Pharmacodynamic effects of alpha-methyl dopa in hypertensive subjects

Pharmaeadynamic effects of alpha-methyl dopa in hypertensive Gaddo Ones& M.D. Albert N. Brest, M.D.* Paul Novack, M.D. Hratch Kasparian, M.D. John H. Moyer, M.D. Philadelphia, Pa.

mhe seauence of reactions leading to of norepinephrine 1 the b:losynthesis proceeds, at least in part, from the conversion of dihydroxyphenylalanine (dopa) to dopamine to norepinephrine.1 In 1938, Holtz2s3 demonstrated in vitro and subsequently in vivo that the enzyme, dopa decarboxylase, catalyzes the decarboxylation of dopa to dopamine. It is now evident that this same enzyme is responsible for the decarboxylation of other aromatic amino acids (including .5hydroxytryptophan) and is active in the formation of other catecholamines (including S-hydroxytryptamine). It has been demonstrated that various compounds which affect the biosynthesis and metabolism of catecholamines can produce an antihypertensive response. Of the numerous compounds known to inhibit aromatic amino acid decarboxylation, alpha-methyl dopa (alpha-methyl-3, 4-dihydroxy-d, I-phenylalanine) has received the most extensive pharmacologic tria1,4-6 and has been found to possess definite antihypertensive abilities. It is the purpose of the present paper to report the effect

of alpha-methyl dopa on cardiac output and renal hemodynamics in human subjects with essential hypertension. Method

and ma#erialr

In order to evaluate the hemodynamic effects of alpha-methyl dopa,? the drug was administered intravenously to 11 hospitalized hypertensive patients. All antihypertensive medications had been discontinued for 4 or more weeks prior to the hemodynamic studies, and all patients were maintained on a regular (5 Gm. of salt) diet. The hemodynamic studies were performed with the subjects in the fasting state, except for hydration with 500 ml. of tap water given 1 hour prior to the procedure. Cardiac outputs were determined by the indicator-dilution technique, using indocyanine green and a Gilford densitometer. Intra-arterial blood pressures were recorded from the brachial artery with a Statham strain-gauge transducer. Pulse pressures and dye curves were recorded on a photographic oscillograph. Renal blood flows were determined by para-

From the Hypertension-Renal Unit, Hahnemann Medical College and Hospital, Philadelphia. Pa. This study was supported in part by grants from the Hahnemann Cardiovascular Clinical Research H6368) and the Southeastern Pennsylvania Heart Association. Received for publication March 25, 1963. *Address: Hahnemann Medical College and Hospital, 230 North Broad St., Philadelphia 2. Pa. tKindly supplied as Aldomet by Merck, Sharp & Dohme. West Point, Pa.

32

Center

(P. H. S..

r’olume A’nmber

67 1

E.ffects of alpha-methyl

aminohippurate clearance, and glomerular filtration rates were measured by inulin clearance. The reported results in each case represent the average of three determinations, all values corrected to 1.73 square meters of body surface area. Cardiac and renal hemodynamic studies were performed in 8 subjects who had rested for 45 minutes in the supine position on a standard tilt table. In these cases, cardiac and renal studies were synchronized with the cardiac outputs studies which were performed during the middle of each clearance period. In 2 additional patients, renal function alone was investigated ; and in 1 other subject, cardiac function alone was assessed. After three determinations, each subject was passively tilted 40 degrees upright, and the cardiac and renal studies were repeated in this position. After the control determinations, alphamethyl dopa was administered in a single intravenous dose (either 2.0 or 2.5 Gm). In each instance the maximum hypotensive response occurred from 10 to 20 hours after administration of the drug; and the cardiac and renal hemodynamic studies were repeated at this time, again with the subjects both in the supine and tilted positions. Results Supine response. The hemodynamic findings in the supine position are recorded in Table I. A significant reduction in blood pressure was observed in each subject after administration of the drug (p < O.OOl), but there were no consistent changes in pulse rate. At the time of the maximum antihypertensive response the cardiac output was reduced in 7 of the 9 subjects (Patients 1, 2, 3, 5, 6, 7, 8); in the other 2 (Patients 4, 9), an increase in cardiac output was observed. The average reduction in cardiac output was 6 per cent (p > 0.1). The calculated total peripheral resistance decreased in all cases (p < 0.01). During the hypotensive response the renal blood flow increased in 4 subjects (Patients 1, 2, 4, II), and decreased in the other 6 (Patients 3, 5, 6, 7, 9, 10). The glomerular filtration rate increased or remained unchanged in 3 subjects (Patients 1,2, 6). In the other 7 subjects the glomerular filtration rate diminished (Patients 3,

