Effect of beta adrenergic blockade on the hemodynamic responses to epinephrine in man

Effect of beta adrenergic blockade on the hemodynamic responses to epinephrine in man

Effect of Beta Adrenergic the Hemodynamic Responses Epinephrine WILLARD S. HARRIS, M.D., CLYDE ARNOLD on to in Man* D. SCHOENFELD, M.D., RICHAR...

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Effect of Beta Adrenergic the Hemodynamic

Responses

Epinephrine WILLARD

S. HARRIS, M.D., CLYDE ARNOLD

on

to

in Man*

D. SCHOENFELD, M.D., RICHARD M. WEISSLER, M.D.,F.A.C.C. Columbus,

D

Blockade

ALEX in 1906

presented evidence that epinephrine activates two different types of receptors. Ahlquist2 in 1948 named these receptors alpha and beta and demonstrated their relative responsiveness to a series of sympathomimetic, or adrenergic, amines. Activation of cardiovascular alpha receptors results in peripheral vasoconstriction, while activation of beta receptors increases the frequency and strength of cardiac contraction and causes peripheral vasodilatation. The classic sympatholytic agents, such as ergotoxine, phenoxybenzamine and phentolamine, appear to block alpha, but not beta, adrenergic receptors. In contrast, three recently introduced analogues of isoproterenol (Fig. l)-dichloroisoproterenol, pronethalol and propranolol-block beta, but not alpha, adrenergic receptors.3-5 Propranolol, the agent used in the present study, is free of the sympathomimetic side effects of dichloroisoproterenol and, unlike pronethalol, does not cause vertigo or nausea and is reportedly noncarcinogenic in anima1s.j Although epinephrine activates both alpha and beta receptors, the over-all hemodynamic effects of moderate doses in man appear to be due mainly to its beta activity. The present study attempts to unmask the alpha activity of epinephrine in man by demonstrating that, after selective beta adrenergic blockade, it produces unopposed alpha-mediated vasoconstriction. The responses to epinephrine after beta blockade are compared with those to isoproterenol, a catecholamine which acts mainly on beta receptors.* The present study is also aimed at determining the hemodynamic conse-

H.

BROOKS,

M.D. and

Ohio

quences blockade

in normal man of beta adrenergic by the new agent, propranolol. METHODS

The subjects, all inmates of the Ohio Penitentiary, were 10 healthy male volunteers, 26 to 42 years old (mean age 33). They had not received medication and, with one exception (Subject l), had not donated blood for at least six weeks previously. Studies were begun at approximately 9 A.M. with subjects fasted overnight, unsedated, and supine. A polyethylene catheter (PE50) was passed percutaneously through an 18 gauge thin-wall needle into an antecubital vein, advanced, with pressure monitoring, into the right ventricle and then pulled back into the right atrium. Cournand needles were positioned in a forearm vein for drug infusions and in a brachial artery. Cardiac outputs were determined by indicator-dilution technic, with right atria1 injection of indocyanine-green dye and continuous sampling of brachial arterial blood through a cuvette densitometer with a constant-rate, motor-driven syringe (Gilford Instruments). Pressure in the right atrium and brachial artery was recorded with Statham P23Db strain-gauge transducers placed in a plane 5 cm. below the sternal angle. Mean pressures were obtained by electronic integration. Heart rate was determined from a standard electrocardiogram (lead II). ‘Total peripheral resistance was calculated from the formula rrPR

BAM - IL&~ x 1332

=

co

where

TPR

=

total

peripheral

resistance

(dynes

sec.

cm+.)

BAM = mean brachial arterial pressure (mm. Hg) RAM = mean right atria1 pressure (mm. Hg) CO = cardiac

output

(ml./sec.)

