The Essential Action of Propranolol in Hypertension

PETER LEWIS MB.,

PhD.

London, England

From the Clinical Pharmacology Unit, Institute

of Obstetrics, Queen Charlotte’s Hospital, London W6 OXG, England. These studies have been supported by the British Heart Foundation, The Wellcome Trust and F. Hoffmann La Roche Ltd., Basle, Switzerland. Requests for reprints should be addressed to Dr. Peter Lewis.

The unique action of propranolol and other beta blockers in lowering raised arterial pressure is discussed. Although the onset of the antihypertensive effect is not immedlate, many trials have confirmed the efficacy of these drugs. Animal experiments have thrown little light on the mechanism of actlon of beta blockers in hypertension: this may be because in animals, especially the rat, peripheral beta adrenoceptor vasodilatation is relatively more important than in man. Five principal theories have been advanced to explain the antihypertensive effect. None of these, the renln, central nervous system, cardiac, baroceptor or metabolite theory, is totally satisfactory. A new theory is proposed suggesting that the essential action is to diminish sympathetic nerve output by damping sensory input to the central nervous system from a heart whose capacity to respond to exercise and stress is blunted by beta adrenoceptor blockade. It is now more than 10 years since the important and unexpected observation was made that pronethalol, on trial as an antianginal drug, lowered arterial pressure in hypertensive patients [ 11. Pronethalol was withdrawn because of toxicity, but its successor, propranolol, is now very widely used for the treatment of hypertension [2,3]. Other drugs with the same basic pharmacologic action, beta adrenoceptor antagonism, have also been introduced for this purpose [4,5]. Beta blockers have a number of disadvantages in clinical practice, but they are outweighed by the low incidence of subjective side effects which they provoke and their subsequent high patient acceptability. Reviewed here is our knowledge of how propranolol acts to lower raised arterial pressure. Consideration of this problem is more than an academic exercise, for without precise knowledge of this mechanism attempts to produce drugs with better therapeutic indices than those of propranolol are necessarily handicapped. The intriguing possibility also exists that the cardiovascular control mechanism with which beta blockers interfere is somehow imolir cated in the pathogenesis of essential hypertension. This review is in five sections. The first describes the antihypertensive effect of propranolol. The second deals with the experimental pharmacology of the drug and its cardiovascular effects in

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I5

Dosage. No aspect of the use of propranolol has caused greater confusion than the question of dosage requirements [ 141. The basic problem is that there are very large interindividual differences in the dose of propranolol required to achieve a hypotensive effect. Some patients may show a hypotensive response with 2 mg/kg/day; others may require in excess of 20 mg/kg/day [lo]. Much of this large variability has been shown to be due to interindividual differences in the bioavailability of propranolol after oral dosing. The plasma propranolol concentration may vary up to twentyfold in different persons

Supine

r

-f[

l

-7

-25

l :k& l

r=-0+99+B*

l

l

0

0

Figure 1. Relation between the logarithm of plasma propranolol concentration (nmol/liter), horizontal axis and percentage change in supine diastolic pressure in 16 patients receiving at least three different doses of propranol01. From Leonetti et al. [2 I].

animals. The third section reviews the similarities and differences between propranolol and other beta blockers, and their clinical effects. The fourth section deals in turn with the renal, central, cardiac, baroceptor and metabolite theories of action. The final section attempts to find common ground among the contradictions. NATURE OF THE ANTIHYPERTENSIVE EFFECT IN MAN Drugs for the treatment of hypertension Potency. are often classified as major or minor antihypertensive agents. The latter, exemplified by the thiazide diuretics, include drugs which have a flat dose response curve and which only induce modest reductions in blood pressure even after the administration of large doses. By contrast, major antihypertensive agents, such as guanethidine or methyldopa, have steep relationships between dose and effect and are capable of reducing blood pressure markedly. Acute hypotension may result from too large a dose. Beta blockers do not fit well into this scheme of things. Propranolol has no effect on blood pressure except when given on a prolonged basis [6,7]. Overdosage of beta blockers does not cause hypotension [8]. However, large clinical studies have shown that the blood pressure reductions obtainable with longterm propranolol treatment are comparable to those produced by autonomic blocking drugs [9,10]. Early reports that propranolol was of low potency [ 11,121 can be attributed to the use of fixed doses not titrated to the optimum for the patient [ 131.

838

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taking the same dose [ 151. The variation occurs because, after almost complete absorption from the gut [ 161, propranolol is carried in the portal blood to the liver where it is avidly taken up [ 171 and largely extracted from the blood by first pass metabolism [ 181. The efficiency of this process varies between persons resulting in large differences in the amount of drug reaching the systemic circulation. An additional complication is that the first pass extraction of propranolol by the liver is saturable. This means that graded increases in oral doses of the drug may produce disproportionately large increases in the resulting plasma propranolol concentration [ 19,201. There is now good evidence that even though the hypotensive effect of prolonged oral therapy correlates poorly with the dose given, there is a good Correlation between the logarithm of the plasma propranolol concentration and the hypotensive effect. This relationship determined in 16 patients receiving at least three different doses of propranolol is shown in Figure 1. The half life of propranolol in systemic blood is rather short after single doses, 3 hours [ 16}, but with prolonged dosing the half life is nearer 5 hours [22]. It is still not clear why propranolol given twice daily is as effective at controlling arterial pressure as it is when given four times daily [23]. This may be related to the larger doses producing relatively better bioavailability of propranolol due to saturation of the first pass effect. Onset of Action. Administration of a single dose of propranolol, either intravenously or orally, does not lower arterial pressure immediately, although cardiac beta blockade as evidenced by bradycardia is rapid in onset [6,7]. There has been some dispute as to the speed with which repeated oral doses of propranolol induce the reduction in blood pressure [24]. Early reports indicated that there was an appreciable delay, the antihypertensive effect taking weeks or months to become manifest. More recently, this has been challenged and it appears that an

