Europ. J. clin. Pharmacol. 7, 1-10 (1974) © by Springer-Verlag 1974

O R I G I N A L S

Effects of =- and t3-Receptor Blockade on Systolic Time Intervals

F. Frei, P. Imhof and U.C. Dubach Research Department, Pharmaceuticals Division, CIBA-GEIGY Limited, Basle, and the Department of Internal Medicine, Uni-

versity Medical Policlinic, Cantonal Hospital of Basle, Switzerland

Received: August 23, 1973, and in revised form: October 10, 1973

Summary. The effects of single oral doses of oxprenolol (20 and 80 mg), phentolamine (20 and 40 mg), and combinations of oxprenolol and phentolamine (80:20 and 20:40 mg, re- spectively) on blood pressure, heart rate and the systolic time intervals (Q-S2e, PEPe, LVETe and PEP/LVET) have been studied under double-blind conditions in seven healthy volun- teers during recumbency and passive tilting. Heart rate was slowed by oxprenolol and slightly increased by phentolamine, but was not affected by either of the combinations. There were only minimal non-significant changes in blood pressure in the subjects, all of whom were normotensive. Of the systolic time intervals, PEPe was most affected: it was prolonged by ox-

prenolol because of reduction in myocardial contractility, and shortened by phentolamine as a result of the cardiostimulant effect of this compound. When the two drugs were adminis- tered in combination, the negative inotropic effects of the fl- blocker always predominated. The changes induced by the drugs were more pronounced during upright tilting than in the recumbent position. Measurement of PEPe provides a suitable means of assessing the influence of cardiovascular drugs on left ventricular function in pharmacological studies in man.

Key words: v.- and fl-blockade, systolic time intervals, oxprenolol, phentolamine, man.

The determination of systolic time intervals recommended by Weissler et al. [55] affords a simple, non-invasive means of assessing the functional state of the left ventricle. Characteristic changes in systolic time intervals have been detected by this method in cases of heart failure [55, 56] and aortic stenosis [2, 22], after the administration of cardiostimulants [18, 39, 42, 54, 57] and cardiodepressive substances [18, 21, 25, 27, 28, 40] and during orthostatic tests [46, 47], Valsalva's manoeuvre [24], and isometric and dynamic exercise [26].

With the aid of this method, the effects on cardiac function in healthy volunteers of single oral doses of the fl-receptor blocker oxprenolol (Trasicor®) and the 0~-receptor blocker phentolamine (Regitin®), given alone and in combination, have been studied. Oxprenolol and phentolamine have opposite effects on the heart: oxprenolol reduces heart rate, the force of myocardial contraction and cardiac output [10, 34], whereas phentolamine has cardiostimulant pro- perties [3, 12, 14, 20, 43]. The investigations were undertaken to discover whether the opposing effects of the two compounds on the heart would be re- flected in the systolic time intervals and to find which would predominate after the administration of the two drugs combined in various ratios. The latter question seemed of particular interest in view of recent reports of the successful treatment of hyper- tension with this combination [49].

Material and Methods

The experiments were carried out on seven healthy male volunteers, aged 24 to 37 years (aver- age 28 years), and weighing 60 to 87 kg (average 69.5 kg). About one hour after a standardized light breakfast, the volunteers received the following single oral doses double-blind and in randomized order: Placebo Phentolamine 20 mg Phentolamine 40 mg Oxprenolol 20 mg Oxprenolol 80 mg Phentolamine 40 mg+Oxpreno lo l 20 mg (dose ratio 2:1) Phentolamine 20 mg+Oxpreno lo l 80 mg (dose ratio 1 : 4).

Altogether 49 tests were performed according to a strict time-table, in an air-conditioned room and always at the same time of day. Each volunteer had at least two days free of treatment between tests. Base-line values were determined after the subjects had lain flat for 10 min; the volunteers were then tilted at an angle of 70 ° and the measurements repeated after I, 3 and 5 min in this position. Since earlier studies had shown that both oxprenolol and phentolamine had their maximum effects between 60 and 120 min after administration, the same

Europ. J. clin. Pharmacol.j Vol. 7 I

2 F. Frei et al. : e- and #-Blockade and Systolic Time Intervals

measurements were repeated 90 rain after ingestion of the compounds.

