Circulatory responses to beta adrenergic blockade with alprenolol

Circulatory Responses to Beta Adrenergic Blockade with Alprenolol Studies in Patients with Chronic Heart Disease

RICHARD E. KERBER, MD* ROBERT H. GOLDMAN, MD EDWIN L. ALDERMAN, MD DONALD C. HARRISON, MD, FACC

Palo Alto, California

From the Cardiology Division, Stanford University School of Medicine, Palo Alto, Calif. This work was supported in part by National Institutes of Health Grants HE09058, HE-05866 and HE-05709. Manuscript received November 27, 1970, accepted January 29, 1971. * Fellow of the Bay Area Heart Research Committee. Address for reprints: Donald C. Harrison, MD, Chief, Cardiology Division, Stanford University School of Medicine, Palo Alto, Calif. 94305.

26

Fourteen patients with acquired heart disease received 0.2 mg/kg body weight of alprenolol, a beta adrenergic blocking agent with intrinsic sympathomimetic properties, during cardiac catheterization. A high degree of beta blockade was demonstrated by injection of 3, pg of isoproterenol before and after alprenolol, the chronotropic effect of isoproterenol being almost completely abolished by alprenolol. After administration of alprenolol, significant decreases at rest and during bicycle exercise were noted in heart rate, cardiac index, maximal rate of rise of left ventricular pressure (dp/dt), left ventricular work and aortic systolic pressure, and (on exercise alone) in tensiontime index and mean systolic ejection rate. Mean right atrial and pulmonary arterial pressures were significantly increased at rest after alprenolol. In patients with heart disease, alprenolol has substantial negative chronotropic and inotropic effects, similar to those of propranolol, which are not overcome by its intrinsic beta stimulating properties.

Beta adrenergic receptor blocking agents have achieved widespread clinical use in the treatment of cardiac arrhythmias and angina pectoris.’ Propranolol, the only beta adrenergic blocking drug currently approved for use in the United States, has negative inotropic properties that limit its effectiveness in patients with congestive heart failure or diminished myocardial reserve.2 Alprenolol, l- (0-allylphenoxy ) -3-isopropylamino-2-propranol hydrochloride (Aptine, H56/28), a new beta adrenergic blocking agent, has recently been synthesized and introduced for study (Fig. 1). When given intravenously, it has been shown to be equipotent with propranolol in its ability to block the chronotropic and inotropic responses to isoproterenol infusion in man.” It is also effective in the treatment of atria1 arrhythmias.4 Moreover, in 5 normal human volunteers, alprenoIo1, in contrast to propranolol, caused no change in cardiac output.” These findings have been attributed to a mild intrinsic beta stimulating effect demonstrable in cats given reserpine and preventable by pretreatment with propranolol.” The present study was undertaken to evaluate the hemodynamic effects of alprenolol in patients with chronic heart disease.

The

American

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of

CARDIOLOGY

CIRCULATORY

“O /

D-

HO

\

xmprotarcnol

‘a3

iJH (Imlprcl

@ )

f3 ‘cn

3

(Indcral

/c”’

NIPI-CH

‘a3

Alprcnolol

(Aptlne @

, 1156/28)

Chemical structures of alprenolol Figure 1. parison) propranolol and isoproterenol.

and

(for

com-

Material and Methods patients undergoing carCase material : Fourteen diac catheterization for evaluation of various forms of heart disease (Table I) were studied. Patients were asked to participate if it was considered that they could tolerate the additional time (30 minutes to 1 hour) required for the study during the course of cardiac catheterization. Patients with suspected intracardiac shunts were excluded. Informed consent was obtained from all patients. Procedure: All patients were fasting, and received 100 mg of orally administered pentobarbital or secobarbital approximately 30 minutes before the start of the procedure. Right and left heart catheterization was performed by way of a forearm vein and the brachial or femoral artery entered percutaneously (Seldinger technique). Transseptal atria1 puncture was performed in 3 patients with severe aortic stenosis in whom it was impossible to traverse the aortic valve in retrograde fashion. Pressures were recorded by use of Statham physiologic pressure mode P23db transducers. Zero pressure was taken to be at the midpoint of the thoracic anteroposterior diameter. Cardiac output was calculated by the Fick method. Oxygen consumption was determined by collecting expired air in a Collins neoprene latex meteorologic balloon and analyzing for oxygen content using a Beckman O2 analyzer, model E2, and COP content by using a Godart capnograph. Arterial and mixed venous blood oxygen content was measured by use of a Beckman spectrophotometer, model B. Maximal rate of rise of left ventricular pressure (dp/dt) was calculated by digital computer analysis of the left ventricular pressure tracing.7

