The effects of beta1-adrenoceptor partial agonist ICI 118.587 on left ventricular function in patients with coronary heart disease

International Elsevier

339

Journal of Cardiology, 5 (1984) 339-349

IJC 00095

The effects of beta,-adrenoceptor partial agonist ICI 118.587 on left ventricular function in patients with coronary heart disease Markku Cardiovascular

J. Iktieimo

and Juha

T. Takkunen

Division, Department of Medicine, Oulu University Central Hospital, Oh,

Finland

(Received 9 May 1983; revision accepted 31 August 1983)

IkSheimo MJ, Takkunen JT. The effects of beta,-adrenoceptor 118.587 on left ventricular function in patients with coronary Cardiol 1984;5:339-349.

partial agonist ICI heart disease. Int J

We investigated the effects of a new selective beta,-adrenoceptor partial agonist, ICI 118.587, on left ventricular function in 14 patients with coronary heart’disease and a history of stable angina pectoris. The drug (0.2 mg/kg) increased peak left ventricular dp/dt from 1518 to 1993 mm Hg/sec (P-c0.001) and left ventricular V,., from 1.63 to 2.08 circ/sec (P < O.OOl),while left ventricular end-diastolic pressure decreased (P -c0.05). Measured by echocardiography, the fractional shortening of the left ventricular minor axis diameter and the mean velocity of the left ventricular circumferential fiber ihortening increased (P < 0.001) and the cardiac index increased by 34%, reflecting increased contractility mainly in the normaI left ventricular wall areas. In coronary heart disease, ICI 118.587 increased left ventricular muscle contractility and output without untoward side effects in the majority of the patients.

Introduction

.

To increase cardiac contractility and thus improve cardiac output has been one cornerstone in drug treatment of the failing heart. Digitalis glycosides have been in use for nearly 200 years, but their value has recently been questioned for chronic use in patients with cardiac failure and sinus rhythm [1,2]. Catecholamines have potent inotropic properties, but they are also chronotropic and arrhythmogenic and result

Correspondence and reprint requests to: Markku J. IkBheimo, M.D., Dept. of Medicine, OuIu University Central Hospital, SF-90220 OuIu 22, Finland. 0167-5273/84/$03.00

0 1984 Elsevier Science Publishers B.V.

340

in increased myocardial oxygen consumption. Hence, several drugs have recently been developed having sympathomimetic activity on the heart but few side effects. ICI 118.587 (Corwin, 1-4-(hydroxyphenoxy)-3-[2-(morpholinecarboxamido)ethylaminolpropan-2-01) is a selective beta,-adrenoceptor partial agonist whose maximal activity is only 43% of that of the maximal effect of isoprenaline, measured in dogs [3]. In normal volunteers ICI 118.587 alters the relationship between the sympathetic stimulus to the heart and its response so that at rest and during moderate physical activity the response is increased while during severe activity the response is decreased [4]. These changes in the response of the heart are seen as an increase in contractility at rest and a decreased rate response during exercise. In coronary artery disease, however, the increased oxygen consumption of the viable myocardium caused by increased contractility may lead to myocardial ischemia and hence the net effect could be deleterious to cardiac function. The aim of our study was to investigate the inotropic effects of ICI 118.587 in patients with coronary heart disease and a history of stable angina pectoris, with special attention to its effects on regional left ventricular wall movements and on the side effects of the drug. Patients