60

PROPRANOLOL IN HYPERTENSION-LEWIS

antihypertensive effect can be induced from 48 to 72 hours after starting treatment, provided an adequate dose is given [21,26,27]. The maximum plasma levels of propranolol are only achieved after three or four days administration of the same oral dose [22]. There may be a later secondary fall some weeks after starting treatment, but this is not completely sure [24]. It would be of considerable interest to study the effect of long-term intravenous infusion of propranol01 in hypertensive patients to answer the question of whether the delay in the onset of hypotension is a genuine pharmacologic effect or whether it purely relates to the attainment of adequate plasma concentrations of the drug. Some beta blockers produce a reduction in blood pressure when they are given in single doses [ 281. Hemodynamics. The first consequence of commencing propranolol therapy, by either oral or intravenous routes, is a decrease in cardiac output, due mainly to a reduction in heart rate [6,7,25]. Blood pressure does not decrease sharply so total peripheral resistance, a derived parameter, must have increased. Cardiac output remains depressed throughout long-term therapy with propranolol [25], and the onset of a reduction in arterial pressure coincides with a return of the total peripheral resistance to pretreatment values. This sequence of events has been confirmed by several groups [6,7]. Predictability of Response. Several workers have attempted to predict which patients would respond best to propranolol therapy. It was an early hope that patients with high cardiac outputs would respond with greater decreases in blood pressure. This appears not to be the case [25]. Patients with established hypertension and significantly increased cardiac outputs respond particularly poorly, despite reductions in fachycardia and cardiac output [30]. Hansson et al. [29] studied a range of factors in an attempt to predict the response to propranolol and thus obtain some insight into the mechanism of the drug’s action. The reduction in blood pressure obtained with prolonged propranolol treatment did not significantly correlate with initial age, weight, heart rate, cardiac output, peripheral vascular resistance, heart rate response to isoproterenol or urinary excretion of norepinephrine. The predictive value of increased plasma renin activity will be mentioned later. EXPERIMENTAL PROPRANOLOL

PHARMACOLOGY

OF

Beta Blockade. Ahlquist [31] deduced that there were two different types of adrenoceptors in the pe-

ripheral sympathetic nervous system. He observed that various sympathomimetic amines exhibited different potencies in different tissues. He termed adrenoceptors subserving excitatory responses in the peripheral vasculation “alpha,” and those subserving peripheral inhibitory effects and cardiac excitation “beta.” Selective antagonists of beta adrenoceptor were developed after the discovery of dichloroisoprenaline [32]. The first such drugs used clinically were pronethalol and propranolol [ 21. It is possible to distinguish different receptor affinities between cardiac and peripheral beta adrenoceptors; these have been termed 01 and ,L32receptors, respectively [33]. /31 selective antagonists have been developed and are often called cardioselective, although it is probable that some @2 adrenoceptors also occur in the myocardium [34]. Propran0101is not cardioselective. Other Pharmacologic Properties. Propranolol is a local anesthetic. This can be demonstrated electrophysiologically and in such tests as the guinea pig wheal test [33,35]. This property is associated with depression of cardiac function and is often referred to as a quinidine-like or membrane stabilizing activity. This property is probably of no great importance in the action of the drug. Propranolol is a racemic mixture of two isomers. Both have equal local anesthetic potency although only the levo-isomer is a beta blocker [36]. The dextro-isomer is not an effective antihypertensive drug in man [37]. In the usual dose of the racemate used clinically, direct depression of myocardial function by the local anesthetic effect does not occur [38]. Propranolol also has a weak adrenergic neurone blocking action [39]. However, both dextro- and levo-propranolol are equally active in this regard. Furthermore, effective adrenergic blockade always results in postural orthostasis which is conspicuously absent when propranolol is used clinically. Cardiovascular Effects in Animals. Propranolol does not have an acute hypotensive action in any animal species. Prolonged therapy with propranolol is also largely ineffective at lowering the arterial pressure in dogs and rats [40]. The rabbit is the only species in which the normotensive animal responds with a decrease in blood pressure when the drug is given by continuous infusion [4i] or orally [42]. The effect of propranolol on arterial pressure in the rat has been extensively studied, and the results are confusing. The administration of a single intravenous dose causes an increase in blood pressure in most circumstances 143,441. The main component of this effect is a peripheral vasoconstriction which has been attributed to blockade of beta adrenocep-

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PROPRANOLOL IN HYPERTENSION-LEWIS

TABLE I

Properties of Some Beta Adrenoceptor Antagonist Drugs Which Have Undergone Clinical Trial as Antihypertensive Agents Intrinsic Cardiacb* - B-Sympatho-

Drug

Adrenoceptor

mimetic

Anesthetic

Selectivity

Activity

Activity

Reference

Propranolol

-

+

1

Twentyfold

[9.10,

+

+

1

Tenfold

[611

Fivefold

[41

+

+

1

Pindolol

-

+

+

20

Bufuralol

-

+

+

Practolol Metoprolol Atenolol

+ + +

+ _

-

Timolol

-

-

+

Sotalol

_

_

Fitzgerald

1461. In hypertensive rats, propranolol is also ineffective as a hypotensive agent even when given for prolonged periods. Renal clip hypertension is unaffected by the drug even when the administration of propran0101is begun before the clips are placed on the renal artery [49,50]. Propranolol is similarly ineffective in desoxycorticosterone acetate (DOCA) saline induced hypertension in rats [40]. However, it has been reported that even though large doses are without effect, very small doses can lower blood pressure in this model [51]. It has also been observed that although propranolol has little effect on the immediate rise in pressure following the implantation of DOCA, some amelioration of the late hypertension is achieved [52]. Results in Japanese spontaneously hypertensive rats are more clear cut. Established hypertension is unaffected [53]. However, treatment of these rats from birth attenuates the normal development of the hypertension [54]. Rats of the New Zealand sponta-

May 31,

131

Low

[4.60,911

1

Fivefold

0.3 1 1

Low

[201 [62,63.651 157.691

10 0.2

.. . .