dopa ,in hypertensive patients

33

4, 5, 7, 9, 10, 11). The average reduction in renal blood flow was 8 per cent (p > O.l), and the average decrease in glomerular filtration rate was 13 per cent (p < 0.05). In each instance the arterial blood pressure decreased proportionately more than the renal blood flow, so that the calculated renal vascular resistance was consistently and significantly reduced (p < 0.05). Erect response. The hemodynamic findings in the erect position, before and after the intravenous administration of alphamethyl dopa, are recorded in Table II. During the hypotensive response, the cardiac output was reduced in 5 of the 9 subjects (Patients 1, 2, 5, 7, 8). In the other 4 (Patients 3, 4, 6, 9) an increase in cardiac output was observed. The calculated total peripheral resistance decreased in all subjects except one (Patient I); in the latter case the increased total peripheral resistance was accompanied by a substantial drop in cardiac output. The over-all average decrease in cardiac output was 8 per cent (p > O.l), and the average reduction in total peripheral resistance was 32 per cent (0.05

7’uble 1. ilemodynumic

rcs~onsc~ ufter ~intravenozts alfiha-methyl

dope (supine position)

Patient C 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

G.D. J.R. D.G. W.S. C.R. C.S. R.\I’. IS. H.M.L. J.M.W. R.B.

Mean % of Control p Value C: Control. blood

123 155 138 153 156 168 144 146 167 148 123

109 123 104 128 116 139 102 101 134 101 88

5.40 3.79 4.93 5.38 6.98 4.80 5.24 4.28 4.90

4.94 3.25 4.50 5.60 5.78 4.07 5.05 3.84 6.15 -

1,820 3,271 2,238 2,274 1,786 2,797 2,197 2,727 2,726

1,764 3,077 1,847 1,828 1,604 2,730 1,615 2,101 1,741

147

113 76
5.08

4.80 94 >O.l

2,426

2,034 84
R: Response to alpha-methyl dopa. MAP: Mean arterial flow (c.c./min.). GFR: Glomerular filtration rate (inulin

Table II. Hemodynamic

blood pressure (mm. Hg). CO: Cardiac clearance) (c.c./min.). FF: Filtration

response after intravenous MAP

alpha-methyl

output fraction.

(liters/min.). TPR: RVR: Renal vas-

dopa (erect position) TPR

co -

Patient c 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

G.D. J.R. D.G. W.S. C.R. C.S. R.W. IS. H.M.L. J.M.W. R.B.

Mean y. of Control p Value Abbreviations

as in Table

I

R

c

R

C

3.55 2.44 3.70 3.88 4.58 5.42 4.05 3.49 5.40

1,606 3,479 2,795 3,509 3,904 3,507 2,175 2,455 3,413

106 140 145 147 176 1.58 147 136 184 153 118

100 103 81 99 84 100 91 88 146 92 70

5.30 3.22 3.41 3.41 6.44 3.86 5.40 4.43 4.30

146

95 65
4.41

I

R 2.253 3,379 1,751 2,040 f ,465 1,475 1,795 2,017 2,160 -

4.06 92 >O.l

2,982

2,037 68 O.OS
I.

patients were in the upright position (D ~- < 0.01)., and renal vascular resistance showed an over-all tendency to increase (p < 0.05). The hemodynamic effects of passive head-up tilting during the hypotensive

response to alpha-methyl dopa are recorded in Table IV. Upright tilting caused a fall in mean arterial blood pres&re in all subjects except one (p < O.Ol), and the cardiac output tended to diminish (p < 0.05). The calculated total peripheral resistance