In addition to systolic time intervals, blood pressure was recorded by the cuff method and heart rate was read from the E. C. G. tracing. To measure the systolic time intervals, the E. C. G., phonocardio- gram and carotid pulse were taken simultaneously. The E. C. G. was recorded with three chest electrodes (Be&mann Electrodes 650 418) applied at the corners of Nehb's triangle. The phonocardiogram was obtained at a frequency of 140 cycles by a heart- sound microphone (Philips 880-13-181) placed parasternalty at the level of the fourth or fifth left

PEP: pre-ejection period, the calculated dif- ference between Q-S2 and LVET.

PEP/LVET: this calculated quotient had the ad- vantage that, unlike the other three parameters, no correction for heart rate was needed.

The values obtained for Q-S~, PEP and LVET were corrected according to the standard formulae given by Weissler et aI. [55] for the regression lines corresponding to heart rate (Q-S2c, PEP°, LVETo). Means and standard errors of the mean ( ~ SEM) for each time interval were calculated from 20--30

Table t. Heart rate, blood pressure and systolic time intervals in the recumbent position and during passive tilting, Absolute values are given [or Q-S2, LVET and PEP; those [or

QA-S~e, A LVETe and A PEPe are corrected [or heart rate; mean :k SEM

Parameters Present Study Number of volunteers: 7 Number of tests: 49

Previous Report (47) Number of volunteers: 15 Number of tests: 15

o~ o o o 0~

i min 3 rain 5 rain 6 rain

HR/min 65±1 83~1 834-1 84~1 66±4 82±5 BP syst. 118±1 117±1 118~1 119~1 115~2 112~2 BP diast, (ram Hg) 71~1 87 !1 884-1 87d:1 67~2 814-3 Q--S~ (msec) 403±3 3584-3 356~2 3534-3 4084-8 3664-9 AQ--S2e -- --94-1 ~ I 0 + 1 ~ 1 1 1 1 -- ~ 6 ± 2 LVET 299+3 2294-2 227-4 -1 2254-2 3004-7 2334-7 A LVETe -- --404-1 --42±1 --434-1 -- --384-2 PEP 104±2 1294-2 129 i2 1284-2 1084-4 134+4 A PEPe -- 32-t-1 324-1 324-1 -- 32-I-2 PEP/LVET 0.348 0.564 0.567 0.571 0.36 0.58

4-0.006 4-0.007 4-0.007 4-0.007 4-0.01 4-0.02

intercostal space. The carotid pulse was recorded with an Infraton pulse sensor of the Brecht and Bouck~e type (Philips 880-13-281) fixed at the point of maximal pulsation of the carotid artery. All the records were made on a Cardiopan 3-channel electrocardiograph (Philips 573) at a paper speed of 100 mm/sec. Care was taken to ensure that the beginning and end of the recordings of the systolic time intervals always coincided with the same phase of respiration. The following time intervals were measured or calculated to the nearest 5 msec from 20--30 consecutive cardiac cycles (Fig. 1) : Q--S~: duration of electromechanical systole,

measured from the beginning of the QRS complex to the beginning of the second heart sound.

LVET: left ventricular ejection time, measured from the beginning of the ascending limb of the carotid pulse wave to the incisura (closure of the aortic valve).

consecutive cardiac cycles. To assess any effects of the drug, the differences between the values meas- ured before and after ingestion of the compound were calculated and compared with the differences found during administration of the placebo. Statisti- cal significance was determined by Student's paired t-test ( * = p < 0 . 1 ; * * = p < 0 . 0 1 ; ***=p<0.001) .

