Br. J. clin. Pharinac. (1979), 7, 365-370
CARDIOVASCULAR EFFECTS OF PRENALTEROL (H 1 33/22) IN NORMAL MAN D.H.T. SCOTT, G.R. ARTHUR, R.N. BOYES & D.B. SCOTT Department of Anaesthetics, Royal Infirmary of Edinburgh, and Astra Clinical Research Unit, Edinburgh, Scotland
1 Prenalterol, (S-(-)- 1-(4 hydroxyphenoxy)-3-isopropylaminopropanol-2 hydrochloride) a cardioselective ,-adrenergic receptor agonist, was infused intravenously into six normal male volunteers to determine the cardiovascular effects of this drug. 2 On different occasions, each volunteer received a placebo infusion, an infusion of 0.5 mg prenalterol and an infusion of 1 mg prenalterol. Cardiac output (impedance cardiography), arterial pressure (sphygmomanometry), heart rate and ECG were measured throughout. 3 Prenalterol produced a statistically significant increase in cardiac output and at the end of the infusion this increase was 24% with 0.5 mg and 29% with 1 mg, mainly due to an increase in stroke volume (18% and 17%) with a lesser change in heart rate (+ 2 and + 7 beats/min). Pulse pressure increased but mean arterial pressure showed little change. Peripheral resistance fell by 18% and 20%. As indicated by systolic time indices myocardial contractility increased. 4 Prenalterol at plasma concentrations in excess of 20 nmol 1-l produced significant inotropic effects but did not markedly increase heart rate at concentrations of 60 nmol 1-1.
Introduction
Prenalterol (H133/22) is the (-) isomer of 1-(4hydroxyphenoxy)-3-isopropylaminopropanol-2 hydrochloride, and is structurally similar to several P-adrenergic receptor agonists and antagonists (Figure 1). Animal studies (Carlsson, Dahloff, Hedberg, Persson & Tangstrand, 1977), and later human studies (Johnsson, Jordo, Lundborg, R6hn, Welin-Fogelberg & Wikstrand, 1978) showed that the racemic mixture (H80/62) possessed f2-adrenergic receptor agonist properties while further work indicated that most of this activity was due to the (-)-isomer, prenalterol. The drugs were found to produce an
inotropic response in the heart with minimal chronotropic activity. This would have important advantages in clinical use, as the limiting factor in treatment with sympathomimetic drugs is often the development of excessive tachycardia and cardiac arrhythmias. This study was designed to assess the cardiovascular effects of intravenously administered prenalterol in normal volunteers. Methods
Six healthy male volunteers aged between 24 and 32 years (weight 60-81 kg) were investigated. All gave written informed consent to participate in the investigation which had received ethical approval from the appropriate hospital committee. Each volunteer 0306-525 1/79/040365-06$01.00
received three infusions in a double-blind manner and in random order, these being 20 ml saline, 0.5 mg prenalterol in 20 ml saline and 1 mg prenalterol in 20 ml saline. The three infusions were separated by a period of at least 1 week. Following a control period of 10 min the appropriate infusion was made into a vein on the dorsum of the right hand at the rate of 4 ml/min over a period of 5 min using a Harvard infusion pump. The volunteers remained supine throughout the infusion period and for the next 30 min. After this they could sit up but were returned to the supine position 5 min before each cardiovascular measurement. They were asked to report any
effects they felt. A Teflon catheter was introduced into a cubital fossa vein of the left arm and this was continually flushed by a slow saline drip. From this catheter blood samples were withdrawn for analysis of plasma drug concentrations. Samples were also taken for routine biochemical and haematological analysis. Intermittent recordings of thoracic electrical impedance, the rate of change of impedance (dZ/dt), electrocardiogram and phonocardiogram were made using an I.F.M./Minnesota Impedance Cardiograph (model 304A) and an ultraviolet chart recorder (Bell and Howell 5-133). The recordings were analysed using a digitizer (Ferranti Freescan) and a computer programme to determine stroke volume (SV), cardiac output (CO), heart rate (HR), pre-ejection period (PEP), left ventricular ejection time (LVET) and o Macmillan Journals Ltd 1979
366
D.H.T. SCOTT, G.R. ARTHUR, R.N. BOYES & D.B. SCOTT
OH
CH3
OCH2CHCH2NHCH
N1
\CH3
OH Figure 1 Chemical structure of prenalterol, S-(-)1- (4- hydroxyphenoxy)- 3- isopropylaminopropanol- 2 hydrochloride.