This investigation was sup* From the Department of Medicine, The Ohio State University College of Medicine. ported by grants from the Central Ohio Heart Association and the U. S. Public Health Service Grants HE-06414, H-6737, and Career Program Award HE-K-13,971. 484

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CH3

/

‘CH3

HO HO ISOPROTERENOL

AH3 /

\

ywNH-“ycH3

I \ co

/

PRONETHALOL AH3

0-CH2-YH-CH2-NH-CH ’ /

\

CH,

OH

485

minutes with continuous recording of the electrocardiogram and arterial and right atria1 pressures. Beginning 15 min. after the end of propranolol administration, data were collected during study periods presented as follows: propranolol control, isoproterenol 2 or 2.5 pg./min., epinephrine 5 pg./min., propranolol control, and isoproterenol 12.5 wg./min. Isoproterenol and epinephrine were administered intravenously at a constant rate by a motor-driven pump (Harvard Apparatus Co.). The total volume of fluid required for infusion was less than 50 ml. for each subject. Hemodynamic determinations were begun during the fourth minute of infusion. The end of each infusion was followed by a 12 min. waiting period before beginning the next procedure. Statistical analyses were performed by Student’s t test.* To test for drug toxicity, urinalyses were performed, and 20 ml. of venous blood was drawn before each study and one week later. Blood determinations were hematocrit, hemoglobin, white blood cell and differential counts, blood urea nitrogen, serum bilirubin, serum glutamic oxaloacetic transaminase, cephalin flocculation, and alkaline phosphatase.

RESULTS

I \ co

Blockade

/ PROPRANOLOL

FIG. 1. Structure pranolol.

of isoproterenol,

pronethalol

and pro-

The carotid arterial pulse was recorded externally with a funnel-shaped pick-up and a Statham P23Db transducer. The carotid pulse, phonocardiogram (Peiker microphone) and electrocardiogram were recorded simultaneously at a paper speed of 100 mm./ sec. with 0.02 sec. time markers. The duration of left ventricular ejection (left ventricular ejection time, LVET) was derived from the carotid pulse as the interval from the onset of the upstroke to the trough of the incisura. The mean rate of left ventricular ejection (MRLVE) was calculated by dividing LVET (sec.) into stroke volume (ml.). The ejection time index, equal to LVET + 0.0016 heart rate, was calculated in order to correct the LVET for heart rate.6 The Q-2 interval was measured as the interval from the onset of the QRS complex of the electrocardiogram to the initial high frequency vibrations of the second heart sound. The “isometric period,” as defined by Raab et al.7 and others, was calculated as the Q-2 interval minus the left ventricular ejection time. Data were obtained from each subject during the periods of study presented in the following order: control, isoproterenol infusion at 2 or 2.5 Fg./min., epinephrine infusion at 5 pg./min., and control. Next, 10 mg. of propranolol* was infused intravenously over 10 to 20 * Generously provided by Dr. Alex Sahagian-Edwards, Ayerst Laboratories, New York, N. Y.

VOLUME17,

APRIL

1966

The results obtained during administration of isoproterenol and epinephrine before and after propranolol are presented in Tables I and II and Figures 2 and 3. The changes in control data produced by propranolol are summarized in Table III. The results of administering a high dose of isoproterenol after propranolol appear in Table IV. To simplify presentation of the data, each control value reported for a subject is taken as the average of his initial and final control data since these did not dzj$er sign$icantly from each other. Control data after propranolol were treated in a similar manner. Effects of Isoproterenol and Epinephrine Before Propranolol: As described, in part, by previous investigators,7~g~10 both agents produced significant and marked increases in heart rate, cardiac output, stroke volume, systolic arterial pressure and mean rate of left ventricular ejection, while decreasing the diastolic arterial pressure, total peripheral resistance and isometric period. Mean arterial pressure was not affected significantly. The mean right atria1 pressure and ejection time index, although decreased by isoproterenol, were unchanged by epinephrine. Eflects of Propranolol: Administration of propranolol produced significant decreases in heart rate (- 10 beats/min.), cardiac output (-0.72 L./min./M2.), stroke volume (- 8 ml.), ejection time index (-9 msec.) and mean rate of left ventricular ejection (34 ml./sec.), significant increases in mean right atria1 pressure (+1.3 mm.

