exercise and antihypertensive therapy

Exercise and Antihypertensive Therapy

PER LUNDJOHANSEN, MD, PhD

The effects of exercise on central hemodynamic mechanisms and the changes induced by treatment have been studied invasively in approximately 500 men with essential hypertension, In patients with mild hypertension, the increase in blood pressure (BP) during dynamic exercise is similar to that seen in normal subjects, but in patients with severe hypertension it is steeper. During dynamic exercise total peripheral resistance is increased in all catego- ries of hypertensive patients, including young subjects with apparently “normal” resistance at rest. The increase in stroke volume in transition from rest to exercise is subnormal, probably reflecting increased stiffness in the left ventricle. Static exercise causes dramatic increase in systolic as well

as diastolic BP. Most antihypertensive agents control BP similarly during exercise and at rest. The hemodynamic mechanisms, however, differ greatly. The p blockers induce a long-term reduction in cardiac output, muscle blood flow and, frequently, endurance capacity. In contrast, a-receptor blockers, calcium antagonists and angiotensin converting enzyme inhibitors all reduce total peripheral resistance and do not decrease blood flow. Increase in endurance time has been reported with long-term calcium antagonist treatment. It would seem logical to select an antihypertensive drug that does not reduce exercise capacity when treating physically active patients with mild and moderate hypertension.

(Am J Cardiol 1987;59:98A-107A)

T 1 he effect of exercise on blood pressure (BP) varies

greatly in hypertensive as well as in normotensive subjects and is dependent on several factors and also on the type of exercise (static versus dynamic).l Although exercise testing may be useful for evaluation of hypertensive patients wanting to participate in vigorous physical activity, it is generally not used on a routine basis2 It is possible, however, that exercise testing could be of importance in determining the prognosis of hypertension, but long-term data are limited.3 It should be stressed that reliable information about the diastolic BP during exercise can only be obtained by intraarterial recording.4*5

Over the years we have performed invasive studies on the hemodynamic response to exercise in more than 500 men with essential hypertension in different stages6 and also studied the hemodynamic response to most of the commonly used antihypertensive drugs.7

Methods In all our studies, BP has been recorded intraarteri-

ally using a catheter in the brachial artery, cardiac output has been measured by the dye dilution tech-

From the Section of Cardiology, Medical Department A, Uni- versity of Bergen, School of Medicine, Haukeland Hospital, Bergen, Norway.

Address for reprints: Per Lund-Johansen, MD, PhD, N-5016 Haukeland Hospital, Bergen, Norway.

nique (Cardiogreen] and heart rate by electrocardio- gram. Central hemodynamics have been recorded at rest in both supine and sitting positions and exercise testing has been performed on an ergometer bicycle in the sitting position with standardized exercise levels of 50, 100 and 150 watts. Recordings have been made during steady state between the fifth and eighth min- ute. Oxygen consumption has been measured by the Douglas bag technique and O2 and CO2 analyzed by Beckman Instruments. All studies have been performed on an outpatient basis in the morning, z hours after a very light meal.8

Untreated Patients Dynamic exercise: In our untreated series we stud-

ied 93 men with essential hypertension, ages 18 to 65 years, and 33 normotensive control subjects6 In patients with mild to moderate hypertension (diastolic BP 90 to 105 mm Hg] in World Health Organization stage I without complications, the increase in BP during exercise up to 150 watts paralleled the increase seen in normal subjects. The increase in the systolic BP was much greater than that in the diastolic BP, and the increase in the mean arterial pressure was generally between the two (Fig. 1). In patients with more severe hypertension the increase in BP during exercise was steeper. When the BP is related to the cardiac index, the curve becomes steeper with increasing age, particularly during severe exercise (Fig. 2).

98A

January 23. 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 59 99A

Several large invasive studies from the 1960s to the 1980s have confirmed these findings,“m14 and similar results were reported in a recent noninvasive study.15

Exercise testing may be useful to disclose early changes in heart pump function and total peripheral resistance index. Our studies from 1967* showed that although our young hypertensive patients (18 to 29 years] had an apparently normal total peripheral resistance index during rest, the total peripheral resistance index was clearly abnormal during exercise: It did not decrease to the same low levels as in normotensive age-matched control subjects. Further, the stroke volume response to exercise was subnormal, probably reflecting early changes in the filling rate of the left

I

r

200

.,.I ,kk-

. .

100 -

30-39 l?‘

200

,1 ~~

I

ventricle. This has been unveiled in recent years by echocardiographic studies and by isotope methodsI

Static exercise: Static exercise such as weight lifting and handgrip testing induce marked increases in the systolic as well as in the diastolic BP. It has been shown that abnormalities of the filling rate of the left ventricle and of cardiac dynamics may be unveiled at an early stage of hypertension during static exercise.” Figure 3 illustrates the difference between the BP response to dynamic exercise (bicycling] and to weight lifting.