PEP: LVET ratio. SV was calculated using the formula of Kubicek, Kottke, Ramos, Patterson, Witsoe, Labree, Remple, Layman, Shoening & Carmela, 1974. PEP was measured from the R wave of the ECG to the start of the rapid change in dZ/dt, since the quality of the ECG obtained from the impedance cardiograph does not permit accurate determination from the Q wave. LVET was measured from the start of the rapid change in dZ/dt to the start of the second heart sound. This shows good correlation with standard methods of determining LVET (Hill & Merrifield, 1976). All data calculated from the impedance cardiograph were taken as the mean value of ten consecutive complexes, with the volunteer apnoeic for the few seconds required for the 10 heart beats. Arterial pressures were recorded using a semiautomatic digital sphygmomanometer (Parama UM15LN), mean arterial pressure (MAP) being calculated as diastolic + pulse pressure. Peripheral resistance (PR) was calculated as MAP divided by CO and expressed as the percent change from zero time. The above cardiovascular measurements were taken at -10, -5, 0, 3, 5, 10, 15, 20, 30, 45, 60, 90 and 120 min and with the exception of -10 and -5 min blood samples were taken at the same time intervals. The infusion lasted from 0 to 5 min. Blood samples were collected into lithium heparin tubes, separated and stored at -180C. Plasma concentrations of prenalterol were estimated at the research laboratory of Hassle AB, M6lndal, Sweden. The specific assay procedure involved extraction of the drug and added internal standard into ether followed by triacylation with heptafluorobutyric anhydride, solvent evaporation and injection on a gas chromatograph equipped with an electron capture detector (personal communication Magnar Ervik). The ECG was recorded continuously on a portable tape recorder (Medilog. Oxford Instruments) for a control period of up to 4 h prior to each infusion and then for 2 h afterwards. During the infusion and monitoring period the ECG and HR were continuously displayed. The taped ECGs were
analysed for arrhythmias using a Pathfinder High Speed ECG Analyser 3. Statistical analysis of the data was made by the Wilcoxon rank test, comparing the value at zero time with that at every time interval for each volunteer. Comparisons were also made between specific measurements during prenalterol infusion and the corresponding placebo infusion data. Results
Table 1 shows the control cardiovascular measurements, the mean change from those values and the range of change during the first 30 min. Statistically significant changes from either control or placebo measurements are also indicated in Table 1. Figure 2 illustrates the mean changes from zero time for heart rate, strok'e volume, cardiac output and PEP: LVET ratio.
Arterialpressure Both infusions of prenalterol were associated with an increase in systolic pressure in each volunteer. As shown in Table 1, the maximum mean increase of 14 mmHg occurred 10 min after the start of the 1 mg infusion. During the placebo infusion there was a slight decrease in systolic pressure but due to technical problems pressures were only measured in five placebo experiments, therefore statistical significance could not be attained. Diastolic pressure showed changes in the opposite direction to systolic pressure with a maximum decrease of 8 mmHg at 10 min with 1 mg, and 7 mmHg at 15 min with 0.5 mg. Conversely the placebo infusion was associated with a gradual rise in diastolic pressure which was maximal towards the end of the experiment (5 mmHg at 90 min) although this was not statistically significant. Mean arterial pressure was virtually constant in all experiments. Heart rate (Figure 2)
The most pronounced change in HR was in the placebo group, with a steady decrease throughout the experiment, amounting on average to 5 to 10 beats/min for the first 30 min and reaching 16 beats/min at 120 min. A small increase in HR occurred with the 1 mg infusion during the first 30 min. The maximum mean increase of 7 beats/min was reached at 5 min. Beyond 45 min the HR fell below control values. There were no statistically significant changes in mean HR with the 0.5 mg
infusion.
CARDIOVASCULAR EFFECTS OF PRENALTEROL
o co r CN N
o C I
I ? I
CX
000)0o z ?
?
r010
'-oN CE)'
CD CD l00 CD
C')0 C'
04MCX
_-N
I
I
bv-
o - * aL
CN
N0010
I I
I I I
I
_ I
+
I
++
r£.0'
1+1
I__
'-000 00N Ct + + +
+ +
0)1a00
'-I *
.
+ I + c
Naco0 Lo
00010
C' -i--
o
N- 00 00 -'
co
L oC-
0Nt10
367
CD
WI1N +11
+
+
++
N+
+
00w _ 00010 + ++ + + + N-
+
++
o 10C') 0)1
0
E E
ID
0
+ +I+
+
+
++ I CO r-
_-' N_
0 0 co co
_- I+
E
_) CD ++
U)
It
0 0
+
0-N'-
+1+
co
V
C')C'o +
o C'
LO)
_r- C14 _-
+
-)NI01-
+ +I
10
'-1+
+
Cv 10 N
N
+
C14C
0Nr- m
M)6 -+oC')
o
+
*
+ I
+
U)
*
0.
0
0
+1+ + 11+
+ +
+ +
C') 00- 00
Q)
C')0
o -W
I
+ I I
++
0
+
g
*
N
O1
It- 0
M 04
C4
++
+ 4
E0
I
I_-N
++
0 D
1- C-
+ I
+
+m
++
++ I
+ +l
oV)CV)N CV) C')t
'- 0 0
00N' m 04 It m
C
3
La
+
v-
V0. -5
C
++'+
I**
0
+ LO U)
*L
S
0 CE)
0
La La _ Lae '-'tO C )N
5omo * 0 CF W + I-
c
Co 0
+
E
+ S -
+-'sj1I
+'-N+
+C)0 C) UO 00 0 0 10
En
00C'r'*
£ aD
0
Q
0 0
M Lo OD
*5 D co 0 0 +-N
0 C 0
'a c C o 0
un
+
+11 I
++
+ I
co c 0.