Harris

486

et al. TABLE

Effects of Isoproterenol

Age (yr.) wt. (kg.)

Subject

BSA (M2. )

Heart Period of Rate Study (beats/min.)

Cardiac Index (L./ min./MS.)

Stroke Volume (ml.)

1

and Epinephrine

,---Pressures BA S/D

(mm. BA Mean

Before Propranolol*

IIg)-----

TPR (dynes sec. cm-j.)

R.\ Me&l

1

77 54.5

1.63

C I E

74 98 93

3 45 4 91 4.88

76 82 86

106/68 108/60 117j60

82 Rl 85

0.1 -0.; 1.6

1184 X08 856

2

34 x4.1

2.08

C I E

66 96 74

3.16 S.06 4.50

100 111 127

112/58 124/59 120/54

80 77 76

0.2 -1.3 1.0

968 .Sb4 640

3

28 78.6

1.93

C I E

69 102 86

4.38 7.16 6.92

125 138 158

145/70 175/72 158/70

94 102 96

4.8 2.0 4.1

832 568 544

4

28 70.1

1.89

C I E

56 78 68

3.14 5.65 4.00

106 137 112

108/53 125146 112,&l

74 74 76

4.3 1.9 4.7

944 544 752

5

39 90.0

2.0

c I E

90 130 110

2.83 4.04 4.77

63 62 87

130/73 120/56 127/62

97 75 83

2.4 1.1 2.7

1336 728 672

6

40

1.85

C I E

53 76 54

3.05 5.34 3.66

106 130 126

131/69 156/65 135/63

94 90 93

3.2 -1.9 3.1

1288 744 1064

75.0 7

42 52.7

1.48

C I E

60 84 72

2.62 3.89 3.57

65 69 73

109/62 114/49 116/56

82 69 77

4.0 0.9 5.8

1608 944 1080

8

36 76.4

1.86

C I E

66 91 89

3.43 5.87 5.85

97 120 122

111/59 126/50 116/54

79 74 79

4.3 0.1 4.4

936 544 552

30 61.8

1.73

C I E

70 100 86

3.30 6.07 5.03

82 105 101

132/69 146/61 133/61

93 87 84

3.4 0.5 30

1256 656 744

26 79.5

1.89

C I E

64 82 72

2.39 3.34 3.40

70 77 89

109/56 128/47 tt4/47

74 68 67

4.0 -0.4 2.2

1240 864 80R

89

119/64

85

3.1

1159

10

Mean

C

67

3.18

Mean

pi

I

94
5.13
103
132/57 <0.010/<0.005

80
2
698 10.001

Mean

pt

E

80
4.66
108
125/58 <0.005/<0.001

82
3.3 >o. 500

771
0

BS.4 = body surface area; BA = brachial artery; S/D = systolic/diastolic; RA mean = right atria1 mean; TPR ance; MRLVE = mean rate of left ventricular ejection; C = control; I = isoproterenol, E = epinephrine, and NM = *Dose of isoprotcrcnol 2 pg./min. for Subjects 1, 2, 3, 5 and 7 and 2.5 pg./min. for Subjects 4, 6, 8, 9 and 10. tp value for difference between the means for control and isoproterenol. tp value for difference between the means for control and epinephrine.

Hg), total peripheral resistance (+321 dynes sec. cm.-5 or +28’%) and the isometric period (f14 msec.); but it did not change arterial pressure (Table III). Although not shown here, similar changes were found when only the control observations made immediately before and after propranolol administration were compared. A rapid onset of action was evident from continuous recordings showing that during the infusion of propranolol, which lasted an average of 13 min., heart rate for the group fell from 69 to 60 beats/min. (p < 0.05), mean right atria1 pressure rose from 2.6 to 4.4 mm. Hg (p < O.Ol), while arterial pressure was not significantly affected.

Effects

of

Isoproterenol

and

= total pcripher.d not me.~wrrd.

