Characterization of the Beta-Adrenoreceptors which Mediate the Isoprenaline-Induced Changes in Finger Tremor and Cardiovascular Function in Man
T.H.Pringle,J.G.Riddell,and R.G.Shanks
Department of Therapeutics and Pharmacology,The Queen’s University of Belfast,Belfast,Northern Ireland
Summary. We have studied the contribution of beta1- and beta2-adrenoceptors to the isoprenaline-induced changes in heart rate,blood pressure, forearm blood flow,peripheral vascular resistance, and finger tremor. This was achieved by a compari-son of the effects of atenolol 50 mg,ICI 118551 25 mg, propranolol 80mg, atenolol 50mg com-bined with ICI 118551 25 mg,propranolol 80mg combined with ICI 118 551 25 mg,and placebo.
Atenolol 50 mg and ICI 118551 25 mg caused similar attenuations in the isoprenaline-induced changes in heart rate and diastolic blood pressure, but the responses after the combination of atenolol and ICI 118551 were similar to those after propra-nolol 80mg.
There was no difference in the forearm blood flow responses to isoprenaline after atenolol 50mg and ICI 118551,but atenolol 50 mg did not reduce peripheral vascular resistance compared with place-bo. Both responses after treatment with atenolol combined with ICI 118551 were similar to those after propranolol 80 mg.
Finger tremor responses to isoprenaline were antagonized by ICI 118 551 alone and in combina-tion with propranolol and atenolol but not by atenolol alone,suggesting that the response is beta2-adrenoceptor-mediated.
We conclude that the cardiovascular responses to isoprenaline are mediated by both beta1- and beta2-adrenoceptors, whereas the finger tremor re-sponse is mediated by beta2-adrenoceptors.
Key words: atenolol,ICI118551,propranolol; beta1-/beta2-adrenoceptors,selectivity
Isoprenaline is a non-selective beta-adrenoceptor agonist, and the inhibition of isoprenaline-mediated responses has often been used to evaluate beta-

adrenoceptor antagonists. Although beta-adreno-ceptor antagonists may cause the same degree of beta1-adrenoceptor antagonism, as judged by equal reduction in exercise tachycardia,differences in their effects on isoprenaline-induced tachycardia occur when the cardioselectivity of the antagonists is different [1].Thus, the attenuation of isopre-naline-induced tachycardia cannot be used to com-pare the degree of beta1-adrenoceptor blockade by different beta-adrenoceptor antagonists. The exact mechanisms for the differences is not entirely clear, but stimulation of unblocked betaz-adrenoceptors can alter the heart rate response both directly and by reflex mechanisms[2].
Several isoprenaline-induced responses in man, such as increases in forearm blood flow[3],finger tremor [4], and a fall in diastolic blood pressure[1], have been used to determine the beta-adrenoceptor selectivity of beta-adrenoceptor antagonists [5,6]. During isoprenaline infusions it is uncertain what role betaj-adrenoceptors play in these responses. For this reason a comparison of beta1-adrenoceptor selectivity by these methods can only be made be-tween doses of beta-adrenoceptor antagonists which cause similar beta-adrenoceptor blockade.It is not known if any of these responses can be used to compare betaj-adrenoceptor selectivity between different doses of the same beta-adrenoceptor antagonist or to compare betaz-adrenoceptor selec-tivity of beta-adrenoceptor antagonists.
We wanted to identify the role of beta1-and beta2-adrenoceptors in these isoprenaline-induced responses by comparing the effects of betaj-(ateno-lol) [7] and betaz- (ICI 118 551) [8] selective adreno-ceptor blocking drugs. We also studied whether atenolol in combination with ICI 118 551 produced the same response as the non-selective antagonist propranolol,and whether ICI 118551 in combina-tion with propranolol had any additional effects on
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the responses induced by infusions of isoprenaline in man.
