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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., 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
THE
AMERICAN
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Beta Adrenergic
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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Beta
.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
17,
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.
Harris I>ANDE, I. s. and \2:HELAN, li. F. The effect of antagonists on the response of the forearm \esscls to adrenaline. ./. Plqsiol., 148: 548, 1959. 13. A~~wooo, M. J. and G~WXJRG, J. The effect of phenoxybenzamine (Dibenzyline) on the \-asculnr response to syinpathornimetic amines in the forearm. .J. Phvhvliol., 158: 219, 1961. 14. ECKSTEIN, J. \Y., \VENDLING, M. G. and ABBOUD, F. M. Forearm venous responses to stimulation of adrcnergic receptors. J. Clin. Inwrf., 44: II 51, 1965. 15. ECWWN, .J. \V. and HAMtLroN, W. K. Fffects of isoproterenol on peripheral venous tone and transmural right atria1 pressure in man. J. Clin. Znuest., 38: 342, 1959. 16. DORNI~ORSI’, .L\. G. and ROBINSON, B. F. Clinical pharmacology of a beta-adrenergic-blocking agent (nethalide). LancPt, 2: 314, 1962. 17. HIS~OP, J. M. and SEGEL, N. The circulatory effects of intravenous pronrthalol in man at rest and during exercise in the supine and upright positions. J. Physd., 169: 112P, 1963. 38. C~IAMBERLAIN, D. 12. and HOWARD, J. The haemodynamic effects of P-sympathetic blockade. &it. Jfear1 ~J., 26: 213, 1964. 19. IIARRISON, D. C. rt al. Effects of beta adrenergic blockade on the circulation with particular refer-
et al.
12. 1)~ LA
20.
ewe to observations in patients with hypcrtrophic subaortic stenosis. Circulation, 29: 84, 1964. Nethalide, a beta SCHRijD,,, G. and LVERKB, 1, adrrncrgic blocking agent. C/in. Pharmad. B
l‘hrral,., 5 : 157, 1964. 21. SONNENRI.ICK, E. H., BKAUNWALD,
E. and MORROW, :\. G. The contractile properties of huinan heart niuscle: Studies on myocardial mechanics of surgically excised papillary muscles. J. Clin. Znurs/., 44: 966, 1965. 22. LYALLACE, A G., MIXHELL, J. I-I., SIWNER, N. S. and SARNOFF, S. J. Duration of the phases of left ventricular systole. Circulation RPS., 12: 611, 1363. 2.3. \VEISSLER, A. M., GAMEL, IV. G., GRODE, 11. E., COHEN, S. and SCIIOBNFELD, C. D. The effect of digitalis on ventricular ejection in normal human subjects. Circulation, 29 : 721, 1964. 24. KUKOVWZ, 12:. R., HESS, M. F,., SHANFELD, J. and HAUGAARD, N. The action of sympathomirnetic amines on isometric contraction and phosphorylase activity of the isolated rat heart. .I. Pharnmcol. @
Eqw. 25. MAYER,
Y-hemp., 127: 122, 1959.
S. E. and MORAN, N. C. Relation between pharmacologic augmentation of cardiac contractile force and the activation of myocardial glycoC? RYfw. J. Phnrmncol. gen phosphorylase.
Tlzrra~., 129: 271, 1960.
THE AMERICAN JOURNAL
OF CARDIOLOGY
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
THE
AMERICAN
JOURNAL
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CARDIOLOGY
Beta Adrenergic
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:
THE AMERICAN
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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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Beta
.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
17,
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.
Harris I>ANDE, I. s. and \2:HELAN, li. F. The effect of antagonists on the response of the forearm \esscls to adrenaline. ./. Plqsiol., 148: 548, 1959. 13. A~~wooo, M. J. and G~WXJRG, J. The effect of phenoxybenzamine (Dibenzyline) on the \-asculnr response to syinpathornimetic amines in the forearm. .J. Phvhvliol., 158: 219, 1961. 14. ECKSTEIN, J. \Y., \VENDLING, M. G. and ABBOUD, F. M. Forearm venous responses to stimulation of adrcnergic receptors. J. Clin. Inwrf., 44: II 51, 1965. 15. ECWWN, .J. \V. and HAMtLroN, W. K. Fffects of isoproterenol on peripheral venous tone and transmural right atria1 pressure in man. J. Clin. Znuest., 38: 342, 1959. 16. DORNI~ORSI’, .L\. G. and ROBINSON, B. F. Clinical pharmacology of a beta-adrenergic-blocking agent (nethalide). LancPt, 2: 314, 1962. 17. HIS~OP, J. M. and SEGEL, N. The circulatory effects of intravenous pronrthalol in man at rest and during exercise in the supine and upright positions. J. Physd., 169: 112P, 1963. 38. C~IAMBERLAIN, D. 12. and HOWARD, J. The haemodynamic effects of P-sympathetic blockade. &it. Jfear1 ~J., 26: 213, 1964. 19. IIARRISON, D. C. rt al. Effects of beta adrenergic blockade on the circulation with particular refer-
et al.
12. 1)~ LA
20.
ewe to observations in patients with hypcrtrophic subaortic stenosis. Circulation, 29: 84, 1964. Nethalide, a beta SCHRijD,,, G. and LVERKB, 1, adrrncrgic blocking agent. C/in. Pharmad. B
l‘hrral,., 5 : 157, 1964. 21. SONNENRI.ICK, E. H., BKAUNWALD,
E. and MORROW, :\. G. The contractile properties of huinan heart niuscle: Studies on myocardial mechanics of surgically excised papillary muscles. J. Clin. Znurs/., 44: 966, 1965. 22. LYALLACE, A G., MIXHELL, J. I-I., SIWNER, N. S. and SARNOFF, S. J. Duration of the phases of left ventricular systole. Circulation RPS., 12: 611, 1363. 2.3. \VEISSLER, A. M., GAMEL, IV. G., GRODE, 11. E., COHEN, S. and SCIIOBNFELD, C. D. The effect of digitalis on ventricular ejection in normal human subjects. Circulation, 29 : 721, 1964. 24. KUKOVWZ, 12:. R., HESS, M. F,., SHANFELD, J. and HAUGAARD, N. The action of sympathomirnetic amines on isometric contraction and phosphorylase activity of the isolated rat heart. .I. Pharnmcol. @
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S. E. and MORAN, N. C. Relation between pharmacologic augmentation of cardiac contractile force and the activation of myocardial glycoC? RYfw. J. Phnrmncol. gen phosphorylase.
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