Exercise and antihypertensive therapy

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<ul><li><p>Exercise and Antihypertensive Therapy </p><p>PER LUNDJOHANSEN, MD, PhD </p><p>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 </p><p>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. </p><p>(Am J Cardiol 1987;59:98A-107A) </p><p>T 1 he effect of exercise on blood pressure (BP) varies </p><p>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 </p><p>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 </p><p>Methods In all our studies, BP has been recorded intraarteri- </p><p>ally using a catheter in the brachial artery, cardiac output has been measured by the dye dilution tech- </p><p>From the Section of Cardiology, Medical Department A, Uni- versity of Bergen, School of Medicine, Haukeland Hospital, Bergen, Norway. </p><p>Address for reprints: Per Lund-Johansen, MD, PhD, N-5016 Haukeland Hospital, Bergen, Norway. </p><p>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 </p><p>Untreated Patients Dynamic exercise: In our untreated series we stud- </p><p>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). </p><p>98A </p></li><li><p>January 23. 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 59 99A </p><p>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 </p><p>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 </p><p>I </p><p>r </p><p>200 </p><p>.,.I ,kk- </p><p>. . </p><p>100 - </p><p>30-39 l? </p><p>200 </p><p>,1 ~~ </p><p>I </p><p>ventricle. This has been unveiled in recent years by echocardiographic studies and by isotope methodsI </p><p>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. </p><p>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 </p><p>DAP </p><p>mn. Hg 17-29 yrs </p><p>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 </p></li><li><p>I____-.__-.__-. </p><p>1OOA A SYMPOSIUM: THE CALCIUM ION, CARDIAC MYOCYTE AND VASCULAR SMOOTH MUSCLE IN HYPERTENSION AND ITS TREATMENT </p><p>also reduced elasticity (possibly due to structural changes) in the arterioles .lg These are the changes we would like to counteract with antihypertensive therapy. </p><p>Effects of Antihypertensive Therapy Diuretics: There seem to be few studies on the </p><p>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. </p><p>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- </p><p>MAP mm Hg </p><p>180 I- </p><p>160 . </p><p>t Normotensives o- - Hypwtentlves </p><p>6 1 1 0 2 4 6 6 IO 12 Cl </p><p>Ilminlm2 </p><p>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 </p><p>crease slowly with propranolol,21 and more rapidly withother ,3 blockersz2 (Fig. 61. </p><p>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 &amp;-selec- eve as well as nonselective P blockers, some with intrinsic sympathicomimetic activity and others without.21.23 </p><p>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 </p><p>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. </p></li><li><p>January 23, 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 59 1OlA </p><p>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 &amp; 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 </p><p>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 </p></li><li><p>RtZA A S-M: THt CALCIUM ION,~CARDlAC MYOCYTE AND VASCULAR SMOOTH MUSCLE IN HYPERTENSION AND ITS TREATMENT </p><p>TABLE I Relative Changes in Heart Rate (HR), Mean Arterial Pressure (MAP) and Cardiac Index (Cl) with Seven /IT Blockers </p><p>HR (%) MAP (%) Cl (%) </p><p>Pts. work work Work m) Supine Sitting (100 watts) Supine Sitting (100 watts) Supine Sitting (100 watts) </p><p>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 </p><p>From reference 23. All supine and sitting values were obtained at rest. </p><p>TABLE II Side Effects During Start of #?-Blocker Therapy </p><p>Pk. </p><p>(n) Side Effects </p><p>Atenolol 13 Metoprolol 12 Timolol 16 </p><p>Penbutolol 13 </p><p>Alprenolol 10 Bunitrolol 11 Pindolol 14 </p><p>Muscular fatigue (3) </p><p>Muscular fatigue (3) Dizzy (I), cold feet (1) Muscular fatigue (3) Dizzy (2) . Muscular fatigue (3) Sleeping problems (2) Muscular fatigue (1) Dizzy (1) </p><p>From reference 23. </p><p>/o (SUPINE 1 </p><p>A MAP </p><p>I </p><p>OR ffl </p><p>t *ii * a010 -&amp;-A, tt 1st </p><p>ttt tat </p><p>\ +20 </p><p>+10 </p><p>0 </p><p>-10 </p><p>-20 </p><p>ACUTE AND CHRONIC CHANGES. VISACOR </p><p>A-A TPRI . ___.... . ,,R </p><p>O-0 SI </p><p>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. </p><p>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. </p><p>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 ,&amp;-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. </p><p>Also, others have found no difference between the &amp;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 </p><p>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. </p><p>Alpha-Receptor Blockers Prazosin, doxazosin and trimazosin: On both a </p><p>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 </p></li><li><p>January 23, 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume SY 1UJA </p><p>decrease in total...</p></li></ul>