Materials and Methods
The study was approved by the Ethical Committee of the Queen’s University of Belfast. Six male vol-unteers (mean age 21.2(1.3)years,mean weight 69.6 (7.1) kg) presented on each study day to a tempera-ture controlled (22-23°C) room after a light meal. No caffeine-containing beverages were allowed in the preceding 12 h. Each received, at weekly inter-vals, in a double-blind randomized order, single oral doses of ICI 118551 25 mg,atenolol 50 mg, propranolol 80mg, atenolol 50mg+ICI 118551 25 mg,propranolol 80mg+ICI 118551 25 mg,and placebo.Ninety minutes later an intravenous saline infusion was commenced in the long saphenous vein at the ankle. Heart rate was monitored contin-ously and was measured from five consecutive R-R intervals on the electrocardiogram.Blood pressure was measured as the mean of two observations with a Hawksley random zero sphygmomanometer on the left arm. Diastolic blood pressure was taken at the fourth Korotkoff sound. Blood flow to the right forearm was measured by venous occlusion plethys-mography using a mercury in rubber strain gauge [9]. The venous cuff was inflated to 60 mmHg for 10 s and then deflated for 5 s. Ten readings were re-corded and the mean taken.Peripheral vascular re-sistance was calculated from the forearm blood flow – mean arterial pressure (arbitary units).Finger tremor was measured with a piezo-electric accele-rometer(Devices Trem 1) attached to the dorsum of the middle phalanx of the left middle finger. The fingers and hand were outstretched in the same plane as the left forearm, which was comfortably supported to the wrist on a wooden splint.The out-put of the accelerometer was displayed directly through a pre-amplifier (Devices 3543) by a pen re-corder (Devices MX4). The pre-amplifier was inter-faced with an Apple Ile microcomputer and the sig-nal was analysed by fast Fourier transformation. The results were expressed as the square root of the total power of the signal from 1 to 25 Hz.
Isoprenaline sulphate 0.5 ug/min, with sodium metabisulphate 0.1% as a preservative, was then in-fused using a Perfusor pump(B.Braun Melsungen AG). After a stabilization period of 4 min heart rate, finger tremor, blood pressure, and forearm blood flow were again measured. These measurements took about 13 min. The rate of infusion was then doubled and after a 4 min stabilization period the same observations were repeated. Serial infusions

T.H.Pringle et al.:Characterization of the β-Adrenoreceptors
of isoprenaline were made through the range 0.5 to 64.0μg/min until the heart rate increased to 110 beats per min or the subject could not tolerate the effects of isoprenaline. The subject rested for 30min and then performed moderate exercise by stepping on and off a box 46 cm high at a rate of 32 steps per min for 3 min. Exercise heart rate was measured within 5 s of completing exercise.
For each treatment dose response curves were constructed for the changes induced by isoprenaline in the cardiovascular measurements and finger tre-mor.For every subject the individual dose response curve of each measurement for each treatment was analysed by linear regression by taking three points for heart rate and forearm blood flow and four points for the other measurements on the steep part of the curve. From the individual regression equa-tion the following indices were calculated: the iso-prenaline dose required to increase heart rate by 25 beats per min (I2s),the dose required to increase systolic blood pressure by 25 mm Hg (IS2s), the dose required to decrease diastolic blood pressure by 25 mm Hg (ID25),the dose required to increase forearm blood flow by 3.0 ml per 100 ml per min (IF3),the dose required to decrease peripheral vas-cular resistance by 18 units (IR18),and the dose re-quired to increase finger tremor by 150% (IT150). Dose ratios were calculated from these indices.
I25,IS2s,ID25,IF3,IR18,and IT1s0 were analysed by Friedman’s two-way analysis of variance and differences between treatments were compared[10]; p<0.02 was considered significant.
It was not possible to perform linear regression on the dose-response curves for finger tremor and peripheral vascular resistance for some of the treat-ments asnot enough points on the steep part of the curve were obtained.For finger tremor and periph-eral vascular resistance the response at isoprenaline 4μg/min after each treatment was compared by Friedman's two-way analysis of variance by ranks.
The data are given as mean (SD) in the text and Table 1 and as mean (SEM) in the figures.