and Methods

Fourteen patients with known or suspected coronary artery disease taken to our hospital for coronary angiography were included in the study (10 males and 4 females, mean age 47 years, range 31 to 57 years). All patients complained of grade III-IV exertional angina pectoris (grading of the New York Heart Association). The exclusion criteria were: symptoms or history of bronchial asthma, any established arrhythmias, grade II-III atrioventricular block, any evidence of a high sympathetic tone at rest (resting heart rate of 110 beats/mm or more), valvular disease, pre-menopausal females, renal, hepatic, hemopoietic or endocrine disorders, and chronic drug therapy for diseases other than those affecting the cardiovascular system. Beta-blocking or other drug therapy was discontinued for at least 3 days before the study. Informed consent was obtained from every patient. Preliminary Fxhocardiographic Study This study was performed the day before coronary angiography, with the patient lying on the left side, and the upper body slightly tilted up. Basal measurements were made immediately and after lying for a half an hour. A placebo solution and cumulative doses of 25, 50, 100 and 200 pg/kg body weight of ICI 118.587 diluted in 10 ml 5% glucose solution were then injected intravenously over a period of 2 min at lo-15 min intervals. Ten to 15 min after each injection cuff blood pressure measurements and echocardiographic examinations were made. The cardiac rhythm was continuously observed using an ECG monitor. The echocardiographic examinations were made with an ATL Mark III real-time echocardiographic system using a mechanical sector transducer with a 90” angle and a frequency of 3.0 megaHertz. The M-mode echocardiogram, electrocardiogram and

341

carotid pulse tracings were recorded with a Honeywell fiber-optic recorder equipped with a black and white adapter using 3M-Dry Silver paper and 50 mm/set paper speed. M-mode echocardiograms were recorded by the same echocardiographer using an accurate standard technique routinely employed in this laboratory [5]. The left ventricular end-diastolic diameter (LVDd) was measured at the beginning of the Q wave in the electrocardiogram and the left ventricular end-systolic diameter (LVDs) was taken to be the shortest distance between the interventricular septum and the left ventricular posterior wall in systole. The left ventricular volumes were calculated using the prolate ellipse formula, and the cardiac output was calculated as the product of the left ventricular stroke volume and the heart rate. Fractional shortening of the left ventricular minor axis diameter in systole (FS) was calculated as (LVDd-LVDs)/LVDd X 100. The mean velocity of the left ventricular circumferential muscle fiber shortening (mVCF) was calculated as previously described [6], using in the calculation the left ventricular ejection time measured from the simultaneously recorded carotid pulse tracing. The regional left ventricular wall movements were estimated visually with the cross-sectional echocardiographic system using the parasternal long axis, the short axes at the mitral valve and papillary muscle levels, and also apical four- and two-chamber views. Hence the left ventricular wall was divided into basal septal, apical septal, apical, diaphragmatic, posterobasal, anterobasal, anterolateral, superior lateral and inferolateral segments. After the procedure, the cardiac rhythm was monitored until the next morning and analysed by a Medilog (Oxford Instruments) 24-hr ECG tape recording system. Pulse rate and cuff blood pressure were measured every half hour during the first 2 hr after the investigation and then every hour for at least the 3 following hr. Hemodynamic

Study

The morning after the preliminary study routine biplane left ventricular cineangiography and coronary arteriography were done without any premeditation. Twenty minutes after the procedure a pig-tail left ventricular catheter was introduced and basal aortic and left ventricular pressures were measured. After that cumulative doses of 100 and 200 pg/kg of ICI 118.587 were injected intravenously at IO-mm intervals and at 10 min after each dose the left ventricular pressures, dp/dt and V max were measured using a Statham P 231a pressure transducer and a Hewlett Packard 5600B data acquisition system. The adequacy of extrapolation for V,,, was checked visually from the monitor screen. The catheter was then immediately pulled back to the aortic root and the aortic pressures were measured. After the study, pulse rate and cuff blood pressure were measured approximately every half hour for the following 6 hr. Laboratory Measurements Venous blood samples were taken before the first study and 24 hr after the hemodynamic study for the measurements of blood hemoglobin, packed cell volume, mean corpuscular volume, erythrocyte sedimentation rate, white cell count, white

342

cell differential count, platelets, blood film, blood sugar, albumin and total protein, serum sodium, potassium, chloride, bicarbonate, urea, calcium, creatinine, bilirubin, alkaline phosphatase, alanine aminotransferase, aspartateaminotransferase and creatine phosphokinase. A urine sample was taken for cell counting and qualitative estimation of urine glucose and protein.

statistics Estimates for the linear, quadratic and cubic trends were made to find the line of best fit, the significance of which was tested by Student’s t-test. Pre- and post-dose laboratory values were compared using paired r-tests.