Efiinephrine

resist-

After

While propranolol blocked almost completely the hemodynamic effects of isoproterenol at 2 or 2.5 wg./min., it actually reversed most of those of epinephrine (Table II, Fig. 2 and 3). After propranolol, isoproterenol no longer affected heart rate, systolic arterial pressure or ejection time index; it produced only slight increases in cardiac output, stroke volume and mean rate of left ventricular ejection, and slight decreases in diastolic arterial pressure, mean right atria1 pressure and total peripheral resistance. In contrast, after propranolol, epinephrine produced significant decreases in heart rate, cardiac output, stroke Propranolol:

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Beta

TABLE

Adrenergic

I (continued)

Ejection Time (msec. )

Ejection Time Index (msec.)

MRLVE (ml./sec.)

285 223 269

408 389 418

266 368 319

355 279 317

70 56 48

311 261 302

423 408 428

323 428 419

408 327 370

97 66 68

296 231 267

404 394 401

421 595 591

375 281 324

79 50 57

300 250 296

390 392 392

354 378 378

413 321 385

113 71 89

265 193 239

402 407 413

239 322 363

352 NM 284

87 NM 45

317 277 315

399 389 395

335 469 309

423 342 403

106 65 88

290 224 293

394 358 402

224 308 249

378 281 345

88 57 52

300 243 273

404 374 406

323 494 447

NM NM NM

NM NM NM

289 212 266

403 375 400

283 495 380

379 272 324

90 60 58

296 248 282

400 374 400

237 310 316

385 306 343

89 58 61

295

403

301

236
386 <0.005

417
301
60
280

406 co.200

377


344
63

Q-2

Interval (msec.)

385

Isometric Period (msec. )

91

volume, ejection time index and mean rate of left ventricular ejection, and significant increases in arterial and mean right atria1 pressures, total peripheral resistance and isometric period. Efects of the High Dose of Isojroterenol After Beta Adrenergic Blockade by Propranolol: The infusion of isoproterenol at a rate of 12.5 pg./min. after propranolol produced significant changes in all the same modalities as had isoproterenol infused at a rate of 2 or 2.5 pg./min. before propranolol, except for arterial diastolic pressure. Symptoms and Laboratory Tests: The administration of propranolol produced no symptoms. VOLUME

17,APRIL

966

Blockade Before but not after propranolol, the infusion of isoproterenol at 2 or 2.5 pg./min. made the subjects aware of a faster, more forceful heart beat. A smaller increase in the force of the heart beat was reported during the administration of isoproterenol at 12.5 pg./min. after propranolol. The administration of epinephrine before propranolol often caused subjects to feel a slight increase in the force of the heart beat, but after propranolol it produced no symptoms other than an occasional feeling of mild tiredness. The results of all blood determinations and urinalyses were normal before and one week after each study. DISCUSSION

The effectiveness of beta receptor blockade by propranolol in man was demonstrated by its virtually complete suppression of the hemodynamic responses to an infusion of isoproterenol at 2 or 2.5 pg./min. A large dose of isoproterenol (12.5 pg./min.) appeared to overcome the blockade partly. While the actions of isoproterenol were merely prevented by beta receptor blockade, most of those of epinephrine were actually reversed, so that heart rate, cardiac output, stroke volume and mean rate of left ventricular ejection decreased, and total peripheral resistance, mean arterial pressure and mean right atria1 pressure increased. These new responses were presumably due to an unmasking by beta receptor blockade of the potent, but usually inapparent, alpha (vasoconstrictive) action of epinephrine.%rr-13 The bradycardia caused by epinephrine after propranolol was probably a vagal-mediated change induced by the acute elevation of arterial pressure, while the slight reduction of stroke volume may have been consequent to increased resistance to ventricular outThe hemodynamic responses to epinephflow. rine after propranolol did not result from changes in body metabolic rate since in another 6 supine subjects, oxygen consumption was unaffected either by 10 mg. of intravenous propranolol or by 5 pg./min. of intravenous epinephrine after propranolol, as shown by unpublished work from our department. The finding that epinephrine, unlike isoproterenol, does not lower mean right atria1 presVenous sure may be explained as follows: capacitance vessels in man contain alpha but not beta receptors.14 Stimulation of these alpha receptors causes venoconstriction. Isoproterenol does not affect venous tone directly, al-

Harris

et al

TABLE II Effects of Isoproterenol

Subject

Period of Study

Hrart Rate [brats/ min.)