Results
Heart Rate and Blood Pressure
All active treatments shifted the dose-response cur-ves to the right compared with placebo (Fig.1).The I2s(Table 1) after placebo was less than for all ac-tive treatments. No difference was observed be-tween ICI 118551 25 mg and atenolol 50 mg but the I2s for both of these treatments was less than the values for propranolol 80mg, atenolol+
T.H.Pringle et al.:Characterization of the β-Adrenoreceptors

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Table 1. Calculated indices (I2s,IS2s,ID2s,IF3,IR18 and IT1so-mean(SD)-ug/min) from the isoprenaline dose-response curves after the administration of placebo,ICI 118551 25 mg,atenolol 50 mg,propranolol 80 mg,atenolol 50mg+ICI 118551 25 mg,and propra-nolol 80mg+ICI 118551 25mg
Placebo ICI 118551 Atenolol Propranolol Atenololb Propranololb
25mg 50mg 80mg ICI 118551 ICI 118551
Heart rate 1.5(0.8) 3.7(0.8) 5.0(2.5) 22.9(15.3)ab,c 23.3 (7.2)3,b,c 26.8(15.8)a,b,c
(25 beats per min
increase-125)
Systolic BP 0.9(0.2) 2.0(1.2)° 5.7(3.4) 18.7(10.5)3,b,c 17.9(9.9)3,b,c 16.8(10.5)a,b.c
(25mmHg
increase-IS2s)
Diastolic BP 1.1(0.5) 6.6(7.0) 3.9(2.1) 23.7(20.9)3,b,c 19.7(12.0)3,b,c 26.6(28.3)a,b,c
(25mm Hg
decrease-ID25)
Forearm blood flow 2.2(2.1) 6.8(5.0) 6.3(6.0) 20.3(11.0)3,b,c 39.5(36.7)a,b,c 28.1(7.9)a,b,c
(3 ml per 100 ml per
min increase-IF3)
Peripheral vascular 1.0(0.6) 2.8(3.2) 16.7(8.4)3 24.8(15.9)3 38.2(37.4)3c
resistance(18 units
decrease-IR18)
Finger tremor 1.3(0.5) 4.0(2.7) 48.5(24.2)3,c 29.2(14.7)3,c
(150% increase-IT150)
ap<0.02 vs placebo;bp<0.02 vs ICI 181551 25 mg;°p<0.02 vs atenolol 50 mg
Fig.1. Isoprenaline-induced changes(mean
with SEM) in heart rate afterthe oral administra-
tion of placebo (O),ICI 118 551 25mg(),ateno-
lol 50mg（），propranolol 80mg（口），atenolol
50mg+ICI 118551 25mg(),and propranolol
80mg+ICI 118551 25 mg() to 6 subjects
ISOPRENALINE SULPHATE,ug/min
ICI 118551,and propranolol+ICI 118551. Dose ratios at I2s were 2.9(1.2) after ICI 118 551,3.5(5.2) after atenolol 50mg,22.8(27.2) after propranolol 80 mg,17.2(6.3) after atenolol+ICI 118551,and 19.3 (9.6) after propranolol+ICI 118551.
The blood pressure responses to the isopre-naline infusions are shown in Fig.2. The IS25 (Table 1) after placebo and ICI 118 551 were similar and both were less than after the other active treat-ments. The IS2s for atenolol1 50 mg was less than for propranolol 80 mg,atenolol+ICI 118551,and pro-

pranolol+ICI 118551. The dose ratio at IS2s was 2.3(1.2) after ICI118551 25 mg,7.1(5.4) after atenolol 50 mg,25.5(32.2) after propranolol 80 mg, 22.3(15.1) after atenolol+ICI118551,and 19.6 (10.2) after propranolol+ICI 118551.
The ID2s(Table 1) for placebo was less than for all active treatments. The ID2s for ICI 118551 25 mg and atenolol 50 mg were similar,but both were less than the ID2s for propranolol 80mg, atenolol+ICI118551, and propranolol+ICI 118551. The dose ratio at ID2s was 6.2(5.4) after
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T.H.Pringleet al.:Characterization of the β-Adrenoreceptors
SYSTOLIC BLOOD PRESSURE INCREASE,mm Hg
DIASTOLIC BLOOD PRESSURE DECREASE,mm Hg

Fig.2A,B. Isoprenaline-induced changes in(A) systolic and (B) diastolic blood pressures(mean with SEM)after the oral administration of placebo,ICI 118551 25 mg,atenolol 50mg,pro-pranolol 80 mg,atenolol 50mg+ICI 118551 25 mg,and propranolol 80 mg+ICI 118551 25mg to 6 subjects.Key as in Fig.1
ISOPRENALINE SULPHATE, pg/min
ICI 118551 25 mg, 3.7 (1.9) after atenolol 50 mg, 20.7(11.5) after propranolol 80 mg,20.0(12.9)after atenolol+ICI 118551,and 25.6(23.8)after propra-nolol+ICI118551.