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Pressure and cardiac output measurements were made at rest and (in 9 patients) during supine exercise, using a bicycle ergometer set to a load believed to be tolerable for the patient during the 5 to 10 minute exercise period (generally 240 kg-m/min) . After a rest period (at least 10 minutes), racemic alprenolol was administered intravenously in a dose of 0.2 mg/kg over 10 minutes. After an additional 20 minute interval, rest and exercise measurements were repeated. During the second exercise period, the bicycle ergometer was set to the same load as before administration of alprenolol. Each patient thus served as his own control. The maximal time elapse between the start of the drug administration and the completion of all measurements was 1 hour. No angiographic procedures were performed until all hemodynamic measurements were completed. In some patients we were not able to obtain all pressure measurements. The following derived values were calculated: 1. Tension-time index (TTI) per beat in mm Hg seconds by using the formula: TTI = ASP x SEP, where ASP = aortic mean systolic pressure in mm Hg; SEP = systolic ejection period in set beat. 2. Tension-time index in mm Hg seconds per min by using the formula: TTI/min = TTI/beat x HR, where HR = heart rate in beats/min. 3. Left ventricular work (LVW) in kg-m/min by using the formula: LVW = (LVSP x CO x 13.6)/ 1,000, where LVSP = left ventricular mean systolic pressure in mm Hg; CO = cardiac output in liters/

m-cw,-,_cH/~3 Hii-CH

Propranolol

RESPONSES

1972

TABLE Clinical

I Information

FuncCase no.

Age

Diagnosis

1

66

2 3

50 58

4

32

CAD, ventricular aneurysm CAD, angina CAD, papillary muscle dysfunction Marfan’s syndrome, AR, MR

5 6 7 8 9 10 11 12 13 14

62 76 57 64

Rhythm

Digitabs

IIB IIB

NSR NSR

-

IIIC

NSR

+

IIB IIIC IV0 IIIC IV0 IIIC IIIC IIIC IIIC IV0 IIIC

NSR NSR AFI NSR NSR NSR AF NSR NSR AF AF

+ + + + + + + + +

tional

54 62 38 51 57 49

RHO, MR. MS Calcific AS Calcific AS CAD, RHO, MR. MS RHO, Al Calcific AS RHO, MS, AR Calcific AS, AR RHO, MS RHO, MS

Class*

+

* Classification according to criteria of the New York Heart Association. AF = atrial fibrillation; AFI = atrial flutter; Al = aortic insufficiency; AR = aortic regurgitation; AS = aortic stenosis; CAD = coronary artery disease; MR = mitral regurgitation; MS = mitral stenosis; NSR = normal sinus rhythm; RHO = rheumatic heart disease; + = receiving digitalis; - = not receiving digitalis.

27

KERBER

TABLE

ET

AL.

