role of vasobilation in the antihypertensive and antianginal effects of labetalol: implications for...

Cardiovascular Drugs and Therapy 2: 369-376, 1988 © Kluwer Academic Publishers. Printed in the U.S.A.

ROLE OF VASODILATION IN THE ANTIHYPERTENSIVE AND ANTIANGINAL EFFECTS OF LABETALOL: IMPLICATIONS FOR THERAPY OF COMBINED HYPERTENSION AND ANGINA

SUMMARY. Beta-adrenergic blockade is establ ished therapy in the management of both hypertension and angina pectoris. This review evaluates the use of combined alpha-adrenergic and beta-adrenergic blockade for these conditions, wi th reference to labetalol. There are three major differences between labetalol and propranolol or s imilar conventional beta- blockers. First, in the mechanism of the antihypertensive effect, peripheral vasodUation plays a prominent role during the use of labetalol . In particular, acute therapy with labetalol rapidly reduces the blood pressure because of this reduction in the systemic vascular resistance. During pro- longed therapy with labetalol over many years, blood pressure remains reduced with a sustained fall in the systemic vascular resistance. Second, in patients wi th combined hypertension and angina pectoris, f ixed doses of labetalol (200 mg twice daily) gave the same blood pressure values, effort tolerance, and nitrate usage as did atenolol 100 mg once daily in a double-blind, double-dummy, crossover study. Labetalol gave higher heart rates at rest and during exercise (both p < 0.01). The higher heart rate wi th labetalol could be an advantage in some patients wi th effort angina and a disadvantage in others. Third, in hypertensive asthmatics , labetalol appears to have a relative bronchosparing effect, when compared with propranolol. The possess ion by labetalol of beta2-st imulating qualit ies ( intrinsic sympathomimetic activity) may explain part of the di lat ing effect and the bronchosparing quality. Thus labetalol 1) lowers blood pressure by a mechanism involving vasedilat ion, 2) has an equiantianginal effect to atenolol yet at a higher heart rate, and 3) may be bronchosparing. Differences among various beta-blockers may be important in matching the properties of the beta-blocker chosen to the requirements of the individ- ual patient.

KEY WORDS. labetalol, hypertension, angina, alpha- plus beta-blockade, vasedflation, bronchospasm.

Labetalol is a combined adrenergic blocking drug already established in the therapy of systemic hypertension. It is a nonselective beta-adrenoceptor antagonist agent with added alphal-antagonist vasodilator properties relatively recently introduced in the United States [1], although long used in Europe. Labetalol is distinguished from propranolol and some other beta-blockers by the addition of vasodilatory properties, mediated by its alphal-adrenergic blocking property, and possibly also by the additional property

Lionel H. Opie Heart Research Unit, Department of Medicine, University of Cape Town, Observatory, South Africa

of intrinsic sympathomimetic activity (ISA) which confers mild beta 2-adrenergic stimulating qualities on the compound. The present article reviews the possible role of these additional vasodilatory properties in the mechanism of the antihypertensive and antianginal effects of labetalol.

Evidence for the Vasodilatory Effects of Labetalol in Hypertension

Alpha1-Adrenergic Blocking Qualities of Labetalol

The peripheral vasodilatory effects of labetalol are well established [2, 3]. Evidence for alphal-adrenergic blocking activity is as follows. First, in human volun- teers, labetalol gives a dose-dependent decrease of the pressor response induced by phenylephrine [4]. Fur- thermore, in hypertensive patients, 1) 50% of the rise of the systemic vascular resistance induced by phenylephrine is antagonized by labetalol [5]; and 2) the dose of phenylephrine required to increase diastolic blood pressure is more than doubled during labetalol therapy [6]. Substantial evidence obtained from animal experiments also shows that labetalol can antagonize alphal-adrenergic stimulation [7]. Furthermore, labetalol also binds to alphal-adrenergic receptors [8]. However, it should be noted that 1) labetalol has a much more powerful beta than alphal-adrenergic blocking effect [7], and 2) the binding of labetalol to

This paper was assessed by an external Editor Address for correspondence and reprint requests: L.H.Opie, MD, Heart Research Unit, University of Cape Town, Medical School Ob- servatory 7925, South Africa

369

370 Opie

alpha-adrenergic receptors is relatively weak when compared with phentolamine [8]. Thus the question is raised whether labetalol might induce vasodilation by mechanisms other than alphal-adrenergic blockade.