Volume Number

67 1

Efects

RPF

Total cular

C

1

R

1

74 73 62 58 131 16 78 -

78 78 52 56 97 16 57

9.05 12.41 11.65 17.22 7.99 63.43 9.68 -

76 62 60

56 52 58

0.16 0.19 0.15 0.18 0.16 0.18 0.13 0.16 0.17 0.15

11.06 17.14 12.24 21.20 9.78 71.11 13.21

614 474 668

0.16 0.19 0.13 0.19 0.19 0.17 0.16 0.19 0.16 0.17

17.56 18.85 13.47

16.09 15.28 9.29

647 92 >O.l

69

60 87
0.17

0.16 94 >o. 1

20.56

17.20 84 <0.05

489 421 349 309 612 88 424 -

813 674 833 537 1,189 177 873 -

843 725 623 551 1,055 162 757 --

406 386 3.50

350 313 381

712 584 614 700

peripheral resistance

resistance (dynes/sec./cm.-5). (dynes/sec./cm.-5 x 103).

RPF

RPF:

Renal

/

plasma

RBF

I

RVR C

472 391 467 301 690 96 488 -

C

35

patients

R

R

373 92 >o. 1

dopa in hypertensive

GFR

RBF

C

404

of alpha-methyl

flow

”

(para-aminohippurate

GFR

R

-,-r-R-

clearance)

FF

(c.c./min.).

Renal

RVR

I

401 364 340 237 510 73 466 -

513 528 304 280 421 62 391 -

691 627 607 423 879 135 833 -

887 910 542 500 725 114 685 -

74 62 57 43 109 14 73 -

77 83 47 43 64 12 51 -

0.18 0.17 0.17 0.18 0.21 0.19 0.15 -

0.15 0.15 0.15 0.15 0.15 0.19 0.13 -

11.07 16.52 17.72 25.80 15.04 87.34 13.10 -

4.58 341 298

360 372 311

803 516 522

631 563 545

75 59 53

72 51 49

0.16 0.17 0.18

0.20 0.14 0.16

17.39 22.07 15.78

349

354 102 >O.l

603

610 102 >O.l

61

5.5 90 >o. 1

0.17

0.16 94 >O.l

24.17

increased with tilting in 5 subjects, and decreased in the other 4. The renal blood flow increased in 4 subjects, including 3 in whom tilting resulted in a fall in orthostatic blood pressure. In the other 6 subjects the reduction in renal blood flow

RBF:

8.07 8.14 10.43 14.18 8.12 62.89 9.41 17.18 11.60 8.64 15.86 66 <0.05

accompanied the reduction in orthostatic blood pressure. Changes in glomerular filtration tended to be minor and inconsistent. In contrast with the control studies, however, the reduction in blood pressure produced by tilting was accompanied by

36

Onesti, Brert, Nozwk,

Table III.

kYaspariun,

and Aloy~r

e$ect qf head-up tilting (control studies)

Hemodynamic MAP

CO

7‘I’R

Patient s 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

~

E

s

G.D. J.R. D.G. W.S. CR. C.S. R.W. IS. H.M.L. J.M.W. R.B.

123 155 138 1.53 156 168 144 146 164 148 123

106 140 145 147 176 158 147 136 184 153 116

5.40 3.79 4.93 5.38 6.98 4.80 5.24 4.28 4.90 -

Mean TOof Control

147

146 100

5.08

E: Erect.

Other

abbreviations

as in Table

s

5.30 3.22 3.41 3.41 6.44 3.86 5.40 4.43 4.30

E

1,820 3,271 2,238 2,274 1,786 2,797 2,197 2,727 2.726

1,606 3,473 2,795 3,503 3,907 3,507 2,175 2,455 3 (4 13

2,426

2,981 123 0.05
4.42 87
p Value S: Supine.

E

I

I.

Table IV. Hemodynamic e$ect of head-up tilting, during the hypotensive response to alphamethyl dopa MAP

TPR

CO -~

-~__

--

-

-~-~~

Patient

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

G.D. J.R. D.G. W.S. CR. C.S. R.W. IS. H.M.L. J.M.W. R.B.

Mean $& of Control

E: Erect.

