Summary

Drugs 11 (SuppI.1): 127-134 (1976) © ADIS Press 1976

Session VI: Mode of Action of {3-Adrenoreceptor Blockers in Hypertension

Chairman: Professor C.I. Johnston (Melbourne)

Haemodynamic Effects of {3-Adrenoreceptor Blockers in Hypertension

B. Ablad, B. Ljung and R. Sannerstedt

Research Laboratories, AB Hassle, Molndal and Department of Medicine I, Sahlgrenska University Hospital, Goteborg

The haemodynamic effect pattern of /3-blockers in hypertension is discussed. The time curve of the antihypertensive effect differs from that of cardiac (3-blockade. The antihyper-tensive effect is characterised by a slower onset at the start of treatment and a more gradual disappearance when therapy is withdrawn. It appears that the crucial effect of /3-blockers in hypertension is a gradually developing reduction in total peripheral vascular resistance. The mechanism of this apparent vasodilator action is unknown. Various possible factors involved are mentioned. One is a reduced efficiency of transmitter release from the peripheral adren-ergic neuron. Such an action may contribute to the antihypertensive effect, as judged by results of animal experiments described.

The antihypertensive effect of a {3-blocker was first demonstrated in patients by Prichard in 1964. Since then a large number of studies have shown that the arterial blood pressure can be reduced in patients with hypertension by various non-selec-tive blockers such as propranolol (prichard and Gillam, 1964, 1966, 1969), aIprenolol (Tibblin and Ablad, 1969), oxprenolol (Simpson and Waal-Manning, 1970), pindolol (Seedat and Stewart-Wynne, 1972), timolol (Franciosa et aI., 1973), and by {31 -selective blockers such as practolol (Esler and Nestel, 1973), metoprolol (Bengtsson,

1976a,b) and atenolol (Hansson et aI., 1973). There appears to be little difference in the anti-hypertensive efficacy of these agents, despite their different pharmacological profIles. In single- or double-blind studies with placebo control, the {3-blockers have been found to reduce systolic blood pressure by about 20mm Hg and the dia-stolic pressure by 10 to ISmm Hg on average (Richardson et aI., 1968; Dorph and Binder, 1969; Frohlich et aI., 1968; Tibblin and Ablad, 1969; Waal-Manning, 1970; Bengtsson 1972a,b, 1976 a,b). These studies usually included patients with

Symposium on hypertension

Table I. Comparison between daily doses used in anti· hypertensive treatment (I) and doses effective in reduc-tion of exercise tachycardia (II) for various /3·blockers. Note that the value for the ratio I: II is more or less constant.

Compound I. Common daily dose in anti· hypertensive therapy (mg)

Propranolol 160-320

Oxprenolol 160-320

Alprenolol 400-800

Pindolol 20-40

Timolol 20-40

Practolol 600-1200

Metoprolol 200-400

II. Reduction of exercise heart rate; comparative oral doses (mg)

40

40-60

100

2-5

5

125

50

Approxi· mate ratio I: II

4-8

4-8

4-8

5-10

4-8

5-10

4-8

moderate hypertension and doses were moderate, corresponding to those shown in table I.

A more conspicuous antihypertensive effect was described with propranolol in three large open studies (Prichard and Gillam, 1969; Hansson et al., 1972; Zacharias et al., 1972). These studies in· cluded patients with severe hypertension and the doses of propranolol were often higher than in the studies discussed above.

1. Time Course of Antihypertensive and Cardiac f,-Blocking Effects

Onset of the antihypertensive effect is gradual. Fig. 1 shows data with oxprenolol reported by Simpson and Waal·Manning (1970), which are sup-ported by several later studies with other (j. blockers (Buhler et al., 1972; Lydtin et al., 1972; Franciosa et al., 1973; Conway, 1976). An ade-quate fixed dose reduced heart rate within one

128

day, and the greater part of the blood pressure reduction occurred within the first week of treat· ment. There are reports, however, that in some patients the antihypertensive effect develops more slowly over several weeks (Prichard and Gillam, 1969; Tibblin and Ablad, 1969; Tarazi and Dustan, 1972).

