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Drugs 40 (Suppl. 4): 54-57, 1990 00 12-6667/90/0400-0054/$2.00/0 © Adis International Limited All rights reserved. DRSUP1932a

Ergometry as a Basis for Judging the Antihypertensive Effect 1.-W. Franz, U. Tonnesmann, D. Erb and R. Ketelhut Cardiac Rehabilitation Center, BfA, Todtmoos, Federal Republic of Germany

The duration and degree of blood pressure reduction produced by antihypertensive drugs is usually assessed by measuring blood pressure at rest; however, these measurements are strongly influenced by the time of day and the subject's physical and emotional state (Kronig 1976; Schulte et aI. 1978; Taylor 1975;Von Eiffet aI. 1978). Moreover, arterial hypertension is characterised both by an elevated resting blood pressure and, especially, by an excessive pressure response to physical and emotional stress (Franz 1986).There is a close correlation between systolic pressure during exercise and the degree of left ventricular hypertropy (Nathwani et aI. 1975; Ren et aI. 1985). Therefore, it may be appropriate to assess antihypertensive efficacy during standardised exercise testing. In a double-blind controlled study, we evaluated the effect ofurapidil and nitrendipine on blood pressure at rest and also during and after standardised ergometric exercise. This method of exercise testing is reported to provide reproducible data regarding the blood pressure response to physical activity (Franz 1982, 1987).

1. Methods 1.1 Patient Selection

at least 3 of the following criteria: systolic pressure > 200mm Hg and/or diastolic pressure > 100mm Hg when exercising at 100W; systolic pressure > 140mm Hg and/or diastolic pressure > 90mm Hg in the fifth minute after exercise, Patients were randomly divided into 2 treatment groups of 15 subjects each; group 1 received urapidil 60mg at 0800 and 1400h and group 2 received nitrendipine 20mg at 0800h and placebo at 1400h. Both groups were similar with regard to age, height, weight, and sex distribution. 1.2 Blood Pressure Measurement Blood pressure and heart rate were measured before exercise while patients were standing and supine (resting blood pressure), every minute during standardised ergometry (beginning at 50W and increasing to 100W in increments, of 10 W/min) [Franz 1980, 1986, 1987] and every minute after exercise for a total of 5 minutes . ! The work range, from 50 to 100W, was selected for this study because it corresponds well to ordinary levels of exertion (Stein 1981; Zerzawy 1981). Since even exercise of this intensity can elicit marked blood pressure elevations (Bachmann 1970; Franz 1979; Littler 1975; Taylor 1975), the vascular risk of arterial hypertension is accurately characterised by this work range. These measurements were taken at 0800 and 1600h on the first study day and were repeated at 0800, 1000 and 1600h after 3 weeks of treatment with the study drugs. The morning dose of both drugs was withheld until after the first series of measurements. Blood pressure was measured by cuff (phase IV for diastolic pressure), always by the same investigator. Values are the mean and the If-test (MannWhitney) was used for statistical analysis.

2. Results 2.1 Blood Pressure Before Treatment

30 previously untreated patients with essential hypertension (11 women, 19 men; age 53 ± 7 years) participated in the study after giving informed consent. For inclusion in the study they had to meet

There was a significant decrease in systolic (p < 0.01) and diastolic (p < 0.05) blood pressure readings in the afternoon compared with the mom-

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ing (154/102mm Hg and I65/108mm Hg, respectively) in group 2 patients ; no significant difference was noted in group I patients. There were no significant differences between morning and afternoon measurements of blood pressure during 100W ergometry or in the fifth minu te after exercise in either group. The resting and exercise blood pressures were similar for the 2 groups of patients.

hours after administration, and mean systolic pressure was significantly reduced in nitrend ipine patients at rest, and during and after exercise. Only the decreases in resting and exercise systolic pressures reached statistical significance in patients treated with urapidil. The final series of blood pressure measurements were taken 2 hours after the second dose ofurapidil and 8 hours after the single dose of nitrendipine. The decline in mean diastolic pressure continued to be statistically significant compared with pretreatment values in both treatment groups; however, the results for systolic pressure varied. It is of interest that the resting blood pressures of patients in group 2 were significantly (p < 0.05) higher in the morning than in the afternoon, before and after nitrendipine therapy, although the pressures measured at rest after ergometry were nearly identical. This finding may reflectthe influence of the patients ' emotional disposition or of diurnal variation on conventional resting blood pressure measurements.

2.2 Antihypertensive Efficacy of Urap idil and Nitrendipine The results of treatment with urapidil or nitrendipine are presented in table I. A significant reduction in mean systolic blood pressure was still evident in patients treated with nitrendipine 24 hours after drug administration. When measured during and after exercise, the mean diastolic pressure was also significantly reduced compared with pretreatment values. However, mean blood pressure measurements did not differ significantly from pretreatment values 18 hours after administration ofurapidil in group I patients. On the study day, both drugs caused a significant decline in mean diastolic blood pressure 2

2.3 Adverse Effects Adverse effects of treatment were minimal, and only I patient (from the nitrend ipine group) with-

Table I. Mean systolic (SSP) and diastol ic (DSP) blood pressures measured at rest and during and after ergometry in patients with hypertension before and after 3 weeks' treatment with urapidil (n 15) or nitrendip ine (n 15)3

=

=

Measurement times 0800h

1000h

urapidil

nitrendipine

urapidil

1600h nitrendip ine

urapidil

DSP

SSP

DSP

SSP

DSP

SSP

DSP

107

165 138***

108 93** *

156 147**

106 98*

154 148

102

103 95**

nitrendipine

SSP

DSP

SSP

DSP

SSP

159 158

107 104

165 158**

108 104

145**

5 minutes after exercise Pre-therapy 151 Post-therapy 154

102 101

154 147*

103 99*

144

102 94**

154 137***

103 90*·*

153 148*

103 98*

152 146

100W exerc ise Pre-therapy Post-therapy

115 111

219 210*

121 114**

202**

115 105**

219 203***

121 105***

212 207

114 107*

. 117 220 205** 108*

At rest (standing) Pre-therapy Post-therapy

215 208

a Statistically significant compared with pretreatment values: *

96** *

= p < 0,05; ** = P < 0,01; *** = P < 0.001.