Cardiac Index (L./min./ IVP)

Stroke Volume

,---(mm. B.4 S/D

(ml.)

and Epinephrine

PXSS”TCS Hg)BA MCZI”

After

Propranolol

TPR (dynes sec. cm 5.)

Ejection Timr (msec.)

Ejrction Time Index (msrr.)

IF”metric Period (msrr.)

1

C I E

50 58 48

2.01 2 50 1.88

66 70 64

108/65 115/67 121/69

82 93 8R

2.5 1.8 29

2008 1832 2296

311 311 324

391 399 390

211 226 197

409 402 429

9n 91 105

2

C I E

57 61 44

2.48 2.48 1.73

92 85 82

118/65 116/64 129/70

87 86 98

2.6 2.1 4.2

1320 1288 2088

323 314 342

420 415 416

281 269 239

428 424 459

105 110 117

3

c I E

57 62 47

2 93 3 45 2.12

101 110 89

139/75 139/70 149/84

96 96 105

4.8 3.5 6.6

1280 1104 1896

304 297 31R

394 393 388

332 371 278

395 384 424

91 87 106

4

C I Is

50 48 35

2.48 2 61 1.69

95 103 92

115/61 110/57 139/75

81 78 100

50 4.3 7.6

1296 1192 2312

314 310 329

386 389 391

303 332 278

434 431 469

120 121 140

5

c

80 81 68

2.64 2.70 2.16

66 67 63

127/72 129/73 154/87

94 95 115

4 1 4.6 83

1360 1344 1984

274 271 298

399 399 405

241 245 21 3

365 360 396

91 89 98

47 48 37

2.87 3 19 2.24

113 123 112

132/71 131/68 143/75

92 92 96

35 22 40

1336 1216 1784

318 315 320

389 394 378

356 390 357

440 425 450

122 110 130

I E

58 54 40

2 26 2 36 1 50

58 65 56

Ill/65 116/66 154/87

82 88 107

5.5 3.8 R.1

1832 1928 3568

283 294 2R3

385 388 355

20.5 221 198

387 392 423

8

C I E

59 60 40

2 65 2.89 1 74

84 90 81

107/59 105/57 120/68

76 74 88

55 5.0 72

1136 1024 1992

306 304 326

400 394 387

274 296 248

N.\f NM Nhl

9

C I E

56 56 48

2.38 2.70 1.93

73 83 70

124/72 120/6X 152/84

92 90 110

5.3 4.4 67

1688 1464 2400

303 298 30x

3x!, 392 382

242 279 227

414 197 431

111 99 123

10

C I E

51 50 40

1.82 1.91 1.32

67 72 63

102/53 97/47 117/64

71 64 81

52 4 1 69

1544 1328 236R

302 305 29x

387 388 365

221 216 211

406 404 4

104 99 118

MC‘?” Mea”

C I

P Mea”

E

57 58
2 45 2.68 <0.005 1.83
4.4 36
1480 1372
304 302 400 31s
394 395 500 386
267 2R7
402
105 100 050 120 <0 005

I E

c:

6

I E

c

7

P

82 87 <0 025 77 10 005

All data, including control values, Abbreviations as in Table 1.

Changes


were obtainrd

TABLE

Mean

Data

After

*

Change propranolal.

