Effect of Beta Blockers on Vascular Resistance in Systemic Hypertension

A.J. MAN IN

Over 20 years ago, it was established that @ blockers could reduce high blood pressure. Current- ly, several p blockers with different ancillary proper- ties are available. They all have the property of blocking PI receptors but differ from each other in a number of other respects: they may or may not block p2 receptors in low doses (PI = receptor selectivity); they may or may not possess varying degrees of partial agonist activity, also known as intrinsic sympathomimetic activity (ISA); they vary in the extent to which they are soluble in fat (lipo- philicity). A review of relevant published findings in- dicates that the effects of fl blockers on cardiac output are not essential for their antihypertensive ef- fect, nor is penetration of these drugs into the brain and cerebrospinal fluid. Reduction in blood pressure during long-term p blocker therapy is always asso-

‘T VELD, MD

ciated with reduction of total peripheral resistance. fl blockers with sufficient ISA to prevent cardio- depression, by exerting less negative inotropic and chronotropic effects on the heart, do not cause ini- tial reflex vasoconstriction in response to cardiac p blockade. Unlike p blockers devoid of ISA, these agents ultimately reduce blood pressure by lowering the increased vascular resistance in hypertension to below pretreatment values. Recent p blocker re- search has revealed a number of ways to manipu- late the characteristically elevated vascular resis- tance in hypertension. Examples of these efforts are the combination of ISA, CY~ or cy2 receptor blockade and direct vasodilating properties in the enantiomers of a single 6 blocker molecule. The practical signifi- cance of these developments remains to be established. (Am J Cardiol 1987;59:21F-25F)

T he /3 blockers were originally developed for the treatment of patients with angina pectoris and cardiac arrhythmias.’ In 1964, Prichard2 observed that pron- ethalol reduced blood pressure in some hypertensive patients with angina pectoris being treated with this drug. At present, there are several p blockers on the market with different ancillary properties [Table I]. Because of the relatively favorable balance between efficacy, safety and tolerability, these agents have be- come drugs of first choice in the treatment of hyperten- sion.” Although all 0 blockers currently available share the capacity of blocking p1 receptors, they differ in many other respects. The most relevant additional properties of p blockers are:

1. a relative selectivity for p1 receptors, incorrectly called cardioselectivity;

2. presence or absence of a certain degree of partial

From the Department of Internal Medicine, Erasmus Universi- ty, Rotterdam, The Netherlands.

Address for reprints: A.J. Man in ‘t Veld, MD, Department of Internal Medicine I, Room CA 327, Erasmus University, Dr. Molcwatcrplcin 40, 3015 CD Rotterdam, The Netherlands.

agonist activity, also known as intrinsic sympathomi- metic activity (ISA];

3. the degree of solubility in fats, which is decisive for the rate at which a p blocker penetrates into the central nervous system and which is known as lipo- philicity.4-12

Short- and Long-Term Hemodynamic Effects In recent studies, the short- and long-term hemody-

namic effects of 10 /3 blockers were compared.13-l5 As Figure 1 shows, despite their major pharmacologic dif- ferences, the various p blockers have little short-term effect and a virtually identical long-term effect on blood pressure. In this respect, therefore, there is little basis for choice among the various drugs in this cate- gory. In addition, it was found that an inverse propor- tionality exists between short- and long-term reduc- tion of heart rate (Fig. 21, cardiac output [Fig. 3) and stroke volume (Fig. 4) on the one hand, and the extent to which a particular /3 blocker possesses ISA on the other. After short-term administration of various P blockers, blood pressure changes little, if at all; the peripheral resistance, which is already increased in hypertension, will increase further in proportion to the

21F

22F A SYMPOSIUM: BETA BLOCKADE, CARDIOSELECTIVITY AND INTRINSIC SYMPATHOMIMETIC ACTIVITY

TABLE I Ancillary Properties of Beta Blockers CARDIACOUTPUT

Drug ISA Pl

Selectivity Lipophilicity

Pindolol Oxprenolol Alprenolol Acebutolol Penbutolol Bopindolol Betaxolol Atenolol Metoprolol Propranolol Timolol Nadolol Sotalol

ISA = intrinsic sympathomimetic activity; 0 = absent; f = weak; + = intermediate; ++ = strong; +++ = very strong.

MEANARTERIALFRESSURE

TIMOLOL

ACUTE (n) AND CHRONIC (W) PERCENTAGE CHANGES

FIGURE 1. Effects of various p blockers on mean arterial blood

pressure. Despite pharmacologic differences, these agents exert

little acute effect, but a virtually identical chronic effect. ISA =

intrinsic sympathomimetic activity.

HEARTRATE

RCENTAGE CHANGES

FIGURE 2. Acute and chronic effects of /? blockers in reducing heart

rate are inversely proportional to the degree of intrinsic sympatho-

mimetic activity (ISA) of the agent.

FIGURE 3. With the exception of the chronic effects of pindolol, the

acute and chronic effects of various /3 blockers in reducing cardiac

output are inversely proportional to the degree of intrinsic sympa-

thomimetic activity (ISA).