1 v-
++-'*
C
m 0 0
'INt
Ctr
V-
.2-c 40
0
C 0
'-00 r- 14 - V~ ~ ~ ~ ~ ~ ~ ~ ~ ~~~~~~0
0 uz 1
+
0
+ C*3 L
++
w
N
*
1- +++
0 0
+ I + '-N +
++
+ 0)
0
co 0
-D c 0 0
'R
+1+ +
+
+1+
OD
c0o0C
COc + I I
++ °
+++
0o co 00 r- r-
r. co co 0D 0D0o
010
64 C1 C4
06 -
C')0
II **
o
o C0
5*o
L
CM
E
o
0
0 CM
0D V e
0
'-01 U1))0
°
0_ oo_
''oo_oo
'oo_
''oo_oo_
'-010
**. N0W'
'oo_
cC0
0
4U I-
'
[email protected]~
-a L 't c
E E
I
E co
-E E g .
J
WE
>E
.C 0cl 0 0 0 0
368
D.H.T. SCOTT, G.R. ARTHUR, R.N. BOYES & D.B. SCOTT
Cardiac output (Figure 2)
CO showed significant increases with prenalterol and decreases with placebo. A rapid mean increase to 29% at 5 min occurred with 1.0 mg and 24% with 0.5 mg. CO remained above control levels for 60 min after prenalterol, but decreased progressively with placebo infusion, reaching a minimum mean value of -22% at 120 min Peripheral resistance
Changes in PR were of similar magnitude to those of CO, but in the opposite direction, MAP being relatively stable. The mean decrease with 1 mg infusions was 20% at 5 min and 14% at 30 min. The corresponding figures for the 0.5 mg infusion were 18% and 11%. There was a steady increase in PR following the placebo infusion, reaching a mean of 30% at 120 min. Pre-ejection period
The PEP was shortened by both doses of prenalterol, this effect lasting 60 min. The maximum mean reduction was 20 ms with 1 mg and 15 ms with 0.5 mg. The placebo caused little change in PEP for the first 30 min, thereafter it increased slightly. Left ventricular ejection time
There was a reduction in LVET lasting 30 min with I mg prenalterol and 10 min with 0.5 mg. The maximum mean shortening was 25 ms with 1.0 mg and 10 ms with 0.5 mg. Initially there was little change in LVET following the placebo infusion, later a slight increase occurred. PEP:L VET ratio (Figure 2)
Figure 2 Mean changes from zero time; heart rate (AHR) beats min-' change, stroke volume (ASV) and cardiac output (ACO) % change, and PEP: LVET ratio (APEP:LVET) absolute change. Placebo infusion (-), prenalterol 0.5 mg (0), prenalterol 1 mg (-).
The PEP : LVET ratio was reduced for. 45 min with both prenalterol infusions, the maximum mean decrease being 0.059 with 1 mg and 0.050 with 0.5 mg. The placebo infusion caused no consistent change in PEP: LVET ratio until 45 min, thereafter there was a small but steady increase.
Stroke volwne (Figure 2)
Subjective effects
There was a mean increase in SV with both doses of prenalterol, being maximal at 5 min (17% with 1 mg and 18% with 0.5 mg). SV remained above control values for 60 min with 0.5 mg and throughout with 1.0 mg. SV decreased slightly with the placebo
One volunteer reported a sensation of being in a mildly stressful situation on both occasions that he received prenalterol. One other volunteer reported a similar feeling during the infusion of the low dose (0.5 mg). These effects were brief and ceased at the end of the infusion.
infusion.
CARDIOVASCULAR EFFECTS OF PRENALTEROL
60 -5
E
40
C
-5
co
a)
20
CD
a-
0 -10
0
10
60
30
Time'
90
|
120
(min)
Figure 3 Mean plasma prerialterol concentrations following 5 min infusion of 0.5img (0) and 1 mg (c).
Continuous ECG monitoring Apart from sinus arrhythmia vwhich was common in all experiments, the only abnorrmalities detected were two ventricular ectopic beats vwhich occurred in one volunteer soon after the end of t-he 1 mg infusion.
Plasma concentrations As shown in Figure 3, a maximium mean plasma concentration of 31 nmol 1-1 was atttained at the end of the 0.5 mg infusion. The correspo)nding value for 1 mg infusion was 63 nmol 1-1. Foll[owing an initial rapid decline in plasma concentrationis of prenalterol lasting approximately 45 min after sti opping the infusion, a prolonged P elimination phasea was observed. Since plasma sampling was terminat:ed at 120 min, it was impossible to make an accuIrate determination of plasma half-life. The plasma concentration daita in the present study indicate that significant inotrop ic effects of prenalterol can occur at concentratior is in the region of 20 nmol 1-', but concentration Is of 60nmoll-h were not associated with more than aa slight increase in HR.