The antihypertensive effect is also characterised by a gradual disappearance after withdrawal of (j·blocker therapy. Fig. 2 shows that heart rate was increased one day after withdrawal of oxprenolol treatment but blood pressure showed a more gradual rise (Simpson and Waal.Manning, 1970). Others have shown that blood pressure may not return to pre·treatment levels for several week~ after cessation of (j·blocker treatment (Bengtsson, 1972a; Vedin et al., 1973).

These findings suggest that the time course of the antihypertensive effect of these agents differs from that of the cardiac (j·blockade, which is also

~o!)., DIw2 ~ 2~~ After starting treatment

Fig. 1. Effects on heart rate and on systolic and dia. stolic blood pressure of administration of oxprenolol 120 to 180mg per day to 18 hypertensive patients. Note de. crease in heart rate and systolic blood pressure during first day and blood pressure reduction during first week of treatment (after Simpson and Waal·Manning. 1970).

Haemodynamic effects of l3-blockers

supported by haemodynamic studies. Tarazi and Dustan (1972) demonstrated that a single IV dose of propranolol reduced cardiac output by about 20% in 10 hypertensive patients (fig. 3). This effect was accompanied by a corresponding in-crease in total peripheral vascular resistance, prob-ably mainly due to increased vasoconstrictor nerve activity elicited via baroreceptor reflex mechan-isms. As a result, the arterial blood pressure was not greatly affected. When the patients were again studied after about 8 and 20 months therapy respectively with propranolol (160 to 320mg daily orally), the cardiac output remained reduced at the level produced by the initially given IV dose. The blood pressure was, however, reduced by 15 to 20% because the initially raised peripheral vas-cular resistance had returned towards pre-treat-ment levels.

These fmdings show that the antihypertensive effect of propranolol is not primarily due to the reduction of cardiac output produced by cardiac ~-blockade. The blood pressure is instead reduced because of a gradually developing reduction of the peripheral vascular resistance. The mechanisms

Fig. 2. Effects on heart rate and on systolic and dia-stolic blood pressure after cessation of antihypertensive treatment with oxprenolol in 6 patients. Note abrupt in-crease in heart rate and more gradual increase in blood pressure after withdrawal of l3-blockade (after Simpson and Waal-Manning, 1970).

... "

10

~ 0 % u ..

10

25

129

I", I,,, l--------------------,,----o%

"- "6- ___ - __ 6

C TPOL IV 7.6 S 19.6MOS 1-----PAOP •• ~Ol(l<_ I

Fig. 3. Haemodynamic effects of acute (IV) and long-term (7.6 and 19.6 months) propranolol therapy in 10 hypertensive patients. Changes in cardiac index (CI), total peripheral resistance (TPR), heart rate (HR) and mean arterial blood pressure (BP) are expressed as a percentage of value before treatment (after Tarazi and Dustan, 1972).

involved in this apparent vasodilator effect are unknown.

Fig.4 shows data by Sannerstedt and co-workers (to be published) on the haemodynamic effects of metoprolol in six hypertensive patients after a single oral dose, and after 3 to 5 weeks treatment respectively. The first dose reduced car-diac output by about 15%. This effect was asso-ciated with some decrease of the systolic and mean arterial pressures and total peripheral resistance was raised less in these patients than after the sin-gle dose of propranolol in the study of Tarazi and Dustan (1972). Continued metoprolol treatment for 3 to 5 weeks caused no further reduction in cardiac output, but the diastolic and mean blood pressures were decreased (mean arterial BP by 17% from pre-treatment level) due to diminished peri-pheral vascular resistance. The right part of the

Symposium on hypertension 130

Rest Exercise Rest Exercise Mean load 675Kpm/mln Mean load 675Kr:xn/min

250 "r--Intra-arterial blood 200 pressure mm Hg

~ 150 ............

