work 50 Materials and Methods Twelve outpatients (5 men and 7 women) with essential hypertension (WHO stages I II) or with a blood

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2 6 HYPERTENSION sential hypertension to clarify the time course of changes in depressor responses, the differences in individual depressor response, and the possible modulation of depressor response by humoral factors VOL 7, NO 1, JANUARY-FEBRUARY 185 Lactate (mmo(/0 work 50 rest 40 Materials and Methods Twelve outpatients (5 men and 7 women) with essential hypertension (WHO stages I ) or with a blood pressure of 160/5 mm Hg or more without cardiovascular complication agreed to participate in this study The duration of hypertension ranged from 1 to 21 years (mean, 8 years). Their ages ranged from 34 to 56 years (mean, 46 years). Their average height and weight were 15.2 ± 7. cm and 66.7 ± 10.2 kg respectively. A careful physical examination and laboratory examination were undertaken to eliminate secondary hypertension. All medication was discontinued more than 6 weeks before the study began. During the 6-week control period, duplicate blood pressure measurements on the nght arm were performed each week with the patient in a sitting position after 5 minutes' rest. The average of these two pressures was calculated for each week. Although systolic blood pressure decreased slightly after 1 week of this control period, both systolic and diastohc blood pressure stabilized within 20/10 mm Hg for the last 5 weeks, and the average of the last 2 weeks' measurements was used as a control value. The average blood pressure value of the last 2 weeks of each 10 weeks of exercise therapy was used for comparison. At the end of the control period and the first and second 10 weeks of exercise therapy, the patients were subjected to a multistage test of submaximal exercise on a Lode electric bicycle ergometer (Lanooy-Standard, Lode's Instrumenten B.V., Groningen, The Netherlands) (Figure 1). With subjects in the sitting position, the initial work load was 0 watt during 4 minutes, and the work load was increased by 10 or 15 watts every 4 minutes until subjects started to experience exhaustion The electrocardiogram was continuously monitored on the oscilloscope so that the patient's condition and heart rate could be carefully watched. The following parameters were measured every 4 minutes: heart rate, blood pressure, and blood lactate concentrations. Squeezed blood from an earlobe was used for blood lactate measurement. Blood lactate levels were determined with a lactate analyzer 640 (Roche Bio-Electronics, Basel, Switzerland).14 Blood lactate concentration for each patient was plotted against exercise work load in watts Lactate levels pass through three phases during graded exercise, and the work load at the first breaking point of lactate was used to calculate the exercise training intensity of each subject (Figure 1). This work load reflects mild aerobic exercise, as beyond this level lactate starts to accumulate in the blood.15 The patients were subjected to this mild aerobic exercise 60 minutes on the bicycle ergometer (Cyclotek, Monark-Crescent AB, Varberg, Sweden) three times a week for the first 10 weeks. 10 weeks, each subject underwent submaximal rest t WBPLA1» M (watts) Workload FIGURE I Protocol for submaximal graded exercise and blood lactate sampling Changes in blood lactate level were plotted at each work load Work load at first breaking point of lactate (WBPLAI) is used for exercise intensity graded exercise to readjust the work load of the aerobic exercise. This renewed work load was used for the next 10 weeks. Three patients did not complete the second 10 weeks of exercise therapy. Before each physical training session duplicate blood pressure measurements with the cuff method were performed on the right arm with the patient in a sitting position after a 5-minute rest. The average of the two measurements was used for the data All patients were subjected to I day's hospitalization before exercise therapy began and again at the end of the first and second 10 weeks of training in order to measure urinary sodium excretion and urinary kallikrein activity. At the start of exercise therapy and the end of each 10 weeks of training, an indwelling venous catheter was placed in an antecubital vein to obtain blood samples. The subject fasted for more than 8 hours before the study. the patient had rested for 30 minutes in a sitting position, blood samples were taken in prechilled vacuum type collection tubes, immediately placed in ice, and centrifuged at 1800 g at 4 C. The plasma and serum were stored at 20 C until they were analyzed Plasma renin activity (PRA) was measured according to the method of Haber et at. l6 with slight modification Plasma angiotensin levels were measured with the modified method of Nussberger and co-workers.' 