II

Hemodynamic

Effects of Alprenoiol

at Rest and During Exercise Exercise

Rest Control (mean & SEM) Heart rate (beats/min) All patients Patients with NSR Blood pressure (mm Hg) Aortic systolic (peak) Aortic mean Aortic diastolic Right atrial mean Pulmonary artery mean Left ventricular end-diastolic Cardiac index (liters/min per m2) Stroke

index (ml/mln

(vol %)

84&4

101 f

87zt 4

-2 -3

co.01 NS NS

+43 +10 +18

(0.01
148& 8 103& 6 76?c 5 12f 3 42z!z 7

1.910.1 27.5& 3.0

-17 -6


3.3zt 33.4&

122 * 5

-5

<0.05

240 f

0.60

+19


8.45&

60

-18


97.3* 7.9

-10

-16

123 i- 5

-6

88z!z 5 70*5 1ozt 1 33+ 4 20* 3

2.3& 0.2 29.31 3.1 128rt 5

7.07 i

% Change

P Value

-17 -14

<0.05

92f5 69&5 1412 43* 5 23~t4

-11 -11 -9 +17 +2 -12

<0.05 NS NS NS NS NS

0.3 3.5

2.6~ 0.3 30.7& 3.5

-21 -8


20

222* 20

-8

(0.05

0.62

9.96& 0.82

+18


1323 f

182

1014f 133

-23


NS

112.4zt

14.5

96.7~1~ 14.8

-14

<0.05

=0.05

12.21 i

2.62

8.41f 1.88

-31


4.9

35.2i 3.5

-13

NS

2877f 314

-27


11620i 1452

-29

<0.05

26f

8

132f

5

8


dp/dt

(mg Hg/sec) Mean systolic ejection

1058 f

(mm Hg set) Tension-time index

868 i

108.4& 9.0 8.58&

1.10

7.171 0.86

39.1*

3.3

40.112.8

+3

NS

40.1&

3211 f

425

2941 f

342

-8

NS

3950 It 454

9917 i

1195

-17

NS

16291 i

22.7& 2.8

+18

NS

15.6&

3.0

18.0i 4.0

+13

NS

8.23z 2.9

+26

NS

3.2f

1.2

3.9& 1.9

+22

NS

per minute

(mm Hg sec/min) LV systolic pressure rate product Systemic vascular

72

rate

(ml/set per m2) Left ventricular work (kg-m/min) Tension-time index per beat

X heart

11982zt 1545

2245

resistance

19.3& 2.2 vascular

resistance 6.5zt

(units)

2.7

NS = not significant;

NSR = normal

sinus rhythm.

min; and 13.6 = conversion factor for the density of mercury. 4. Mean systolic ejection rate (SER) in ml/set per rn” by using the formula, SER = SI/SEP, where SI = stroke index in ml/mz; and SEP = systolic ejection period in see/beat. 5. Pulmonary vascular resistance (PVR) in arbitrary resistance units (ru) by using the formula : PVR = (PAm - PAWm)/CO, where PAin = mean pulmonary arterial pressure in mm Hg; PAWm = mean pulmonary arterial wedge pressure in mm Hg; CO = cardiac output in liters/min. 6. Systemic vascular resistance (SVR) in arbitrary resistance units (ru) by using the formula: SVR = (Aom - RAm)/CO, where Aom = mean aortic presgure in mm Hg ; and RAm = right atria1 mean pressure in mm Hg. 7. The product of left ventricular peak systolic pressure and heart rate in arbitrary units. These values were not derived in all patients if the tracings were believed not adequate to permit accurate

28

Alprenolol (mean =t SEM)

101 *: 7

131* 5 90+3 72& 5

5.9332 0.39

Left ventricular

Control (mean f SEM)

P

(0.01

-12 -8

3

Value

<0.05

75&6 70+ 4

17*

per m2>

% Change

85i 7 76zt 4

7ztl 30+4

Total body 02 consumption (ml/min per m2> Arteriovenous O2 difference

(units) Pulmonary

Alprenolol @lean f SEM)

calculation. Data were analyzed for statistical cance by use of a paired t-test.

signifi-

Resdts Twelve patients were given isoproterenol hydrochloride, 3 pg, as a rapid intravenous “bolus” injection, and the effect on heart rate was measured. This was done after taking the initial resting pressure measurements, and was repeated after the taking of the postalprenolol restitig measurements, generally 30 to 40 minutes after the start of alprenolol administration. The average maximal heart rate increase after the first challenge of isoproterenol was 23 -+ 5 beats/min, whereas after administration of alprenolol an average maximal increase of only 1 + 1 beat/min occurred with isoproterenol (P CO.01). The hemodynamic results of administration of alprenolol are summarized in Table II. Significant

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NO DRUG

RESPONSES

TO ALPRENOLOL

ALPRENOLOL

ALPRENOLOL

tzza

T

S.E.

