, 1972

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measurements were carried out in the ascending aorta and left ventricle with Teflon catheters connected to Statham P23Db transducers, and in the right atrium with a catheter connected to a P23BB transducer. Left ventricular pressure (dp/dt) was determined by means of a resistance-capacitance (R/C) differentiator. Magnified left ventricular end-diastolic pressure was also recorded. These measurements were recorded on a multi-channel photographic recorder.* Cardiogenic shock was produced by serial ligations of branches of the left circumflex coronary artery until a consistent drop in systemic pressure below 80 mm. Hg was observed. This was accompanied by a considerable decrease in coronary and peripheral flows. Thirty to 60 minutes after shock was produced, a constant intravenous infusion of 300 pg per kilogram per minute L-dopa, dissolved in 250 to 300 C.C. of 5 per cent dextrose in water, was administered over a period of one hour. Hemodynamic data were collected during the postsurgical control period, the shock state, at 15 minute intervals during one hour of and 15 minutes after L-dopa infusion, L-dopa treatment was discontinued. Statistical significance was assessed by paired data analysis. Variability was expressed in terms of the standard error of the mean @EM). Group II. Because of the poor solubility of L-dopa, it was necessary to use 250 to 300 C.C. of 5 per cent dextrose in water to completely dissolve the 300 pg per kilogram per minute L-dopa dose needed for the one hour observation test period. Experiments were designed to study the effect of this amount of fluid loading upon regional hemodynamics. Following serial coronary artery ligation, an equivalent amount of fluid loading was given over a period of one hour to nine dogs in cardiogenic shock. Similar hemodynamic measurements to those obtained in Group I were made. Group III. The responses to alpha and beta blockade were tested in eight dogs after the administration of L-dopa. Diben*Sixteen corder

channel modification DR-8, White Plains,

of Electronics N. Y.

for

Medicine

Re-

zyline (2 mg. per kilogram of body weight continuous intravenous infusion) was given to five dogs and propranolol (0.06 mg. per kilogram of body weight single bolus intravenous infusion) was administered to three animals after a significant L-dopa effect was present. Recordings were obtained at 1, 2, 3, 5, 10, 15, and 30 minutes after the administration of these blocking agents. Results

Hemodynamic measurements prior to, during, and subsequent to L-dopa infusion are summarized in Table I. Per cent variation in measured parameters is illustrated in Figs. 1 to 3. Group I. L-dopa administration did not cause any hemodynamic changes for the first three to five minutes after infusion. However, a significant cardiovascular response was always observed after 15 minutes of infusion, and this increased progressively until it reached a maximum 45 to 60 minutes after the onset of L-dopa administration (Figs. 1, 2, and 4). HEART RATE. Heart rate and rhythm were not significantly changed during the period of infusion or after discontinuation of the drug. REGIONAL FLOWS. Aortic flow dropped during cardiogenic shock to 44 ~5 per cent of control values. After 15 minutes of L-dopa infusion, the aortic flow increased significantly to 71 f 8 per cent of control values and remained at about that level throughout the period of treatment (72 %:8 per cent). After the drug was stopped, the flow dropped to 51 &7 per cent of the control level. Left anterior descending (LAD) coronary flow was markedly reduced in the shock state to 55 &6 per cent of the control values. During the period of infusion, coronary flow rose progressively (Fig. 1) above the normotensive control levels (109 ~!~14 per cent after 15 minutes, 124 f 18 per cent after 30 minutes, 133 f 19 per cent after 30 minutes, and 133 &16 per cent after 60 minutes). Fifteen minutes after the treatment was discontinued, LAD coronary flow was 14 per cent above normotensive control values and 60 per cent above the shock level. Mesenteric flow decreased to 58 ~6 per

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L-dopa in cardiogenic shock

Table I. Mean hemodynamic

3.53

changes with L-dopa in dogs with cardiogenic shock .

.

Control Variables

Heart rate (beats/min.) Aortic flow (L./min.) LAD coronary flow (ml./min.) Coronary vascular resistancet Mesenteric flow (ml./min.) Mesenteric vascular resistance1 Renal flow (ml./min.) Renal vascular resistancet Aortic pressure (mm. Hg) Systolic Diastolic Left ventricular pressure (mm. Hd Systolic End-diastolic LV dp/dt (mm. Hg/sec.) Total peripheral vascular resistances Tension-time index/min. (mm. Hg/sec.)