7 Serum angiotensin converting-enzyme (ACE) activity was determined according to the modified method of Cushman and Cheung' 8 ; the tripeptide hippuryl-histidyl-leucine was used as a substrate. The hippunc acid liberated was measured spectrophotometncally Plasma bradykinin levels were assayed by the method of Nishino and colleagues', plasma was drawn into a chilled tube that contained ethylenediaminetetraacetic acid and 1-10phenanthroline as a kinmase inhibitor, trasylol and

3 EXERCISE THERAPY FOR HYPERTENSlON/ZCnwiaga et al. 7 soybean-trypsin inhibitor as a kallikrein inhibitor, and polybrene as an inhibitor of factor X activator; bradykinin levels were measured radioimmunologically after extraction with ether Plasma prostaglandin E levels were measured radioimmunologically after extraction of the plasma sample with ethyl acetate and isopropanol and after chromatography of the extracts on silicic acid. 20 Plasma norepinephnne and epinephnne levels were measured by the tnhydroxyindole method after extraction by high-performance liquid chromatography. 2 ' Urinary kallikrein activity was determined according to the fiuorophotometnc method; prolyl-phenylalanyl-arginine-4-methylcoumaryl- 7-amide was used as a substrate. 22 Urinary sodium concentration was determined by flame photometry Student's t test and a paired t test were used for statistical assessment of between-group and withingroup differences. All values are mean ± SE Results Changes in Baseline Data Changes in baseline data are summarized in Table 1 There was no constant decrease in body weight Heart rate was unchanged after 10 weeks of exercise but decreased after 20 weeks of exercise compared with the initial value. Exercise intensity, which was determined by calculating the work load at the first breaking point of blood lactate, was increased after each 10 weeks of exercise as a result of the training effect Table 2 summarizes the average heart rate at each exercise intensity during graded exercise. exercise therapy, heart rate at same exercise intensity was significantly less, indicating training effect TABLE 1 Changes in Blood Pressure and Baseline Data Before and Exercise Therapy Parameters No Before Blood pressure Systolic (mm Hg) Diastolic (mm Hg) Mean (mm Hg) Exercise intensity (watts) Weight (kg) Heart rate (beats/min) 153±4 157± ±l 0±2 2±2 48±5 52 ± ± ±3 3 82±2 8I±3 10 weeks t 13±5t 4 ±3* 4 + 3t $ t * 67+10* 20 weeks 136±4t O + 3t 105±3t 78±8t * 63.6±3 IX ±2* Values are mean + SE Blood pressure values represent the average of the last 2 weeks' measurements of each period. *p < 0 05, compared with corresponding initial value tp < 0.001, compared with corresponding initial value. Xp < 0 01, compared with corresponding initial value p < 0.05, compared with corresponding value at 10 weeks of TABLE 2 Time Course Change in Heart Rate (beats/mm) During Graded Exercise in the Patients Who Completed 20 Weeks of Exercise Therapy Grade of exercise Rest 1st exercise intensity (52 ± 7 watts) 2nd exercise intensity (67 ± 10 watts) 3rd exercise intensity ( watts) Before 81 ±3 3±4 10 weeks t 0±4 Values are mean ± SE *p < compared with corresponding initial value t/7 < compared with corresponding initial value 20 weeks 77 ±2* 108 ±4t 117±3 6± Changes in Resting Blood Pressure During Exercise Therapy Changes in resting blood pressure during exercise therapy are summarized in Tables 1 and 3 and in Figure 2. In Table 1 each blood pressure value represents the average of the last 2 weeks' measurements of each period. In hypertensive subjects who completed the first 10 weeks of exercise therapy, we observed a significant reduction of both systolic and diastolic blood pressures, and in patients who completed 20 weeks of exercise therapy, we observed further reduction of diastolic blood pressure. The time course of changes in average blood pressure of the group during the first and second 10 weeks is expressed in Figure 2 The depressor response was inconsistent for the first 5 weeks of exercise therapy, after which it stabilized, and no further depressor response was seen. Adjusting the work load in response to increased physical fitness caused further reduction of the blood pressure, especially in diastole. In Table 3 depressor responses of each patient are graded according to the guidelines established by the Japanese Ministry of Health and Welfare on estimating the depressor effectiveness of antihypertensive drugs weeks of exercise therapy, 6 of subjects (50%) showed reduction of systolic/diastolic (mean) pressures by more than 20/10 (13) mm Hg, and after 20 weeks 7 of subjects (78%) showed a similar response (Table 3). Thus, after 20 weeks most of the patients showed good depressor response to exercise therapy. TABLE 3 Grade and Efficacy of Blood Pressure Reduction Exercise Therapy ASystolic/ Adiustolic 10 weeks 20 weeks (mm Hg) AMean No b No % >30/ / /-5 + /±4 Total no > ± % 50% % 22%