Results The clinical, electrocardiographic, echocardiographic and angiographic data of the patients are presented in Table 1. In 4 patients there were signs of previous myocardial infarction in the ECG, echocardiographic investigation or left ventricular cineangiography. Four patients had one-vessel, 2 patients had two-vessel and 6 patients had three-vessel coronary artery disease (2 50% stenosis of the artery). In echocardiography regional abnormalities of left ventricular wall movements were found in 7 patients.

Preliminary Study The preliminary echocardiographic study was made in all 14 patients. ICI 118.587 caused a linear increase in mean systolic pressure (Fig. 1, Table 2) and it was higher than the baseline value after all doses. With 25 pg/kg cumulative dose it was lower than with 50 pg/kg (P < 0.05), with 100 pg/kg (P < 0.05) or with 200 pg/kg (P < 0.01). The mean diastolic blood pressure did not increase significantly from the

mmHg, SBP

150

I

1 4

1

Basehne

25

Fig. 1. Systolic and diastolic

50

L

100

blood pressures

1

200 ugl during

kg

the preliminary

study.

M

M

M F

M

F F

M M

M

M

4

5

6 7

8

9 10

11 12

13

14

44

44

41 40

44 51

54

44 57

46

51

39 54 45

Age (Y0

ECG

Q II,III,aVF

Q Ill, aVF

T inv V 2-5 normal

normal QS v 1-3

normal

normal normal

QS v l-3

normal normal T inv aVL. v l-4 normal

Resting

echocardiographic test

105 W, angina, no ST changes 90 W, angina, no ST changes

normal not done

75 W,2mmSTJ 50W,3mmST3-

30 W, angina, no ST changes 135 W. angina, 4 mm ST1 2OOW,4mmSTl 50 W, no ST changes not done

150 W. 2 mm ST1 normal 30 W, 3 mm STJ

Exercise

and angiographic

A

minor coronary changes 75% LAD, Cx total occlusion, 50% Rc, 50% PDA 75% LAD, 75% Cx. Rc total occlusion 50% LAD, 50% Cx, 50% LOM, 90% Rc

50% LM, LAD total occlusion, 75% Cx, 75% LOM, 75% Rc minor coronary changes 90% LAD, 50% Cx. 75% LOM, 75% Rc

190

201 241

47 45

59 124 41 207 anterolateral and inferior H, apical 62 133 60 198

66

48 258 apicoseptal A 59 189 54 114

total LAD 90% 50%

occlusion of proximal and distal Rc LAD LAD

164

45

75% PDA, 50% Rc

D

ml

LVEDV = LV end-diastolic volume; H = hypokinesis; A = akinesis; D = dyskinesis. Cx = circumflex: LOM = left obtuse marginalis: Rc = right; PDA = posterior descend-

inferior

apical A, other H

normal normal

normal basal septal and anterolateral H

normal

H except normal basal septal and posterior septal AD, inferolateral H inferolateral H normal

H

174 150 170

LV cineangiography EF% LVEDV 61 61 55

75% LM, 75% LAD, 75% Rc 75% LAD 90% LAD

normal normal anterolateral

angiogram

Coronary

LV wall movements in 2-D echo

data.

LV = left ventricular; 2-D = cross-sectional; EF = ejection fraction; Coronary arteries: LM = left main: LAD = left anterior descending: ing; numbers indicate the percentile narrowing of lumen diameter.