Discussion
,B-adrenergic receptor agorlists are frequently employed in the management of patients requiring cardiovascular support (Goldiberg, 1977). Of the traditional drugs, adrenaline a]nd noradrenaline have a-receptor stimulating propertiies which may reduce blood flow to vital organs, espcecially the kidneys and have a marked tendency to c-ause tachycardia and arrhythmias. Isoprenaline, aIso prone to cause arrhythmias and tachycardia, produces vasodilation, especially in the muscle beds , such that the mean arterial pressure usually falls, despite an increase in cardiac output. Dopamine is s aid to produce a more
369
specific vasodilation of the renal, mesenteric, coronary and intracerebral circulations, but still retains aadrenergic receptor stimulating properties at higher doses. Moreover arrhythmias occur frequently as the dosage is increased (Goldberg, 1977). A cardioselective (f,) adrenoceptor stimulating drug should avoid the decreases in MAP caused by vasodilation. A drug with more pronounced inotropic than chronotropic properties would allow a greater increase in cardiac output before serious tachycardias occur. Dobutamine, a derivative of dopamine, which has recently been introduced as an inotropic agent with little chronotropic activity has a weak a-adrenoceptor stimulating effect and a very short duration of action (Tuttle & Mills, 1975; Jewitt, Mitchell, Birkhead & Dollery, 1974). Animal studies with prenalterol have shown that it is a selective /I-adrenoceptor agonist free from aadrenoceptor activity and with only minor chronotropic effects in doses sufficient to produce an inotropic response (Carlsson et al., 1977). The present study has demonstrated that in normal volunteers prenalterol produced a rise in cardiac output most of which is due to an increase in stroke volume. The heart rate changes from control were slight. The fall in peripheral resistance might have been the result of a direct effect of the drug; however the animal experiments did not demonstrate any significant vasodilator activity. Alternatively, the fall in peripheral resistance could be explained by a reflex reduction of vascular tone maintaining a constant mean arterial pressure despite the increase in cardiac output. As an absolute measurement of contractility, systolic time indices have their limitations, but they are simple, non-invasive and combine well with impedance cardiography. All three indices measured showed that prenalterol produced the changes expected from a drug with positive inotropic effects. It should be noted from Figure 2 that 0.5 mg produced inotropic effects which were only marginally less than 1 mg. The relative freedom from arrhythmias in the twelve drug infusions is encouraging. The fact that two ventricular extrasystoles were detected in one subject soon after the infusion of 1 mg is insufficient to predict an arrhythmogenic tendency of the drug in clinical use. The effects of the drug lasted considerably longer than the duration of the infusion. The increase in cardiac output following 1.0 mg was still statistically significant at 30 min when it was 17% above control values. Study of the individual plasma concentration curves seems to indicate that inotropic effects were present when the concentration exceeded 20 nmol 1-l. On the other hand even when the concentration was as high as 60 nmol l-' increases in HR were still only slight. From our data, the elimination half-life could not be
370
D.H.T. SCOTT, G.R. ARTHUR, R.N. BOYES & D.B. SCOTT
accurately determined but it appeared to be approximately 2 h. This volunteer study indicates that prenalterol could
be a useful addition to the range of cardiac stimulating drugs, and warrants further investigation in the treatment of cardiac dysfunction.
References CARLSSON, E., DAHLOFF, C.G., HEDBERG, A., PERSSON, H. & TANGSTRAND, B. (1977). Differentiation of
cardiac chronotropic and inotropic effects of betaadrenoceptor agonists. Naunyn-Schmiedeberg's Arch. Pharmac., 300, 101-105. GOLDBERG, L.I. (1977). Recent advances in the pharmacology of catecholamines. Intens. Care Med., 3, 233-236. HILL, D.W. & MERRIFIELD, A.J. (1976). Left ventricular ejection and the Heather Index measured by noninavasive methods during postural changes in man. Acta Anaesth. Scand., 20,313-320.
JEWITT, D., MITCHELL, A., BIRKHEAD, J. & DOLLERY, C.
(1974). Clinical cardiovascular pharmacology of dobutamine, a selective inotropic catecholamine. Lancet, ii, 363-367.
JOHNSSON, G., JORDO, L., LUNDBORG, P., RONN, O., WELIN-FOGELBERG, I. & WIKSTRAND, J. (1978).
Haemodynamic and tolerance studies in man with a new, orally active, selective ,B-adrenoceptor agonist H80/62. Eur. J. clin. Pharmac., 13, 163-170. KUBICEK, W.G., KOTTKE, F.J., RAMOS, M.U., PATTERSON, R.P., WITSOE, D.A., LABREE, J.W., REMPLE, W., LAYMAN, T.E., SHOENING, H. &
CARAMELA, J.T. (1974). The Minnesota impedance cardiograph-theory and applications. Bio-med. Engng., 9,410-416. TUTTLE, R.R. & MILLS, J. (1975). Dobutamine: development of a new catecholamine to selectively increase cardiac contractility. Circulation Res., 36, 185-196.