*Values = t2p
(n = 20)

139 * 1.4 f 29.3 *

7* 0.1 3.7

2.44 * 1.55 * 0.5 *

0.36 19.5 0.05

10.5 * 14 0.84 * 0.17

1

c2%

1 *f;;i;;yffg

135 * 5 0.64 f 0.06 15 * 1.6 3.7 * 90 * 0.5 *

0.8 8.8 0.1

68 + 6.8 3.85 + 2.05

125 * 1.03 * 31.6 *

g;,i.

4 0.11 4.2t

2.4 =I= 0.3 143 * 16 0.5 * 0.06 7.2 0.18

81.8 1.46

80 f 65 *

7.2t 4.9t

68 f 50 *

2.4 3.4

102 * 2.1 3 * 0.6 1719 + 126 4.3

69~ 7* 883 * 11

2.1 1.4 43

90 * 4t 6* 1.3 1335 * 125t 6.8

7706 *

403

9742 *

=I= 810

1.4 * 147.8 * 0.38 f

80 * 1.05 *

100 * 2.4 70=!= 2.5

13101

132 * 9 1.04 f: 0.1t 39.1 * 4.81

567t

0.19t 21-t 0.04

123 * 0.61 * 17.9 * 5.23

9 0.1 3 8

+ 1.2 -

* 7.6 + 0.5

61 * 1.33 *

16.7 0.3

81.8 * 56 *

7.6t 4.4

61 * 46 *

16.7t 2.7

93 * 4* 1736 * 4.8t

5.q 0.7 206t

88k 20 f 907 * 13.3

934t

9260

10812

*

3.17 6t 74

+ 848

Mean f SEM. compared to shock. * sec. l cm.-5 . sec. . cm.-5

cent of control values in the shock state, increased significantly after 15 minutes of treatment (to 97 &IO per cent), exceeded the normotensive control level at 30 minutes (108 &I2 per cent), and then decreased slightly to 95 &I4 per cent of normal at 60 minutes (Fig. 1). Upon discontinuation of the drug, mesenteric flow dropped to 6.5 &I6 per cent of control levels. Renal flow was 65 ~7 per cent of control values during cardiogenic shock and tended to increase during L-dopa infusion (Fig. I), but the maximum increase (78 ~7 per cent) was not statistically significant in comparison with the shock level. PRESSURES. Left ventricular systolic pressure was reduced to 68 lt2 per cent of control values during the shock state, and after L-dopa administration increased progressively to reach a level of 91 f 5 per cent of normotensive control values after 60

minutes of L-dopa infusion (Fig. 2). It decreased again to hypotensive values after discontinuation of the drug. Ascending aorta systolic pressure exhibited a similar trend (Fig. 2), increasing progressively to 91 &S per cent of control values at 60 minutes and decreasing to 77 h.5 per cent 15 minutes after discontinuation of the drug. Aortic diastolic pressure increased significantly from a level of 72 ~5 per cent of control values during shock state to 81 %6 per cent of control values after 60 minutes and decreased to 66 &4 per cent after L-dopa infusion was stopped (Fig. 2). Left ventricular end-diastolic pressure decreased in a progressive fashion, from 227 ~48 per cent of control values in the shock state to 138 &I27 per cent 60 minutes after the onset of L-dopa infusion (Fig. 2). However, this change proved to be statistically nonsignificant.

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Lozano et al.

L-DOPA SHOCK

LAD CORONARY FLOW

t < 0.01 + > 0.05

15’

3OOttg/kg/min 30’

45’

60’

GF.

80

SIGNIFICANT NON SIGNIFICANT

IMEAN~SEM

Fig. 1. Effects of L-dopa on heart rate and regional flows. The gray line represents 100 per cent of pre-shock level values and the data are presented as mean per cent values relative to control, * standard errors of mean @EM). Paired t test was used for comparison of the results of L-dopa treatment to the shock state. The first column corresponds to shock state and the following columns to 15, 30, 45, and 60 minute administration of L-dopa, respectively. The last column gives measurements made 15 minutes after the drug infusion was stopped.