~

100 ------- 160 Heart

~ rate 150

i i i I i I beats/m\'4o

'] ~ Cardiac 14 130 output

120 I/min 13

:I HO

r "-- 70

~ 60 i i i i I I

'] 50

~ I i i i i i

Systemic20 _ '20j volume 0 / vascular 18 ml 11

~~f 100

~ 90 ... . --... 10 80

i i i Befhre

i A~er

i i i Befhre

i Mer Before After Alter Alter Before After After After

treat- meto- metoprolol treat- meto- met~rolol treat- meto- metoprolol treat- meto- met~rolol ment prolol ISO-22Smg ment prolol ISO- 2Smg men! prolol ISO-225mg ment prolol ISO- 2Smg

50mg daily.3-Sw SOmg daily.3-5w 50mg daily.3-Sw 50mg daily.3-5w

Fig. 4. Haemodynamic effects of metoprolol in human arterial hypertension WHO stage 1-2. Mean values from findings in six patients studied at rest and during bicycle ergometer exercise, recumbent.

figure shows that the haemodynamic responses recorded during exercise were affected to a degree which approximately corresponded to that seen at rest.

The results of these and other haemodynamic studies (Wilson et aI., 1968; Franciosa et aI., 1973; Hansson et al., 1974) suggest that the haemo-dynamic effect pattern of different /3-blockers may vary to some extent because of differences in the pharmacodynamic profiles of the antagonists. However, all of them have one important property in common; they produce a gradually developing reduction in the vascular resistance and this action is the basis for their antihypertensive effect.

2. Possible Mechanisms of Reduction in Peri-pheral Vascular Resistance

This apparent vasodilator effect is probably related to /31 -receptor blockade. This is indicated by the fact that the commonly used antihyper-tensive doses of various /3-blockers show about the same difference as the respective doses required for about equal inhibition of a /31 -mediated re-sponse like exercise tachycardia (table I). Studies with the dextro isomers of propranolol and alpren-0101 indicate that the membrane stabilising effect does not contribute to the antihypertensive effect produced by the racemic forms of these com-

Haemodynamic effects of j3-blockers

pounds in the doses usually given (Waal-Manning, 1970; Prichard and Boakes, 1972; Rahn et al., 1974). The following mechanisms have been sug-gested to be primarily involved in the gradually developing reduction of vascular resistance and blood pressure in hypertensive patients:

a) Antagonism of cardiac j3-receptors, leading to altered homeostatic control via changes in baroreceptor activity (prichard and Gillam, 1966) and peripheral vascular tone (Frohlich et at, 1968)

b) Antagonism of (3-receptors in the central nervous system, leading to reduced sympa-thetic discharge to blood vessels and heart (Day and Roach, 1974; Lewis and Haeusler, 1975)

c) Blockade of sympathetic control of renin release from the kidney (Biihler et al., 1972)

d) Action on the peripheral adrenergic neuron, leading to reduced release of transmitter (Lewis, 1974; Ljung et at, 1976).

3. Effect of j3-Blockers on Adrenergic Trans-mission

Of the above alternatives, the action on the peri-pheral adrenergic neuron is the one least discussed. We have studied this question in spontaneously hypertenSive rats (SHR) of the Okamoto type (Ljung et at, 1976). Folkow and co-workers (Weiss et at, 1974) showed that long-term treat-ment with propranolol and metoprolol in young SHR reduced the development of high blood pres-sure. We have reproduced this antihypertensive effect in an experiment where propranolol or metoprolol was given for six months in a daily oral dose of about 7Omg/kg to a group of SHR starting at the age of 6 weeks. A group of SHR from the same litter served as controls. After six months treatment the intra-arterial blood pressure, mea-sured on conscious relaxed animals, was signifi-cantly lower in the treated rats than in the con-trols.

131

We believe that this antihypertensive effect of (3-blockers in SHR bears some relevance to that observed in hypertensive patients. One reason is that appropriate doses of the dextro isomer of pro-pranolol are devoid of antihypertensive effect both in SHR (Weiss, personal communication) and in hypertensive patients (Waal-Manning, 1970). Fur-thermore, we have analysed the plasma levels of metoprolol in rats subjected to this treatment schedule in a separate study (Fellenius, personal communication) and compared them with the plasma levels obtained in patients undergoing effective antihypertensive therapy with meto-prolol. It was found that the 24 hour plasma levels of metoprolol in rats were less than half of those in the patients, despite the fact that the daily dose of metoprolol was about 20 times higher in rats than in the patients. This discrepancy can be as<:ribed mainly to the fact that metoprolol has a shorter plasma half life and a much lower bioavail-ability in the rat than in man.