Spontaneous hemodynamic changes in untreated patients (longitudinal study): Our patients younger than 40 who had no treatment (n = 28) were restudied after 10 years by exactly the same methods as in the first study.ls Over these 10 years the BP during at-rest sitting had changed remarkably little, but during severe exercise (150 watts) there was a significant increase in diastolic and mean arterial BPS while systolic BP was unchanged. In spite of the very small changes in pressure, total peripheral resistance index had increased by about 25% at rest as well as during exercise and the stroke volume and cardiac index had decreased both at rest and during exercise. Heart rate showed small changes-a slight decrease at 150 watts-as expected from 10 years of aging. At a 17-year follow-up, these changes had progressed (Fig. 4). It is likely that these functional changes reflect increased stiffness of left ventricle with reduced filling rate and

DAP

mn. Hg 17-29 yrs

FIGURE 1. Intraarterial systolic (A) and diastolic (8) blood pressure at rest, sitting and during dynamic exercise in normotensive ( l ) and hypertensive (0 ---) men. The lines represent mean values. VOp = oxygen uptake.8

I”____-.__-.__-.

1OOA A SYMPOSIUM: THE CALCIUM ION, CARDIAC MYOCYTE AND VASCULAR SMOOTH MUSCLE IN HYPERTENSION AND ITS TREATMENT

also reduced elasticity (possibly due to structural changes) in the arterioles .lg These are the changes we would like to counteract with antihypertensive therapy.

Effects of Antihypertensive Therapy Diuretics: There seem to be few studies on the

acute effects of diuretics in hypertensive subjects during exercise. At rest, total peripheral resistance index is unchanged and the decrease in BP is due to decrease in plasma volume and cardiac index. During long-term use the decrease in exercise BP is usually similar to the decrease seen at rest, and is maintained through a long-term reduction in total peripheral resistance index. In our study from 1970zo (in which we used 100 mg of hydrochlorothiazide daily) there was no significant decrease in the cardiac pump function either at rest or during exercise, but the stroke volume tended to be slightly decreased during exercise at 150 watts. This high dosage of thiazide decreased the total peripheral resistance index by about 15% at rest and during exercise, but did not increase the subnormal cardiac index (Fig. 5). Plasma volume was reduced 7%. Thus, only a partial normalization of central hemodynamic param- eters was achieved.

Beta blockers: From an exercise performance point of view, treatment of hypertension with ,f3 blockers seems to be an even greater paradox than it is when using these compounds for treating hypertension during rest. It is well established that the short-term effect of the classic /3 blocker propranolol is an immediate decrease in heart rate, stroke volume and cardiac index, a compensatory increase in total peripheral resistance index and practically no change in BP. Over time, total peripheral resistance index and BP de-

MAP mm Hg

180 I-

160 .

t Normotensives o- - Hypwtentlves

6 ” ” ” ‘1 ’ 1” 0 2 4 6 6 IO 12 Cl

Ilminlm2

FIGURE 2. The increase in mean arterial blood pressure (MAP) during exercise related to cardiac Index (Cl) In hypertensive (0 ---) and normotensive ( l ) men in different age groups. Mean vaiues.8

crease slowly with propranolol,21 and more rapidly withother ,3 blockersz2 (Fig. 61.

We have studied the long-term effects of 8 /3 blockers (atenolol, metoprolol, timolol, alprenolol, bunitrolol, penbutolol, pindolol and visacor) at rest and during exercise in 101 men representing &-selec- eve as well as nonselective P blockers, some with intrinsic sympathicomimetic activity and others without.21.23

All but one of these p blockers decreased BP at rest as well as during exercise by about 10% to 20% (visa- car induced only a 6% decrease in BP]. The effect on systolic and diastolic BP was generally similar. During rest situations P blockers with intrinsic sympathicomimetic activity-pindolol and penbutolol-decreased

FIGURE 3. intraarterial blood pressure in a 65-year-old hypertensive man at rest sitting and during 150 watts of dynamic exercise (bicycling) (left), and during static exercise (maximal contraction of biceps muscle) (right). During bicycling blood pressure increases slowly and a plateau is reached after 2 minutes. During static work systolic and diastolic pressure Increase wlthln seconds. Arrows show start of exercise and the numbers the blood pressure.

January 23, 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 59 1OlA

heart rate insignificantly, but during exercise all /3 blockers induced dramatic decreases in heart rate by about 20% to 30%. /3 blockers with intrinsic sympathicomimetic activity or those blocking only the & recep- tors reduced cardiac index less than the other p blockers because of a compensatory increase in the stroke volume. Nevertheless, with all these p blockers

FIGURE 4. Spontaneous changes in central hemodynamics at rest, sitting and during exercise at 50, 100 and 150 watts from 17-year follow-up data. Cl = cardiac index; HR = heart rate; MAP = mean arterial pressure; SI = stroke index; TPRI = total peripheral resistance index; W = watt- mean values. Stars show level of statistical difference between first and last study l = p <0.05; ** = p <O.Of; l ** = p <O.OOl.