Vasodilation by Beta-Adrenergic Receptor Stimulation

Several lines of evidence favor a role for direct vasodilation [9] and more specifically beta-adrenergic receptor stimulation in the mechanism of the vasodilation of labetalol. Intra-arterial labetalol increased femoral arterial blood flow in the dog hindlimb by a mechanism which did not appear to involve alphal-receptor blockade, as shown by major differences between the effects of prazosin in innervated and denervated limbs, whereas there were smaller and insignificant differences in the case of labetalol. The vasodilation caused by labetalol was largely abolished by intravenous propranolol,in keeping with a role for a beta-mediated mechanism [10]. Tadepalli and Novak [4] evaluated the cardiac stimulating qualities versus the peripheral vasodilation in their assessment of the beta-stimulating properties of labetalol. In reserpine-treated ad- renalectomized cats, labetalol induced a modest tachycardia which was reversed by propranolol. They do not support the idea of a "direct vasodilatory action" of labetalol, independent of beta-stimulation, as has been suggested [9, 11]. Their data lead them to suggest that the intrinsic sympathomimetic action of labetalol, in their preparation, was more marked on the cardiac than on the vascular beta-adrenergic receptors. Thus the animal experiments suggest that labetalol has an additional vasodilatory effect, beyond that mediated by alphal-receptor blockade, probably caused by beta-receptor stimulation. However, there appear to be no convincing data to substantiate the claim [10] that the vasodilatory effect of labetalol is specifically beta2 and not beta1 in its receptor effects.

Labetalol: Acute Vasodilatory Effects on Blood Pressure in Humans

Especially noteworthy is that the early studies by Richards et al. [12] showed that the infusion of labetalol to normotensive human subjects was accom- panied by a rapid drop in arterial pressure within 2 minutes. In contrast, an intravenous infusion of atenolol caused no fall in arterial pressure at 15 minutes and significant falls only after 1 to 3 hours in the case of the diastolic pressure [13]. Similar differences have been found between oral labetalol and atenolol by Holtzman et al. [14], who showed that the major mechanism of labetalol's hypotensive effect was

by acute vasodilation. In severely hypertensive subjects, labetalol (100 to 125 mg intravenous bolus) was compared with propranolol (10 mg intravenous bolus); within 5 minutes labetalol had had a hypotensive effect which was sustained for 3 hours, whereas propranolol did not decrease the pressure at all [15]. (The hemodynamics of the acute intravenous effects of labetalol given to hypertensives are reviewed by Frish- man [11].)

Labetalol: Subacute and Chronic Vasodilatory Effects in Hypertension

During short-term (5 weeks) oral therapy with labetalol, systemic vascular resistance decreased whereas with propranolol it increased [16]. With atenolol, metoprolol, and acebutolol there were few changes, suggesting a difference between selective and nonselective beta-blockers at this stage of therapy (Figure 1).

In an important long-term study, Lund-Johansen[3] examined both the acute and chronic blood pressure lowering effect of labetalol and followed up 15 patients after 1 and 6 years of labetalol therapy (mean dose 400 mg daily, 3 of 15 patients with 800 mg labetalol daily also given 25 mg hydrochlorothiazide). During the acute intravenous study, the blood pressure was mostly reduced by a fall in the systemic vascular resistance (-14%) but also partially by reduction in the cardiac output (-10%). During the chronic follow-up study, the systemic vascular resistance was reduced 15% to 20% after 6 years, and the cardiac index was essentially unchanged. In contrast, in 8 untreated hypertensive subjects studied over a 17-year period, the cardiac index progressively fell whereas the total systemic vascular resistance increased. Therefore the long-term fall in vascular resistance achieved by labetalol becomes all the more significant (Figure 2; also see Figure 1). As a caveat, it is however important to note that the untreated patients appeared to have borderline hypertension with lower initial values than did the labetalol group.