TOTAL PERIPHERAL RESISTANCE. Total peripheral resistance decreased significantly from 193 h2.5 per cent during the shock state to 111 f 16 per cent after 60 minutes of infusion (Fig. 2). TENSION-TIME INDEX (TTI). TTI increased significantly from a shock value of 64 ~4 per cent of normotensive control values to 89 &lO per cent after 60 minutes of treatment and then decreased slightly to 86 f 14

per cent after discontinuation of L-dopa (Fig. 2). LEFT VENTRICULAR dp/dt,,,. Left ventricular dp/dt,,, was reduced to 51 f 3 per cent of control values during shock and increased progressively during L-dopa infusion reaching a level of 101 ~12 per cent after 60 minutes (Fig. 2). Upon discontinuation of the drug, left ventricular dp/dt,,, decreased to shock levels (51 f 20 per

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L-dopa in cardiogenic

L-DOPA SHOCK

L.V. dp/dt

15’

3OOC(g/kg/mln 30’

45’

shock

355

, 60’

CFF.

max

* < 0.01 + > 0.06

1 MEAN

SIGNIFICANT NON SIGNIFICANT

Fig. 2. Hemodynamic effects of L-dopa. to the period after the onset of L-dopa discontinuation of the drug.

The first infusion.

fSEM

column corresponds The last column

cent, with considerable variability). Group II. Compared with Group I dogs which were treated with L-dopa in 300 C.C. of glucose in water, the nine control dogs in cardiogenic shock treated with this amount of 5 per cent dextrose in water (Fig. 3) provided remarkably different results. After 60 minutes of infusion with dextrose in water, LAD coronary flow increased from 55 ~6 per cent of control values during shock to 63 &14 per cent of

to shock state and the following columns shows the measurements 15 minutes after

normotensive control values, in contrast with 133 &16 per cent (2 p < 0.005) in the group treated with L-dopa infusion. Left ventricular dp/dt max increased to 53 f 4 per cent with fluid loading alone, whereas the group with L-dopa increased to 101 f 12 per cent (2 p < 0.005). After 60 minutes of infusion with dextrose in water, left ventricular end-diastolic pressure showed a significant increase from 227 ~~48 per cent of control values during shock to 684 ~207 per cent (2 p < 0.02). A totally divergent

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Losano et al.

CORONARY (LAD) ‘1.

FLOW.

RENAL

FLOW.

was infused for ten minutes. A marked decrease in systemic pressure (to 80 mm. Hg) was usually observed but there was no change in the LAD coronary flow (Fig. 6). These results were reproducible in each experiment. Discussion

low

‘E

LVEDP

1

Fig. 3. Comparison of the treatment with L-dopa and equivalent volume loading with 5 per cent dextrose in cardiogenic shock. All values represent per cent changes from pre-shock control values (grey line) * standard errors of the mean during shock, after 15 minutes, and after 60 minutes of infusion with L-dopa. The dogs treated with L-dopa are represented by the closed circles and the solid line. The open circles and the interrupted line indicate fluid loading. Note that L-dopa increased the coronary flow and left ventricular dp/dt,,,, but decreased left ventricular end-diastolic pressure significantly.

trend was observed in the group receiving L-dopa, in which the left ventricular enddiastolic pressure decreased to 138 ~27 per cent of control values after treatment. Renal flow and left ventricular systolic pressure were similar in both groups (2 p > 0.05). Group III. After a steady response to L-dopa was obtained, propranolol was administered intravenously to five dogs. This resulted in a marked decrease in heart rate, LAD coronary flow, and in left ventricular Only a slight change in the dp/dt,,,,. systemic pressure was observed between 5 to 15 minutes after propranolol was administered intraienously (Fig. 5). In another three dogs, after a stabilized effect with L-dopa was noted, dibenzyline

Effects of L-dopa on the cardiovascular system have been reported in both humans and animals.2-4rn-17 Occasional symptoms of periodic sympathetic overactivity have been reported in patients taking L-dopa orally as part of the treatment of Parkinsonism.4s5 Finlay and associates*5 reported a reduction in the pre-ejection period in patients with or without cardiac failure treated with I,-dopa. The most common circulatory side effect observed in patients treated with L-dopa is the occurrence of postural hypotension.4sS It is believed that L-dopa impairs carotid and aortic baroreceptor function,” catecholamine action,‘*rn and causes abnormal of the renin-angiotensin sysresponses tem.18a1g Watanabe, Chase, and Cardon14 provided evidence that a central effect caused by the conversion of L-dopa to dopamine in the brain was responsible for blood pressure modification in patients taking L-dopa. The cardiovascular responses to L-dopa might be elicited through its metabolic transformation to other vasoactive amineszo as well as indirectly through a nervous system regulatory mechanism acting on the cardiovascular control centers. Evidence has been reported’ that L-dopa may rapidly pass through the blood-brain barrier, and thus act directly on central nervous system processes. A survey of applicable literature revealed no data on the effects of L-dopa in cardiogenie shock; we therefore carried out experiments in anesthetized dogs in the shock state. The predominant effects of L-dopa appeared to be a significant increase in coronary flow and left ventricular dp/dt,,,, as well as a reduction in total peripheral resistance. These results were found to be independent of volume loading as such (Fig. 3). No significant changes were observed in heart rate and rhythm during L-dopa infusion with the dosage used. In contrast, Bloor, Leon, and White3 found a