... Threefold

WI f4.591 [651

1561 and Shand [151 with modifications.

tors mediating vasodilatation in muscle [44]. The rat appears to have a very marked beta vasodilator tone. In contrast, the guinea pig shows little change in arterial pressure when given propranolol in large doses; the essential species difference resides in the relatively greater importance of beta-mediated vasodilatation in the rat [45]. Another contribution to the pressor effect of propranolol in the rat is the release of adrenal catecholamines. This is mediated by the local anesthetic effect of propranolol, and dextro-propranolol is equally active [46]. This effect is partly responsible for the antagonism by propranolol of the hypotensive effects of guanethidine, hydralazine and methydopa in the rat [47], since it is abolished by adrenalectomy

840

Potency Interindividual Variation in per mg of drug Plasma Cpncentra(propranolol = 1) tion After Oral Oose

Oxprenolol Alprenolol

*From

Local

1976

The

neously hypertensive strain appear more responsive to propranolol [55]. It is difficult to draw any useful conclusions from these animal experiments. It is evident that the effect of propranolol is markedly speciesdependent, the rat is quite unlike man in its responses, whereas the rabbit is rather similar. These differences appear to be related to the relative importance of peripheral beta-mediated vasodilator tone. OTHER BETA BLOCKERS AND THEIR CLINICAL EFFECTS

Since the introduction of propranolol as an antihypertensive agent in 1964 a number of other beta blocking drugs have undergone clinical trial in hypertension. As these compounds differ in some respects from propranolot, it is of interest to compare their clinical effects in the hope of casting some light on the central problem of how propranolol lowers arterial pressure. Beta blockers differ in several respects. Firstly, their antagonist activity at beta adrenoceptors can be indiscriminate or selective, inhibiting only cardiac type @l receptors. Secondly, the compounds may possess intrinsic sympathomimetic activity, that is, they may be partial beta agonists. Thirdly, they may or may not have loca! anesthetic activity. Fourthly, the metabolism and distribution of the drugs differ. This will influence the degree of interindividual variation in response to the drug and also whether the drug penetrates the central nervous system. Finally, and least importantly, the potency of the drug per unit weight may differ. Some of these parameters are listed for 10 beta blockers in Table I. Many data on the clinical efficacy of these compounds have been published, although it is not easy

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to compare directly responses to different beta blockers used in different studies. The following conelusions appear of interest: (1) All the beta blockers listed, despite their different properties, lower blood pressure by the same amount. Patients who respond to one drug will respond to another and will show the same degree of response to any of the drugs [4,58-611. Patients may prefer one drug to another because the subjective side effects differ [4]. (2) There is some indication that practolol, a polar cardioselective drug, is slightly less effective than the other nonselective drugs [9,62]. Whether this lesser potency is due to dose limitation by side effects [65] is not clear. (3) The cardioselective drugs lower plasma renin activity less than the noncardioselective drugs [63,64]. They also have less effect on cardiac output which is unchanged at rest [66]. (4) The possession of intrinsic sympathomimetic activity seems to make little difference to the hypotensive effect of beta blockers, but with treatment the heart rate is higher with these agents [67]. (5) Local anesthetic effect per se seems unimportant since dextro-propranolol is not an effective antihypertensive [37]. However, this property is associated with lipid solubility and hence penetration of the central nervous system. Drugs which lack local anesthetic activity, such as practolol, are only sparingly lipid-soluble. Data on levels of beta blockers within the central nervous system are few, but practolol [68], atenolol [68] and metoprolol [69] probably achieve only very low concentrations in the brain. POSSIBLE MECHANISMS OF THE ANTIHYPERTENSIVE EFFECT

Four main theories have been advanced to explain the antihypertensive effect of propranolol. Of these, the renin and central nervous system theories have attracted considerable recent interest and experimentation. Two others, the cardiac and baroreflex theories, have attracted little experimental investigation. The fifth theory, which attributed the effect to a metabolite of propranolol, is mentioned only to dismiss it. Renin theory. The secretion of renin by the kidneys is subject to both hormonal and neural control [70]. Stimulation of the sympathetic renal nerve results in renin release [71]. In 1970 the interesting observation was made that beta adrenoceptors mediated this neural release [72]. Shortly after this, Michelakis and McAllister [73] reported that propranolol suppressed both the basal and stimulated level of plasma renin activity in hypertensive patients.

In 1972 Buhler et al. [27] published a report that provoked much controversy and provided a tremendous stimulus for research into beta blockers in hypertension. They proposed the hypothesis that the antihypertensive effect of propranolol was due to its action in suppressing renin release. Forty-seven hypertensive patients had been treated with propranol01 for up to a year. In each patient plasma renin activity was determined before they received drug therapy. Two key observations were made. (1) The reduction in arterial pressure with propranolol treatment correlated with the decrease in plasma renin activity (Figure 2). (2) The patients with the highest plasma renin activity values had the greatest reduction in blood pressure. Patients classified as having low renin levels in relation to urinary sodium excretion had the least response to propranolol. From these observations, the investigators concluded that the essential action of propranolol in exerting an antihypertensive effect was to suppress renin secretion. For many reasons, this attractively simple idea seemed unlikely to be true. Many clinicians who had treated patients with propranolol and other beta blockers believed that the great majority of patients would have responded to the drug if the dosage had been increased sufficiently, and it was unlikely that all responders could have had high renin levels. Secondly, there was great skepticism of any theory that implied that renin secretion played an important role in essential hypertension. Finally, diuretics had been successfully used in hypertension for many years, and these drugs were known to increase plasma renin activity. Thus, there was a general prejudice against the hypothesis, although little direct evidence that it was mistaken. A number of careful investigations of the hypothesis have now been published. Many workers have attempted to dissociate the hypotensive and the hyporeninemic effects of propranolol. In fairness to Buhler et al., it must be said that some of these claims to dissociate plasma renin activity changes and hypotensive effects do not directly test the original hypothesis. Several reports have appeared showing that suppression of a diuretic- or vasodilator-induced hyperreninemia with beta blockers did not correlate with a decrease in blood pressure [74-761. This point about diuretic-induced hyperreninemia is not directly at issue [ 771. The original theory only related to the basal plasma renin activity in patients being treated with beta blockers. From the many contributions to this debate, evidence will be cited from two. Morgan and colleagues [28] conducted a careful survey of the relationship between the changes in plasma renin activity and the antihypertensive effect

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PFtOPRANOLOL IN HY!‘ERTENSION-LEWIS

of both propranolol and pindolol. They made several observations which effectively dissociate the two effects. Firstly, single oral doses of propranolol reduced plasma renin activity within 4 hours whereas arterial pressure was unaffected. Oral pindolol, on the other hand, reduced blood pressure within 4 hours but did not affect plasma renin activity. SecIN