(Received June5, 1978)
CARDIOVASCULAR EFFECTS OF PRENALTEROL (H 1 33/22) IN NORMAL MAN D.H.T. SCOTT, G.R. ARTHUR, R.N. BOYES & D.B. SCOTT Department of Anaesthetics, Royal Infirmary of Edinburgh, and Astra Clinical Research Unit, Edinburgh, Scotland
1 Prenalterol, (S-(-)- 1-(4 hydroxyphenoxy)-3-isopropylaminopropanol-2 hydrochloride) a cardioselective ,-adrenergic receptor agonist, was infused intravenously into six normal male volunteers to determine the cardiovascular effects of this drug. 2 On different occasions, each volunteer received a placebo infusion, an infusion of 0.5 mg prenalterol and an infusion of 1 mg prenalterol. Cardiac output (impedance cardiography), arterial pressure (sphygmomanometry), heart rate and ECG were measured throughout. 3 Prenalterol produced a statistically significant increase in cardiac output and at the end of the infusion this increase was 24% with 0.5 mg and 29% with 1 mg, mainly due to an increase in stroke volume (18% and 17%) with a lesser change in heart rate (+ 2 and + 7 beats/min). Pulse pressure increased but mean arterial pressure showed little change. Peripheral resistance fell by 18% and 20%. As indicated by systolic time indices myocardial contractility increased. 4 Prenalterol at plasma concentrations in excess of 20 nmol 1-l produced significant inotropic effects but did not markedly increase heart rate at concentrations of 60 nmol 1-1.
Introduction
Prenalterol (H133/22) is the (-) isomer of 1-(4hydroxyphenoxy)-3-isopropylaminopropanol-2 hydrochloride, and is structurally similar to several P-adrenergic receptor agonists and antagonists (Figure 1). Animal studies (Carlsson, Dahloff, Hedberg, Persson & Tangstrand, 1977), and later human studies (Johnsson, Jordo, Lundborg, R6hn, Welin-Fogelberg & Wikstrand, 1978) showed that the racemic mixture (H80/62) possessed f2-adrenergic receptor agonist properties while further work indicated that most of this activity was due to the (-)-isomer, prenalterol. The drugs were found to produce an
inotropic response in the heart with minimal chronotropic activity. This would have important advantages in clinical use, as the limiting factor in treatment with sympathomimetic drugs is often the development of excessive tachycardia and cardiac arrhythmias. This study was designed to assess the cardiovascular effects of intravenously administered prenalterol in normal volunteers. Methods
Six healthy male volunteers aged between 24 and 32 years (weight 60-81 kg) were investigated. All gave written informed consent to participate in the investigation which had received ethical approval from the appropriate hospital committee. Each volunteer 0306-525 1/79/040365-06$01.00
received three infusions in a double-blind manner and in random order, these being 20 ml saline, 0.5 mg prenalterol in 20 ml saline and 1 mg prenalterol in 20 ml saline. The three infusions were separated by a period of at least 1 week. Following a control period of 10 min the appropriate infusion was made into a vein on the dorsum of the right hand at the rate of 4 ml/min over a period of 5 min using a Harvard infusion pump. The volunteers remained supine throughout the infusion period and for the next 30 min. After this they could sit up but were returned to the supine position 5 min before each cardiovascular measurement. They were asked to report any
effects they felt. A Teflon catheter was introduced into a cubital fossa vein of the left arm and this was continually flushed by a slow saline drip. From this catheter blood samples were withdrawn for analysis of plasma drug concentrations. Samples were also taken for routine biochemical and haematological analysis. Intermittent recordings of thoracic electrical impedance, the rate of change of impedance (dZ/dt), electrocardiogram and phonocardiogram were made using an I.F.M./Minnesota Impedance Cardiograph (model 304A) and an ultraviolet chart recorder (Bell and Howell 5-133). The recordings were analysed using a digitizer (Ferranti Freescan) and a computer programme to determine stroke volume (SV), cardiac output (CO), heart rate (HR), pre-ejection period (PEP), left ventricular ejection time (LVET) and o Macmillan Journals Ltd 1979
366
D.H.T. SCOTT, G.R. ARTHUR, R.N. BOYES & D.B. SCOTT
OH
CH3
OCH2CHCH2NHCH
N1
\CH3
OH Figure 1 Chemical structure of prenalterol, S-(-)1- (4- hydroxyphenoxy)- 3- isopropylaminopropanol- 2 hydrochloride.