Results

I. Systolic Time Intervals before Drug Administra- tion: Effect of Passive Tilting

As shown in Table 1, the systolic time intervals measured both in the recumbent position and during passive tilting agreed with the normal values pub- lished by Stafford et al. [47]. Passive tilting to 70 ° resulted in an average increase of 18 beats per minute in heart rate and of 13 mm Hg in diastolic pressure, whereas systolic pressure remained unchanged. The

F. Frei et al. : ~- and/7-Blockade and Systolic Time Intervals 3

corrected duration of electromechanical systole decreased only slightly during tilting, by 9 - 1 1 msec (A Q-Seo); left ventricular ejection time, on the other hand, was notably shortened, by 40 -43 msec (A LVETo), and the pre-ejection period prolonged by 32 msec ( ~ PEP°). The PEP/LVET quotient increased from 0.35 to 0.57. The duration of passive tilting had no effect on these values, as almost identical changes were found after 1, 3 and 5 rain.

PEP = Q - S ~ , - - LVET

Fig. 1. Simultaneous recording of electrocardiogram, carotid pulse and phonocardiogram at a paper speed of 100 mm/sec. LVET = left ventricular ejection time, Q - S ~ = total electro-

mechanical systole, PEP = pre-ejection period

2. Effect o /~- and fl-Bloc£ade on Heart Rate and Blood Pressure

As compared with placebo, oxprenolol in doses of 20 and 80 mg led to aslight fall in heart rate during recumbency and reduced the orthostatic increase in heart rate (Fig. 2). These changes were not statistically significant (p<0.1) and were not related to the dose administered. Phentolamine caused a slight, non-significant increase in the heart rate while lying. However, the tachycardia produced by passive tilting was significantly increased to an extent proportional to the dose administered.

No effect on heart rate was found when oxpren- olol and phentolamine were administered together, and both dosage ratios (oxprenolol:phentolamine = 4:1 and 1 : 2) produced almost identical results. The effects of the two compounds on blood pressure were less clear-cut (Fig. 3). Both systolic and dia- stolic blood-pressures were widely scattered and no statistically significant effects could be demonstrated, although there was a tendency for both pressures to fall in response to the combination of oxprenolol 80 mg and phentolamine 20 mg.

3. Effect of ~- and fl-Bloc£ade on the Systolic Time Intervals

3.1 Q - S ~ (Fig. 4). The rate-corrected duration of electromechanical systole (A Q-S=~) in recum-

A HR beats/min

"101

-20-

supine

n,,7 ~..SEM

~Placebo A20 mg Phentolamine A40 mg Phentolamine 020 mg 0xprenolol ~80 mg 0xprenolol Q20 mg 0xprenolol + 40 mg Phentolamine ~B0 mg 0xprenolol + 20 mg Phentolamine

t {..

"+ :>=J<~:l:'l : ~ m < ~ . i . ~

g .i i i

1 min HUT 3 min HUT 5 min HUT

Figure 2 Fig. 2. Change in heart rate (A HR) before and 90 min after administration of placebo and active drug to recumbent subjects and after passive tilting for 1, 3 and 5 min. n = number of subjects, HUT = head-up tilt, R 4-SEM = mean 4-standard error of the

mean, * = p < 0.1, * * = p < 0.01, * * * = p < 0.001

1"

4 F. Frei et al. : ~- and/~-Blockade and Systolic Time Intervals

bency was not affected by the compounds tested, whereas after tilting for 5 rain it was significantly prolonged by oxprenolol alone and in combination with phentolamine. Phentolamine, on the other hand, led to a statistically non-significant reduc- tion in the duration of systole (p < 0.1), which was to a slight extent dose-related.

3.2 L V E T (Fig. 5). Phentolamine produced no change in the rate-corrected left ventricular ejection time (A LVET0) in comparison with a placebo. Oxprenolol alone, or in combination with phentol-

A SAP mm HG

nm7 ~±SEM

amine did show a slight tendency to shorten this interval, but not by a significant amount (p < 0.1).

