Exercise and antihypertensive therapy
Post on 28-Aug-2016
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 hy- pertension it is steeper. During dynamic exercise to- tal 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 reflect- ing increased stiffness in the left ventricle. Static ex- ercise causes dramatic increase in systolic as well
as diastolic BP. Most antihypertensive agents con- trol BP similarly during exercise and at rest. The he- modynamic mechanisms, however, differ greatly. The p blockers induce a long-term reduction in car- diac output, muscle blood flow and, frequently, en- durance capacity. In contrast, a-receptor blockers, calcium antagonists and angiotensin converting en- zyme inhibitors all reduce total peripheral resistance and do not decrease blood flow. Increase in endur- ance time has been reported with long-term calci- um 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 sub- jects 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 hyper- tensive 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 per- formed 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 pa- tients 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 exer- cise 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, partic- ularly during severe exercise (Fig. 2).
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 resis- tance 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 vol- ume response to exercise was subnormal, probably reflecting early changes in the filling rate of the left
ventricle. This has been unveiled in recent years by echocardiographic studies and by isotope methodsI
Static exercise: Static exercise such as weight lift- ing 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 re- sponse 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 se- vere exercise (150 watts) there was a significant in- crease 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 in- creased by about 25% at rest as well as during exercise and the stroke volume and cardiac index had de- creased 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
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
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 dur- ing 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 in- dex. 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 exer- cise, 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 dur- ing 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 in- dex, a compensatory increase in total peripheral resis- tance index and practically no change in BP. Over time, total peripheral resistance index and BP de-
MAP mm Hg
t Normotensives o- - Hypwtentlves
6 1 1 0 2 4 6 6 IO 12 Cl
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 sympathicomi- metic activity-pindolol and penbutolol-decreased
FIGURE 3. intraarterial blood pressure in a 65-year-old hyperten- sive 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 sympathi- comimetic 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 in- dex; HR = heart rate; MAP = mean arterial pressure; SI = stroke index; TPRI = total periph- eral resistance index; W = watt- mean values. Stars show level of statistical difference between first and last study l = p
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
(n) Side Effects
Atenolol 13 Metoprolol 12 Timolol 16
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
t *ii * a010 -&-A, tt 1st
ACUTE AND CHRONIC CHANGES. VISACOR
A-A TPRI . ___.... . ,,R
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 depres- sion in cardiac index.
In an extensive study on physical performance and muscle metabolism during ,6 blockade, Kaiserz4 report- ed 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 ,&-selec- tive and nonselective ,f3 blockers on work capacity, no differences were demonstrated with regard to muscle strength, muscle power and VOZ max. However, aero- bic endurance was decreased more by a nonselective than by a /%-selective /? blocker when similar de- creases 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 pro- pranolol 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 doxazo- sin 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 pe- ripheral 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 cen- tral 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 exer- cise of about 15% to 2570, partly due to decrease in total peripheral resistance index (through the (Y block- ade] and partly due to decrease in heart rate and cardi- ac index (by the P blockade). However, during long- term treatment stroke volume increases and com- pensates for the decreases in both heart rate and cardi- ac index much less than that achieved by pure p block- ade. In a 6-year follow-up cardiac index had returned to pretreatment level, and the decrease in BP was en- tirely due to reduction in total peripheral resistance index.3
Calcium antagonists: Although all the calcium an- tagonists 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 de- crease 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 diltia- zem, 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 intrave- nously] 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
** ** , , XT XT / / . . . . 10 10 ,- ,-
, l - , l - . .
, , / /
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 resis- tance 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 exer- cise because of the decrease in total peripheral resis- tance index while cardiac index increased. Heart rate decreased slightly with diltiazem and was unchanged on nifedipine. Diltiazem did not induce any acute re- flex 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 felodi- pine: Lund-Johansen and Omvik47 studied the central hemodynamic effects of long-term nifedipine treat- ment (long-acting form). After 1 year BP and total pe- ripheral resistance index were reduced about 17% without any changes in heart rate, stroke index or car- diac index (Fig. 9). No patients complained of reduced physical capacity. Because stroke index was subnor- mal 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 exer- cise. The decrease in BP is clearly related to reduction in total peripheral resistance index without any de- crease in cardiac pump function measured as cardiac
10 - :
/-- . . * ,&-*
. . . &-
,I / 5 // I I
,I , I ,
I , I a 1 I 1 1 500 1000
SI ml /stroke/m*
[ PRAZOSIN n= 10 1
MAP mm Hg T
100 l ** k , . , , , , , , , ( , ,
V02 ml/ min/ m*
V02 ml /minim*
TPRl,dyn set cms5m2
HR x MAP beats /min mm Hg
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.
FIGURE 9. Changes in central he- modynamics during l-year thera- LA GO 1000
py with nifedlpine. Mean values.47 Abbreviations as in Figure 4.
51 mi stroke m 1 70
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 endur- ance 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 sub- ject.] 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 oth- ers.54 It is possible that the central mechanisms of clon- idine controlling BP during rest are overridden by oth- er 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 sat- isfactory BP control during exercise (Fig. lo), associ- ated with a decrease in total peripheral resistance in- dex and no change in cardiac index.55
Changes in lifestyle: In general, physical training in patients with mild to moderate essential hyperten- sion may lower BP at rest as well as during exer- cise,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 hyper- tension drug treatment should be started first, and it is unclear whether physical training will lower BP fur- ther. 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 dur- ing exercise makes it unlikely that such testing will be
[ENALAPRIL tn=lZ)] Before -
mmHg Aftrr o---o
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 dy- namic exercise is similar to what is seen in normoten- sive age-matched control subjects, but the hemody- namic 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 in- crease in BP per liter increase and cardiac output is steeper, reflecting the insufficient decrease in total pe- ripheral 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 &-selec- tive and the nonselective drugs. Muscle blood flow is reduced. The arteriovenous oxygen difference is in- creased. This reduced heart pump function during ex- ercise 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 pro- longed endurance work a reduction in the perfor- mance is common. Alpha-receptor blockers, calcium antagonists and angiotensin converting enzyme inhib- itors all reduce BP at rest as well as during exercise through a decrease in total peripheral resistance, but through very different mechanisms. The calcium an- tagonists 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 dihydro- pyridine 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 antihyper- tensive 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 re- duce heart pump function or physical endurance. The calcium antagonists would suit these requirements.
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