CHANCE OIAS’IOLIC mmHg

-45

ondly, during prolonged treatment, there was no correlation between the decrease in blood pressure and the decrease in plasma renin activity with either beta blocker (Figure 3). Thirdly, initial plasma renin activity values were not predictive of the response to either drug. Leonetti et al. [21] conducted an interesting study

BLOOO PRESSURE

-40

I

I

-35

-30

-7s

-20

1

1

1

1

-IS

-p

-5

1

I

I

0,

T

+2

l r)

I

I

-0.2

0

0

i

0 : 8

8 CHANGE !N PC ASMA RENIN ACTlVlli

8

ng/ml/hr

-loo

F&e 2. Relation between proprano/o/-induced changes in diasto!ic blood pressure and decrements in plasma reniq activity in 47 hypertensive patients with low (triangle), normal (circles) and high renin (squares). From Bijhler et al. 1271.

L20 0

.

. 0

-1.0

0.2

-05 0

00 0

.

.

0

. .

. 0

0

0

l

.

0

0

0

0 0

.

01:

00

0. Oq.

00

..**o

. 00

l .

0 0

. 0

.

0

.

0 0 .

iz

- -25

l*

0

ii

Figure 3. Relation between diastolic blood pressure changes and plasma renin activity ikluced in ambulant patients treated with chronic propranokl, open circles, or pindolol, closed circles. There was’ no si@7ificant corre!ation between these variables. From Morgan et al. [28].

5 %

0

.

(pmol A,ml’h’)

’

O *a*0 0

Change in PRA

0

3

0 0

0

042

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Journal of Medlclne

5

--50

Volume

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PROPRANOLOL IN HYPERTENSION-LEWIS

in which they measured propranolol concentrations, thus eliminating the greatest source of interindividual variation. Their approach was to administer propran0101 to hypertensive patients and to investigate whether the hypotension and renin suppression responses bore the same relationship to increasing plasma levels of the drug. There was a significant relationship between the plasma concentration of propranolol and the reduction of both plasma renin activity and arterial pressure. However, plasma renin activity was reduced at concentrations of propranolol which were without effect on arterial pressure (Figure 4). It was thus clearly shown that the dosage requirements for the two effects were different. Various other observations tangential to the renin theory may be cited. Pindolol will increase plasma renin activity in the rabbit [41] and in man [78], and will cause a fall in blood pressure in both species. The recent introduction of drugs which inhibit the renin angiotension system at other points, such as the converting enzyme inhibitor, SQ 20881, and the competitive angiotensin II inhibitor, saralasin, have enabled the role of the renin angiotensin system in essential hypertension to be dissected rather more closely [79]. Neither of these agents affects blood pressure in hypertensive patients unless they are salt-depleted [80,81]. If these specific blocking agents do not affect arterial pressure, it seems unlikely that propranolol could do so by affecting the secretion of renin. It is interesting to speculate why Buhler et al. observed such a good correlation between the fall in plasma renin activity and the reduction in arterial pressure when others have not. Firstly, they included in their study some patients with malignant or renovascular hypertension in which there is no doubt that renin is an important component [82]. Secondly, their study was essentially one to determine the effects of small doses of propranolol. Some of their nonresponders in the group with low renin might well have responded had the dose been increased. Thirdly, the possibility remains that some of their patients with low renin might have been Black. There are indications that these patients are relatively resistant to the effect of beta blockers [83]. The “Central” Theory. The central nervous system control of the cardiovascular system has been the subject of considerable research in recent years. Several adrenergic neuronal circuits have been shown to participate in arterial pressure regulation [84,85], and there is now a sound rationale for proposing that drugs that act at peripheral adrenoceptors might exert effects on central circuits provided they reach an effective concentration within the central nervous system. A central mechanism of action has been clearly demonstrated for the adrenergic

drugs methyldopa [86] and clonidine [87,88], which probably activate an alpha adrenergic site in the medulla oblongata. The hypothesis that propranolol exerts some of its antihypertensive action by a mechanism within the central nervous system has been suggested by various investigators [90,91]. This suggestion was first made by exclusion, there being no plausible explanation as to why beta adrenoceptor blockade in the peripheral autonomic nervous system should alter arterial pressure. However, there is now a body of more direct evidence. Central Effects in Man. There is no direct evidence that propranolol exerts a central hypotensive effect in man, and it is difficult to see how such evidence might be obtained. However, certain observations do suggest that propranolol can affect the functioning of the central nervous system in man. Electroencephalographic changes have been observed in schizophrenic patients given doses of propranolol [92].

pr:;Z&

76-250

15-75 nmol/l

1

>250

nmol/l

L

s

nmoi/l

L

s

Figure 4. Incidence of decrease in (a) plasma renin activity equal to or greater than 50 per cent, (b) heart rate equal to or greater than 10 per cent, (c) diastolic blood pressure equal to or greater than 10 per cent, at low (15 to 75 nmol/iiter), intermediate (76 to 250 nmol/liter), and high (250 nmol/liter) plasma concentrations of propranol01, in 16 patients lying supine: S, standing upright: F, after furosemide intravenously. From Leonetti et al. [2 l].