250 p < 0.01

EXERCISE

REST Figure 2. Response at rest and exercise.

of cardiac

index to alprenolol

0 p c 0.01

infusion

decreases after alprenolol administration were noted in values for heart rate, aortic systolic pressure, cardiac index (Fig. 2)) left ventricular dp/dt (Fig. 3) and left ventricular work. Decreased values for mean systolic ejection rate, tension-time index per minute (Fig. 4) and the product of left ventricular systolic pressure and heart rate were statistically significant on exercise but not at rest, whereas changes in tension-time index per beat were not significant in either condition. Mean right atria1 and pulmonary arterial pressures rose significantly at rest, but not on exercise. Changes in aortic mean and diastolic pressure, left ventricular end-diastolic pressure, stroke index and systemic and pulmonary vascular resistance were not significant.

REST

pcODI

EXERCISE

Figure 3. Response of maximal rise of left ventricular dp/dt to alprenolol infusion at rest and exercise.

peak

of alprenolol, as did maximal left ventricular dp/dt and mean systolic ejection rate (the latter changed significantly only on exercise). These changes are in large part related to the slowing of heart rate induced by alprenolol, as indicated by the not statistically significant change in the stroke index. In 4 patients at rest and in 2 on exercise, there was no slowing of heart rate after administration of alprenolol : in 1 patient (Case 12), the

NO DRUG ALPRENOLOL

Discussion The negative chronotropic effects of alprenolol, shown previously in supraventricular arrhythmias,* were again demonstrated in this group of 14 patients, 10 of whom had sinus rhythm. Using somewhat smaller doses of alprenolol, other investigators have demonstrated decreases in heart rate of 128 and 13 percent? at rest in patients with acute myocardial infarction and other forms of heart disease. We found a drop of 8 percent at rest and 14 percent on exercise. The greater effect of alprenolol during exercise seen in this and several other hemodynamic indexes is presumably related to the significant role played by sympathetic stimulation of the heart in the circulatory response to exercise.‘O Myocardial contractility : Cardiac index fell significantly at rest and exercise after administration

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1972

I”’

4000

5, 1: s s! F I x

2000

1000

iz p

0

p * 0.05

REST Response of tension-time Figure 4. alprenolol infusion at rest and exercise.

p * 0.01

EXERCISE index

per minute

to

KERBER ET AL.

TABLE

III

Hemodynamic

Case no.

Effects of Alprenolol

Condi-

Heart Rate (beats/

tion

min)

in Patients

Cardiac Stroke Index (liters/ Index min per (ml/min per m2) m*)

Not Demonstrating

a Decline in Heart Rate After Drug Administration

A-V Or Diff.

LVSPm

(vol. %)

(mm Hg) (mm Hg)

LVEDP

set)

MSER (ml/set per m2)

dpldt (mm Hg/

LVW

TTl/min (mm Hg/ set per

TTl/beat

(kg-m/ min)

(mm Hgl set)

x

min)