PEP: LVET ratio. SV was calculated using the formula of Kubicek, Kottke, Ramos, Patterson, Witsoe, Labree, Remple, Layman, Shoening & Carmela, 1974. PEP was measured from the R wave of the ECG to the start of the rapid change in dZ/dt, since the quality of the ECG obtained from the impedance cardiograph does not permit accurate determination from the Q wave. LVET was measured from the start of the rapid change in dZ/dt to the start of the second heart sound. This shows good correlation with standard methods of determining LVET (Hill & Merrifield, 1976). All data calculated from the impedance cardiograph were taken as the mean value of ten consecutive complexes, with the volunteer apnoeic for the few seconds required for the 10 heart beats. Arterial pressures were recorded using a semiautomatic digital sphygmomanometer (Parama UM15LN), mean arterial pressure (MAP) being calculated as diastolic + pulse pressure. Peripheral resistance (PR) was calculated as MAP divided by CO and expressed as the percent change from zero time. The above cardiovascular measurements were taken at -10, -5, 0, 3, 5, 10, 15, 20, 30, 45, 60, 90 and 120 min and with the exception of -10 and -5 min blood samples were taken at the same time intervals. The infusion lasted from 0 to 5 min. Blood samples were collected into lithium heparin tubes, separated and stored at -180C. Plasma concentrations of prenalterol were estimated at the research laboratory of Hassle AB, M6lndal, Sweden. The specific assay procedure involved extraction of the drug and added internal standard into ether followed by triacylation with heptafluorobutyric anhydride, solvent evaporation and injection on a gas chromatograph equipped with an electron capture detector (personal communication Magnar Ervik). The ECG was recorded continuously on a portable tape recorder (Medilog. Oxford Instruments) for a control period of up to 4 h prior to each infusion and then for 2 h afterwards. During the infusion and monitoring period the ECG and HR were continuously displayed. The taped ECGs were
analysed for arrhythmias using a Pathfinder High Speed ECG Analyser 3. Statistical analysis of the data was made by the Wilcoxon rank test, comparing the value at zero time with that at every time interval for each volunteer. Comparisons were also made between specific measurements during prenalterol infusion and the corresponding placebo infusion data. Results
Table 1 shows the control cardiovascular measurements, the mean change from those values and the range of change during the first 30 min. Statistically significant changes from either control or placebo measurements are also indicated in Table 1. Figure 2 illustrates the mean changes from zero time for heart rate, strok'e volume, cardiac output and PEP: LVET ratio.
Arterialpressure Both infusions of prenalterol were associated with an increase in systolic pressure in each volunteer. As shown in Table 1, the maximum mean increase of 14 mmHg occurred 10 min after the start of the 1 mg infusion. During the placebo infusion there was a slight decrease in systolic pressure but due to technical problems pressures were only measured in five placebo experiments, therefore statistical significance could not be attained. Diastolic pressure showed changes in the opposite direction to systolic pressure with a maximum decrease of 8 mmHg at 10 min with 1 mg, and 7 mmHg at 15 min with 0.5 mg. Conversely the placebo infusion was associated with a gradual rise in diastolic pressure which was maximal towards the end of the experiment (5 mmHg at 90 min) although this was not statistically significant. Mean arterial pressure was virtually constant in all experiments. Heart rate (Figure 2)
The most pronounced change in HR was in the placebo group, with a steady decrease throughout the experiment, amounting on average to 5 to 10 beats/min for the first 30 min and reaching 16 beats/min at 120 min. A small increase in HR occurred with the 1 mg infusion during the first 30 min. The maximum mean increase of 7 beats/min was reached at 5 min. Beyond 45 min the HR fell below control values. There were no statistically significant changes in mean HR with the 0.5 mg
infusion.
CARDIOVASCULAR EFFECTS OF PRENALTEROL
o co r CN N
o C I
I ? I
CX
000)0o z ?
?
r010
'-oN CE)'
CD CD l00 CD
C')0 C'
04MCX
_-N
I
I
bv-
o - * aL
CN
N0010
I I
I I I
I
_ I
+
I
++
r£.0'
1+1
I__
'-000 00N Ct + + +
+ +
0)1a00
'-I *
.
+ I + c
Naco0 Lo
00010
C' -i--
o
N- 00 00 -'
co
L oC-
0Nt10
367
CD
WI1N +11
+
+
++
N+
+
00w _ 00010 + ++ + + + N-
+
++
o 10C') 0)1
0
E E
ID
0
+ +I+
+
+
++ I CO r-
_-' N_
0 0 co co
_- I+
E
_) CD ++
U)
It
0 0
+
0-N'-
+1+
co
V
C')C'o +
o C'
LO)
_r- C14 _-
+
-)NI01-
+ +I
10
'-1+
+
Cv 10 N
N
+
C14C
0Nr- m
M)6 -+oC')
o
+
*
+ I
+
U)
*
0.
0
0
+1+ + 11+
+ +
+ +
C') 00- 00
Q)
C')0
o -W
I
+ I I
++
0
+
g
*
N
O1
It- 0
M 04
C4
++
+ 4
E0
I
I_-N
++
0 D
1- C-
+ I
+
+m
++
++ I
+ +l
oV)CV)N CV) C')t
'- 0 0
00N' m 04 It m
C
3
La
+
v-
V0. -5
C
++'+
I**
0
+ LO U)
*L
S
0 CE)
0
La La _ Lae '-'tO C )N
5omo * 0 CF W + I-
c
Co 0
+
E
+ S -
+-'sj1I
+'-N+
+C)0 C) UO 00 0 0 10
En
00C'r'*
£ aD
0
Q
0 0
M Lo OD
*5 D co 0 0 +-N
0 C 0
'a c C o 0
un
+
+11 I
++
+ I
co c 0.