Unfortunately there are no entirely strict data, done on patients in comparable parallel study groups, to compare the long-term effects of labetalol with those of any of the conventional beta-blockers. However, in a somewhat similar group of patients also studied by Lund-Johansen [17], 10 patients were given atenolol (mean dose 100 mg daily) over a 5-year period. Mean arterial pressure fell but there was no change in the systemic vascular resistance (see Figure 1). The decrease in blood pressure was ascribed to a fall in cardiac output, which in turn was caused by a reduced heart rate, especially during exercise.

Labetalol for Hypertension Plus Angina 371

I BETA=BLOCKERS AND SYSTEMIC VASCULAR RESISTANCE I

+30 -

X ~ X labetalol 0 ------. ~- - -A atenolol

< +20 / A ? O ~ 0 - - 0 propranolol

/ / ' , ,, \

, . , o / , , \ / \

_z ~ o "e, . . . . ~ . . . . . .A. t't" V

uJ

Z X < -10- "r

o ~ X ~ x

-20

i I I I I ACUTE 4-5wks 6-12 20 5-6

months months yrs

Fig. 1. Systemic vascular resistance (or SVR index) after acute therapy, after approximately 1 month of therapy, after 6 to 12 months, and after 5 to 6 years of therapy with labetalol, atenolol, or propranolol. Data from [55] for acute labetalol, [16] for 4 to 5 weeks, and [3] for I to 6 years of labetalol. For atenolol, acute data estimated from [I4]; 4- to 5-week data averaged from [16] and [56]; 1- to 5-year data from [17]. For propranolol data, see [57] except for 5-week data [16].

Thus, even though the patient groups are not strictly comparable, it would seem reasonable to conclude that 1) labetalol left the patients with cardiac output closer to normal after 6 years of therapy than did atenolol after 5 years of therapy, and that 2) labetalol had a sustained vasodilatory action, whereas atenolol did not (see Figures 1 and 2).

Conclusion: M e c h a n i s m s of Ac t ion of Labetalol in Hyper tens ion

The above studies show that labetalol, besides its established beta-blocking qualities, has a vasodilatory action which acutely and chronically reduces the systemic vascular resistance to play a prominent role in its antihypertensive effect.

Mechanism of Antianginal Effects of Labetalol

Whereas a clear distinction emerges between the effects of labetalol and other more conventional beta-

BETA-BLOCKERS AND CARDIAC OUTPUT I

I- n I,-- :D o o < n- < o

z

iii (D

z

-r o

+10 1 X~X labetalol A.--A atenolol

O-- / X 0 ~ 0 proDranolol

,,S--x- \ ___x \ \

- 10- \ \ A ~

-30

I ! I l ACUTE 4-5 wks 6-12 20 5-6

months months yrs

Fig. 2. Cardiac output (or cardiac index) for same groups as in Figure 1, with same data sources•

blockers concerning their effects on the hemodynamics of acute and chronic hypertension, it is much less evi- dent that labetalol differs from conventional beta- blockers in its antianginal effect. Evidence favoring a specific role for the vasodilatory properties of labetalol would include proof of 1) an alpha-adrenergic-dependent mechanism in effort angina, 2) a role for alpha-adrenergic mechanisms in vasospastic angina, or 3) a greater coronary vasodilation achieved by labetalol than by conventional beta-blockers.

Possible A lpha-Adrenerg ic -Dependen t

M e c h a n i s m s in Ef for t Angina

A relatively new concept in the pathogenesis of effort angina is that ischemia is precipitated bot h by an excess demand of oxygen and by a decreased supply of oxygen. During the development of effort angina, there appears to be a degree of relative coronary vasoconstriction. The experimental studies of Ross and colleagues [18] showed in their dog model with coronary stenosis that exercise-induced vasodilation was limited by a tone-dependent component. Considerable experimental work suggests that alpha-adrenoceptor stimulation may attenuate the metabolically induced coronary vasodilatory effects of exercise and that alpha-blockade inhibits this type of response [19-23]. These proposals are allied to that of Mudge et al. [24] who found that patients with coronary artery disease had limited coronary vasodilatory reserve in response

372 Opie

to a cold pressor test; such an alpha-mediated component was shown by the use of phentolamine. Likewise Berkenboom et al. [25] found that intracoronary phentolamine improved exercise-induced angina.

These and other data [26] suggest that postsynaptic alphas-receptors may be involved in the relative vasoconstriction which limits the coronary vasolatory response to ischemia.