LVSP, Heart Rate

6

R, C D

14D* 140*

1.4 1.1

10 8

9.4 11.4

7

R, C D

54 54

2.5

46

152 144

10 12

1,268 1,060

135.3 122.9

99.94

51.7 50.4

2,791 2,721

11,664

43

5.2 5.5

113.72

2.3

E, C D

74 74

3.6

49

200

29

1,629

144.1

2.8

38

7.2 8.6

150

32

1,180

115.6

212.20 126.57

68.0 48.0

5,032 3,660

16,800 15,300

9

R, C D

72 72

2.3 1.3

32 18

7.0 10.2

12

R,C D

80 90

2.5 2.1

31 23

6.7 7.2

158 158

40 42

E. D D

75 75

2.8 2.6

37 35

7.9

100 110

10

7

14

* = A-V tricular LVSPp TTI =

9.5

10,044

39 37

9,504 9,072 1,275 1,073

6

106.9 79.3

105.31 92.44

45.8 45.8

3,660 4,120

15,840

123.3 106.0

63.9

30.0 36.3

2,250 2,723

9,375 10,500

65.8

14,960

atrial flutter. O2 Diff. = arteriovenous oxygen difference; C = control; D = drug administration; dp/dt = maximal rate of rise of left venpressure; E = exercise: LVEDP = left ventricular end-diastolic pressure; LVSPm = left ventricular mean systolic pressure; = left ventricular peak systolic pressure; LVW = left ventricular minute work; MSER = mean systolic ejection rate; R = rest; tension-time index.

TABLE

IV

Hemodynamic

Effects of Propranolol

Author

and Alprenolol

Propranolol Dose

Heart Rate

Cardiac Index

(mg/kg)

(%)

(%)

in Patients with Heart Disease at Rest and During Exercise*

Stroke Index

Ao Mean Pressure

RA Mean Pressure

Mean Pressure

PA

LVEDP

SVR

MSER

dp/dt

LVW

per min

(%)

(%)

(%)

(%)

(%)

(%)

(%)

(%)

(%)

(%)

TTI

Rest Sonnenblick Sowton

et al.20

and Hamer*?

Wolfson

et al.?”

-12

-19t

-2i

5 w

-10

-2ot

-15

5 mg

-12

-13t

0.17

~________~_~~ -2

-4

-7 +197

Robin et al.2*

0.10

-14

-38

-27

0.15

-15

-15

-6

10 mg

-13

-20

-7

5 mg 0.20

-12

-25

-12

-4

+50

-8

-17

-6

-2

+43

et al.*’

Lund-Larsen & Sivertssenn Alprenolol

study

-21 -30

03

Parker et al.zg Ulrych

_~

-2

-1 +8

+70

-32

-26

-8 +20

0

-40

-6

-20

-5

-16

-8

-15

+25 +10

+18

+18

-10

-18

-16

-22

Exercise Epstein

et al.‘0

0.15

-19

-22t

0.17

-26

-25t

-101

5 mg

-15

-2ot

-5$

Parker et al.20

0.15

-15

-20

-1

-7

Alprenolol

0.20

-14

-21

-8

-11

Sonnenblick Sowton

et al.20

and Hamer27

study

-15

0 3

+10 +17

+20

+5

+2

-12

* Data expressed as percentage changes before and after propranolol administration. t = cardiac output; t = stroke volume. Ao = aortic; RA = right atrial; SVR = systemic vascular resistance; other abbreviations

30

-34

-8 +13

-14

Not all changes as in Table

The

-23

-24

-8

-27

-20

-31

-27

are statistically

significant;

III.

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CARDIOLOGY

CIRCULATORY

heart rate before administration of alprenolol was 80/min and after administration 90/min, possibly due to incomplete recovery from an intervening exercise period. In these 6 cases, the hemodynamic data (Table III) still reveal significant decreases in cardiac and stroke index, dp/dt and mean systolic ejection rate--changes that cannot be attributed to alteration in heart rate. Since peak dp/dt and mean systolic ejection rate have been noted to bear a relation to myocardial contractility 11,12alprenolol would appear to have negative indtropic effects independent of its negative chronotropic effects. Alterations in left ventricular systolic and end-diastolic pressures and the prod: uct of systolic pressure and heart rate, which have also been shown to affect peak dp/dt,ll were not of sufficient magnitude to account for the changes in dp/dt observed in this group of patients. Myocardial oxygen requirements: Beta adrenergic receptor blocking agents have proved effective in the treatment of angina pectoris,13 probably by lessening myocardial oxygen requirements,14 especially in response to exercise.15 Myocardial oxygen demand has been shown to be correlated with a number of factors, including the area beneath the systolic pressure curve (tension-time index) ,16 peak systolic ventricular pressure,l’ the product of peak ventricular pressure and heart rate,18,19 and left ventricular external work.20 All of these measures except the tension-time index showed significant declines at rest and exercise after alprenolol. The tension-time index per beat did not vary significantly after alprenolol, but the tensiontime index per minute showed an 8 percent fall at rest (not significant) and a 27 percent fall on exercise (P
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RESPONSES