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PROPRANOLOLIN HYPERTENSION-LEWIS

Behavior and mood in normal subjects were unaffected by single doses of the drug, but they felt more troubled than when they took the placebo [92]. These investigators point out that this effect might well be secondary to peripheral effects, such as bradycardia, and that mood changes do not necessarily imply a primary central action. Similar reservations have been made about the weak anxiolytic effects of propranolol [94]. Side effects in patients receiving propranolol treatment for high blood pressure do include changes in central nervous system functions. These include vivid dreams (1.46), depression (0.64), hallucination (0.63), somnolence (0.49) and insomnia (0.14). The figures refer to the percentage incidence collated from trials involving 1,435 patients [24]. In animals, large doses of propranolol have been shown to be sedative and anticonvulsant [ 951. Some evidence that propranolol has a central effect in man has been deduced from the fact that there is a steep relationship between an oral dose and a decrease in arterial pressure. For example, over the dose range of 120 to 460 mg, the decrease in blood pressure is incremental, whereas for atenol01 [96] and practolol [65] the dose response relationship for equivalent dose ranges is flat. It has been suggested that the increasing fall in blood pressure levels with large doses is due to the onset of a central effect not seen with the more polar compounds which only exert peripheral effects. This argument is attractive, but it fails to explain why oxprenolol and bufuralol [20] also have flat dose response curves; these compounds penetrate the central nervous system and are active when given intraventricularly to animals. Conversely, sotalol has a steep dose response curve and is only sparingly lipid-soluble [65]. Central Administration in Animals. Kelliher and Buckley [97] administered propranolol intraventricularly to the anesthetized cat. They observed a decrease in arterial pressure which could be abolished if brain catecholamines had been previously depleted with reserpine. However, the effect was not due to central beta blockade since dextro-propranolol, the nonbeta blocking isomer, was equally active in this preparation. Since dextro-propranolol is not a hypotensive agent in man [37], Kelliher and Buckley effectively discounted the possibility that a central action contributed to the clinical effects of the drug. Various other observations made in anesthetized animals, such as those of Stern et al. [98] who showed that in cats propranolol was more active when given into the carotid or vertebral artery than when it was given peripherally or that propranolol exerted a central nervous system effect in dogs and cats [99-

044

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The American Journal of Medicine

1011, are essentially undermined by this original observation that the effect in the anesthetized animal was a nonspecific one. Because nonspecific effects appear prominent in anesthetized animals, most recent work has been carried out in conscious animals. Here, the results are quite different. In the conscious rabbit, intraventricular levo-propranolol exerts a hypotensive effect but dextro-propranolol does not [ 1021. This finding has been confirmed in the conscious cat [ 1031, and it has also been shown that the nonbeta blocking dextro isomer of alprenolol is inactive centrally, whereas the beta blocking isomer has a central hypotensive effect. In the dog, intraventricular propran0101has a less consistent effect [ 104,105]. A further complication in these experiments is that all beta blockers with local anesthetic activity cause an initial rise in arterial pressure when they are given intraventricularly. Analysis of this effect, which occurs in the cat [99,106] and rabbit [ 1021, shows that other local anesthetics without beta blocking activity [ 1071 have this effect and that it is related to an initial catecholamine release [ 1081 probably in the hypothalamus. Penetration of-the Central Nervous System. In the animal experiments described in the previous section, direct injection of propranolol into the central nervous system was shown to result in a prolonged decrease in arterial pressure in the conscious animal. A major criticism of this work has been that such a central injection of drugs may result in very high local concentrations in the brain and that, in clinical practice, such levels are unlikely to be achieved after parenteral or oral administration. Thus, in both the conscious cat and rabbit, the effective intraventricular dose of propranolol is 0.1 mg/ kg. However, propranolol is a highly lipid-soluble drug and achieves high partition between brain and plasma [ 1091, and so comparable brain concentrations might result after parenteral doses. The brain concentrations of propranolol were determined after intraventricular injections in rabbits and were found to be between 1 and 5 pglg at the time of peak hypotensive response. The intravenous infusion of propranolol in a dose that results in a very similar decrease in blood pressure, 1 mg/kg, also results in very similar brain concentrations [ 1 lo]. The hypothalamus to plasma concentration ratio after an intravenous infusion in the rabbit is 15 to 1. Thus, because of the physicochemical properties of the substance, very high brain concentrations are not achieved when the drug is injected intraventricularly, because the drug equilibrates with plasma. Conversely, when the drug is given intravenously, high brain concentrations are rapidly built up. Specific

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binding of propranolol to adrenergic receptor material in the brain has also been suggested [ 1111. The brain to plasma concentration ratio for propranolol has also been measured in man [ 1 lo]. A series of patients with paraquat poisoning were treated with a dextro propranolol infusion in an attempt to displace the paraquat from its lethal binding to lung. Four patients died while receiving this regimen, and opportunity was taken to measure propran0101both in the plasma and in the brain postmortem. The average ratio of brain to plasma concentration was 15, similar to that seen in rabbits, and the values for hypothalamic propranolol concentration were comparable (1 to 9 kg/g) to those associated with the central hypotensive effect in the rabbit. An effective plasma propranolol concentration in patients receiving prolonged oral therapy is between 50 and 150 ng/ml [ 141. There thus seems little doubt that in these patients hypothalamic concentrations between 1 and 4 pglg can be achieved. As shown, these concentrations are similar to those which exert a central nervous system effect in rabbits. Pharmacokinetic considerations are important in evaluating experiments when local injections of beta blockers are made. Offerhaus and Van Zweiten [ 1121 infused propranolol into either the. vertebral artery or the femoral artery of anesthetized cats. They found both routes of administration caused similar decreases in arterial pressure and thus argued that no central nervous system effect was involved. However, the brain concentrations of propranolol produced would have been similar by either route due to recirculation of the drug and concentration within nervous tissue. Sympathetic Nervous Activity. If propranolol were exerting a central hypotensive effect then a consequence of its action would be to diminish sympathetic nervous activity. Recording of sympathetic nerve activity, therefore, offers a direct method of confirming or refuting the hypothesis. The recording of activity in sympathetic nerves is a technic which has been widely applied to such problems concerning the central cardiovascular [87,88] effects of drugs [ 1131. Hypotensive agents which lower arterial pressure by a peripheral effect induce a reflex increase in sympathetic nervous activity. However, if the hypotensive effect has a central element then sympathetic nervous activity may actually decrease despite the reduction in blood pressure. Direct recording from the sympathetic nervous system is possible in animals, and such technics have been used to demonstrate the central hypotensive effect of clonidine [87] and its location to the central baroreflex loop [88]. However, application of this technic of sympathetic nerve recording to analysis of the effect of