Forearm Blood Flow,Peripheral Vascular
Resistance,and Finger Tremor
All the active treatments attenuated the forearm blood flow response to isoprenaline compared with placebo (Fig.3A).The IF3(Table 1) for placebo was increased by all active treatments. There was no dif-ference in the IF3 for ICI 118551 25 mg or atenolol 50 mg. Both were less than those for propranolol 80mg, atenolol+ICI118551, and propranolol 80mg+ICI 118551.

As insufficient of the dose response curve for peripheral vascular resistance (PVR)for ICI 118551 25 mg(Fig.3B) was obtained, neither IR18 or the dose ratio could be calculated for ICI 118551 25 mg.The IR18 for placebo and atenolol 50mg were similar and each was less than that for propra-nolol 80 mg,atenolol+ICI 118551,and proprano-lol+ICI 118551.Dose ratios at IR18 were 7.0(3.2) after atenolol 50mg,43.0 (70.0) after ateno-lol+ICI 118551, 27.1 (25.1) after proprano-lol+ICI 118551,and 23.1(21.3) after propranolol 80mg.
At the 4 ug/min dose of isoprenaline the periph-eral vascular resistance after placebo,28.5 (9.0),and atenolol 50 mg,22.2(8.6),were similar. Both were greater (p<0.02) than the other active treatments. There was no difference in the responses after
T.HI.Pringle et al.:Characterization of the β-Adrenoreceptors

511
FOREARM BLOOD FLOW INCREASE,ml/100ml/min
PERIPHERAL VASCULAR RESISTANCE DECREASE,units
Fig.3A,B. Isoprenaline-induced changes in(A)
forearm blood flow and(B) peripheral vascular
resistance(mean with SEM) after the oral ad-
ministration of placebo, ICI 118551 25 mg,
atenolol 50 mg,propranolol 80 mg,atenolol
50mg+ICI 118551 25 mg,and propranolol
80 mg+ICI 118 551 25 mg to 6 subjects.Key as
in Fig.1
ISOPRENALINE SULPHATE,pg/min
ICI 118551 25mg, 15.4 (4.9),and propranolol 80mg,8.0(4.4),but both were greater(p<0.02) than after atenolol+ICI 118 551,5.0 (6.5),and pro-pranolol+ICI 118551,4.8(3.7).
The IT1s0(Table 1) could not be calculated for two of the treatments, asthe dose response curves for ICI 118551 25mg and propranolol+ ICI 118551 did not include enough points on the steep part of the curve(Fig.4).The IT1s0 for propra-nolol was greater than that for both atenolol and atenolol+ICI 118551. There was no statistically significant difference between IT1so for placebo and

that for atenolol 50 mg. The IT1so for both placebo and atenolol 50mg were less than propranolol 80mg and atenolol+ICI118551. Dose ratios at IT1so were 3.2 (1.9) after atenolol 50 mg,25.0(13.0) after atenolol+ICI 118551,and 41.8(25.1)after propranolol 80 mg.
At the 4 μg/min dose of isoprenaline the finger tremor response after atenolol 50 mg,185(62)%, was no different from placebo, 377 (250)%,but both caused less attenuation(p<0.02) compared with ICI 118551 25 mg,44(32)%,propranolol 80 mg,9 (14)%,atenolol+ICI 118551, 3 (18)%, and propra-
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T.H.Pringle et al.:Characterization of the B-Adrenoreceptors
%INCREASE
FINGER TREMOR
Fig.4.Isoprenaline-induced changes in finger tremor(mean with SEM) after the oral administra-tion of placebo, ICI 118551 25 mg,atenolol 50mg, propranolol 80 mg,atenolol 50mg+ICI 118551 25 mg,and propranolol 80mg+ICI 118551 25 mg to 6 subjects.Key as in Fig.1
ISOPRENALINE SULPHATE,Hg/min
nolol+ICI 118551,11(28)%. At this dose of isopre-naline ICI 118551 25 mg produced less attenuation (p<0.02) than either atenolol+ICI 118551 or pro-pranolol+ICI 118551.
Exercise Heart Rate
All five active treatments reduced the exercise heart rate (p<0.02) compared with placebo, 166.5(10.8) beats per min. ICI 118551 25 mg, 161.7(5.84)beats per min, produced a small reduction. The other four active treatments all produced similar reductions in exercise heart rate (atenolol 50mg 131.3 (7.0), pro-pranolol 80mg 136.5 (7.9),atenolol+ICI 118551 132.0(6.1),and propranolol+ICI 118551 138.0 (8.7) beats per min),which were greater(p<0.02) than that after ICI 118551 25 mg.