M F M

1 2 3

Sex

electrocardiographic,

Clinical,

Patient

1

TABLE

2

88.8

+16.4

85.9

515.4

134 k15.8 86 k12.1 64 + 6.7 3.3 + 0.78 0.96+ 0.18 29.1 + 5.9 156.2 k42.7 58.2 *27.3

Pre dose 2

83.8

k17.4

133 k15.3 86 * 9.9 63 f 6.8 3.3 * 0.83 0.98+ 0.18 29.5 * 5.3 155.7 t40.2 56.1 k24.5

Placebo baseline

BP = blood pressure; mVCF = mean velocity of left ventricular circumferential axis diameter in systole; LV = left ventricular; EDV = end-diastolic volume; * P 4 0.05, ** P < 0.01, *** P -c 0.001.

Rate-pressure product (mm Hg/minxlO’)

)

136 f 17.5 84 + 14.5 65 i 8.1 3.6 5 0.95 0.995 0.17 29.4 + 5.1 162.1 k44.1 58.6 +22.4

Pre dose 1

study.

Systolic BP (mm Hg) Diastolic BP (mm Hg) Heart rate (beats/mm) Cardiac index (l/min per mz mVCF (circ/sec) FS (g) LV EDV (ml) LV ESV (ml)

Results of the preliminary

TABLE

f 17.0 **

98.1

522.4

***

99.8

k21.0

muscle fiber shortening; FS = fractional shortening ESV = end-systolic volume. Mean f SD. Difference

95.3

100 pg/kg

200 n g/kg

106.3

k22.7

*** of left ventricular minor from baseline (placebo):

***

+20.5 *** 146 +17.4*** 149 + 23.9 *** k10.5 86 f 10.1 88 *12.4 f 8.1 ** 68 f 8.6 *** 71 + 6.7 *** + 0.10 *** 4.1 + 0.12 *** 4.5 * 0.13 *** rt 0.22 *** 1.30+ 0.28 *** 1.35? 0.26 *** + 6.3 *** 36.6 i 7.0 *** 38.4 f 7.2 *** f48.6 157.9 k 46.3 158.4 +51.9 k29.2 *** 43.9 * 30.3 *** 39.9 f 23.3 ***

50 pg/‘kg

dose

140 f 13.7 * 146 84 + 9.9 85 68 f 7.5 *** 67 3.9 * 0.12 ** 4.0 1.19k 0.24 *** 1.25 33.7 + 6.8 *** 35.5 152.9 k44.9 157.6 46.6 k 27.7 *** 45.5

25 pg/kg

ICI 118.587 cumulative

345

v. GO

r .

30

/ I --l_ I

Baseline

25

50

Fig. 2. Fractional shortening cardiographic study.

200

100

uglkg

of the left ventricular

minor

axis diameter

during

the preliminary

echo-

baseline (Fig. 1). The heart rate increased significantly, but there was no significant dose-related trend for heart rate. The mean left ventricular end-diastolic diameter and corresponding end-diastolic volume did not change significantly, but there was a linear decrease in the left ventricular end-systolic diameter and corresponding volume (P < 0.001). With the 200 pg/kg cumulative dose the end-systolic volume was lower than with 25 pg/kg, 50 pg/kg and 100 pg/kg (P -c0.01, P < 0.01 and P -e0.05, respectively). The mVCF increased linearly and with 25 pg/kg it was lower than with 100 pg/kg (P < 0.01) or with 200 pg/kg (P < 0.001). With the 50 pg/kg cumulative dose it was lower than with 200 pg/kg (P < 0.01). FS also increased linearly (Fig. 2) and with 25 pg/kg it was lower than with 50,100 and 200 pg/kg (P -c0.05, P < 0.01 and P < 0.001, respectively). With 200 pg/kg it was higher than with 500 and 100 pg/kg (P -c0.01 and P -c0.05, respectively). Cardiac index increased linearly and with the 200 pg/kg cumulative dose it was higher than with 25, 50 and 100 pg/kg (P < 0.001, P < 0.01 and P < 0.05, respectively) (Fig. 3).