=

conlrol

t Per cent change

=

data

-10 72 -8

-1/+2 +I”, +321 +9 -9 -34 +23 +14

before

after proprannlol

Propranolol Per Cent Changet

p Value

Change*

-0


-I5


-23 -8

>0.500/<0.200 >o 500
propranolol

-

data before

+43 +28

-,I

control

change control

85 86 050 >0.500 99 001
III

in Control

Heart rate (beats/min.) Cardiac index (L./min./ M -1 Stroke volume (ml.) Pressure (mm. Hg) Brachial artery Brachial artery mea” Right atria1 mean TPR (dynes sec. cm -5.) Ejection time (maec.) EjPctio” time index (mxc.) MRLVE (ml./sec.) Q-2 interval (msrc.) Isometric period (msec.)

118/66 118/64 500/<0 138/76 OOl/
>0

propranolol

x

data

100.

after



I6 40s

<0

administration.

though the hypotensive effect of larger doses than were used in the present study may lead reflexly to alpha-mediated venoconstriction.r4Js Beta stimulation lowers mean right atria1 pressure by increasing cardiac emptying and reducing peripheral resistance. The failure of epinephrine, despite its beta-stimulating action, to lower mean right atria1 pressure may be due to its concomitant action of alpha-mediated venoconstriction. The present results clearly demonstrate that resting normal man propranolol in supine, produces significant decreases of cardiac output, heart rate, stroke volume and mean rate of left ventricular ejection, and increases of mean right atria1 pressure, total peripheral resistance and the isometric period. It should be noted that The our subjects did not appear apprehensive. bradycardiac effects of propranolol were conTHE

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.Adrenerg-ic

489

Blockade

0

CONTROL

m

CONTROL

w

ISOPROTERENOL

AFTER

PROPRANOLOL

80

60

-

40

600

2D

300

0 P < ,001

P c.025

BEFORE

AFTER

0 P<.Dol

1 P-z.001

AFTER

BEFORE

CARDIAC INDEX (L /mm /m 2,

-

N.S.

P<

BEFORE

01

AFTER PERIPHERAL RESISTANCE

HEART RATE (bwh/min)

tdwas-see-cm-51

FIG. 2. Effects of isoproterenol (2 to 2.5 pg./min. intravenously) before and after intravenous propranolol (10 mg.). Data from 10 normal subjects. The bars represent mean values ( fS.E.). firmed by unpublished studies of another 17 supine normal subjects, studied at rest without cardiac catheterization or previous medication other than placebo saline. In this group, heart rate slowed from 64 to 58 beats/min. (p < 0.01) during a 15 min. intravenous infusion of pro-

pranolol. These effects of propranolol nlay refleet its suppression of pre-existing beta adrenergic activity or may be due to a nonspecific direct, perhaps depressant, action on the heart. The present data do not indicate which mechanism is responsible.

TABLE IV

Effects of High Dose of Isoproterenol (12.5 pg./min.) After Propranolol Heart Rate (beats/ min.)

Subject*

2 3 4 5 6 7 8 9 10

60 72 60 110 58 73 62 67 68

MeaIl Control Pi

meant
70 57 005

Cardiac Index (L./min./ Mz.)

2 50 4 78 3 77 3 68 3 76 4.15 3 74 3.78 3.05 3 69 2 50
Stroke Volume (ml.)

,----~(mm. BA S/D

87 130 119 67 120 84 112 98 85

124/65 168/68 137/63 125/63 136/65 130/60 120/56 139/68 142/65

100 83 <0.005

136/64 119/66 <0.010/<0

PKSWreS Hg)-----_ B.4 R.4 Meall Mean

88 98 96 80 91 84 76 97 90

400

89 86 <0.400

* Subject 1, who did not receive a high dose of isoproterenol, is omitted. t Mean control data after propranololfor these 9 subjects. $p value for difference between control mean and high-dose isoprotercnol Abbreviations as in Tablr I.

VOLUME

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APRIL

1966

1.0 0.5 20 0.8 -1.9 -0.9 08 0.9 -1 1 02 46
mean,

TPR (dynes sec. cm-s.)

Ejection Time (msec.)

Ejection Time Index (msec.)

326 268 288 203 307 239 279 281 274

422 383 381 387 393 369 380 383 380

1336 832 1056 864 1064 1104 864 1176 1264 1062 1421
n = 9.