However, in general, no attempts have been made to differentiate between the effects of alpha1- and alphas- adrenergic blockade except for the study of Heusch and Deussen [27]. They induced coronary stenosis in a dog model and increased poststenotic coronary tone by sympathetic stimulation, which in turn induced an alphas-mediated coronary vasoconstriction. In patients with angina pectoris already treated by beta- blockers, alpha~-adrenergic blockade by the agent indoramin ameliorates both effort and pacing-induced angina [28]. The proposed mechanism was a reduction of both the myocardial oxygen demand as the systemic vascular resistance fell, with an increased myocardial oxygen supply as the coronary vascular resistance fell. However, specific proof of alphas-mediated effects was not obtained. On balance, it seems as if evidence that alphas-receptor antagonism plays a role in the therapy of effort angina is not yet solid. Although labetalol can ameliorate effort angina [29], there is at present no proof that its vasodilatory properties confer on labetalol a superior antianginal effect when compared with conventional beta-blockers.

Evidence for a Coronary Vasodilator Activity of Labetalol

In a study on 12 patients with established coronary artery disease, Prida et al. [35] showed that coronary venous outflow was increased by labetalol, using coronary sinus temperature measurements. However, the fall in the coronary vascular resistance was only small (13%) and at a low level of significance (0.05%); furthermore, during exercise, when the evidence for alpha-adrenergic mediated increase in coronary tone is stronger [25], there was no change during labetalol therapy. Rather, during exercise, the effects of labetalol appeared to be those of a beta-blocker (decreased left ventricular minute work, decreased left ventricular dP/dt). Indirect evidence with the alphal-blocking agent indoramin, added to preexisting beta-blockade (therefore with some similarities to labetalol) shows that the coronary vascular resistance fell as the coronary sinus outflow rose [28]. However, the myocardial Os consumption rose during these experiments, which could explain away the changes in the coronary flow.

Peripheral Vasodilatory Effects in Angina

It appears that the effect of labetalol on the systemic vascular resistance in normotensive patients with angina has not been studied. However, a reduced systemic vascular resistance is likely to contribute to an antianginal effect by afterload reduction.

Possible Alpha-Adrenergic-Dependent Mechanisms in Vasospastic Angina

An increased coronary vasomotor tone may play a role in various anginal syndromes including vasospastic angina, and some studies suggest a role for alpha- mediated adrenergic vasoconstriction.

Localized alpha-mediated vasoconstriction may contribute to coronary artery spasm in some patients [30, 31]. A diffusely enhanced coronary vasomotor tone (not the same as localized coronary spasm) may also play a role in cold-induced angina, acting through an alpha-adrenergic-mediated mechanism [24]. In addition, increased blood pressure at rest and exercise may reflect an increased systemic vascular resistance as a result of cold exposure [32]. However, it must not be assumed that increased alpha-adrenergic activity has a proven role in coronary spasm. Thus the alphal- blocker prazosin failed to improve variant angina [33]. Even the nonspecific blocker phentolamine had vari- able effects in variant angina, so that the relation between alpha-adrenergic receptor activity and coronary spasm remains an "elusive link" [34].

Conclusion: Labetalol and Angina

There is thus far no proof that the vasodilatory properties of labetalol play any specific effects in angina pec-

Table 1. Comparison of effects of labetalol with atenolol during exercise testing

Exercise Testing Atenolol Labetalol Parameters Blinded Blinded

Time (min) 12.8 _+ 1.4 11.0 _+ 1.5 Heart rate (beats/min) 108 ± 4.6 127 + 5.1" SBP 160 ± 10.0 160 ± 11.0 DBP 95 ± 4.9 90 ± 3.8 Double-product 17,780 -4-_ 1,525 20,436 +_ 1,799

Adapted from [47]. Note errors (here corrected) in calculation of double-product in original article. Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure. The effects oflabetalol (200 mg twice daily) were compared with those of atenolol (100 mg daily) in a double-blind, crossover trial in 10 patients with systemic hypertension and angina pectoris. Mean _+ SEM. *p < 0.01 for comparison, p value for double-product comparison <0.07 (two-tailed).


toris, nor is there substantial evidence for an alphal- adrenoceptor increased coronary vascular vasomotor tone in effort or in vasospastic angina. There are also few studies comparing labetalol with conventional beta-blockers in effort or in vasospastic angina. None- theless, incomplete evidence suggests that labetalol could be as effective as conventional beta-blockers in the therapy of effort angina.