_L I

Baseline Fig. 3. Cardiac

I

25

index during

50

100

the preliminary

200

“g/kg

echocardiographic

study.

346

In cross-sectional echocardiographic studies in those 7 patients with regional abnormalities of left ventricular wall muscle contraction, the abnormal wall movements remained unchanged in relation to the normal areas after the drug doses except that in patient no. 5 the inferolateral hypokinesis normalised and in patient no. 13 the hypokinetic inferior wall became dyskinetic without causing angina1 pain. Two patients felt a warm sensation and 1 patient an “odd” sensation and 1 patient complained of chest palpitation without rhythm disturbances in the ECG monitor. There were no rhythm disturbances during the study. In 11 patients ECG tape recording was made after the study until the next morning and in 4 patients occasional unifocal (in 1 patient also bifocal) ventricular ectopic beats were found without any clustering in the post-study hours. No side effects were reported after the study. Hemodynamic

Study

A complete hemodynamic study was made in 11 patients. Patient no. 8 inadvertently received a beta-blocking drug the next morning after the preliminary study and patient no. 9 was found to be leucopenic (blood sample taken before the preliminary study), and thus the hemodynamic study was not done. After the first drug dose in the hemodynamic study, patient no. 10 complained of angina1 pain; LVEDP increased from 16 to 31 mm Hg, ST segment depressions and ventricular ectopy were found in the ECG, and therefore the second drug dose was not given. In the other patients no side effects were found during or after the hemodynamic study. The heart rate increased significantly after the drug doses (Table 3) and with the 200 pg/kg cumulative dose it was significantly lower than with 100 pg/kg (P < 0.05). The systolic blood pressure increased after the 200 pg/kg cumulative dose (P -c0.05) and LV peak systolic pressure also increased (P < 0.05), but the difference in the results between baseline and 100 pg/kg was not significant. The 200 pg/kg dose caused a significant increase in the diastolic aortic pressure (P -c0.05). The 200 pg/kg dose caused a decrease in left ventricular end-diastolic pressure (P -c0.05)

TABLE

3

Results of the hemodynamic

study. Baseline

ICI 118.587 200 n g/kg

100 pg/kg Heart rate (beats/mm) Systolic BP (mm Hg) Diastolic BP (mm Hg) LV peak pressure (mm Hg) LV EDP (mm Hg) LV dp/dr (mm Hg/sec) LV Vma,(circ/sec)

68 f 7.5 125 + 14.5 80 + 5.2 125.3 + 15.3 10.8 k 3.4 1518.3 * 267.8 1.635 0.21

79

*

6.9 ***

130.6 f 22.8 8.7 f 7.4 2027.8 k461.6 *** 2.12* 0.40 ***

BP = blood pressure; LV = left ventricular; EDP = end-diastolic * P c 0.05, ** P c 0.01. *** P -e 0.001. Number of patients = 11.

pressure.

74 134 83 128.6 7.2 1993.4 2.08 Difference

+ 8.6 * + 20.4: k 7.8 * + 12.3 * f 4.1 * k431.9 *** + 0.34 *** from

baseline:

347

mmHg/sx

10~

clrc ZIS

.I --__

2( I-

LV Vmax LV dpldt

1

1.0 a

Baseline

100

Fig. 4. Left ventricular dp/dt

200 uglkg and V,.,

during the hemodynamic

study.

but there were no significant differences in the results between 100 and 200 pg/kg doses. LV dp/dt and LV V,,,increased significantly (P -cO.OOl), but the differences in the results between 100 and 200 pg/kg doses were not significant (Fig. 4).

Laboratory Values Monocytes and bicarbonate values were higher after the two studies (P < 0.05) and the total plasma protein also decreased (P < O.Ol), but there were no abnormal values in individual patients. In other laboratory values there were no significant differences.