4 8 HYPERTENSION VOL 7, No 1, JANUARY-FEBRUARY f 160 I control period Systolic 11st exercise intenslty<52t7 watts) 2nd exercise intenslty<67do watts)~ FIGURE 2 Time course of changes in average resting blood pressure of the patients (n = ) who completed 20 weeks of exercise therapy M exercise times 1 weeks « Changes in Humoral Factors During Exercise Therapy Changes in humoral factors during exercise therapy are summarized in Table 4. Exercise therapy produced a significant reduction in plasma catecholamine levels and an increase in plasma prostaglandin E levels and urinary excretion of sodium. No changes were observed in the renin-angiotensin system, the kalhkreinbradykinin system, and ACE activity after 10 weeks Only plasma angiotensm levels increased significantly after 20 weeks. A slight increase in PR A was observed in some responders after 20 weeks (Table 4) TABLE 4 Changes in Humoral Factors Before and Exercise Therapy Humoral factors No Before 10 weeks Plasma Epinephnne (pg/ml) Norepinephnne (pg/ml) Prostaglandin E (pg/ml) PRA (ng/ml/hr) Angiotensm (pg/ml) Bradykimn (pg/ml) Serum ACE (nmol/ml/min) 24-Hour unne excretion Kallikrein (/imol/min/day) Sodium (meq/day) ±I4 85±I4 340 ±28 3I6±28 0±30 ±36 1 2±0 3 1 l±04 5O±7 58 ±8 I83± ±l ± ± ± ± ±13 3 PRA = plasma renin activity. ACE = angiotensin-converting enzyme Values are mean ± SE *p < 0 05, compared with corresponding initial value tp < 0 001, compared with corresponding initial value Xp < 0 01, compared with corresponding initial value p < compared with corresponding value at 10 weeks of exercise Differences in Individual Depressor Response The pretraining renin profiles of those six patients in whom 10 weeks of exercise was effective in reducing blood pressures by more than 20/10 mm Hg were compared with those of the remaining six patients. The PRA of good responders was approximately one-third that of poor responders (Figure 3). A significant negative correlation (r = 0 7 8,/?< 0 0 1) was found between initial value of PRA and the corresponding blood pressure reduction of each subject (Figure 4) Discussion The major finding of this study was that the effectiveness of exercise therapy in hypertensive patients is dependent on the initial value of PRA. In patients with lower PRA 10 to 20 weeks of exercise therapy tended to result in a greater reduction of blood pressure. The blood pressure lowering effect of exercise therapy was associated with a concomitant increase in prostaglandin E synthesis and urinary excretion of sodium and a 2±2t 28±3t 230 ±27* 224 ±28* 380±64t 370 ±78* 1 l±0 2 0±0! 52 ±5 58±6 I25±O3 1O3±O3 1 23±1 5 I8 70±l ± ± * 20 weeks 23 ±3* I82±41t 27±45* 1 3±O3 I + * I88± ±l ± ±23 3

5 EXERCISE THERAPY FOR HYPERTENSION/K/vonflga et al Plasma Renin Activity (ng/ml/hr) p 05 good responder (n»6) T poor responder (n-6) FIGURE 3 The difference m plasma renin activity between the patients with mean blood pressure reduction of more than 13 mm Hg (good responder) and those with less than 13 mm Hg (poor responder) Plasma ^ *- Renin Activity (ng/mlau) y 6+7 log x r p«=0 01 FIGURE 4 Correlation between initial plasma renin activity and mean blood pressure reduction after 10 weeks of exercise training (n = ) Logarithmic expression is used for horizontal scale. reduction of plasma levels of catecholamines, but not with any change in the renin-angiotensin system nor the kallikrein-bradykinin system. The Effectiveness of Exercise Therapy in Hypertensives Although some recent reports suggest the effectiveness of exercise therapy in mildly hypertensive subjects, other reports contradict those results. 