FIGURE 5. Hemodynamic effects of chronic thiazide therapy (100 mg hydrochlorothiazide dally for 1 year, n = 15). Mean values. Ab- breviations as in Figure 4; V02 = oxygen uptake.20

a chronic depression in cardiac pump function at rest as well as during exercise was seen [Table I, Fig. 7).

In a 5-year follow-up study with atenolol the hemodynamic situation was largely the same as after 1 year.23 Oxygen supp y 1 to the tissues is maintained by increase in the arteriovenous oxygen difference. Mus- cle blood flow is reduced.

Untreated essential hypertcns~on

17years (n.81

HAP TPRl mm Hg dyn 5% cm-5 m 2

R5 5OW 100 w 150 w R5 sow 100 w 15ow

70 r L----z-I

60

i / I ‘....

,,$v-~.~.,:llr~~

. a 50.

0’ ,‘..: . . .

40 .: P

,* *I

RS w w 50 100 ISOW

5ow lOOW

l - 1965

o--- -75

O.“... 82

I

J-

150”

RtZA A S-M: THt CALCIUM ION,~CARDlAC MYOCYTE AND VASCULAR SMOOTH MUSCLE IN HYPERTENSION AND ITS TREATMENT

TABLE I Relative Changes in Heart Rate (HR), Mean Arterial Pressure (MAP) and Cardiac Index (Cl) with Seven /IT Blockers

HR (%) MAP (%) Cl (%)

Pts. work work Work

m) Supine Sitting (100 watts) Supine Sitting (100 watts) Supine Sitting (100 watts)

Atenolol 13 -24 -20 -29 -17 -17 -19 -16 -27 -20 Metoprolol 12 -21 -24 ‘-20 -13 -11 -9 -20 -24 -17 Timolol 16 -26 -26 -27 -16 -17 -14 -20 -32 -25 Penbutolol 13 -23 -24 -25 -17 -19 -17 -20 -24 -15 Alprenolol 10 -20 -20 -16 -11 -7 -6 -13 -23 -10 Bunitrolol 11 -13 -15 -17 -15 -13 -12 -18 -23 -24 Pindolol 14 -11 -11 -19 -15 -15 -15 -13 -17 -14

From reference 23. All supine and sitting values were obtained at rest.

TABLE II Side Effects During Start of #?-Blocker Therapy

Pk.

(n) Side Effects

Atenolol 13 Metoprolol 12 Timolol 16

Penbutolol 13

Alprenolol 10 Bunitrolol 11 Pindolol 14

Muscular fatigue (3)

Muscular fatigue (3) Dizzy (I), cold feet (1) Muscular fatigue (3) Dizzy (2) . Muscular fatigue (3) Sleeping problems (2) Muscular fatigue (1) Dizzy (1)

From reference 23.

“/o (SUPINE 1

A MAP

I

OR ffl

t *ii * a010 -‘&-A, tt 1st

ttt tat

\ +20

+10

0

-10

-20

ACUTE AND CHRONIC CHANGES. VISACOR

A-A TPRI . ___.... . ,,R

O-0 SI

o---o Cl FIGURE 6. Immediate and chronic hemodynamic effects of first dose of the cardioselective B blocker visacor. Mean values, n = 12. Note the decrease in total peripheral resistance startlng already after 2 hours.** Abbreviations as in Figure 4.

When P-blocker treatment is begun, many patients accustomed to vigorous physical activity complain of reduced exercise capacity and a feeling of tiredness and heavy legs during the first weeks of treatment (Table II).23 These complaints seem to disappear and most patients are able to continue their level of habitu- al physical exercise in spite of the long-term depression in cardiac index.

In an extensive study on physical performance and muscle metabolism during ,6 blockade, Kaiserz4 reported that muscle strength (measured as maximal isoki- netic torque) and maximal dynamic muscle power (measured as highest power output during a 30-second maximal cycle-exercise test) were unaltered by /3 blockade. But when maximal exercise was prolonged to 30 to 60 seconds, anaerobic endurance time was decreased and aerobic power measured as maximal oxygen uptake (VOz max) during cycle exercise was also reduced. When comparing the effects of ,&-selective and nonselective ,f3 blockers on work capacity, no differences were demonstrated with regard to muscle strength, muscle power and VOZ max. However, aerobic endurance was decreased more by a nonselective than by a /%-selective /? blocker when similar decreases in heart rate and VOZ were attained. This is probably due to different effects on metabolic factors.