S

--

!

E

s

E

s

109 123 104 128 116 139 102 101 134 101 88

100 103 81 99 84 100 91 88 146 92 70

4.94 3 25 4.50 5.60 5.78 4.07 5.05 3.84 6.15

3.55 2.44 3.70 3.88 4.58 5.42 4.05 3.49 5.40

1,766 3,077 1,847 1,828 1,604 2,730 1,615 2,101 1,741

2,253 3,379 1,751 2,040 1,466 1,475 1.795 2,017 2,160

113

95 84
4.80

4.06 8.5
2,034

2,037 100.1

p Value S: Supine.

E

~

Other

abbreviations

as in Table

I

I

__-

I.

a significant decrease in renal vascular resistance (p < 0.05). Discussion The hemodynamic studies performed with intravenous alpha-methyl dopa suggest that the drug lowers blood pressure primarily by peripheral arteriolar relaxa-

tion. Although there was an accompanying decrease in cardiac output in the majority of cases, the latter response was not consistent, In those instances in which the cardiac output did diminish, however, the anticipated reflex arteriolar constriction (which under normal circumstances minimizes a fall in blood pressure when cardiac

Volume Number

67

E#ects of alpha-methyl

1

RPF

dopa in hypertensizle patients

FF

GFR

RBF

37

RVR __-

s

I

472

E 401 364 340 237 510 73 466

391 467 301 690 96 488 406 386 3.50

s 813 674 833 537 1,129 177 873

E

s

E

691 627 607 423 879 135 833

74 73 62 58 131

74 62 57 43 109 14 73 -

0.16 0.19 0.13 0.19 0.19 0.17 0.16

0.18 0.17 0.17 0.18 0.21 0.19 0.16 -

11.06 17.14 12.24 21.20 9.78 71.11 13.21 -

11.07 16.52 17.72 25.80 15.04 87.34 13.10

:i -

404

SIE

S

E

458 341 298

712 584 614

803 516 522

76 62 60

75 59 53

0.19 0.16 0.17

0.16 0.17 0.18

17.56 18.85 13.47

17.39 22.07 15.78

348 86
694

603 86
69

61 88
0.17

0.17 100

20.56

24.17 115
RPF

RBF

GFR

-__

~_____

~~E~~~E~~~E~~F~E~~R~E 489 421 349 309 612 88 424 -

513 528 304 280 421 62 391 -

843 725 623 551 1,055 162 757

887 910 542 500 72.5 114 685 -

78 78 52 56 97

77 83 47 43 64 12 51 -

0.16 0.19 0.1.5 0.18 0.16 0.18 0.13 -

0.15 0.15 0.15 0.15 0.15 0.19 0.13

9.05 12.41 11.65 17.22 7.99 63.43 9.68 -

350 313 381

360 372 311

614 474 668

631 563 545

56 52 58

72 51 49

0.16 0.17 0.15

0.20 0.14 0.16

16.09 15.28 9.29

373

3.54 95 >O.l

647

610 9.5 >O.l

60

5.5 92 >O.l

0.16

0.16 100

17.20

:;

output is decreased) appears to have been prevented, or at least reduced, by alphamethyl dopa. The inconsistent, and probably insignificant, effect of the drug on cardiac output is emphasized in Tables III and IV, which compare the effect of tilting on blood pressure during control studies and during the administration of

8.07 8.14 10.43 14.18 8.12 62.89 9.91 17.18 11.60 8.64 15.86 92
alpha-methyl dopa. In both instances, the cardiac response to tilting was essentially the same, i.e., and approximate 15 per cent reduction in cardiac output. In contrast, whereas peripheral vascular resistance increased in the control studies (Table III), there was no significant percentage change in peripheral vascular resistance