3.3 PEP (Fig. 6). The pre-ejection period was the most markedly affected of all the systolic time inter- vals. Phentolamine produced a statistically signifi- cant decrease in the rate-corrected pre-ejection period (~, PEPc), whereas oxprenolol alone, and in combi- nation with phentolamine, caused a definite and statistically significant prolongation. The effects of phentolamine, and to a slight extent also of oxprenolol, were found to be dose-related. No

UPlacebo Z~20 mg Phentolamine &40 mg Phentolamine 020 ~g Oxprenolol 080 mg Oxprenolol ~20 mg Oxprenolol + 40 mg Phentolamine ~80 mg Oxprenolol + 20 mg Phentolamine

.5.!-t .lO,--t

A DAP mm HG

lmin HUT 3 min HUT 5 rain HUT

Figure 3

Fig. 3. Change in systolic (A SAP) and diastolic (A DAP) blood pressures before and 90 min after administrat ion of placebo and active drug to recumbent subjects and after passive tilting for 1, 3 and 5 rain. n = number of subjects, HUT = head-up tilt. R ±

SEM = mean-I- s tandard error of the mean, * = p < 0.1, ** = p < 0.01, **"~= p < 0.001

F. Frei et al. : a- and fl-Blockade and Systolic Time Intervals S

Z~Q-S2c rnsec

.20-

.10-

-10-

-20- supine

n=7 ~[-~ SEM

BPlscebo A20 mg Phentolamine A40 mg Phentolamine 020 mg 0xprenolol 080 mg Oxprenolol Q20 mg 0zprenolol + 40 ~g Phentolamine ~80 mg Oxprenolol + 20 mg Phentolamine

1 rain HUT 3 rain HUT 5 rain HUT

Rgure 4

Fig. 4. Change in rate-corrected total electromechanical systole (A Q - S 2 e ) before and 90 rain after administration of placebo and active drug to recumbent subjects and after passive tilting for 1, 3 and 5 rain. n = number of subjects, H U T = head-up tilt, 2 ±

SEM = mean-b standard error of the mean, * = p < 0.1, ** = p < 0.01, *** = p < 0.001

A LVET c m s e c

- 5 -

- 5 -

- I supine

n=7 ± SEM

mPlacebo 20 mg Phentolamlne

A40 mg Phentolamine 020 mg 0xprenolol 080 rag Oxprenolol Q20 mg Oxprenolol + 40 mg Phentol~mine ~80 mg 0xprenolol + 20 mg Phentolamine

t min HUT 3 rnin HUT 5 rain HUT

IP

Figure 5 Fig. 5. Change in rate-corrected left ventricular ejection time (LVETc) before and 90 min after administration of placebo and active drug to recumbent subjects and after passive tilting for 1, 3 and 5 rain. n = number of subjects, H U T = head-up tilt, R ~

SEM = mean i standard error of the mean, * = p < 0.1, ** = p < 0.01, *** = p < 0.001

6 F. l%ei et al.: e- and/3-Blockade and Systolic Time Intervals

A~E~

.20-

.~10.

-10-

nlsec n,,7 R t SEM

~PlaceDo ~20 mg Phen%olmmine A40 mg Phentol~mine 020 mg Oxprenolol ~80 mg Oxprenolol 020 mg Oxprenolol + 40 mg Phentolamine ~80 mg 0xprenolol + 20 mg Phentolamine

~ T

•

supine 1 min HUT 3 min HUT 5 min HUT

Figure 6

Fig. 6. Change in rate-corrected pre-ejection period (PEPo) before and 90 rain after administration of placebo and active drug to recumbent subjects and after passive tilting for 1, 3 and 5 rain. n = number of subjects, HUT = head-up tilt, .~ 4- SEM = mean 4-

standard error of the mean, * = l~ < 0.1, '~=~ = p < 0.01, "~':*-----p < 0.001

Z~.PEP/LVET n - 7 ~=SEM

* 0.050-

-0.050= supine 1 min HUT

MPlacebo A20 mg Phentol~mine A40 rag Phentola~ine 020 mg Oxprenolol 080 mg Oxprenolol ~20 mg Oxprenolol + 40 mg Phentolamine ~80 mg 0xprenolol + 20 mg Phentolamine

3 min HUT 5 rain HUT

Figure 7

Fig. 7. Change in PEP/LVET quotients before and 90 min after administration of placebo and active drug to recumbent subjects and after passive tilting for 1, 3 and 5 rain. n = number of subjects, HUT = head-up tilt, X 4-SEM = mean :k standard error of

the mean, * = p < 0.1, * * = p < 0.01, ~"=:'~'----p < 0.001

F. Frei et al. : e- and fl-Blockade and Systolic Time Intervals 7

difference was apparent between the effects of the two combinations.