Also, others have found no difference between the &selective and the nonselective blockers on short- term isometric25 and dynamic? exercise. However, during long-term exercise it has been shown that propranolol caused a greater reduction in total exercise time than metoprolol. 27 Also, other investigators have reported reduction in exercise capacity during long- term /3 blockade.28-30

For this reason there has been an increasing inter- est in treating hypertension by drugs that do not cause a decrease in cardiac index or exercise performance, particularly when dealing with very physically active subjects.

Alpha-Receptor Blockers Prazosin, doxazosin and trimazosin: On both a

short- and long-term basis, these drugs lower BP through entirely different hemodynamic mechanisms than the /3 blockers. Only a few minutes after doxazosin injection (1.0 to 0.7 mg intravenously) a dramatic

January 23, 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume SY 1UJA

decrease in total peripheral resistance index and in BP is seen without any decrease in cardiac index or any reflex tachycardia. 32 During long-term use prazosin decreases BP entirely through a decrease in total peripheral resistance index associated with increase in stroke volume and in cardiac index31 (Fig. 8). Similar results have been reported for trimazosin.33 Thus, these compounds induce greater normalization in central hemodynamics at rest as well as during exercise than do diuretics and p blockers.

Combination of Alpha and Beta Blockade Labetalol: Short- and long-term hemodynamic

studies34-36 have shown that labetalol induces a marked decrease in BP at rest as well as during exercise of about 15% to 25’70, partly due to decrease in total peripheral resistance index (through the (Y blockade] and partly due to decrease in heart rate and cardiac index (by the P blockade). However, during long- term treatment stroke volume increases and com- pensates for the decreases in both heart rate and cardiac index much less than that achieved by pure p blockade. In a 6-year follow-up cardiac index had returned to pretreatment level, and the decrease in BP was entirely due to reduction in total peripheral resistance index.3”

Calcium antagonists: Although all the calcium antagonists used in hypertension basically have the same mode of action-reduction in total peripheral resis-

Cl I/min /r? ( TIMOLOL

tance index through partial calcium blockade in the arterioles37-it should be emphasized that the effect on heart rate varies. Their negative inotropic effect does not seem to be of clinical significance.

Verapamil: Verapamil decreases total peripheral resistance index and BP at rest and during exercise. The heart rate at rest is hardly affected, but during exercise it is reduced by approximately 10% (thus, much less than by conventional /3 blockade). There is a compensatory increase in stroke volume and no decrease in heart pump function, measured as cardiac index, either at rest or during exercise.38 Most patients will probably need a daily dosage of 320 mg38,3s to obtain satisfactory BP control.

Diltiaxem: The hemodynamic effects of diltiazem at rest and during exercise resemble those induced by verapami1.40~47 In a comparison with propranolol in hypertensive patients Yakamado et al42 reported that both propranolol, 60 mg daily, and diltiazem, 180 mg daily, reduced BP and heart rate at rest and during exercise, but the decrease in heart rate was greatest with propranolol. Maximal exercise duration was not different. In patients with mild hypertension diltiazem, 240 mg daily, induced less decrease in BP during exercise than metoprolol, 200 mg daily.43 In a study on the short-term effects of diltiazem (0.2 mg/kg intravenously] on central and peripheral hemodynamics a decrease in total peripheral resistance index was found and also dilatation of large arteries.44 Cardiac

vo:, ml /mrn/m7 HR beats/mln

TPRI dyn set cm~5 rn’

,03 HRxMAP beats/mn mmWg

28 I-

20 20

;/___I :/___I

** ** ,’ ,’ XT’ XT’ /’ /’ .’ .’ .’ .’ 10 10 ,- ,-

, l - , l - .’ .’

t

,’ ,’ /’ /’

./ ./

4. 44, , , , , , 1 , 1 , , , , I , 1 1 1 I I 1 1 500 500 loo0 loo0

VO, ml/mln /m2

FIGURE 7. Changes in central hemodynamics after l-year treatment with timolol therapy. Note the marked depression in cardiac index and in heart rate.23 Abbreviations as in Figure 4.

__-___._. _- . ,._ . ..-. 1(, .^--- .I,...

AND VASCULAR SMOOTH MUSCLE IN HYPERTENSION AND 1T.i TREATMENT

index and heart rate increased initially, but returned to pretreatment values while total peripheral resistance index remained reduced.

Klein et a145 compared diltiazem with nifedipine in a J-week trial in 20 hypertensive patients and found that both drugs decreased BP at rest and during exercise because of the decrease in total peripheral resistance index while cardiac index increased. Heart rate decreased slightly with diltiazem and was unchanged on nifedipine. Diltiazem did not induce any acute reflex tachycardia in contrast to nifedipine. In a placebo- controlled study Pool et a146 found that diltiazem, 360 mg daily, decreased BP and heart rate and increased the maximum duration of exercise.