STROKEVOLUME

ANDOLOL t-l PRACTOLOL

ATENOLGL

momkr4oLoL 1 a1 TIMOLOL

pYll=ICl ACUTE (0) AND CHRGNIC m) PERCENTAGE CHANGES

FIGURE 4. Acute and chronic effects of j3 blockers on stroke volume

are inversely proportional to the degree of intrinsic sympathomi-

metic activity (ISA).

decrease of the cardiac output [Fig. 5). It was also ob- served that, with respect to this reflex increase of vas- cular resistance, there is no difference between selec- tive and nonselective @ blockers. Apparently, whether or not the vascular & receptor is blocked (the so-called unopposed (Y effect) has no bearing on this phenome- non. There is little difference between the short- and long-term effects of a particular /3 blocker on cardiac output (Fig. 3). Since, nevertheless, blood pressure has decreased, this decrease has to be due to a decrease of peripheral vascular resistance (Fig. 5). However, be- cause initially the vascular resistance is higher when a p blocker has little or no ISA, a considerable differ- ence in the absolute level of peripheral resistance will persist in the long run, as well.

The short-term effects of the various /I blockers on

May 15, 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 59 23F

VASCUlARRESISTANCE

FIGURE 5. Peripheral vascular resistance increases in proportion to

the decrease in cardiac output. Moreover, there is no difference

between selective and nonselective B blockers with regard to this

reflex increase in vascular resistance. ISA = intrinsic sympathomi-

metic activity.

ACUTEEFFECTS

RNDOLOL

40 PRACTOLDL

I ALmENOLOL

I ACERUTOLOL

PENEWTOLOL

METDmOLOL

mOmANDLO1

FIGURE 6. Cardiac output and vascular resistance are inversely

proportional to each other when /!I blockers are given acutely. ISA =

intrinsic sympathomimetic activity.

cardiac output are somewhat more pronounced than their effects on heart rate (Fig. 2 and 3). Accordingly, stroke volume also decreases [Fig. 4). Stroke volume decreases more when little or no ISA is present. If, during long-term treatment, blood pressure and vascu- lar resistance decrease, stroke volume increases again.

Hemodynamic Patterns By definition, cardiac output and vascular resis-

tance are inversely proportional to each other for both short and long term (Fig. 6 and 7). The increase in vascular resistance due to reduction of cardiac output does not differ between selective and nonselective p blockers. With all p blockers, the decrease in blood pressure is a consequence of a decrease of vascular resistance. Because vascular resistance during treat- ment with p blockers with ISA is lower initially than

CHRONICEFFECTS

FIGURE 7. Cardiac output and vascular resistance remain inversely

proportional to each other with long-term administration of 0

blockers. ISA = intrinsic sympathomimetic activity.

ACUTEEFFECTS

I 5m 1106 ACEBUTOLDL

I 86m 1117

PENBUTOI.OL

I 1187

MFrOrnOLDL

,235 ATENOLOL

FIGURE 8. Decreases in stroke volume and increases in peripheral

resistance are inversely proportional after acute @ blockade. B

blockers with considerable intrinsic sympathomimetic activity

(ISA), however, cause no cardiodepression and do not trigger a

reflex increase in vascular resistance.

with ,6 blockers without this ancillary property, it will remain lower during long-term therapy.

The nature of the decrease in stroke volume after short-term /3 blockade is shown in Figure 8. There exists an inversely proportional relation between the extent of decrease of stroke volume and the extent of increase of peripheral resistance. This suggests that the combination of decreased cardiac contractility due to the p blockade and increased vascular resistance (afterload) are responsible for this inverse correlation. /3 blockers with a substantial amount of ISA cause no cardiodepression and, consequently, they do not trig- ger a reflex increase of vascular resistance. This as- sumption is corroborated by the fact that the decrease in vascular resistance, which is the cause of the de- crease in blood pressure with the various p blockers, is associated with an increase in stroke volume (Fig. 9).

24F A SYMPOSIUM: BETA BLOCKADE, CARDIOSELECTIVITY AND INTRINSIC SYMPATHOMIMETIC ACTIVITY

CHRONICEFFECTS

77

MC]29 1 ACEEUTOLOL 1 , F'ENBIJTOLOL

07 75 METOFROLOL

ATENOLOL

(rnOrnANOLOLI

t

J'S8 1 TIMOLOL

FIGURE 9. Decrease In vascular resistance, the mechanism by

which the @ blockers lower blood pressure, is associated with an

increase in stroke volume. ISA = intrlnslc sympathomimetic

activity.

Hemodynamic Changes After the Onset of Beta Blockade

Detailed hemodynamic studies during the onset of the antihypertensive action of p blockers with ISA are lacking. Therefore, we studied hemodynamic changes after starting therapy with pindolol for 24 hours in 10 patients with uncomplicated essential hypertension.16 Heart rate and intraarterial pressure were measured for 24 hours with placebo and after starting pindolol, 10 mg twice daily. During the second study cardiac output was also measured every hour by means of the thermodilution technique. During both 24-hour stud- ies the patients had complete bedrest.