Labetalol for Hypertension Plus Effort Angina

In patients with hypertension and effort angina, the mechanisms for angina are very complex and include the frequently associated coronary artery disease, the increased oxygen demand of the hypertrophied myo-

cardium, the possibility of a true hypertrophic car- diomyopathy in association with hypertension, which could cause myocardial hypertrophy out of proportion to the blood pressure level [36, 37], reduced coronary vascular reserve in the absence of coronary artery disease [38], and increased coronary vasomotor tone pro- voked either during rest or by exercise. The latter mechanism has been well investigated in normotensive patients with angina [39, 40].

It is already known that vasodilator therapy by verapamil is effective therapy for the combination of hypertension and angina [41]. Lubbe and White [42] studied the effects of labetalol in 17 patients with established hypertension and angina who were already treated with a variety of conventional beta-blocking agents as well as nitroglycerin (Table 2). They used an

Table 2. E[[ects and side e[[ects of labetaloI when used for patients with combined hypertension and angina

Mean Daily Dose Comparison with No. of Labetalol Other Antianginal

Author [Ref. No.] Patients (mg) Effects Agents Side Effects

Besterman and Spencer 18 [45]

Halprin et al. [43] (included in the series of Frishman)

810

6 950

Frishman et al. [44] 10 BP effect starts at 300 mg; 9/10 patients controlled by mean dose of 764 mg daily.

Initial antianginal effect at 600 rag, mean antianginal dose 1,050 mg

Lubbe and White [42] 17 653

Jee and Opie [47] 10 400 mg daily fixed

Decreased blood pressure, None increased effort tolerance, decreased anginal pains, no comparisons--open trial

Decreased blood pressure None and heart rate, increased effort tolerance, decreased anginal pains and nitroglycerin consumption, no comparison--single- blind trial

Decreased BP and heart None rate, increased effort tolerance, decreased anginal attacks, decreased double- product during exercise

Apparently superior to conventional ~-blockade, no strict comparisons, no effort test data

Equal antihypertensive and antianginal effects of atenolol and labetalol with higher heart rates during atenolol treatment

None

Double-blind comparison with atenolol 100 mg and labetalol 400 mg fixed dose

Reduced tear flow

General fatigue Libido reduced Failure of

erection Mild fatigue Decreased

libido

Dizziness Impotence

Scalp tingling

None reported

6/18 1/18 2/18 1/18

1/6

1/6

1/10 1/10

2/17

Abbreviations: BP, blood pressure.

374 Opie

average dose of 653 mg/day of labetalol, which sub- stituted for the existing beta-blocking therapy. Angina pectoris, assessed by a subjective scoring system, significantly improved during the labetalol period. However, the trial was not blinded, the design did not require titration of the beta-adrenergic blocking agent originally used, and effort tests were not undertaken. Halprin et al. [43] and Frishman et al. [44] in a care- fully controlled study titrated the doses of labetalol to reduce systolic and diastolic blood pressure and to reduce spontaneous attacks of angina pectoris; it was noted that a higher dose of labetalol (mean daily dose 1,050 rag) was required to have antianginal than antihypertensive effects. In an open study, Besterman and Spencer [45] found that a mean dose of labetalol, 810 mg/day, reduced the blood pressure in the supine and standing positions and also during exercise; exercise tolerance was improved and angina disappeared or decreased.

Although it was argued by Opie et al. [46] that labetalol would merit special therapeutic evaluation in clinical situations where alpha-mediated vasoconstriction could be important, including hypertension and angina pectoris, there were no strict comparisons between labetalol and other beta-blocking agents. The trial of Jee and Opie [47] showed that labetalol compared well with another established antianginal agent, atenolol, in a double-blind study with effort tests, and that the antianginal effect could be achieved at higher heart rates both at rest and during exercise (see Table 1) when labetalol was compared with atenolol therapy.