L-dopa in cnrdiogenic

300

CAf?6&l~~~N’C CONTROL

30’

shock

357

L- DOPAug/kg/min 60’

ECG AORTIC

FLOW

CORONyA;

FLOW

LT

FLOW

RENAL L.\I. dp/dt

mox

AORTIC

PRESSURE

L. V

PRESSURE

Fig. 4. Treatment of cardiogenic shock with L-dopa in an and renal flows, left ventricular dp/dt mSy, aortic and left normotensive control period, during cardiogenic shock, L-dopa improved aortic and coronary flows, dp/dt max, did not improve.

62 per cent increase in heart rate in intact, conscious dogs. Goldberg and WhitsettZ reported L-dopa caused peripheral vasoconstriction, but the dosage used in their study was higher than that used in ours. During the L-dopa administration, aortic and mesenteric flows increased, but renal flow did not change significantly. The reasons why L-dopa did not enhance the renal circulation during cardiogenic shock is open to speculation. A marked vasoconstriction of the renal circulation is usually present in cardiogenic shock and it is evident from our experiments that it is not overcome by L-dopa. Dopamine, the main metabolic product of L-dopa, generally dilates the renal and mesenteric vascular beds. However, in large doses, dopamine can produce vasoconstriction in the renal and mesenteric circulation with vasodilation in other regional vascular beds.‘O The large amounts of norepinephrine freed from its stores by L-dopa administration could also cause vasoconstriction of the renal circulation.12~r7 Eventually, prolonged renal ischemia in severe cardiogenic shock impairs renal function, and this influences the response of the kidney to L-dopa therapy. In order to determine whether L-dopa or its metabolites produce these alterations

experimental dog preparation. ECG, aortic, coronary ventricular pressure recorded simultaneously during a and 30 to 60 minutes after administration of L-dopa. aortic and left ventricular pressures, but renal flow

in hemodynamics through stimulation of the alpha- or beta-adrenergic receptors, either alpha or beta blockade was instituted while L-dopa was infused. Alpha blockade during L-dopa infusion caused the blood pressure to fall because it lowered total peripheral vascular resistance. At the same time, coronary flow remained the same, probably due to the unopposed stimulation of the beta-receptors. Beta blockade resulted in a reduction of the coronary flow and the dp/dt previously increased by L-dopa (Fig. 5). This suggests that L-dopa or one of its metabolites stimulates the betareceptors which dilate the peripheral coronary circulation and also enhances contractility.2 L-dopa by itself caused a slight increase in systolic pressure which was associated with a simultaneous decrease in total peripheral vascular resistance. This suggests that beta stimulation increased inotropism, and this restored blood pressure. We conclude that in the dosage used, L-dopa or its metabolites stimulate both alpha- and beta-receptors, but most of the hemodynamic alterations were due to its beta action. L-dopa administration improved contractility and coronary flow in cardiogenic shock and this improvement continued

358

Am. Heart I. March, 1972

Lozano et al.

L-DOPA

L-DOPA+ PROPRANOLOL

L-DOPA

L-DOPA+ DIBENZYLINE

ECG AORTIC

FLOW

CORONAR&

FLOW

LT. RENAL

FLOW 2;

L.V. dp/dt

CORONM;

max t ISA

AORTIC

PRESSURE

L.V.

PRESSURE

Fig. 5. After experimental creases heart tricular dp/dt,,, pressure.

AORTIC

2’

FLOW

LT. RENAL FLOW L.V. dpldt max AORTIC

PRESSURE

C.V. PRESSURE

a maximum response to L-dopa in cardiogenic shock, propranolol derate, coronary flow, and left venwithout significantly altering blood

while it was administered. Upon discontinuation of the drug, hemodynamic measurements returned to near shock levels. Thus, although L-dapa provided temporary improvement in the regional circulations in experimental animals, its application to the treatment of shock in humans must still be ascertained. Summary L-dopa was administered to 20 dogs in cardiogenic shock. Beneficial effects were noted three to five minutes after infusion began, but more significant effects were observed within 15 minutes, reaching a maximum 45 to 60 minutes after infusion. The principal changes observed were: (1) a significant increase in coronary flow, (2) a significant rise in left ventricular dp/dhnax, and (3) a decrease in total peripheral vascular resistance. Aortic and mesenteric flows increased significantly. Renal flow did not improve throughout the Ldopa infusion. L-dopa benefits were probably due to a stimulation of the betareceptors. We are grateful to Mr. Myles Prevost, Mr. Willis Pea, Miss Elaine Calmenson, and Mrs. Jeanne Bloom for their technical assistance. REFERENCES 1. Hornykiewicz, and pathological

FLOW

0.