TO ALPRENOLOL

Clinical implications: Our findings are in striking contrast to the results of Forsberg and Johnson,” who administered 10 mg of alprenolol to 5 normal human volunteers and reported no statistically significant variation in heart rate, arterial pressure, cardiac output, stroke volume and right atria1 pressure. They attributed these findings to alprenolol’s mild intrinsic beta receptor stimulating action0 and postulated that the latter caused cardiac stimulation sufficient to overcome the depressant effect of the beta receptor blockade. Patients with congestive heart failure are dependent on an increased sympathetic tone to maintain cardiac output.25 In such persons, beta adrenergic receptor blockade would be expected to have more profound effects than in the normal subject in the supine, resting position, with a low level of sympathetic activity. Since most of our patients had severe, symptomatic heart disease with congestive heart failure and were generally in functional class 3 or 4 (New York Heart Association), as suggested by the low resting control mean cardiac index of 2.3 -+ 0.2 liters/min per m2, they would be expected to be more dependent on increased sympathetic tone to maintain cardiac output. In this clinical setting the mild sympathomimetic effects of alprenolol would appear inadequate to compensate for the hemodynamic consequences of beta adrenergic blockade. The dose of alprenolol (0.2 mg/kg) employed in this study is somewhat higher than that used by previous investigators. It was chosen because previous work suggested this dose to be effective in the treatment of supraventricular arrhythmias.4 Ventricular ectopic beats and ventricular tachycardia have also been treated with intravenously administered alprenolol in dosages similar to ours.2s We did not investigate the hemodynamic effects of orally administered alprenolol, as would be utilized in the long-term treatment of chronic arrhythmias or angina. Comparison of alprenolol and propranolol: The hemodynamic effects of propranolol in heart disease have been extensively studied.8,10~14~27-2g These studies are summarized in Table IV, and the data from this study of alprenolol have been included for comparison. It can be seen that in all hemodynamic indexes measured, the 2 agents are essentially similar. Thus, in the dosage employed in this study, the cardiovascular effects of alprenolol are comparable to those of propranolol in patients with heart disease. Acknowledgments We acknowledge the invaluable technical assistance of Miss Mary Elizabeth Stone, Mrs. Beverly Forster,

Miss Elaine Kiess and Mrs. Kathryn McDonald. Alprenolol was kindly supplied by Dr. Benjamin G. Covino, Astra Pharmaceutical Company, Inc., Worcester, Mass.

31

KERBER ET AL.

References 1. Epstein

16.

2.

17.

3. 4. 5.

6. 7. 8. 9.

10.

11. 12. 13. 14. 15.