3.4 PEP/LVET (Fig. 7). The alterations observed in the relation between these parameters (PEP/ LVET) after administration of the compounds resembled the changes noted in the pre-ejection period, i.e. phentolamine reduced the quotient and oxprenolol and the drug combinations increased it. Statistically significant differences, however, were less often demonstrable and the effects were not so clearly dose-dependent as were changes in the pre- ejection period. Again, there was no definite differ- ence between the effects of the two combinations.

Discussion

Systolic time intervals may be influenced by many factors.

Heart rate has little effect on PEP but a marked influence on LVET [55]. Both time intervals become shortened if heart rate is increased and prolonged if it is slowed. To eliminate the effects of changes in heart rate on the systolic time intervals, the corrected values of Weissler et al. [55] should be calculated (PEP°, LVETo). An increase in diastolic pressure prolongs PEP [41, 48, 53] and LVET [41], whilst a reduction has the contrary effect.

A fall in end-diastolic ventricular volume (de- creased stroke volume) with concomitant reduction of passive stretching of myocardial fibres leads to prolongation of PEP [17, 29, 48, 53] and to shorten- ing of LVET [17, 53, 58], and conversely, an increase in end-diastolic volume and thus greater passive stretching of the fibres shortens PEP and prolongs LVET. Myocardial contractility is the principal determinant of the systolic time intervals. An in- crease in contractility, whether due to digitalis [54, 57], elevated serum calcium concentrations [42] or exogenous catecholamines [18, 36], results in short- ening of PEP and LVET. If contractility is diminished, e.g. by E-blockade [18, 21, 25, 27, 28, 40], or by heart failure [55], PEP is prolonged, whilst LVET~ remains constant or falls in proportion to the severity of the cardiac failure. Given a constant stroke volume (preload) and constant aortic pressure (after-load), the duration of PEP and LVET is determined solely by myocardial contractility. The PEP/LVET ratio does not actually provide more information than either of its components, but it does have the advantage that it does not need to be corrected for heart rate. The duration of electro- mechanical systole, Q-S2, which corresponds to the sum of PEP and LVET, is subject to the same changes as its components.

The effects of fl-blocking compounds on systolic time intervals have been investigated by several authors.

Prolongation of PEP has been found after pro- pranolol and, to a lesser extent, also after practolol [18, 25, 40]. The PEP/LVET ratio has been reported to be increased after propranolol [27]. Hunt et al. [21] tested the effects of intravenous doses of pro- pranolol (10 mg), alprenolol (10 rag), oxprenolol (10 rag), practolol (40 mg), and pindolol (0.2 rag) and found that only propranolol prolonged PEP, whereas the other fl-blockers, all of which have in- trinsic sympathomimetic activity, either had no effect or even shortened it.

The effects of 0c-blocking agents on systolic time intervals have been little studied. Gould et al. [13] reported that PEP was reduced by 18 msec and LVETc prolonged by 15 msec after the intravenous administration of phentolamine, 0.3 rag/rain for 12 rain; the PEP/L\~T quotient also decreased from 0.312 to 0.240. There appear to have been no pre- vious studies of the effects of combinations of ~- and fl-receptor blockers.

Many acute cardiovascular effects of oxprenolol [5, 10, 15, 30, 34] and phentolamine [3, 6, 12, 14, 20, 33, 43] have already been described. Oxprenolol reduces heart rate and myocardial contractility, although to a slightly lesser extent than propranolol because of its intrinsic sympathomimetic activity. The decrease in cardiac output that it causes is almost entirely due to slowing of the heart rate, since stroke volume remains largely unchanged.

Total peripheral resistance increases slightly, which results in a small rise in diastolic pressure. The reduction in cardiac output and myocardial contractility causes a slight drop in systolic pressure, although the mean arterial pressure remains un- changed.