1 v-
++-'*
C
m 0 0
'INt
Ctr
V-
.2-c 40
0
C 0
'-00 r- 14 - V~ ~ ~ ~ ~ ~ ~ ~ ~ ~~~~~~0
0 uz 1
+
0
+ C*3 L
++
w
N
*
1- +++
0 0
+ I + '-N +
++
+ 0)
0
co 0
-D c 0 0
'R
+1+ +
+
+1+
OD
c0o0C
COc + I I
++ °
+++
0o co 00 r- r-
r. co co 0D 0D0o
010
64 C1 C4
06 -
C')0
II **
o
o C0
5*o
L
CM
E
o
0
0 CM
0D V e
0
'-01 U1))0
°
0_ oo_
''oo_oo
'oo_
''oo_oo_
'-010
**. N0W'
'oo_
cC0
0
4U I-
'
[email protected]~
-a L 't c
E E
I
E co
-E E g .
J
WE
>E
.C 0cl 0 0 0 0
368
D.H.T. SCOTT, G.R. ARTHUR, R.N. BOYES & D.B. SCOTT
Cardiac output (Figure 2)
CO showed significant increases with prenalterol and decreases with placebo. A rapid mean increase to 29% at 5 min occurred with 1.0 mg and 24% with 0.5 mg. CO remained above control levels for 60 min after prenalterol, but decreased progressively with placebo infusion, reaching a minimum mean value of -22% at 120 min Peripheral resistance
Changes in PR were of similar magnitude to those of CO, but in the opposite direction, MAP being relatively stable. The mean decrease with 1 mg infusions was 20% at 5 min and 14% at 30 min. The corresponding figures for the 0.5 mg infusion were 18% and 11%. There was a steady increase in PR following the placebo infusion, reaching a mean of 30% at 120 min. Pre-ejection period
The PEP was shortened by both doses of prenalterol, this effect lasting 60 min. The maximum mean reduction was 20 ms with 1 mg and 15 ms with 0.5 mg. The placebo caused little change in PEP for the first 30 min, thereafter it increased slightly. Left ventricular ejection time
There was a reduction in LVET lasting 30 min with I mg prenalterol and 10 min with 0.5 mg. The maximum mean shortening was 25 ms with 1.0 mg and 10 ms with 0.5 mg. Initially there was little change in LVET following the placebo infusion, later a slight increase occurred. PEP:L VET ratio (Figure 2)
Figure 2 Mean changes from zero time; heart rate (AHR) beats min-' change, stroke volume (ASV) and cardiac output (ACO) % change, and PEP: LVET ratio (APEP:LVET) absolute change. Placebo infusion (-), prenalterol 0.5 mg (0), prenalterol 1 mg (-).
The PEP : LVET ratio was reduced for. 45 min with both prenalterol infusions, the maximum mean decrease being 0.059 with 1 mg and 0.050 with 0.5 mg. The placebo infusion caused no consistent change in PEP: LVET ratio until 45 min, thereafter there was a small but steady increase.
Stroke volwne (Figure 2)
Subjective effects
There was a mean increase in SV with both doses of prenalterol, being maximal at 5 min (17% with 1 mg and 18% with 0.5 mg). SV remained above control values for 60 min with 0.5 mg and throughout with 1.0 mg. SV decreased slightly with the placebo
One volunteer reported a sensation of being in a mildly stressful situation on both occasions that he received prenalterol. One other volunteer reported a similar feeling during the infusion of the low dose (0.5 mg). These effects were brief and ceased at the end of the infusion.
infusion.
CARDIOVASCULAR EFFECTS OF PRENALTEROL
60 -5
E
40
C
-5
co
a)
20
CD
a-
0 -10
0
10
60
30
Time'
90
|
120
(min)
Figure 3 Mean plasma prerialterol concentrations following 5 min infusion of 0.5img (0) and 1 mg (c).
Continuous ECG monitoring Apart from sinus arrhythmia vwhich was common in all experiments, the only abnorrmalities detected were two ventricular ectopic beats vwhich occurred in one volunteer soon after the end of t-he 1 mg infusion.
Plasma concentrations As shown in Figure 3, a maximium mean plasma concentration of 31 nmol 1-1 was atttained at the end of the 0.5 mg infusion. The correspo)nding value for 1 mg infusion was 63 nmol 1-1. Foll[owing an initial rapid decline in plasma concentrationis of prenalterol lasting approximately 45 min after sti opping the infusion, a prolonged P elimination phasea was observed. Since plasma sampling was terminat:ed at 120 min, it was impossible to make an accuIrate determination of plasma half-life. The plasma concentration daita in the present study indicate that significant inotrop ic effects of prenalterol can occur at concentratior is in the region of 20 nmol 1-', but concentration Is of 60nmoll-h were not associated with more than aa slight increase in HR.