Discussion
One of the major difficulties of attributing respon-ses to beta1-or beta2-adrenoceptors is that they have not been clearly defined. The standard dynamic re-sponse for beta1-adrenoceptors-the effect on exer-cise-induced tachycardia- was described[11] be-fore the presence of beta2-adrenoceptors in the human heart was demonstrated [12]. The role of these beta2-adrenoceptors in exercise-induced ta-chycardia is unknown. The cardiovascular respon-ses to the non-selective beta-adrenoceptor agonist isoprenaline result from beta1- and beta2-adreno-ceptor stimulation,but the contribution of each is

unclear. The finger tremor response to isoprenaline is said to be largely beta2-adrenoceptor mediated [4],but this statement is based on comparative data.
In this study ICI 118551 25 mg had a small but significant effect on exercise heart rate. This is most likely due to blockade of betay-adrenoceptors in the heart, as other investigators have found that that while ICI118551 20mg is beta2-selective [5,13] some loss of selectivity is evident with increasing dose. It is possible that blockade of cardiac beta2-adrenoceptors also reduces exercise-induced tachy-cardia, but the increase in heart rate is said to be secondary to beta1-adrenoceptor stimulation[14]. Atenolol 50 mg, propranolol 80 mg alone, and pro-pranolol in combination with ICI 118551 25mg were all more potent and caused a similar reduction of exercise-induced tachycardia.The dose of pro-pranolol was chosen to ensure that its beta1-adreno-ceptor antagonism was similar to that of atenolol 50 mg. The pharmacokinetic profile of propranolol varies between individuals [15] and it is possible that this might have influenced the responses observed. However,previous studies have shown that the ef-fect of propranolol on exercise-induced tachycardia did not vary significantly from 2 to 4h[16].There is also evidence that the beta-adrenoceptor antagon-ism of atenolol[17] and ICI 118 551 [18] persists for this period of time.
The increase in the finger tremor response medi-ated by isoprenaline is generally thought to be due to beta2-adrenoceptor stimulation [4].This effect has been used to determine the betaj-selectivity of beta-adrenoceptor antagonists[5,6,17].We were unable
T.H.Pringle et al.:Characterization of the β-Adrenoreceptors
to obtain dose ratios for finger tremor with the beta2-selective antagonist ICI 118551 alone or com-bined with propranolol, as the dose of isoprenaline given during this treatment was limited by the heart rate response and insufficient of the steep part of the dose response curve for finger tremor response was obtained.
The ballistocardiac vibrations contribute to only 10% of resting finger tremor[19] and do not effect the finger tremor response during intravenous isopre-naline infusions[20].Atenolol 50 mg caused more at-tenuation of both heart rate and systolic blood press-ure than ICI118551,whereas ICI 118551 25mg produced more rightward shift of the dose response curve for finger tremor than atenolol. The finger tre-mor response appears to be independent of the car-diovascular responses to isoprenaline.
The combined effect of atenolol and ICI 118551 attenuated the finger tremor more than atenolol 50 mg but not ICI 118 551 25 mg,and it is therefore unlikely that beta1-adrenoceptors play a major role in the isoprenaline-induced increases in finger tre-mor. The addition of further beta2-adrenoceptor blockade tended to cause more attenuation of the isoprenaline dose response curves for finger tremor, as propranolol combined with ICI 118551 caused further rightward shift of the dose response curve than propranolol 80 mg alone. This suggests that the betaz-adrenoceptor mediated increases in finger tremor are the most important during isoprenaline infusion. The finger tremor response remains a use-ful indicator of betaz-adrenoceptor function,little influenced by beta1-adrenoceptor stimulation,and can therefore be used to compare the beta2-selectiv-ity of beta-adrenoceptor drugs.However,for drugs which produce selective betaz-adrenoceptor block-ade the dose of isoprenaline is limited by heart rate increase and insufficient of the dose response curve is obtained to calculate dose ratios. Although at the 4μg/min dose of isoprenaline there was no dif-ference between ICI 118551 25 mg and propranolol 80 mg, it can be seen from Fig.4 that propranolol 80 mg produces a more rightward shift of the dose response curve. At these doses propranolol pro-duced a larger beta2-blockade than ICI 118551.