32

Beta-adrenergic receptor SE, Braunwald E: blocking drugs. Mechanisms of action and clinical applications. New Eng J Med 275:1106-1112, 11715-1183, 1966 Stephen SA: Unwanted effects of propranolol. Amer J Cardiol 18:463-472, 1966 Johnson G, Norrby A, Solve11 L: Potency and time-effect relationship in man of propranolol and H ‘56/28. Acta Pharmacol (Kobenhaven) 25: suppl2:95-105, 1967 Kerber RE, Goldman RH, Gianelly RE, et al: Treatment of atrial arrhythmias with alprenolol. JAMA 214:18491852, 1970 Hemodynamic effects of For&erg SA, Johnson G: propranolol and H 56/28 in man-a comparative study of two beta-adrenergic receptor antagonists. Acta Phamrmacol (Kobenhaven) 25: suppl 2:75-83, 1967 Ablad B, Brogard M, Ek L: Pharmacological properties of H 56/28-a beta-adrenergic recepto#r antagonist, Acta Pharmacol (Kobenhaven) 25: suppl 2:9-40, 1967 analyHenry WL, Crouse L, Stenson R, et al: Computer sis of cardiac catheterization data. Amer J Cardiol 22: 696-705, 1968 Lund-Larsen PG, Sivertssen E: Hemodynamic effects of propranolol and H 56/28 in patients with acute myocardial infarction. Acta Med Stand 186:187-191, 1969 Wasserman AJ, Proctor JD, Allen FJ, et al: Human cardiovascular effects of alprenolol, a beta-adrenergic blocker: hemodynamic, antiarrhythmic, and antianginal. J Clin Pharmacol 10:37-49, 1970 Epstein SE, Robinson BF, Kahler RL, et al: Effects of beta-adrenergic blockade on the cardiac response to maximal and submaximal exercise in man. J Clin Invest 44:1745-l 753, 1965 Gleason WL, Braunwald E: Studies on the first derivative of the ventricular pressure pulse in man. J Clin invest 41:8&91, 1962 Levine HJ, Neil1 WA, Wagman RJ, et al: The effect of exercise on mean left ventricular ejection rate in man. J Clin Invest 41:1050-1058, 1962 Gillam PMS, Prichard BNC: Use of propranolol in angina pectoris. Brit Med J 2:337-339, 1965 Wolfson S, Heinle RA, Herman MV, et al: Propranolol and angina pectoris. Amer J Cardiol 18:345-353, 1966 Gianelly RE, Goldman RH, Treister B, et al: Propranolol n patients with angina pectoris. Ann Intern Med 67: 1216-1225, 1967

18. 19.

20.

21.

22

23.

24.

25.

26.

Sarnoff SJ, Braunwald E, Welch GH, et al: Hemodvnamic determinants of .oxygen consumption of the heart. With special reference to the tension-time index. Amer J Physiol 192:148-156, 1958 Monroe RG, French GN: Left ventricular pressure-volume relationships and myocardial oxygen consumption in the isolated heart. Circ Res 9:362-374. 1961 Cooper T, Braunwald E, Morrow AG: Pulsus alternans in aortic stenosis. Circulation 1864-70, 1958 Relation of heart rate and systolic blood Robinson B: pressure to the onset of pain in angina pectoris. Circulation 35:1073-1083, 1967 Sonnenblick EH, Ross J, Braunwald E: Oxygen consumption of the heart. Newer concepts of its multifactorial determination. Amer J Cardiol 22:328-336, 1968 Bjorntorp P: The treatment of angina pectoris with a new beta receptor blocking agent (H 56/28). Acta Med Stand 182:285-291, 1967 Aubert A, Nyberg G, Slaastad R, et al: Prophylactic treatment of angina pectoris. A double-blind cross-over comparison of alprenolol and pentanitrol. Brit Med J 1: 203-206, 1970 Frolich ED, Tarazi RC, Dustan HP, et al: The paradox of beta-adrenergic blockade in hypertension. Circulation 37:417-423, 1968 Ulrych M, Frolich EP, Dustan HP, et al: Immediate hemodynamic effects of beta-adrenergic blockade with propranolol in normotensive and hypertensive man. Circulation 37:411-416, 1968 Chidsey CA, Braunwald E, Morrow AG: Catecholamine excretion and cardiac stores of norepinephrine in congestive heart failure. Amer J Med 39442-451, 1965 Linko E, Siitonen L, Ruosteenoja R: A new beta-adrenergic receptor blocking agent H 56/28, in the treatment of cardiac arrhythmias. Acta Med Stand 1&1:547-

55’5, 1967 27. 28.

29.

Sowton E, Hamer J: Hemodynamic changes after betaadrenergic blockade. Amer J Cardiol 18:317-320, 1966 Robin E, Cowan C, Puri P, et al: A comparative study of nitroglycerin and propranolol. Circulation 36:175-186, 1967 Parker JO, West RO, DiGiorgi S: Hemodynamic effects of propranolol in coronary heart disease. Amer J Cardiol 21:11-19, 1968

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