3s

Onesti, Bred, Yovack,

heasparian,

arttl Xoye~

during the hypotensive response to alphamethyl dopa (Table IV). Sannerstedt and associates8 investigated the hemodynamic response to alpha-methyl dopa during exercise. Their studies also suggested that the hypotensive response to the drug is due mainly to peripheral arteriolar relaxation, and that the effect on cardiac output is inconsistent. It is notable that, despite a significant reduction in blood pressure, renal blood flow increased in 4 of 10 patients in the supine position, and in 5 of 10 in the erect position. A moderate reduction in renal blood flow occurred in the other patients. In each instance, however, renal vascular resistance was consistently reduced. These findings suggest a favorable action of alpha-methyl dopa on the renal arterial circulation. It is of interest in this regard that the enzyme, dopa decarboxylase, is found in high concentration in the renal parenchyma.“,g The present studies indicate that intravenous alpha-methyl dopa does indeed possess significant antihypertensive properties. Although a greater orthostatic antihypertensive effect was achieved, a significant reduction in blood pressure occurred in all cases in the supine position as well. In general, the disparity between supine and erect blood pressure responses was less than that observed with guanethidine and the ganglioplegic drugs. The hemodynamic response after the acute administration of alpha-methyl dopa differs significantly from that obtained with guanethidine. 10 The hypotensive effect produced by the latter drug appears to be due primarily to a reduction in cardiac output, with minor effect on peripheral vascular resistance. Renal blood flow and glomerular filtration are consistentlv reduced, whereas the renal vascular resistance is increased or else little changed. Consequently, the renal hemodynamic response after the acute administration of guanethidine tends to be detrimental. In contrast, alpha-methyl dopa tends to exert a beneficial effect on renal hemodynamics, especially its consistent reduction in renal vascular resistance, thereby suggesting potential usefulness of the drug in hypertensive patients with renal functional impairment.

The ideal alltih~,pel-tellsi\-e thug;, from a hemodynamic standpoint, is not J-et available. Such a compound should be universalljr effective n~ld equally- active in both the supine and erect positions, should have a predominant nrteriolar “relaxant” action, and should not conlpromise blood flow to the vital organs or decrease cardiac output. Summary

The decarboxylase inhibitor, alphamethyl dopa, is a potent antihypertensive agent. The h>-potensive action of the drug appears to be due primarily to peripheral arteriolar relaxation. Its ability to reduce renal vascular resistance suggests its potential usefulness in the hypertensive patient with renal functional impairment. REFERENCES 1.

5.

6.

7.

8.

9.

10.

Blaschko,H.: The developmentof current conceptsof catecholamineformation, Pharmacol. Rev. 11:307, 1959. Holtz, P.: Dopadecarboxylase, Naturwissenschaften 27:?24, 1939. Holtz, I-‘., and Heise, R.: Fermentativer Abbau van I-Dioxyphenylalanin (Dopa) durch Niere, .2rch. exoer. Path. Pharmakol. 191:87. 1938. Gillespie,’ L.: Clinical pharmacology of newer antihypertensive agents, monoamine oxidase and decarboxylase inhibitors, bretylium tosplate and guanethidine, Ann. New York .4cad. SC. 88:1011, 1960. Oates, J. ;I., Gillespie, L., Jr., [‘denfriend, S., and Sjoerdsma, A.: Decarboxylase inhibition md blood pressure reduction by alpha methyl-3 &dihydrosy-DL-phenylalanine, Science 131:1890, 1960. Brest, k1. N., Seller, R. H., Onesti, G., Sekine, G., and Moyer, J. H.: Decarboxylase inhibitors in the treatment of hypertension, in Hypertension: Recent advances. The Second Hahnemann Symposium on Hypertensive Disease, Philadelphia, 1961, Lea & Febiger, p. 430. Hirkler. R. B., Hoskins, R. C., Hamlin, G. T., III: The clinical evaluation of faulty orthostatic mechanisms, M. Clin. North America 44:1237, 1960. Sannerstedt, R., Varnauskas, E., and Werkii, L.: Hemodynamic effects of methyl dopa (Aldomet) at rest and during exercise in patients with arterial hypertension, Acta med. scandinav. 171:75, 1961. Holtz, P.: Role of I-dopa decarboxylase in the biosynthesis of catecholamines in nervous tissue and the adrenal medulla, Pharmacol. Rev. 11:317, 1959. Novack, P.: The effect of guanethidine on renal, cerebral and cardiac hemodynamics, in Hypertension: Recent advances.6 p. 444.