Nifedipine, nisoldipine, nitrendipine and felodipine: Lund-Johansen and Omvik47 studied the central hemodynamic effects of long-term nifedipine treatment (long-acting form). After 1 year BP and total peripheral resistance index were reduced about 17% without any changes in heart rate, stroke index or cardiac index (Fig. 9). No patients complained of reduced physical capacity. Because stroke index was subnormal before therapy, an increase in stroke index after 1 year of BP reduction was expected but was not found. It is possible that the lack of increase in exercise stroke index could be related to a slight degree of negative

inotropic effect of nifedipine that is not seen during rest situation, but unveiled during exercise.

Levenson et a148 reported similar changes in central hemodynamics and also an increase in forearm blood flow.

When treatment with calcium channel blockers is begun, central hemodynamics change very quickly. In an acute study on nisoldipine,4g we found that 1 hour after a lo-mg tablet was given orally total peripheral resistance index had decreased by 20%. The decrease in BP was partly counteracted by reflex tachycardia [the increase in heart rate and cardiac index was about 12%), but still the immediate decrease in BP was 10%. With continued treatment reflex tachycardia disap- peared and 1 year after treatment was started heart rate was unchanged. The decrease in BP [about 15%)

was related to a decrease in total peripheral resistance index (about 18%).

Good BP control during exercise has been reported with other dihydropyridine derivatives, nitrendipine, 20 mg daily,sO and felodipine.51+52

In summary, the calcium antagonists have been shown to induce satisfactory control of BP during exercise. The decrease in BP is clearly related to reduction in total peripheral resistance index without any decrease in cardiac pump function measured as cardiac

I I

Cl I/mln/m*

10 - :

/-- . . *’ ,&-‘*

. . . &-

,I’ /’ 5 // I I

,I’ , I ,

I , I a 1 I 1 1 500 1000

SI ml /stroke/m*

/----;-------i

[ PRAZOSIN n= 10 1

MAP mm Hg T

100 l ** k , . , , , , , , , ( , ,

500 1000

V02 ml/ min/ m*

HR beatstmin

500 1000

V02 ml /minim*

TPRl,dyn set cms5m2

500 1000

HR x MAP beats /min mm Hg

28ooor

FIGURE 8. Changes in central hemodynamics during l-year treatment with prazosin. Note the marked decrease in TPRI and the increase in exercise stroke index and in cardiac index .31 Abbreviations as in Figure 4.

January 29,

FIGURE 9. Changes in central hemodynamics during l-year thera- LA ‘GO 1000

py with nifedlpine. Mean values.47 Abbreviations as in Figure 4.

51 mi stroke ‘m 1 70

I

304 LG.

500 1000

index. However, the subnormal cardiac index seen in hypertensive patients is not corrected. Complaints of reduced physical capacity have not been reported and a few studies have indicated a slight increase in endurance time-in contrast to P-blocker treatment, which tends to decrease endurance time.

Other drugs: The hemodynamic changes induced by other antihypertensive agents will be discussed very briefly. (See reference i’ for a review of this subject.] Not all antihypertensive agents control BP as well during exercise as during rest. Thus, with long- term clonidine treatment we found that in spite of good BP control during rest, either no decrease or only a small decrease in BP during severe exercise was seen.53 Similar observations have been made by others.54 It is possible that the central mechanisms of clonidine controlling BP during rest are overridden by other factors or mechanisms during exercise.

It should be stressed, however, that another new and important class of antihypertensive agents, the angiotensin converting enzyme inhibitors, induce satisfactory BP control during exercise (Fig. lo), associated with a decrease in total peripheral resistance index and no change in cardiac index.55

Changes in lifestyle: In general, physical training in patients with mild to moderate essential hypertension may lower BP at rest as well as during exercise,56,57 but there are few large controlled studies and the BP-lowering effect of training does not seem to be very pronounced. In patients with more severe hypertension drug treatment should be started first, and it is unclear whether physical training will lower BP further. However, because physical exercise has other beneficial effects on the heart, it should be encouraged in hypertensive patients.

Low salt diet: Omvik and Lund-Johansen5* studied the hemodynamic effects of a 35% reduction in salt intake in 19 men with borderline or mild hypertension. After about 1 year the changes in BP at rest as well as during exercise were disappointingly small (only

about a 4% decrease in intraarterial BP]. No reduction in total peripheral resistance index was seen. The modest BP decrease was associated with a decrease in cardiac index, partly due to a slight reduction in heart rate and partly due to a slight decrease in stroke index.