Phentolamine produces slight tachycardia and increases myocardial contractility and cardiac out- put. The increase in heart rate is partly a reflex response to vasodilatation and partly the result of fl-adrenergic stimulation. The vasodilator effect of phentolamine is attributable to blockade of ~-re- ceptors [31, 35], to a direct relaxing effect on vascular smooth muscle [50, 51], and possibly to stimulation of vascular fl-receptors [59]. It has been demonstrat- ed that phentolamine augments the synthesis and liberation of catecholamines [7, 8, 9]. Since total peripheral resistance falls, there is usually a slight drop in diastolic pressure.

The present investigations have confirmed the known effects of oxprenolol and phentolamine on the reduction in heart rate produced by recumbency

8 F. Frei et al.: ~- and fl-Blockade and Systolic Time Intervals

and the increase caused by passive tilting. When the two compounds were administered in com- bination no clear-cut effect on heart rate could be demonstrated. Blood pressure was not signifi- cantly affected by the compounds, although there was some tendency for systolic and diastolic pres- sures to decrease in response to the combination of 80 mg oxprenolol and 20 mg phentolamine.

Oral doses of oxprenolol of 20 and 80 mg pro- longed PEP~ in recumbency by 4.2 and 5.0 msec, respectively. In comparison with the changes pro- duced by propranolol [18, 25], this increase is negligible, probably because of the intrinsic sym- pathomimetic effect of oxprenolol. Phentolamine 40 mg shortened PEPe by 5.7 msec, a value consider- ably lower than the decrease of 18 msec reported by Gould et aI. [13] after intravenous injection of the drug. LVETc was inconsistently and not significantly shortened by oxprenolol, and was not affected by phento'amine. The PEP/LVET ratio rose signifi- cantly after oxprenolol and fell slightly after phentolamine. After the combined administration of oxprenolol and phentolamine the systolic time intervals did not differ from those recorded after the administration of oxprenolol alone. There was no difference between the effects of the two dosage ratios, which implies not only that the positive ino- tropic effects of phentolamine on the heart were negated by oxprenolol, but also that the inotropic action of the beta-blocker always predominated.

Only slight changes in the systolic time intervals were induced by the test preparations in recumbent subjects. Much greater effects were found during passive tilting, a stimulus which by itself leads to marked sympathicotonic circulatory responses [1, 4, 11, 16, 19, 23, 32, 37, 38, 44, 45, 52]. In control tests made before the preparations were administered, the overall duration of electromechanical systole, Q-S~o, during tilting diminished only slightly, whereas there was a marked increase of 32 msec in PEPs, and an equally marked decrease of 40--43 msec in LVET~. These orthostatic changes in the time intervals can be attributed chiefly to the greatly reduced stroke volume (--30 to --40%) [4, 52],which overrides the reduction of PEP° normally produced on tilting upright by greater release of catechol- amines. The recorded values of PEP° and LVETc are the resultants of changes affecting the time intervals in opposite ways, namely decreased stroke volume and increased sympathetic tone. After the adminis- tration of oxprenolol, the sympathetic effects on the heart due to tilting upright were blocked. In both doses and in both combinations with phentolamine, oxprenolol prolonged PEP° by 8--16 msec, which

was appreciably greater than the values of 4.2--5 msec recorded in the recumbent position. The effects of phentolamine were also more pronounced in the upright than in the recumbent position, PEP° being reduced by 10--17 msec as compared with 1.7-5.7 msec in recumbent subjects.

Thus, it may be concluded that under certain circumstances the determination of PEPo can provide reliable information about changes in the contractil- ity of the left ventricle, and that this parameter is suitable for the pharmacological evaluation of compounds acting on the cardiovascular system of man. It has also been demonstrated that the method is more sensitive if measurements are made in the upright position. Comparison of systolic time inter- vals showed that when oxprenolol and phentol- amine were administered in combination, the ino- tropic effects of the fl-blocker predominated over those of the s-blocker, even when the dosage ratio varied greatly. The chronotropic effects of the two compounds cancelled each other.

Acknowledgments. The authors wish to acknowledge the expert technical assistance of Mrs. H. Scherrer and Drs. L. Brunner and G. Keller.

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