propranolol was not possible until a method became available for measuring sympathetic nervous activity in the conscious animal. Such a method involving the chronic implantation of recording electrodes in the splanchnic nerve was devised by Schmitt et al. [ 1141 in the dog. A similar technic was used to study the rabbit [ 1151 since this species responds to intravenous infusion of propranolol with a decrease in blood pressure [ 4 1,l lo]. Long-term electrodes were implanted in the greater splanchnic nerve of rabbits, and the animals were allowed a recovery period of several days. Recordings were then made in conscious and in undisturbed animals. The pattern of electrical activity in the splanchnic nerve is characteristically phasic, bursts of activity being synchronized with respiration. The effect of propranolol on arterial pressure and sympathetic nervous activity was investigated by infusing drugs intravenously for a 2 hour period following a 1 hour control period. Splanchnic nerve activity and mean arterial pressure were recorded. Five treatments were given: a single treatment to each group comprising eight animals. Control infusion of saline solution had no effect on either arterial pressure or splanchnic nerve activity. The vasodilator, sodium nitroprusside, reduced arterial pressure and induced a reflex increase in splanchnic nerve activity. Dextro-propranolol, the nonbeta blocking isomer, had no significant effect on arterial pressure or splanchnic nerve activity. Propranolol infusion reduced both arterial pressure and splanchnic nerve activity. By contrast practolol, in a larger dose, failed to reduce splanchnic nerve activity. Figure 5 illustrates the results from one experiment with propranolol and Figure 6 shows all the collated results. These experiments provide direct evidence that, in the conscious rabbit at least, part of the hypotensive effect of intravenous propranolol is mediated by an effect in the central nervous system. The only other possible site of action of this effect is on the afferent loop of the baroreceptor reflex arc, and this seems extremely unlikely. Central Control of Arterial Pressure. Since the central hypotensive effect of propranolol is only exerted by the levo isomer, it seems likely that the effect is mediated by beta adrenoceptor blockade. It may, therefore, be helpful to review current ideas on how central adrenergic systems are thought to maintain arterial pressure. More is known about adrenergic neuronal systems than about any other neurotransmitter system in this context, but knowledge is still extremely fragmentary [84,85]. At least three systems of adrenergic neurones appear to be concerned with the regulation of arterial pressure (Fig-

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1mg akg-’ - h-l. i.v. Control iplanchnic ‘iacharges

Hour

First

Hour

Second

Hour

Nerve

WL

1seC

Figure 5. Effect of (f)-propranolol infusion ( 1 mg kg- ‘h- ’ intravenously) llll~i\lllllllll~llllllllllilll~ll~l~llllll lerllll,i,,,,,,,,,,,sl,,a,,ll,~ l,.,ll,l~l~1,1111111IIIIIIIJlk~~,~,~~~~~~~~ on sympathetic nerve activity and arterial pressure in a conscious rabbit. a, 3lood lOOsplanchnic nerve discharges as original mmHg _ _ oscilloscope records and as integrated %wiure Oactivity over 6-s periods (b): c, arterial pressure (each record was taken at the Integrated SN end of the time period indicated): d, 100 64 66 Mivity/h mean values of integrated splanchnic irbitrary Units nerve activity per hour and of mean blood pressure measured over the com62 60 Integrated Mean BP/h 65 plete hour by planimetry (e). From Lewis and Haeusler [I 151. mm Hg

Integrated SN Activity

I _I_

DL-P

D-P

P

MAP 20. 7. loFall olooSNA Figure 6. Effect of five treatments by intravenous infusion for 2 hours on mean arterial pressure (MAP) and sym. pathetic nerve activity (SNA) in conscious rabbits. S = saline; NP = sodium nitroprasside 1 mg/kg/hour: DL-P = dL-propranolol 1 mg/kg/hour; D-P = dpropranolol 1 mg/kg/hour; P = practolo/ 10 mg/kg/hour. Eight animals in each group, “p < .OS, ““p < .O 1

60. 7. O:hange -6O-

l.COERULEU8-HYPOTHALAMUS e. F-N

SOLITARY

3. MEDULLA-SPINAL

TRACT CORD

Figure 7. Central adrenergic pathways implicated in arterial pressure control as defined in animal experiments.

PROPRANOLOL

ure 7). The cell bodies of most adrenergic neurones are located in the medulla and upper brain stem [ 1161. Axons of these cells ramify widely both up and down the neuraxis. Perhaps the most clearly defined adrenergic pathway is that which arises in the nucleus coeruleus and runs to the posterior hypothalamus. Electrical stimulation of the posterior hypothalamus results in a local release of norepinephrine accompanied by an increase in arterial pressure [ 1171. Local injection of 6-hydroxydopamine in this area will reduce the effect of electrical stimulation, suggesting that the release of hypothalamic norepinephrine excites the pressor circuit. Drugs which are known to release norepinephrine from adrenergic neurones increase arterial pressure when they are given into the cerebrospinal fluid [ 105,108,118] and this action probably takes place at the adrenergic nerve endings in the posterior hypothalamus since it is modified by anesthesia [ 1191. There is a second of norepinephrine-containing system neurones whose axons descend from the medulla terminating in the lateral horn of the spinal cord. The axons of this so-called bulbospinal tract terminate close by the cell bodies of the pregangionic sympathetic nervous outflow. There is contradictory evidence on the function of this bulbospinal tract. Some workers consider it to be excitatory [ 120,121]; others have produced electrophysiologic evidence that it is inhibitory to the sympathetic outflow [ 1221. The third adrenergic nerve circuit concerned with arterial pressure regulation is less well defined. Observations on the mode of action of clonidine suggest that this agent has its site of action within the medulla [ 1231. It has been shown that the hypotensive action of clonidine mimics sensitization of the baroreceptor reflex [88,124]. These two observations suggest that there are adrenergic neurones terminating on the baroreflex loop which have an inhibitory action on arterial pressure. It seems unlikely that any interneuron in the baroreflex loop is in fact adrenergic since the reflex is intact after severe central depletion of norepinephrine [ 1251. From this crude sketch of the known adrenergic circuits within the central nervous system, the most likely site of action for diminution of sympathetic nervous activity via adrenoceptor antagonism is in the posterior hypothalamus, but is as yet little experimental evidence bearing upon this point. Cardiac Theory. There is no doubt that the decrease in cardiac output produced by propranolol contributes to its hypotensive action. What is at issue is whether the decrease in cardiac output is itself responsible for other changes in the peripheral circulation leading to the reduction in blood pressure or whether these changes are quite independent of