Conclusions Exercise testing is time-consuming and the diffi-

culty of obtaining accurate values for diastolic BP during exercise makes it unlikely that such testing will be

220-

2GC-

;83-

J6J-

l-C-

(23-

133-

eo -

[ENALAPRIL tn=lZ)] Before -

mmHg Aftrr o---o

SAP

DAP

h < 444 - 5 Flow 1oow 153w

FIGURE 10. Intraarterial systolic and diastolic blood pressure at rest and during exercise before and after l-year therapy with enalapril.55

used to any great extent in the diagnostic evaluation of hypertensive patients. In untreated patients with mild and moderate hypertension, the BP response to dynamic exercise is similar to what is seen in normotensive age-matched control subjects, but the hemodynamic changes differ. The decrease in total peripheral resistance seen during exercise is less marked in the hypertensive than in the normotensive subject, and the cardiac pump function during exercise is slightly decreased. With more severe hypertension the increase in BP per liter increase and cardiac output is steeper, reflecting the insufficient decrease in total peripheral resistance ,8 When hypertensive subjects are left untreated over several years, these changes prog- ress. The heart pump function deteriorates, but fortu- nately very slowly as long as coronary artery disease is not developed.18

Most antihypertensive agents decrease BP during dynamic exercise to a similar extent as that during rest. However, the hemodynamic profiles for the different compounds vary greatly. With ,&blocker treatment there is a long-term depression in cardiac output and heart rate with small differences between the &-selective and the nonselective drugs. Muscle blood flow is reduced. The arteriovenous oxygen difference is increased. This reduced heart pump function during exercise frequently causes impaired physical capacity in the starting phase of B-blocker treatment. During long- term treatment the reduction in short-term exercise performance seems to be modest, but during prolonged endurance work a reduction in the performance is common. Alpha-receptor blockers, calcium antagonists and angiotensin converting enzyme inhibitors all reduce BP at rest as well as during exercise through a decrease in total peripheral resistance, but through very different mechanisms. The calcium antagonists of dihydropyridine-type cause initial reflex tachycardia; in contrast, verapamil and diltiazem tend to decrease heart rate. During long-term use the reflex tachycardia tends to disappear also for the dihydropyridine derivatives. The calcium antagonists do not decrease cardiac output or muscle blood flow, and complaints of reduced physical capacity are rare. Some studies indicate an increase in endurance time.

Today a large variety of antihypertensive agents are available. It is still not known which type of antihypertensive treatment will lead to the best prognosis with respect to morbidity and mortality. As long as this is unsettled, it would seem logical to treat-in particular physically active patients-with drugs that will not reduce heart pump function or physical endurance. The calcium antagonists would suit these requirements.

References 1. Mitchell jH, Blomquist G, Haskell WL. James FW. Miller Jr HS, Miller WW. Strong WB. Classification of sports. \ACC 1985:6:1198-1199. 2. Frohlich ED, Lowenthal DT. Miller Jr HS. Pickering TH, Strong WB. Task Force IV: systemic arterial hypertension. JACC 1985;6:1218-1221. 3. Dlin RA. Hanne N, Silverberg DS. Bar-Or 0. Follow-up of normotensive men with exaggerated blood pressure response to exercise. Am Heart 11983; 106:316-320. 4. Rasmussen PH, Staats BA. Driscoll DJ, Beck KC, Bonekat W, Wilcox WD. Direct and indirect blood pressure during exercise. Chest 1985;87:743-748. 5. Karlfors T, Nielsen R. Westling H. On the accuracy of indirect auscultatory