Discussion
,B-adrenergic receptor agorlists are frequently employed in the management of patients requiring cardiovascular support (Goldiberg, 1977). Of the traditional drugs, adrenaline a]nd noradrenaline have a-receptor stimulating propertiies which may reduce blood flow to vital organs, espcecially the kidneys and have a marked tendency to c-ause tachycardia and arrhythmias. Isoprenaline, aIso prone to cause arrhythmias and tachycardia, produces vasodilation, especially in the muscle beds , such that the mean arterial pressure usually falls, despite an increase in cardiac output. Dopamine is s aid to produce a more
369
specific vasodilation of the renal, mesenteric, coronary and intracerebral circulations, but still retains aadrenergic receptor stimulating properties at higher doses. Moreover arrhythmias occur frequently as the dosage is increased (Goldberg, 1977). A cardioselective (f,) adrenoceptor stimulating drug should avoid the decreases in MAP caused by vasodilation. A drug with more pronounced inotropic than chronotropic properties would allow a greater increase in cardiac output before serious tachycardias occur. Dobutamine, a derivative of dopamine, which has recently been introduced as an inotropic agent with little chronotropic activity has a weak a-adrenoceptor stimulating effect and a very short duration of action (Tuttle & Mills, 1975; Jewitt, Mitchell, Birkhead & Dollery, 1974). Animal studies with prenalterol have shown that it is a selective /I-adrenoceptor agonist free from aadrenoceptor activity and with only minor chronotropic effects in doses sufficient to produce an inotropic response (Carlsson et al., 1977). The present study has demonstrated that in normal volunteers prenalterol produced a rise in cardiac output most of which is due to an increase in stroke volume. The heart rate changes from control were slight. The fall in peripheral resistance might have been the result of a direct effect of the drug; however the animal experiments did not demonstrate any significant vasodilator activity. Alternatively, the fall in peripheral resistance could be explained by a reflex reduction of vascular tone maintaining a constant mean arterial pressure despite the increase in cardiac output. As an absolute measurement of contractility, systolic time indices have their limitations, but they are simple, non-invasive and combine well with impedance cardiography. All three indices measured showed that prenalterol produced the changes expected from a drug with positive inotropic effects. It should be noted from Figure 2 that 0.5 mg produced inotropic effects which were only marginally less than 1 mg. The relative freedom from arrhythmias in the twelve drug infusions is encouraging. The fact that two ventricular extrasystoles were detected in one subject soon after the infusion of 1 mg is insufficient to predict an arrhythmogenic tendency of the drug in clinical use. The effects of the drug lasted considerably longer than the duration of the infusion. The increase in cardiac output following 1.0 mg was still statistically significant at 30 min when it was 17% above control values. Study of the individual plasma concentration curves seems to indicate that inotropic effects were present when the concentration exceeded 20 nmol 1-l. On the other hand even when the concentration was as high as 60 nmol l-' increases in HR were still only slight. From our data, the elimination half-life could not be
370
D.H.T. SCOTT, G.R. ARTHUR, R.N. BOYES & D.B. SCOTT
accurately determined but it appeared to be approximately 2 h. This volunteer study indicates that prenalterol could
be a useful addition to the range of cardiac stimulating drugs, and warrants further investigation in the treatment of cardiac dysfunction.
References CARLSSON, E., DAHLOFF, C.G., HEDBERG, A., PERSSON, H. & TANGSTRAND, B. (1977). Differentiation of
cardiac chronotropic and inotropic effects of betaadrenoceptor agonists. Naunyn-Schmiedeberg's Arch. Pharmac., 300, 101-105. GOLDBERG, L.I. (1977). Recent advances in the pharmacology of catecholamines. Intens. Care Med., 3, 233-236. HILL, D.W. & MERRIFIELD, A.J. (1976). Left ventricular ejection and the Heather Index measured by noninavasive methods during postural changes in man. Acta Anaesth. Scand., 20,313-320.
JEWITT, D., MITCHELL, A., BIRKHEAD, J. & DOLLERY, C.
(1974). Clinical cardiovascular pharmacology of dobutamine, a selective inotropic catecholamine. Lancet, ii, 363-367.
JOHNSSON, G., JORDO, L., LUNDBORG, P., RONN, O., WELIN-FOGELBERG, I. & WIKSTRAND, J. (1978).
Haemodynamic and tolerance studies in man with a new, orally active, selective ,B-adrenoceptor agonist H80/62. Eur. J. clin. Pharmac., 13, 163-170. KUBICEK, W.G., KOTTKE, F.J., RAMOS, M.U., PATTERSON, R.P., WITSOE, D.A., LABREE, J.W., REMPLE, W., LAYMAN, T.E., SHOENING, H. &
CARAMELA, J.T. (1974). The Minnesota impedance cardiograph-theory and applications. Bio-med. Engng., 9,410-416. TUTTLE, R.R. & MILLS, J. (1975). Dobutamine: development of a new catecholamine to selectively increase cardiac contractility. Circulation Res., 36, 185-196.
(Received June5, 1978)