D.: Physiologic, biochemical backgrounds of Levodopa and

Fig. 6. Effects of dibenzyline (2 mg. per kilogram) superimposed on L-dopa, maximum action. Coronary flow remains almost unchanged in spite of the decrease in systolic pressure, showing unopposed beta stimulation. possibilities for the future, Neurology 20:1, 1970. 2. Goldberg, L. I., and Whitsett, T. L.: Cardiovascular effects of Levodopa, Clin. Pharmacol. Ther. 12(2):376, 1971. 3. Bloor, S. M., Leon, A. S., and White, F. C.: Effects of Levodopa on systemic and coronary hemodynamics of intact, conscious dogs, Am. J. Cardiol. 26:626, 1970. 4. Keenan, R. E.: The Eaton collaborative study of Levodopa therapy in Parkinsonism: A summary, Neurology 20:46, 1970. 5. McDowell, F. H., and Lee, J. E.: Levodopa, Parkinson’s disease, and hypotension, Ann. Intern. Med. 72(5):751, 1970. 6. Corday, E., Vyden, J. K., Lang, T. W., Boszormenyi, E., Carvalho, M., Gold, H., Goldman, A., and Rosselot, E.: Reevaluation of the treatment of shock secondary to myocardial infarction, Chest 56:200, 1969. M., Vyden, J. K., Bernstein, H., 7. Carvalho, Gold, H., and Corday, E.: Hemodynamic effects of 3-hydroxytyramine (dopamine) in experimentally induced shock, Am. J. Cardiol. 23:217, 1969. D. M., Mark, A. L., Schmid, P. G., 8. Schuelke, and Eckstein, J. W.: Coronary vasodilation produced by dopamine after adrenergic blockade, J. Lab. Clin. Med. 74(6):1008, 1969. 9. Talley, R. C., Goldberg, L. I., Johnson, C. E., and McNay, J. L.: A hemodynamic comparison of dopamine and isoproterenol in patients in shock, Circulation 39~361, 1969. 10. Goldberg, L. I., Talley, R. C., and McNay, J. L.: The potential role of dopamine in the treatment of shock, Progr. Cardiovasc. Dis. 12(1)&l, 1969. 11. Whitsett, T. L., Halushka, P. V., and Goldberg, L. I.: Attenuation of postganglionic sympathetic nerve activity by L-dopa, Circ. Res. 27:561, 1970.

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12. Liu, P. L., Krenis, L. J., and Ngai, S. H.: The effect of Levodopa on the norepinephrine stores in rat heart, Anesthesiology 34(1):4, 1971. 13. Duvoisin, R. C.: Hypotension caused by L-dopa. Br. Med. J. 3:47, 1970. 14. Watanabe, A. M., Chase, T. N., and Cardon, P. V.: Effect of L-dopa alone and in combination with an extracerebral decarboxylase inhibitor on blood pressure and some cardiovascular reflexes. Clin. Pharmacol. Ther. 11(5):740, 1970. . 15. Finlay, G. D., Whitsett, T. L., Cucinell, E. A., and Goldberg, L. I.: Augmentation of sodium and potassium excretion, glomerular filtration rate and renal plasma flow by Levodopa, N. Engl. J. Med. 284(16):865, 1971.

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16. Carrasco, H. A., Lozano, J. R., Lang, T. W., Meerbaum, S., and Corday, E.: L-dopa: Its effects on the cardiovascular system, Geriatrics. In press. 17. Leon, A. S., Solomon, H. M., Ross, I., Golden, R. M.. and Abrams. W. B.: Cardiovascular activity of L-dopa. Ciin. Res. 18(2):340, 1970. 18. Barbeau, A., Gillo-Joffroy, L., Boucher, R., Nowaczynski, W., and Genest, J.: Reninaldosterone system in Parkinson’s disease, Science, 165:291, 1969. 19. Barbeau, A.: Dopamine and blood pressure regulation, Clin. Res. 17(4):634, 1969. 20. Horst, W. D., Jester, J., and Sheppard, H.: The fate of Levodopa@C in isolated perfused rat hearts, Fed. Proc. 89(2):414, 1970.