blood pressure measurement during exercise. Acta Med Scond l966:180: suppl449:91-102. 6. Lund-Johansen P. The hemodynamics of essential hypertension. In: Rob- ertson IJS, ed. Clinical Aspects of Essential Hypertension.(Handbook of Hy- pertension, Vol. 1). Amsterdam: EJsevier. 1983:151-173. 7. Lund-Johansen P. Hemodynamic effects of antihypertensive agents. In: Doyle AE, ed. Handbook of Hypertension. Vol. 5: Clinical Pharmacology of Antihypertensive Drugs. Amsterdam: Elsevier, 1984:39-66. 8. Lund-Johansen P. Haemodynamic changes in early essential hypertension. Acto Med Stand 1967;suppJ 482:1-102. 9. Sannerstedt R. Hemodynamic response to exercise in patients with arterial hypertension. Acta Med Stand 1966;suppl 458:180:1-83. 10. Amery A, Julius S, Whitlock LS, Conway J. Influence of hypertension on the hemodynamic response to exercise. Circulation 1967;36:231-237. 11. Julius S. Conway 1. Hemodynamic studies in patients with borderline blood pressure elevation. Circulation 1968;38:262-288. 12. Julius S, Amery A, Whitlock LS, Conway J. Influence of age on the hemodynomic response to exercise. Circulation 1967:36:222-230. 13. Levy AM, Tabakin BS, Hanson JS. Hemodynamic responses to graded treadmill exercise in young untreated labile hypertensive patients. Circulo- tion 1967;35:1063-1072, 14. Widimsky J. Jandova R, Ressl J. Haemodynomic studies in juvenile hypertension at rest and during supine exercise. Eur Heart \ 1981;2:307-315. 15. Schulte W, Fehring C, Neus H. Cardiovascular reactivity to ergometric exercise in mild hypertension. Cardiology 1983;70:50-56. 16. Fouad FM, Tarazi RC, Gallagher JH. McIntyre WJ, Cook SA. Abnormal left ventricular relaxation in hypertensive patients. Clin Sci 1980;59: 4115-415s. 17. Alicandri C, Fouad FM, Tarazi RC, Bravo EL, Greenstreet RL. Sympathet- ic contribution to the cardiac response to stress in hypertension. Hyperten- sion 1983;5:147-154. 18. Lund-Johansen P. Spontaneous changes in central hemodynamics in essential hypertension-a lo-year follow-up study. In: Onesti G, KJimt CR, eds. Hypertension. Determinants, Complications, and Intervention. New York: Grune 6 Stratton. 1979:201-209. 19. Folkow 8. Vascular changes in hypertension. Therapeutic considerations. Drugs 1985;suppf 2:29:1-8. 20. Lund-Johansen P. Nemodynamic changes in long-term diuretic therapy of essential hypertension. Acto Med Stand 1970;187:509-518. 21. Tarazi RC, Dustan HP. Beta-adrenergic blockade in hypertension. Am 1 CardioJ 1972;29:633-640. 22. Lund-Johansen P, Omvik P, Haugland H. The first dose hemodynamic responses to visacor (ICI 14X-292) in essential hypertension. Acto Med Scond 1984;suppJ 6931121-125. 23. Lund-Johansen P. Central haemodynamic effects of beta-blockers in hypertension. A comparison between atenolol, metoprolol, timolol. penbutolol, alprenolol, pindolol and bunitrolol. Eur Heart 1 1983;suppJ D:4:1-12. 24. Kaiser P. Physical performance and muscle metabolism during beta- adrenergic blockade in man. Acto PhysioJ Stand 1984;suppJ 536:1-44. 25. Houben H. Thien Th, de Boo Th, Lemmens W, Binkhorst R, van’t Larr A. Hemodynamic effects of isometric exercise and mental arithmetic in hypertension treated with selective and nonselective beta-blockade. Clin Pharma- co! Ther 1983;34:164-169, 26. Leenen FHH, Coenen CHM, Zonderland M, Maas AHJ. Effects ofcardio- selective and nonselective beta-blockade on dynamic exercise performance in mildly hypertensive men. Clin Pharmacol Ther 1980;28:12-21. 27. Lundborg P, Astrom H. Bengtsson C. Fellenius E. van Schenck H. Svens- son L, Smith U. Effect of beto-adrenoceptor blockade on exercise performance and metobolism. Clin Sci 1981;61:299-305. 28. Franz I-W, Lohmann FW. Der Einfluss einer chronischen sog. kordiose- lektiven und nicht-kardioselektiven Beta-Rezeptoren-blockade auf den blut- druck. die 02-Aufnahme und den Kohlen-hydrotstoffwechsel. Ergometrische Untersuchungen bei Hochdruckkranken. Z Kardiol 1979;68:503. 29. van Lehmann M, Keul J, Wybitul K, Fischer H. Auswirkung einer selekti- ven und nichtselektiven Adrenozeptorblockade wahrend Korperarbeit auf den Energiestoffwechsel und das sympotho-adrenerge System. Drug Res 1982;32:261-266. 30. Kindermann W, Scheerer W. Salas-Fraire 0, Biro G. Wolfing A. VerhaJ- ten der korperlichen Leistugsfahigkeit und des Metabolismus unter akuter Betal-und Betel/2-Blockade. Z Kardiol 1984;73:380-387, 31. Lund-Johansen P. Hemodynamic changes at rest and during exercise in long-term prazosin therapy for essential hypertension. Postgrad Med 1 1975;suppl 1:58:45-52. 32. Lund-Johansen P, Omvik P, Haugland H. Acute and chronic haemodynamic effects of doxazosin in hypertension at rest and during exercise. Br [ CJin Pharmocol 1986:suppl:21,455-545. 33. Nelson GIC. Silke B, Hussain M, VermaSP, Taylor H. Rest and exercise hemodynamic effects of sequential alpha-I-adrenoceptor (trimazosin] and beta-adrenoceptor (propranolol) antagonism in essential hypertension. Am Heart [ 1984;108:124-131. 34. Fagard R, Lijnen P, Amery A. Response of the systemic and pulmonary circulation to JabetaJoJ at rest and during exercise. Br r CJin Pharmacol 1982;13:suppl1:13S-175. 35. Koch G. Haemodynamic adaptation at rest and during exercise to long- term antihypertensive treatment with combined alpha- and beta-adrenocep-