After the blood pressure measurements the (3-blocker treatment was withdrawn for 48 hours. The rats were then sacrificed and the portal veins were prepared. One vein from a previously treated SHR and one vein from a control SHR were mount-ed in the same organ bath for isometric recording of force. Contractile responses to exogenous nor-adrenaline and to electrical transmural stimulation of the sympathetic nerves were recorded and quan-titated by electronic integration of the phasic con-tractile activity.

Fig. 5 shows the dose-response curves with exogenous noradrenaline. The curves obtained in preparations from treated animals did not signifi-cantly differ from those recorded in control prep-arations. Furthermore, it was found that the maxi-mum tension responses to noradrenaline were equal in the treated and untreated groups. This finding indicates that the previous (3-blocker treat-ment had not caused any change in the vascular (3-receptor sensitivity.

In contrast, a Significant difference was ob-served in the frequency response curves obtained

Symposium on hypertension

.. · 8 .7 .. Fig. 5. Dose-response curves of the isolated rat (SHR)

portal vein to exogenous noradrenaline (NA). Note lack of difference from control (n = 10) of preparations from animals exposed to long-term treatment with propranolol (n - 5) and metoprolol (n = 5), respectively, in an approximate daily dose of 70mg/kg.

with sympathetic nerve stimulation (fig. 6). Com-pared with the control curve there was a statisti-cally significant depression of the responses in the preparations from the treated animals. The depres-sion was most pronounced in the low 'physi-ological' frequency range of 0.5 to 2Hz. As can be seen in the amplified diagram in the figure, the responses were reduced by about 50% at a fre-quency of 2Hz. The maximal response to sympa-thetic nerve stimulation was slightly reduced in preparations from propranolol-treated rats, and in general the responses in these preparations tended to be depressed more than in those from rats treated with metoprolol. One possible explanation of this difference is that metoprolol has been given in a rather low dose, as was suggested by the plasma level data discussed above.

As the vascular a -receptor sensitivity was un-changed in these preparations, this reduction of the responses to postganglionic sympathetic nerve stimulation found in all pr.eparations from animals exposed to long-term {3-blockade most likely re-flects a sustained decrease in the amount of trans-mitter released per nerve impulse from the vas-

132

omotor nerves. This prejunctional action of the {3-blockers is apparently of relatively slow onset since we have found no corresponding reduction of the response to nerve stimulation in portal veins acutely exposed to the {3-blockers in relevant con-centrations.

RESPONSE 100 {pef (en' ot mo. NA)

A

METOPROLOL

RESPONSE ~ (ptt (tn' of max NA)

B c

p

rRE~NCY 1HZ) O+----r--~~--~--~+ o z

Fig. 6. Frequency-response relationships of the SHR portal vein obtained with transmural field stimulation. In A complete curves (log scale); in B the relationships within the 'physiological' range is illustrated in e linaar plot. Note that neurogenic responses of portal veins from rats treated with metoprolol (n = 5) and propranolol (n = 5) are suppressed within the low frequency range (after Ljung et aI., 19761.

Haemodynamic effects of ~-blockers

Our data thus suggest that this prejunctional action of {3-blockers on adrenergic transmission is characterised by gradual onset and persistence for some time after withdrawal of {3-blocker treat-ment. This time curve apparently corresponds to that of the clinically observed antihypertensive effect of the {3-blockers. The same suggestion has previously been made by Lewis (1974), who showed that long-term treatment with practolol reduced the pressor response to generalised pre-ganglionic sympathetic nerve stimulation in the pithed rat.

References

Bengtsson, c.: Comparison between alprenolol and chlor-thalidone as antihypertensive agents. Acta Medica Scandinavica 191: 433-439 (1972a).

Bengtsson, C.: Comparison between alprenolol and pro-pranolol as antihypertensive agents. Acta Medica Scan-dinavica 192: 415-418 (1972b).