<0

274 303 005

386 394 <0.025

(ml./ XC.)

Q-2 Interval (mwc.)

Isometric Period (maec.)

266 485 413 327 391 351 401 349 310

439 318 368 NM 376 289 N,M 350 343

113 50 X0 NM 69 50 NM 69 69

MRLVE

366 273

355 415 005

71 108 10.005

Harris

490 0

EPINEPHRINE

m

EPINEPHRINE

et al. BEFORE AFTER

PROPRANOLOL PROPRANOLOL

20

L

IO

0

-10

CARDIAC (L /m1n

HEART

INDEX /In21

MEAN ARTERIAL PRESSURE (mm Hg)

STROKE

RATE

(beats / m,”

1

MEAN RIGHT ATRIAL PRESSURE (mm

VOLUME (ml

1

PERIPHERAL RESISTANCE (dynes-set-cm-51

Hg)

FIG. 3. Changes due to epinephrine (5 pg./min. intravenously) before and after intravenous propranolol (10 mg.). Data from 10 normal subjects. The bars represent mean changes from control (*S.E.) due to epinephrine. Those before propranolol are measured from control values before propranolol; those after propranolol from control values after propranolol. All changes are significant differences from control measurements except for the two indicated by asterisks.

Most previous investigators, using pronetha101, have not found significant hemodynamic changes resulting from beta adrenergic blockade in normal supine subjects at rest.16-z” In a group of 8 subjects without circulatory disease, SchrGder and Werk+ found that oral pronetha101 produced no significant changes in heart rate, cardiac output, stroke volume, or peripheral resistance. Bishop and &gel17 found that in a group of 5 normal subjects at rest, an “infusion of pronethalol decreased cardiac output 5 per cent and reduced the heart rate without changing stroke volume.” These studies differ from ours in several ways, including the beta adrenergic blocking agent used. Perhaps, in the doses given, propranolol blocks beta adrenergic receptors more effectively than does pronethalol. _ Positive inotropy inZZjection Time Index: creases the velocity of myocardial contraction

in isolated cardiac musclezl and in the intact left ventricle.” Determination of the duration of the phases of left ventricular systole provides a convenient means for demonstrating this relation in intact man. The ejection time index (left ventricular ejection time corrected for heart rate) varies directly with stroke volume6 and inversely with myocardial inotropy.23 Positive inotropy would appear to be implicated by a rise of stroke volume without prolongation of the ejection time index or by shortening of the ejection time index without a fall of stroke volume. In the present study, epinephrine increased stroke volume 21 per cent with minimal, if any, lengthening of the ejection time index, while isoproterenol elevated stroke volume 16 per cent with an actual fall in the ejecThese data are consistent tion time index. with an increase of inotropy by both catecholamines. The unequal effects on the ejection THE

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Beta Adrenergic index, despite comparable elevations of stroke volume, would suggest that inotropy was increased more by isoproterenol than by epinephrine. This interpretation is supported by studies of the isolated, perfused rat heartz4 and the open-chest dog preparationz5 which have demonstrated a considerably greater inotropic action for isoproterenol than for epinephrine. The shortening of the ejection time index by propranolol and by epinephrine after proprano101 may be explained, at least in part, by the fall of stroke volume. Isometric Period: Beta adrenergic activation appears to shorten the isometric period since isoproterenol and epinephrine caused a marked diminution before but not after beta receptor blockade. Indeed, with the emergence of alpha adrenergic activation during the administration of epinephrine after propranolol, the isometric period was actually lengthened. Q-2 Index: Preliminary analysis of unpublished data from 120 normal sub.jects indicates that the Q-2 interval can be corrected for heart rate by the regression equation: time

Q-2 index

= Q-2 interval

+

0.0021

heart rate

In the present study the Q-2 index (Q-2 interval corrected for heart rate) was significantly shortened by both isoproterenol and epinephrine before propranolol but was unaffected by either catecholamine after propranolol or by propranolol itself. These data suggest that the prolongation of the uncorrected Q-2 interval by epinephrine after propranolol could be accounted for entirely by the slowing of the heart rate. SUMMARY