6 " 8 Many factors have to be considered with respect to the differences in the results, including the different subtypes of essential hypertension, individual differences of the response to exercise, and the quality and quantity of exercise. None of the studies has considered the individual differences of the response to exercise therapy of hypertensive subjects. In the present study the relationship between the grade of individual depressor response and the multihormonal response was examined. When the patients were divided into good responders and poor responders, statistical significance was seen only in the preexercise value of PRA (Figure 3). The PRA of good responders was approximately one-third that of the poor responders. We also found a close negative correlation (r = -0.78, p < 0.01) between PRA and the depressor effect of exercise therapy (Figure 4). Thus, hypertensives with lower renin appear to respond more positively to exercise therapy. Slight increase of PRA and significant increase of angiotensin observed after exercise therapy (Table 4) may reflect volume loss in these patients. The quality and quantity of exercise also were found to be important. In the studies that failed to observe blood pressure reduction, the intensity of exercise was hard and mostly at a level above 60% Vo 2 max. 6^ In contrast, in the studies that showed significant blood pressure reduction, the intensity of exercise was mild to moderate and around the level of 50% Vc^max. 1 5 l0 Therefore, the intensity of exercise seems to be a key factor in exercise therapy of hypertensive subjects. It is sometimes hard to determine Vc>2max in hypertensive subjects because of further elevation of blood pressure during graded exercise. To avoid this problem we measured blood lactate levels at each work load of submaximal graded exercise. These two correlations were plotted on a graph and the work load at the first breaking point of lactate was used as the training work load for each hypertensive patient (Figure 1). This work load reflects aerobic exercise and coincides approximately with 50% Vo 2 max in healthy subjects (unpublished data). We believe this method can safely provide accurate quantitative exercise to each hypertensive patient with wide variations of physical fitness. We observed the time course of changes in resting blood pressure throughout the study. According to this observation, blood pressure began to decrease after 1 to 2 weeks, and after 5 weeks of exercise blood pressure became constantly and significantly lower compared with the initial value (Figure 2) In normal subjects, we know that after 10 weeks of physical training, Vc^max increases 10% to 20%. 24 As a result, the initial training work load may represent less of a relative stress as training progresses Therefore, we measured work load at the first breaking point of blood lactate during graded exercise after 10 weeks of exercise therapy and found that it increased 30% to 35% as shown in Table 1. Then, for the next 10 weeks, work load was increased to this new level, and we found further reduction of diastolic blood pressure (Figure 2). Thus increasing work load in response to increased physical fitness seems to be important for the sufficient depressor effect of exercise therapy for hypertensive subjects. Changes in Humoral Factors and Possible Role of Underlying Mechanisms We examined multiple humoral responses plasma levels of catecholamines, prostaglandin E, renin, angiotensin, bradykinin, and angiotensin-converting

6 130 HYPERTENSION VOL 7, No 1, JANUARY-FEBRUARY 185 enzyme, and urinary kallikrein and sodium excretion before and after exercise (Table 4). A significant reduction of plasma catecholamine levels and a significant increase of plasma prostaglandin E concentrations were noted in association with significant blood pressure reduction; however, there was no statistically significant relationship between these two factors and the grade of depressor response. This finding may indicate that each factor cannot be solely responsible for the underlying mechanism of depressor response and that there may be other unknown factors The absence of a significant relationship also may be due to the small number of subjects studied and the error inherent in measurements such as plasma catecholamine concentrations. Of the previously published studies only that of Bjorntorp" investigated the changes in humoral factors in conjunction with blood pressure reduction in hypertensive subjects during exercise therapy He observed blood pressure reduction in obese patients with exercise therapy in association with the reduction of plasma insulin and speculated that the reduction of plasma insulin might play a role in mediating blood pressure reduction by reducing sodium reabsorption in the kidney or decreasing catecholamine turnover in the sympathetic nervous system. Winder and colleagues 26 reported that physical training results in a diminished increase in plasma catecholamine concentrations at a given level of exercise, although