Bengtsson, C.: The cardioselective adrenergic {3-blocker metoprolol in the treatment of essential hypertension. Initial out-patient study comparing metoprolol and placebo treatment. (I) Acta Medica Scandinavica (In press, 1976a).

Bengtsson, C.: A comparative study of metoprolol and propranolol in the treatment of mild essential hyper-tension. A double-blind crossover study and a long-term follow-up. (II) Acta Medica Scandinavica (In press, 1976b).

Biihler, F.R.; Laragh, LH.; Baer, L.; Vaughan, E.D. Jr. and Brunner H.R.: Propranolol inhibition of renin secretion. New England Journal of Medicine 287: 1209-1216 (1972).

Conway, F.J.: The antihypertensive effect of propranolol and other {3-adrenoceptor blocking agents; in Davies and Reid (Eds) Central Action of Drugs in the Regula-tion of Blood Pressure (Pitman Medical Publishing Co Ltd, London (In press, 1976).

Day, M.D. and Roach, A.G.: Cardiovascular effects of {3-adrenoceptor blocking agents after intracerebroven-tricular administration in conscious normotensive cats. ainical and Experimental Pharmacology and Physi-ology 1: 333-340 (1974).

Dorph, S. and Binder, C.: Evaluation of the hypotensive effect of {3-adrenergic blockade in hypertension. Acta Medica Scandinavica 185: 443-448 (1969).

133

Esler, M.D. and Nestel, P.J.: Evaluation of practolol in hypertension. British Heart Journal 35: 469-474 (1973).

Franciosa, LA.; Freis, E.D. and Conway, J.: Antihyper-tensive and hemodynamic properties of the new {3-adrenergic blocking agent timolol. Circulation 48: 118-124 (1973).

Frohlich, E.D.; Tarazi, R.C.; Dustan, H.P. and Page, I.H.: The paradox of {3-adrenergic blockade in hypertension. Circulation 37: 417-423 (1968).

Hansson, L.; Malmcrona, R.; Olander, R.; Rosenhall, L.; Westerlund, A.; Aberg, H. and Hood, B.: Propranolol in hypertension. Report on 158 patients treated up to one year. Klinische Wochenschrift (Berlin) 50: 364-369 (1972).

Hansson, L.; Aberg, H.; Jameson, S.; Karlberg, B. and Malmcrona, R.: Initial clinical experience with ICI 66,082, a new ~-adrenergic blocking agent in hyper-tension. Acta Medica Scandinavica 194: 549-550 (1973).

Hansson, L.; Zweifier, A.J.; Julius, S. and Hunyor, S.N.: Haemodynamic effects of acute and prolonged {3-adrenergic blockade in essential hypertension. Acta Medica Scandinavica 196: 27-34 (1974).

Lewis, M.J.: Effect of acute and chronic treatment with practolol in cardiovascular responses in the pithed rat. Journal of Pharmacy and Pharmacology 26: 783-788 (1974).

Lewis, P.J. and Haeusler, G.: Central nervous effects of {3-blockers in hypertension; in Berglund, Hansson and Werko (Eds) Pathophysiology and Management of Arterial Hypertension, p.203-209 (Lindgren & Soner AB, Molndal, Sweden, 1975).

Ljung, B.; Ablad, B.; Dahlof, C.; Henning, M. and Hult-berg, E.: Impaired vasoconstrictor nerve function in spontaneously hypertensive rats after long-term treat-ment with propranolol and metoprolol. Blood Vessels (In press, 1976).

Lydtin, H.; Kusus, T.; Daniel, W.; Schierl, W.; Achenheil, M.; Kempter, H.; Lohmoller, G.; Niklas, M. and Walter, L.: Propranolol therapy in essential hyperten-sion. American Heart Journal 83: 589-595 (1972).

Prichard, B.N.C.: Hypotensive action of pronethalol. British Medical Journal 1 : 1227-1228 (1964).

Prichard, B.N.C. and Boakes, A.J.: The use of drugs with {3 and a inhibitory action to treat hypertension. Fifth International Congress on Pharmacology, Abstracts of volunteer papers, p.185, San Francisco, California, USA (1972).