As yet there are no studies specifically designed to assess the possible antianginal efficacy of the alphal- adrenergic antagonist component of labetalol. For example, the increased peripheral vascular resistance with conventional agents may be detrimental during acute mental arithmetic [48] or during acute exercise [5]. The increase in blood pressure associated with exercise is at least in part mediated by alpha-adrenergic- induced peripheral vasoconstriction [5]. Furthermore, emotional stress causes a reduction in coronary blood flow, probably mediated by coronary vasoconstriction [49] and therefore presumably the result of excess alpha-adrenergic activity.

Conclusion: Labetalol for Combined Angina and Hypertension

Labetalol is as effective as atenolol, with higher heart rates during labetalol therapy both at rest and during exercise. Labetalol needs comparison with atenolol in situations wherein the alphal-antagonist component of labetalol could be a specific advantage.

Advantages and Disadvantages of Labetalol Compared with Conventional Beta-Blockers

Possible Advantages

Labetalol can be expected to play a significant role in the therapy of those hypertensive conditions where increased sympathetic tone with increased a,pha- adrenergic activity is of special significance, with resultant increases in peripheral vascular resistance, e.g., as in pheochromocytoma or clonidine withdrawal [50]. Other such conditions would include 1) early hypertension or labile hypertension; 2) sustained severe hypertension; 3) hypertension induced by stress or cold; 4) hypertension in black patients [51, 52]; 5) some patients with angina at rest; 6) when a higher heart rate is required than during treatment with propranolol and some other conventional beta-blockers, especially when it is thought that a low heart rate may be detrimental to the hemodynamic status of the patient, as in elderly patients; and 7) sometimes in asthmatics with hypertension, when labetalol is a safer drug than propranolol [53, 54]. The explanation for the latter finding may be labetalol's capacity to stimulate beta2-adrenergic receptors (ISA). However, any beta- blocker including labetalol should only be given with great care to true asthmatics, and only after other types of antihypertensive therapy including calcium antagonists have failed.

Possible Disadvantages

There could be circumstances in which a higher heart rate than with conventional beta-blockers could be a disadvantage. For example, during the therapy of un- stable angina, the lower heart rate might confer additional anti-ischemic protective qualities. In postinfarct prophylaxis, only conventional beta-blockers such as propranolol, metoprolol, and timolol have been demonstrated to show post-infarct protection. There- fore in postinfarct patients with hypertension or hypertension and angina, a conventional beta-blocker is pre- ferred to labetalol. Finally, in the therapy of patients with supraventricular arrhythmias, the more marked inhibitory effects of beta-blockers on the atrioventric- ular-node could be an advantage when compared with labetalol.

Gaps in our Knowledge

It is not known whether the beta-stimulating properties of labetalol are truly beta2-selective or not, nor are


there any convincing compar i sons wi th pindolol , an agen t wi th es tab l i shed m a r k e d in t r ins ic sym- p a t h o m i m e t i c ac t iv i ty . Likewise, c l inical compar i sons

of the h e m o d y n a m i c effects of labe ta lo l wi th p indolol or wi th o ther vasod i la to ry be ta -adrenerg ic blockers such as cel iprolol are not ava i lab le . There are no t rue

ou tcome t r ia l s compar ing labe ta lo l in hyper tens ion wi th more convent ional be ta -b lockers such as pro-

pranolol , nor wi th cardioselect ive agents such as a tenolol or metoprolo l or acebutolol . In a s thmat i c s , the re are no compar isons be tween labe ta lo l and t rue cardiose lec t ive be ta -b lockers such as atenolol , meto-

prolol, or acebutolol .

Conclusion

The a d d e d vasod i la to r p roper t ies of the combined a lpha - and be ta -adrenerg ic blocker, labe ta lo l , are im- p o r t a n t in the mechan i sm of i ts an t ihype r t ens ive effect, so t h a t the blood pressure can chronica l ly be de-

creased by different mechan i sms from those involved in the case of convent ional be ta -b lockers . Labe ta lo l also has an t i ang ina l proper t ies . There is, however, t hus far no convincing case t h a t l abe ta lo l differs in the m e c h a n i s m of i ts effects from convent iona l be ta-

blockers, a l though an equ ipo ten t an t i ang ina l effect can be ob ta ined a t a h igher hea r t r a te wi th labe ta lo l t h a n wi th a tenolol .

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role of vasobilation in the antihypertensive and antianginal effects of labetalol: implications for...

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