IN HYPERTENSION-LEWIS

the cardiac effect. The decrease in blood pressure and the reduction in cardiac output are dissociated in time [6,25], and may be brought about by different doses of propranolol [21]. However, since cardiac beta blockade is almost the only common feature of all the antihypertensive beta blockers, the conviction that this action is central to the hypotensive effect is widely held [56]. It must be pointed out, however, that cardiac beta blockade is not associated with a reduction in resting cardiac output for several of the cardioselective beta blockers. How then might cardiac beta blockade affect the peripheral circulation? Two proposals have been made. The first, usually called the autoregulation theory, postulates that a persistent reduction in cardiac output leads to vasodilatation in the peripheral circulation as a focal response to chronic underperfusion. Presumably, for some of the drugs, this underperfusion only occurs during exercise. Autoregulation undoubtedly occurs in isolated perfused organs, but there is little direct evidence that such a mechanism exists to control perfusion in the intact whole body. The experiments of Guyton and colleagues [126] are often quoted in this context. These workers infused blood into decerebrate spinalized dogs. These animals showed a slow circulatory adjustment which was without any nervous reflex control of the circulation. However, the contribution such mechanisms might make in a conscious man with intact reflexes is uncertain. An interesting variant on the cardiac theory was recently proposed by Fitzgerald [56]. The link proposed here between cardiac adrenoceptor blockade and peripheral resistance is still somewhat mystical. He suggests that intermittent adrenoceptor blockade results in a persistent reduction in cardiac contractility not necessarily reflected as a decrease in cardiac output but leading to subtle circulatory adjustments which reverse the tendency to pressure elevation. Heart size may be reduced by long-term propranolol therapy [ 1271, but the rapid reversal of hypotension following the withdrawal of propranolol makes this theory difficult to sustain, although it does suggest some experimental approaches to the problem. Baroreceptor Theory. Prichard and Gillam [9] suggested that if propranolol increased the sensitivity of the baroreflex then this would explain the hypotensive effect of the drug. Furthermore, the preservation of baroreflex function as evidenced by the lack of postural hypotension would be consistent with this mechanism. Baroreflex sensitivity has been tested in normal subjects after single intravenous injections of propranolol [ 1281, and in hypertensive patients receiving prolonged oral therapy [29]. In both cases, some increase in sensitivity was noted. However,

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there are two objections to be leveled at these experiments and at the theory in general. In the first place, heart rate is slowed by propran0101and since baroreflex function in man can only be quantitated by measuring changes in the heart rate after alterations in blood pressure, the interpretation of such tests is difficult. The use of absolute changes or percentage changes in heart rate leads to different interpretations, and there is no answer as to which is correct. A second more general objection to the baroreflex theory is that it seems un,likely that change in baroreflex sensitivity could ever lead to long-term changes in arterial pressure. Baroreflex sensitivity is blunted in hypertension [ 1291, but this is thought to be a secondary adaptive change. In experimental hypertension baroreflex sensitivity becomes blunted after hyoertension is established [130]. However, some doubt has been cast recently upon this orthodox view: the central sensitization of the baroreflex has been implicated as the basic mechanism of action of the antihypertensive drug clonidine [88,124]; if this is confirmed in man, then an example would exist of a long-term change in arterial pressure resulting from change in baroreflex function. Metabolite Theory. It has been suggested that the hypotensive effect of propranolol might be due to a metabolite of propranolol with different pharmacologic activity [ 1311. As Fitzgerald [56] has pointed out, this is unlikely. The dextroisomer of propranolol forms the same metabolites as racemic propranolol, and yet it has no antihypertensive action. The metabolites of propranolol have a shorter half-life than the parent drug and would not account for its long duration of action. Finally, the metabolites of other beta blockers are quite different from those of propranol01. Some beta blockers are polar compounds and are not metabolized. COMMENTS Each of the theories propounded to explain the antihypertensive action of propranolol is unsatisfactory. The baroreflex and cardiac theories are short both of a sound theoretic basis and of experimental data. The renin theory cannot be the mechanism for the antihypertensive action of propranolol in the many patients with essential hypertension in whom renin is not a contributory factor and who require doses of propranolol much larger than those necessary to suppress renin. The central nervous system theory has not been disproved for propranolol, but since several other beta blockers which do not penetrate the central nervous system are equally effective antihypertensive agents this certainly casts doubt upon its validity. 848

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Is any compromise possible? One would be to propose that propranolol has a variety of actions, all of which contribute to a greater or lesser extent to the antihypertensive action depending on the pathophysiology of the particular patient’s hypertension: this is an intellectually unsatisfying solution and one whose adoption will not advance the subject. It would be equally sterile to speculate upon possible new pharmacologic actions which the beta blockers might be found to possess at some future date. Is there no mechanism which might draw together the mass of clinical and experimental data which we already possess? The logical starting point in reviewing the data is to consider the most prominent pharmacologic actions common to all the beta’blocking drugs. This is the blockade of cardiac beta adrenoceptors. However, the consequences of this blockade differ according to the drug. It is only during exercise or stress that each drug exerts the same action, namely, the blunting of the expected increase in cardiac output and heart rate. The cardiac theories of propranolol’s action have attempted to relate these changes to the antihypertensive effect by invoking direct hemodynamic links. However, another consequence of the blunting of cardiac responses to stimuli is a diminution in autonomic nervous input to the central nervous system. The heart and great vessels present a continuous barrage of sensory input via pressure and volume receptors to integrator circuits within the “head ganglion” of the autonomic nervous system. During exercise, blood pressure does not change markedly, but cardiac output and heart rate do. Beta blockade must thereby considerably diminish changes in the afferent input to the central nervous system, and it is change in activity which influences higher control centers. Although the mean heart rate and cardiac output may not be changed markedly by beta blockade, the extremes between which these parameters swing will be constricted. May it not be that this peripherally mediated “tranquilization” of the autonomic afferent input brings about a progressive damping effect on the central sympathetic nervous system, decreasing its excursions of activity and, in time, its mean level of output? This “input damping” theory would explain the following observations which are among the most difficult to reconcile with any of the other theories discussed. (1) All the beta blockers have the same hypotensive effect although their effects other than on cardiac beta receptors are very disparate. (2) There is a short but appreciable time delay in the antihypertensive effect, suggesting that the decrease in blood pressure is not directly consequent