January 23. 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 59 107A

tor blockade by labetalol. Br Heart J 1979;41:192-198. 38. Lund-Johansen P. Short- and long-term (six year) hemodynamic effects of labetalol in essential hypertension. Am J Med 1983;74:24-31. 37. Aoki K. Sato K. Pathophysiolagical background for the use of calcium antagonists. J Cardiovasc Pharmacol 1985;7:suppl 4:528-532. 38. Lund-Johansen P. Hemodynamic long-term effects of verapamil in essential hypertension at rest and during exercise. Acta Med &and 1984;suppl 681:109-115. 39. Herpin D. Amiel A, Boutaud P, Wajman A, Demange J. Effect of calcium antagonist verapamil on resting blood pressure and pressor response to dynamic exercise. Acta Cardiol 1985;40:277-290. 40. Chaffman M, Bragden RN. Diltiazem. A review of its pharmacological properties and therapeutic efficacy. Drugs 1985;29:387-454. 41. Aoki K. Sato K. Kondo S, Yamamoto M. Hypotensive effects of diltiazem to normals and essential hypertension. Em J Clin Pharmacol1983;25:475-480, 42. Yamakado T. Oonishi N. Kondo S. Noziri A, Nakano T. Takezawa H. Effects of diltiazem on cardiovascular responses during exercise in systemic hypertension and comparison with propranolol. Am J Cardiof 1983; 52:1023-1027. 43. Trimarco B, DeLuca N, Ricciardelli B, Volpe M, Venerio A, Cuocolo A, Cicala M. Diltiazem in the treatment of mild or moderate essential hypertension. Comparison with metaprolol in a crossover double-blind trial. J Clin Pharmacol 1984;24:218-227. 44. Safar ME, Simon ACh, Levenson JA, Cazor JL. Hemodynamic effects of diltiazem in hypertension. Circ Res 1983;52:suppl 1:169-173. 45. Klein W, Brand D, Vrecko K. Harringer M. Role of calcium antagonists in the treatment of essential hypertension. Circ Res 1983;52:suppl 1:174-181. 48. Pool PE, Seagren SC, Sale1 AF, Skalland ML. Effects of diltiazem on serum lipids. exercise performance and blood pressure: randomized, double- blind, placebo-controlled evaluation for systemic hypertension, Am J Cardiol 1985;56:86H-91H. 47. Lund-Johansen P. Omvik P. Haemodynamic effects of nifedipine in essential hypertension at rest and during exercise. J Hypertension 1983: 1:159-x3.

48. Levenson JA. Safar ME, Simon AC. Bautier )A. Griener L. Systemic and arterial hemodynamic effects of nifedipine (20 mg) in mild-to moderate hypertension. Hypertension 1983;5:suppl V:V-57-V-60. 49. Lund-Johansen P. Omvik P. Haugland H. Acute and chronic hemodynamic effects of nisoldipine in essential hypertension at rest and during exercise. Acta Med Stand suppl,in press. 50. Franz I-W, Wiewel D. Antihypertensive effects on blood pressure at rest and during exercise of calcium antagonists, beta-receptor blockers, ond their combination in hypertensive patients. J Cardiovasc Pharmacol 1984: 6:S1037-S1042. 51. Clement DL. De Pue NY. Effect of felodipine and metoprolol on muscle and skin arteries in hypertensive patients. Drugs 1985;29:suppl 2:137-143. 52. Lorimer AR. McAlpine HM, Rae AP, Simpson IA, Barbour MP. Forret EA, Kent Hill TW. Veitch Lawrie TD. Effects of felodipine on rest and exercise heart rate and blood pressure in hypertensive patients. Drugs 1985;29:suppl 2:154-164. 53. Lund-Johansen P. Hemodynamic effects of clonidine in man. In: Onesti G, Fernandes M, Kim KE. eds. Regulation of Blood Pressure by the Central Nervous System. New York: Grune 8 Stratton, 1976:355-365. 54. Virtanen K. Janne J, Frick MH. Response of blood pressure and plasma narepinephrine to propranolol, metoprolol and clonidine during isometric and dynamic exercise in hypertensive patients, Eur J Clin Pharmacol 1982;21:275-279. 55. Lund-Johansen P. Omvik P. Long-term haemodynamic effects of enalapril [alone and in combination with hydrochlorothiazide) at rest and during exercise in essential hypertension. J Hypertension 1984;2:suppI 2:49-56. 58. Fagard R. M’Buyamba J-R, Staessen J, Vanhees L, Amery A. Physical activity and blood pressure. In: Bulpitt CJ, ed. Handbook of Hypertension. Epidemiology of Hypertension. Amsterdam: Elsevier, 1985:106-130. 57. Kiyonaga A. Arakawa K, Tanaka H, Shinda M. Blood pressure and hor- monal responses to aerobic exercise. Hypertension 1985;7:125-131. 58. Omvik P, Lund-Johansen P. Hemodynamic effects at rest and during exercise of long-term sodium restriction in mild essential hypertension. J Hypertension 1986, in press.

exercise and antihypertensive therapy

Documents