The effects of beta adrenergic receptor blockade by propranolol on the hemodynamic responses to isoproterenol and epinephrine were investigated in 10 supine normal volunteers. Intravenous propranolol (10 mg.) lowered heart rate, cardiac output and stroke volume, raised mean right atria1 pressure and total peripheral resistance without affecting arterial pressure, and blocked almost completely the hemodynamic responses to 2 or 2.5 pg./min. of isoproterenol. An infusion of isoproterenol at 12.5 pg./min. partially overcame the beta blockade. During beta blockade most of the responses to an infusion of epinephrine at 5 Ng./min. were reversed, with heart rate, cardiac output and stroke volume decreasing, and arterial and mean right atria1 pressures and total peripheral resistance increasing. Before beta blockade the VOLUME 17, APRIL 1966

Blockade isometric period of left ventricular systole was shortened by isoproterenol and epinephrine. After beta blockade it was unaffected by isoproterenol but lengthened by epinephrine. The changes in control data produced by propranolol are consistent either with the blockade of pre-existing beta adrenergic activity or with a nonspecific direct, possibly depressant, action on the heart. The data demonstrate that beta adrenergic receptor blockade by propranolol may be used to unmask the potent alpha (vasoconstrictive) action of epinephrine in man. ACKNOWLEDGMENT We are indebted to Mr. Maury C. Koblentz, Commissioner of the Division of Correction, The Ohio Department of Mental Hygiene and Correction, and Warden Ernest L. Maxwell at the Ohio Penitentiary for their help in organizing this study. We are also grateful to Messrs. John Manos, Russell Smith, Wayne Rose, James Behrends, Paul Mahar and John Kuziak for their able technical assistance. REFERENCES 1. DALE, H. H. On some physiological actions of ergot. J. Physiol., 34: 163, 1906. 2. AHLQUIST, R. P. A study of the adrenotropic receptors. Am. J. Physiol., 153: 586, 1948. 3. POWELL, C. E. and SLATER, I. H. Blocking of inhibitory adrenergic receptors by a dichloro analog of isoproterenol. J. Pharmacol. &J E@er. Therap., 122: 480, 1958. 4. BLACK, J. W. and STEPHENSON, J. S. Pharmacology of a new adrenergic beta-receptor-b&king compound (nethalide). Lancet, 2: 311, 1962. 5. BLACK, J. W., CROWTHER, A. F., SHANKS, R. G., SMITH, L. H. and DORNHORST, A. C. .4 new adrenergic beta-receptor antagonist. Lancef, 1: 1080, 1964. 6. WEISSLER, A. M., HARRIS, L. C. and WHI.TE, G. D. Left ventricular e.jection time index in inan. J. Appl. Physiol., 18: 919, 1963. 7. RAAB, W., DEPAULA E SILVA, P. and STARCIIESKA, Y. K. Adrenergic and cholinergic influences on the dynamic cycle of the normal human heart. Cardiologia, 33: 350, 1958 8. SNEDECOR, G. W. Statistical Methods Applied to Experiments in Agriculture and Biology, ed. 5. Ames, Iowa, 1956. Iowa State College Press. 9. GOLDENBERG, M., PINES, K. L., BALDWIN, E. DEF., GREENE, D. G. and ROH, C. E. The hemodynamic response of man to norepinephrine and epinephrine and its relation to the problem of hypertension. Am. J. Med, 5: 792, 1948. 10. DODGE, H. T., LORD, J. D. and SANDIER, H. Cardiovascular effects of isoproterenol in normal subjects and subjects with congestive heart failure. Am. Heart J., 60: 94, 1960. 11. YOUMANS, P. L., GREEN, H. D. and DENISON, A. B., JR. Nature of the vasodilator and vasoconstrictor receptors in skeletal muscle of the dog. Circulation Res., 3: 171, 1955.

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