Discussion As previously found [3,4], ICI 118.587 also had a positive inotropic effect on left ventricular function in our patients. The mVCF, FS, V,,,and LV dp/dt all increased significantly after the drug doses in spite of decreasing LVEDP, while the mean systolic blood pressure only increased up to 16 mm Hg and the diastolic blood pressure increased only minimally. The increases in blood pressure, mVCF and FS in the preliminary study were fairly linear and thus apparently dose-dependent. The increase in the heart rate was small although significant and there was no significant trend for heart rate. The LV dp/dt and V,,,decreased, although insignificantly, after the second drug dose, being inconsistent with the linear increase of mVCF and FS in the preliminary study. LV dp/dt and V,,,were measured through a fluid-filled left ventricular catheter, which is inaccurate for absolute values of V,,,,

348

but more reliable for measurement of serial changes. Those hemodynamic measurements reflect global left ventricular function, whereas standard M-mode echocardiography measures the function of the left ventricular posterior wall and the basal interventricular septum, areas which possibly most often remain intact in patients with advanced coronary artery disease. Movements of those areas were normal in 11 of our 14 patients. In pressure measurements enhancement of the movements of normal areas of the left ventricular wall caused by sympathomimetic stimulation may be balanced by opposite effects on abnormal areas because of disproportion between oxygen consumption and supply to the viable myocardium. Only in 1 patient did the hypokinetic wall area become dyskinetic, but, on the other hand, in another patient hypokinetic motion of the inferolateral wall normalised due to the drug. The accuracy of visually detecting minor changes in left ventricular wall movement with cross-sectional echocardiography is, however, not good, so that the value of those findings remains limited. The mean cardiac index of our patients measured by M-mode echocardiography increased linearly, the maximal increase being 1.2 l/min per m2, i.e. 36% of the mean baseline value. Simonsen et al. found a 25% increase in the cardiac index with a similar cumulative dose of ICI 118.587 [7]. Using prenalterol the increases of cardiac output have been approximately 17-18s in patients with congestive heart failure or coronary artery disease [g-lo]. In our study the standard M-mode technique apparently overestimated the changes of cardiac index, largely measuring the movements of normal ventricular areas and not the global left ventricular function and output. In 10 of our patients, beta-blocking drug treatment was discontinued 4 days before the study and hence they could have been more sensitive than normal to the sympathomimetic effect of the drug. Decreased numbers of beta-adrenergic receptors have been shown after adrenergic therapy [ll], but whether beta-blocking therapy increases these receptors is as yet unclear. On the other hand, the agonist effect of the drug depends on the sympathetic tone of the patient: when there are large amounts of circulating catecholamines in the blood the drug is more betablocking than beta-stimulating and vice versa [12,13]. In studies using prenalterol the resting cardiac index has been fairly low [8,9], which may, per se, cause sympathetic stimulation and hence lower responses to beta,-agonists than in our study, where left ventricular function was either normal or slightly depressed. In those studies using prenalterol the resting heart rate was higher (mean 75 and 76 beats/min) than in our study [8,9]. Different levels of sympathetic tone may explain the difference between our results and those of Pouleur et al. [14], who, using ICI 118.587, found increases in motion of abnormal areas of the left ventricular wall in patients with coronary artery disease and a history of myocardial infarction, and no changes in the function of normal left ventricular areas. The mean resting heart rate of their patients was 77 beats/mm and the total ejection fraction increased from 56 to only 59%, although significantly. Klein et al. using prenalterol in patients with previous myocardial infarction found a much greater increase of ejection fraction, from 55 to 72% [15], which agrees with our results. The left ventricular end-diastolic diameter did not change and the rate-pressure