One hour after pindolol therapy began, arterial pressure was already decreased significantly com- pared with baseline and placebo values (p <0.05) (Fig. 10). The maximum antihypertensive effect was seen 3 to 4 hours after administration t-15 f 3% compared with placebo, p <O.Ol). The maximum decrease in sys- temic pressure was caused by vasodilation; systemic vascular resistance had decreased by 25 f 6% (p <O.Ol) at that time, without significant effects on heart rate and cardiac output compared with baseline val- ues. In comparison with placebo values, however, heart rate was significantly reduced from 80 f 3 to 67 f 2 beats/min (p <O.Ol). After 24 hours, arterial pressure and systemic vascular resistance were reduced by 14 f 2 (p <O.Ol) and 25 f 4% (p <O.OOl), respectively. By that time cardiac output was increased by 16 f 5% (p <o.oq.

This study shows that the nonselective ,f3 blocker pindolol, with considerable ISA, exerts its full antihy- pertensive effect after oral dosing within the absorp- tion phase of the drug. Apparently, there is no time delay between the blockade of @ receptors per se and the antihypertensive effect. This contrasts with /3

nance of the antihypertensive effect of pindolol are associated with a decrease of the elevated vascular resistance in essential hypertension. This also con- trasts with the hemodynamic profile of @ blockers lack- ing ISA, whether or not they are cardioselective (Fig. 51.

Pathophysiologic Considerations From a hemodynamic point of view, hypertension

of longer duration is characterized by increased pe- ripheral resistance and a normal or decreased cardiac output. Regarding effects on heart rate, there is no difference between hypertensive and normotensive subjects. Consequently, stroke volume is normal to subnormal in patients with hypertension.

p blockers without ISA have little effect on the he- modynamic abnormalities in hypertension: the pe- ripheral resistance remains increased and increases

-I

FIGURE 10. One hour afler administration of pindolol, arterial pres-

sure was significantly reduced compared with baseline and placebo

values (0). This was caused by vasodilation. Reproduced with

blockers devoid of ISA.17-lg The onset and mainte- permission from Am Heart J.16

May 15, 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 59 25F

even further, while stroke volume remains subnormal (Fig. 11). A /3 blocker with sufficient ISA to prevent a decrease of cardiac output at rest produces clearly dif- ferent results. In this case, the decrease in blood pres- sure is accompanied by a decrease in vascular resis- tance to below the pretreatment level, and stroke volume returns to normal.

Future Prospects of Vasodilating Beta Blockers It appears that p blockers devoid of ISA worsen the

underlying hemodynamic abnormality of longstand- ing arterial hypertension; i.e., they further increase vascular resistance. Depending on the degree of ISA, p blockers with this property leave the elevated vascular resistance relatively untouched or decrease it some- what below pretreatment levels. Just as propranolol has been the prototype for all p blockers for over 20 years, pindolol is the prototype for vasodilating /3 blockers. Pindolol is unique in that the cardiac effect of ISA approximately equals the loss of basal sympa- thetic tone caused by blockade of cardiac fl receptors. Therefore, a baroreflex-mediated increment in vaso- constrictor nerve activity in response to cardiodepres- sion after /3 blockade is prevented. Both short and long

120 MEAN ARTERIAL PRESSURE ‘I,, ;;;: T\

-B-W,

‘;: y-----> HEART RATE

CARDIAC OUTWT 100

%

1; y.-------:

60 -

STROKE VOLUME sh

VASCULAR RESISTANCE %

PROI’RANOLOL

-------- PlNDOLOL

0 4 8 12 TIME IN HOURS

FIGURE 11. fl blockers without intrinsic sympathomimetic activity

have little effect on the hemodynamic abnormalities of hyperten-

sion: peripheral resistance remains increased and even increases

further, while heart rate, cardiac output and stroke volume remain

below normal levels.

TABLE It The Vasoditating Beta Blockers

Receptor Blockade ISA p Direct

Drug 011 ffP PI 82 Blocker Vasodilation

Pindolol 0 0 + + +++ 0

Labetalol f 0 + + f 0

Celiprolol 0 f + + 0 Prizidilol 0 0 + + 0 + Carvedilol 0 0 + + 0 + Medroxalol f 0 i- + + +

Bucindolol f f i- + + +

ISA = intrinsic sympathomimetic activity; 0 = absent: f = weak: + = present; +++ = strong.

term, the decrease in arterial pressure during treat- ment with pindolol is associated with a normal cardiac output at rest and return of vascular resistance to nor- mal. More recent developments in /3 blocker research have led to a number of alternative ways to manipulate the characteristically elevated vascular resistance in hypertension [Table II]. Examples of these efforts are the combination of ISA, CY~ or (Ye receptor blockade and direct vasodilating properties in the enantiomers of a single @ blocker molecule. The practical significance of these potentially interesting developments in /3 blocker research remains to be established.

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