plasma catecholamine levels increased during exercise. Our observations of the reduction of resting plasma catecholamine levels after exercise therapy indicate that diminished sympathoadrenergic activity might participate in blood pressure modulation. It is of interest that plasma prostaglandin E levels increased in parallel with the fall in blood pressure and the increase in urinary sodium excretion. Furthermore, this depressor response was more pronounced in the hypertensive subjects with lower plasma renin activities (Figure 4). In conscious dogs, renal prostaglandin E 2 secretion is reportedly increased two- to fourfold after mild to moderate exercise but no change occurs after severe exercise. 27 Nowak and Wennmalm 28 reported a significant increase in levels of plasma prostaglandin E with moderate exercise in normotensive subjects. Although Lijnen and co-workers 2 failed to observe the significant increase of plasma prostaglandin levels during exercise in hypertensive subjects, the severe exercise employed in their study might explain the difference in the results. There are at least two sources of the origin of the plasma prostaglandins during exercise: one from kidney and the other from skeletal muscle We observed a two- to threefold increase of plasma prostaglandin E concentrations after exercise therapy. Although we do not know in what proportion it is liberated from kidney, skeletal muscle, or both, we speculated that prostaglandin E might modulate blood pressure in at least three different ways First, it may increase sodium secretion from kidney, which results in the reduction of plasma volume. This hypothesis is likely because of the concomitant increase of urinary sodium excretion in the present study and because hypertensive subjects with low renin levels, who happened to respond better to exercise therapy, are known to be associated with increased plasma volume. 30 Second, prostaglandin E may cause local vasodilation after liberation from the skeletal muscle. 28 Third, prostaglandin E may inhibit norepinephrine release from nerve terminals, 31 which might cause further reduction of sympathetic nerve activity. The precise role of the prostaglandins in modulating blood pressure in association with exercise needs further elucidation. Conclusion The present study results suggest the effectiveness of aerobic exercise at approximately 50% Vo 2 max in the treatment of mild hypertension. The depressor response was found to be more pronounced in patients with lower renin activity Sympathetic inactivation and increased plasma prostaglandin E levels may participate in underlying mechanisms for the depressor effect of exercise therapy in hypertensive subjects. Acknowledgments The authors gratefully acknowledge Yoshihiko Monyama and Yuko Ohashi for their help in performing exercise therapy and Tomoko Johno for her skillful laboratory help References 1 Hanson JS, Nedde WH Preliminary observations on physical training for hypertensive males CircRes l70,27(suppl I) Rost R. Hollmann W, Liesen H Korperliches Training mit Hochdruckpatienten, Ziele und Probleme Herz 176, Choquette G, Ferguson RJ Blood pressure reduction in "borderline" hypertensives following physical training Can Med Assoc J 173, Sannerstedt R. Wasir H. Henmng R, Werko L Systemic haemodynamics in mild arterial hypertension before and after physical training Clin Sci Mol Med 173,45 I45s-14s 5 Kukkonen K, Rauramaa R, Voutilainen E, Lansinnes E Physical training of middle-aged men with borderline hypertension Ann Clin Res I82.l4(suppl 34) Sannerstedt R Rehabilitation in arterial hypertension Adv Cardiol 178, Johnson WP, Grover JA Hemodynamic and metabolic effects of physical training in four patients with essential hypertension Can Med Assoc J 167, De Plaen JF, Detry JM Hemodynamic effects of physical training in established arterial hypertension Acta Cardiol Boyer JL, Kasch FW Exercise therapy in hypertensive men JAMA 170, RomiinO. Camuzzi AL. Villal6n E, KlennerC Physical training program in arterial hypertension Cardiology 181, Hartley LH. Mason JW, Hogan RP, et al Multiple hormonal responses to graded exercise in relation to physical training J Appl Physiol 172, ^06 Winder WW. Hickson RC, Hagberg JM. Ehsam AA. Mclane JA Training-induced changes in hormonal and metabolic responses to submaximal exercise J Appl Physiol 17, Kosunen K, Pakannen A, Kuoppasalmi K, et al Cardiovascular function and the renin-angiotensin-aldosterone system in long-distance runners during various training periods Scand J Clin Lab Invest 180,

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