349

product increased significantly, which may indicate an increased oxygen demand of the myocardium, although only 1 patient had angina1 pain and signs of myocardial ischemia during the hemodynamic study. This patient had three-vessel coronary artery disease and the lowest ejection fraction (41%). The left ventricular catheter as a cause of myocardial ischemia in this patient seemed unlikely, because the rhythm disturbances appeared after the hemodynamic changes. In other patients the drug caused no unpleasant feelings and no rhythm disturbances during either of the studies or after them. Occasional ventricular ectopy, found in 4 patients, appeared the following night and was thus not attributable to the drug effect. In conclusion, in patients with stable angina pectoris, ICI 118.587 has a positive inotropic effect on myocardial muscle, increasing its contractility and, hence. cardiac output, but the chronotropic effect of the drug is minor. The drug caused virtually no side effects, no arrhythmias and no adverse effects on the movements of abnormal left ventricular wall areas in most of the patients, although in 1 patient with severe coronary artery disease it possibly induced myocardial ischemia. If the positive inotropic effect of the drug persists during long-term oral use and if the therapy improves the prognosis of patients requires further studies.

References 1 Hull SM. Discontinuation of maintenance digoxin therapy in general practice. Lancet 1977;2:1054-1055. 2 Hamer J. The modern management of congestive heart failure. London: Lloyd-Luke Ltd., 1982:83. 3 Nuttall A, Snow HM. The cardiovascular effects of ICI 118.587: a beta,adrenoceptor partial agonist. Br J Pharmacol 1982;77:381-388. 4 Marlow HF. Wardleworth AG, Booth LM, Harry JD. The haemodynamic effects of ICI 118.587. a beta-adrenoceptor partial agonist, in healthy volunteers. Br J Clin Pharmacol 1982;13:269P-270P. 5 Ik%heimo M. Takkunen J. Echocardiography in assessment of mitral valve disease II. Left atrium and left ventricle. Ann Clin Res 1977;9:321-329. 6 Cooper RH, O’Rourke RA, Karliner JS, Peterson KL, Leopold GR. Comparison of ultrasound and cineangiographic measurements of the mean rate of circumferential fiber shortening in man. Circulation 1972;46:914-923. 7 Simonsen S. Acute haemodynamic effects of ICI 118.587 in cardiomyopathy (abstract). Eur J Clin Invest 1982;12:49. 8 Hutton I, Tweddel AC, Bastian BC, Murray G. Comparison of the vasodilator prazosin and the selective beta,agonist prenalterol on rest and exercise haemodynamics in CHF. Acta Med Stand 1981;suppl 652:163-168. 9 Tweddel AC, Murray RG, Pearson D, Martin W, Hutton I. Cardiovascular effects of prenalterol on rest and exercise haemodynamics in patients with chronic congestive cardiac failure. Br Heart J 1982;47:375-380. 10 Hutton I, Murray RG, Boyes RN, Rae AP, Hillis WS. Haemodynamic effects of prenalterol in patients with coronary heart disease. Br Heart J 1980;43:134-137. 11 Galant SP, Duriseti L, Underwood S, Insel PA. Decreased beta-adrenergic receptors on polymorphonuclear leukocytes after adrenergic therapy. N Engl J Med 1978;299:932-936. 12 Pouleur H, Detry JM, Mancia G. Inotropic drugs of the future. Eur J Clin Invest 1982;12:44-443. 13 Marlow HF. Snow HM, Rouse W, Main BG. ICI 118.587, a cardioselective beta-adrenoceptor partial agonist (abstract). Eur J Clin Invest 1982;12:49. 14 Pouleur H, Rousseau MF, Mengeot P, Vesiter C, Vincent MF, Brasseur LA. Improvement of global and regional left ventricular function in patients with previous myocardial infarction by a new beta,adrenoceptor partial agonist ICI 118.587. Eur Heart J 1982;3(suppl D):123-127. 15 Klein W, Brandt D, Maurer E. Hemodynamic assessment of prenalterol: a cardioselective beta-agonist in patients with impaired left ventricular function. Clin Cardiol 1981;4:325-329.