Whereas exercise heart rate and isoprenaline-in-duced finger tremor response are largely mediated by beta1- and beta2-adrenoceptors respectively,the cardiovascular responses appear to be mediated by both receptors. The reduction of isoprenaline-in-duced tachycardia during beta-adrenoceptor block-ade may reflect either cardiac betaj- and beta2-adrenoceptor antagonism and an additional effect of the vagal reflex action on the heart [5]. Thus, ICI 118 551 and atenolol both shift the isoprenaline

513
dose response curve to the right but to a lesser ex-tent than propranolol and the combination of atenolol and ICI 118551.
In the presence of beta-adrenoceptor antagonists the systolic blood pressure responses to isoprenaline are complex [21]. While ICI 118551 did not signifi-cantly attenuate the increase in systolic blood pres-sure response compared with placebo, atenolol shifted the dose response curve to the right,suggest-ing that this a predominantly betaj-adrenoceptor mediated response. However, the agonist salbuta-mol, at a dose which maintained its beta2-adrenocep-tor selectivity, produced a betaz-adrenoceptor medi-ated rise in systolic blood pressure [18]. Our findings that propranolol and the combination of atenolol and ICI 118551 caused further attenuation of the systolic blood response suggest that beta2-adreno-ceptors also mediate the isoprenaline response when there is simultaneous betaj-adrenoceptor blockade.
In animals the venous return to the heart is in-creased by isoprenaline [22], and in man this ap-pears to be mediated by beta2-adrenoceptors [23]. Although the increase in contractility through betar-adrenoceptor activation is the most likely mechan-ism for the isoprenaline-induced increase in systolic blood pressure, it is possible that beta2-adrenocep-tors may play a role by increasing preload or by di-rectly stimulating beta2-adrenoceptors in the myocardium[5].
The fall in diastolic blood pressure produced by isoprenaline is probably due to beta2-adrenoceptor mediated peripheral vasodilatation [1]. In this study atenolol caused a small but definite attenuation of this response. As selectivity of beta-adrenoceptor antagonists is not absolute, it is possible that the ef-fect on the diastolic blood pressure indicates a small amount of betaz-adrenoceptor blockade, or alterna-tively that betaj-adrenoceptors play a role in this re-sponse.Others [5,24] have found a greater dif-ference in the diastolic blood pressure responses after atenolol and ICI 118551. It is therefore most likely that the ability of the combination of the two drugs to produce a similar response to propranolol was due to the additive effects of predominant beta1-antagonism of atenolol and the beta2-anta-gonism of ICI 118 551.
The blood flow to a limb is dependent on the perfusion pressure and the calibre of the resistance vessels [25]. Our results suggest that isoprenaline acts on both of these to increase forearm blood flow.Atenolol,through its predominant blockade of cardiac betaj-adrenoceptors, reduced the ino-tropic effects of isoprenaline on the heart but re-duced peripheral vascular resistance.The action of ICI 118551 was to prevent the fall in peripheral
514
vascular resistance through beta2-adrenoceptor blockade, and the blockade of the inotropic effects by antagonism of cardiacbeta2-adrenoceptors seems to be of less importance. The net effects on forearm blood flow were similar when the atenolol 50mg and ICI 118551 were given alone,but in combination the effects of the two drugs produced the same effect as propranolol.
In conclusion, we have demonstrated that the cardiovascular responses during isoprenaline stimu-lation are mediated by both betaj- and betaz-adreno-ceptors. When these responses are used to compare beta1-adrenoceptor selectivity of beta-adrenoeptor antagonists it is important that doses are chosen which are equipotent at the betat-adrenoceptor. In-hibition of exercise heart rate remains the best index of beta1-adrenoceptor blockade. Of the isoprenaline-induced responses investigated only finger tremor is mediated predominantly by beta2-adrenoceptors during isoprenaline infusions and can be used to compare beta2-adrenoceptor blockade of beta-adrenoceptor antagonists without reference to their ability to antagonize beta1-adrenoceptors.
Acknowledgements. We are grateful to Imperial Chemical Industries, ple for supplying ICI 118 551.
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Received:October 12,1987
accepted in revised form:June 17,1988
Dr.T.H.Pringle
Department of Cardiology
Ninewells Hospital
Dundee DD1 9SY
Northern Ireland ICI-118551