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upon blockade of a receptor in a control pathway, there must be some slower adjustment in a regulatory circuit. (3) Although practolol scarcely penetrates the central nervous system it diminishes urinary catecholamine output in man, suggesting a centrally mediated reduction in sympathetic activity [ 1321. This central action must, therefore, be mediated by an action of the drug outside the brain and reduction of an excitatory input would suit this case very well. (4) The doses of beta blocker required to produce an adequate antihypertensive response are greater than those required to produce a moderately effective blockade of cardiac beta receptors. The dose necessary must produce a very high degree of beta blockade continuously. Otherwise the larger increases in adrenergic stimuli during exercise and stress would overcome the blockade and induce an input breakthrough. (5) Beta adrenoceptor agonist drugs which are used clinically in asthma and in obstetrics for premature labor, exert a hypotensive effect [133]. This is very difficult to explain unless the common action exerted by both agonists and antagonists at the beta receptor is to make more constant the level of stimulation and this leveling is of greater importance than the mean rate of stimulation at the receptor. This theory attempts to reconcile several of the mechanisms discussed earlier. It is very closely related to the baroreflex theory as originally stated [9], but the receptors whose input is being damped are not confined to these. The baroceptors respond to

IN HYPERTENSION-LEWIS

pressure, not flow, and as Frohlich has pointed out [ 1343, pressure does not change much in the initial stages of beta blockade or during exercise. The theory also agrees with the main starting point of the cardiac theories but diverges when the link between cardiac beta blockade and peripheral resistance is made. Finally, it invokes a central action for all the drugs but one not mediated by adrenergic blockade within the central nervous system. Those drugs which do produce such blockade are presumably acting at two points on the same control circuit: thus, no additive effects are produced. The renin system is another peripheral element whose oscillations form an input to the central nervous system which would be diminished by beta blockade. The value of any hypothesis is judged on whether it fits current facts and whether it can be tested experimentally. In this case a critical experiment would be to observe the effect on arterial pressure of fluctuations in cardiac output induced pharmacologically or with intravascular balloons. If such an increase in input to the central nervous system was capable of inducing a sustained increase in sympathetic outflow and arterial pressure then further investigation would be warranted.

ACKNOWLEDGMENT I should like to thank my colleagues Drs. C. T. Dollery, G. Haeusler and J. L. Reid for their help and encouragement in the experimental work mentioned in this paper.

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Weber MA, Thornell IR, Stokes GS: Effects of beta adrenergic blocking agents on plasma renin activity in the conscious rabbit. J Pharmacol Exp Ther 188: 234, 1974. Whittington-Coleman PJ: Hypotensive effect of propranol01. Br Med J 2: 189, 1969. Dasgupta NK: On the mechanism of ffie pressor response due to propranolol. Br J Pharmacol 34: 2OOP. 1968. Yamamoto J, Sekiya A: On the pressor action of propran0101in the rat. Arch Int Pharmacodyn 179: 372, 1969. Yamamoto J, Seklya A: Differences in the cardiac and pressor responses to propranolol of rats and guinea pigs. Jap J Pharmacol 24: 253. 1974. Lydtin H. Sommerfeldt H: The effect of D and DL propran0101 on blood pressure and cerebral norepinephrine in rats with DOCAhypertension. Int J Clin Pharmacol 6: 328,1972. Brunner H, Hedwall PR, Meier M: Influence of an adrenergic B receptor blocking agent on the effect of various hypotensive agents in the hypertensive rat. Experientia 21: 231, 1965. Grewal RS, Kaul CL: .Mechanism of the antagonism of the hypotensive action of guanethidine by propranolol. Br J Pharmacol36: 771,197O. Lundgren Y: Blood pressure and vascular design in renal hypertension in rats after prolonged propranolol treatment. Acta Physiol Stand 91: 409, 1974. Menard J, Alexander JM, Giudicelli JF, Auzan C, Chevillard C: Lack of antihypertensive effects of chronic administration of dL-Propranolol in Grollman’s rats. Arch Int Pharmacodyn 202: 298,1973. Dusting GJ, Rand MI: An antihypertensive action of propraholol in DOCA/salt-treated rats. Clin Exp Pharmacol Physiol 1: 87, 1974. Day MD. Peters AS: Effect of propranolol treatment on the development of DOCA/saline hypertension in rats. Br J Pharmacol54: 253P. 1975. Forrnan BH, Mulrow PJ: Effect of propranolol on blood pressure and plasma renin activity in the spontaneously hypertensive rat. Circ Res 35: 215, 1974. Weiss L, Lundgren Y. Folkow B: Effects of prolonged treatment with adrenergic beta-receptor antagonists on blood pressure, cardiovascular design and reactivity in spontaneously hypertensive rats. Acta Physiol Stand 91: 447, 1974. Lee DR, Simpson FO: Effect of propranolol on blood pressure, heart rate and exchangeable sodium in genetically hypertensive and normotensive rats. Proc Univ Otago Med Sch 51: 51. 1973. Fitzgerald JD: The mode of action of beta adrenoceptive antagonists in essential hypertension. Pathophysiology and Management of Arterial Hypertension (Berglund 0, Hansson L, eds), Goteborg 1976 (in press). Steinberg J, Wasir H, Amery A, Sannerstedt R, Wesko L: Comparative haemodynamic studies in man of adrenergic B, receptor blocking agents without (H93726) and with (H87/07) intrinsic sympathomimetic activity. Acta Pharm Toxicol 36 (suppl 5): 76, 1975. Laver MC, Fang P, Kincaid-Smith P: Double-blind comparison of two beta-blocking drugs with previous therapy in the treatment of hypertension. Med J Austral 1: 174. 1974. Lohmoller G, Frohlich ED: A comparison of timolol and propranolol in essential hypertension. Am Heart J 89: 437,1975. Beaton GR, Rosendorff C, Kramer R, Simpson RD: A comparison of propranolol and prindolol in the treatment of essential hypertension. Curr Ther Res 16: 268. 1974. Waal HJ: Hypotensive, antiarrhythmic and chronotropic

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