Prichard, B.N.C. and Gillam, P.M.S.: Use of propranolol ('Inderal') in treatment of hypertension. British MedicalJournal 2: 725-727 (1964).

Prichard, B.N.C. and Gillam, P.M.S.: Propranolol in

Symposium on hypertension

hypertension. American Journal of Cardiology 18: 387-391 (1966).

Prichard, B.N.C. and Gillam, P.M.S.: Treatment of hyper-tension with propranolol. British Medical Journal 1: 7-16 (1969).

Rahn, K.H.; Hawlina, A.; Kersting, F. and Planz, G.: Studies on the antihypertensive action of the optical isomers of propranolol in man. Naunyn Schmiede-berg's Archives of Pharmacology 286: 319-323 (1974).

Richardson, D.W.; Freund, J.; Gear, A.S.; Mauck, H.P. Jr. and Preston, L.W.: Effect of propranolol on elevated arterial blood pressure. Circulation 37: 534-542 (1968).

Sannerstedt, R.; Brorson, L. and Auren, M.: Haemo-dynamic profile of metoprolol - a new cardioselective adrenergic /3-receptor blocking agent - in human ar-terial hypertension (In preparation, 1976).

Seedat, Y.K. and Stewart-Wynne, E.: ainical experiences with prindolol (Visken) in the therapy of hyperten-sion. South African Medical Journal 46: 1524-1526 (1972).

Simpson, F.O. and Waal-Manning, H.J.: Hypertension and (}.adrenergic blockade. New Horizons in Medicine (I) Symposium, Sydney, Australia, February 23, 1970, p.59 (published by Sandoz).

Tarazi, R.C. and Dustan, H.P.: Beta adrenergic blockade in hypertension. Practical and theoretical implications of long-term haemodynamic variations. American

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Journal of Cardiology 29: 633-640 (1972). Tibblin, G. and Ablad, B.: Antihypertensive therapy with

alprenolol, a (}.adrenergic receptor antagonist. Acta Medica Scandinavica 186: 451-457 (1969).

Vedin, J.A.; Wilhelmsson, C-E. and Werko, L.; Com-parative study of alprenolol and methyldopa in pre-viously untreated essential hypertension. British Heart Journal 35: 1285-1292 (1973).

Waal-Manning, H.l.: Lack of effect of d-propranolol on blood pressure and pulse rate in hypertensive patients. Proceedings of the University of Otago Medical School 48: 80-81 (1970).

Weiss, L.; Lundgren, Y. and Folkow, B.: Effects of pro-longed treatment with adrenergic (}.receptor antagon-ists on blood pressure, cardiovascular design and reac-tivity in spontaneously hypertensive rats (SHR). Acta Physiologica Scandinavica 91: 447-457 (1974).

Wilson, D.F.; Watson, O.F.; Peel, 1.S.; Langley, R.B. and" Turner, A.S.: Some haemodynamic effects of 'Trasi-cor' (Ciba 39,089/Ba). New Zealand Medical Journal 68: 145-149 (1968).

Zacharias, F.l.; Cowen, K.J.; Prestt, J.; Vickers, J. and Wall, B.G.: Propranolol in hypertension: A study of long-term therapy, 1964-1970. American Heart Journal 83: 755-761 (1972).

Author's address: Professor B. Ablad, AB Hassle, Fack, S-431 20 Molndal I (Sweden).

Drugs 11 (SuppI.1): 134-143 (1976) © ADIS Press 1976

Summary

Etfects of j3-Adrenoreceptor Blocking Drugs on Adrenergic Transmission

M.J. Rand, M. Law, D. F. Story and M. W. McCulloch

Department of Pharmacology, University of Melbourne, Melbourne

The peripheral actions of /3-adrenoreceptor antagonists on adrenergic transmitter mechanisms have been reviewed.

In addition to receptor blockade, i3-adrenoreceptor antagonists may in high concentra· tions inhibit neuronal uptake of noradrenaline; inhibit monoamine oxidase; inhibit the uptake of noradrenaline into transmitter storage vesicles and inhibit the extraneuronal