96**

Drugs .40 (Suppl. 4) 1990

56

drew from the study after complaining of restlessness and oedema in the lower limbs.

3. Discussion Essential hypertension is characterised both by elevated blood pressure at rest and, especially, by an excessive pressure response to physical and emotional stress (Franz 1986). Not all antihypertensive agents decrease blood pressure under both circumstances: a-methyldopa (Stoker et al. 1979), cIonidine (Lund-Johansen 1981), reserpine (Patyna 1981),diuretics (Franz 1980, 1982), prazosin (Franz 1983), and the angiotensin converting enzyme inhibitor captopril (Kostis et al. 1984) fail to reduce the systolic pressure response to exercise, whereas calcium antagonists (Franz ' et al. 1986) and ,B-blockers (Franz et al. 1987; Lund-Johansen 1979; Patyna 1981 ; Reybrouck et al. 1977) do attenuate the pressure response. Because patients with hypertension are also endangered by larger increases in blood pressure during exercise and a delayed return to baseline levels after work (Franz 1986; Littler et al.1975; Sokolow et al. 1982; Taylor 1975), the antihypertensive efficacy of new agents should be evaluated during exercise. Measurement of 'resting' blood pressure 5 minutes afterergometry may also be preferable to measurement of conventional resting blood pressures. Variation in these latter measurements, as demonstrated with nitrendipine recipients in our study, can lead to an over- or underestimation of the efficacy and duration of antihypertensive action . This variability makes it difficult to compare the efficacyof2 different drugs in groups of patients treated in .parallel. In contrast, there is no significant deviation in blood pressure measured in the fifth minute after ergometry. This result has been previously reported (Franz 1986, 1987). Therefore, blood pressure measurements 'made after standardised exercise would avoid misinterpretation of efficacy and would be more valid as regards the duro ation of antihypertensive action. In this study, a similar decrease in exercise blood pressure was recorded 2 hours after a dose of either

drug; however, the duration of action of nitrendipine was longer compared with that ofurapidil, the former still having a significant effect 24 hours after administration. An increase in urapidil dosage or another dosing schedule, perhaps treatment 3 times daily, may also significantlydecrease morning blood pressures.

References Bachmann K, Zerzawy R, Riess PJ, Z6lch KA. Blutdruck-telemetrie - kontinuierliche, direkte Blutdruckmessung im Alltag und beim Sport. Deutsche Medizinische Wochenschrift 95: 741, 1970 Franz IW. Untersuchungen iiber das Blutdruckverhalten wahrend und nach Ergometrie bei Grenzwerthypertonikern im Vergleich zu Normalpersonen und Patientenmit stabiler Hypertonie. Zeitschrift fiir Kardiologie 68: 107, 1979 Franz IW. Differential antihypertensive effect of acebutolol and hydrochlorothiazide/amiloridehydrochloride combination on elevated exercise blood pressure in hypertensive patients . American Journal of Cardiology 46: 301-305, 1980 Franz IW. The effect of 13-receptor antagonists and diuretics and their combination on blood pressure-rate product during ergometric work in hypertensive patients . Zeitschrift fiir Kardiologie 71: 129-137, 1982 . Franz IW. The effects of prazosin and acebutolol and their cornbination on blood pressure and pressure-rate product during ergometric work in hypertensive patients . Zeitschrift fur Kardiologie 72: 746-754, 1983 Franz IW. Ergometry in hypertensive patients. Springer Verlag, Berlin, 1986 . Franz IW. Exercise hypertension : its measurement and evaluation. Herz 12: 95, 1987 Franz IW, Behr U, Ketelhut R. Resting and exercise blood pressure with atenolol , enalapril and a low-dose combination. Journal of Hypertension 5 (Suppl. 3): S37-S41, 1987 Franz IW, Behr U, Ketelhut R, Wiewel D. Antihypertensive Wir· kung von Gallopamil und Metoprolol auf den Ruhe- und Belastungsblutdruck bei Hochdruckkranken.Herz/Kreislauf 18: 632-637, 1986 Kostis JB, Ruddy M, Cosgrove N, Schneider SH, Krieger S, et al, Different exercise response of hypertensives to 13-blockers and angiotensin converting enzyme inhibitors. European Heart Journal 5 (Suppl, I): 141, 1984 Kronig B. Blutdruckvariabilitat bei Hochdruckkranken. Hiithig, Heidelberg, 1976 Littler WA, Honour AJ, Pugsley DJ, Sleight .P. Continuous recording of direct arterial pressure in untreated patients: its role in the diagnosis and management of high blood pressure. Circulation 51: 1101-1106, 1975 . Lund-Johansen P. Hemodynamic consequences of long-term 13blocker therapy: a 5 year follow-up study of atenolol. Journal of Cardiovascular Pharmacology I: 487-495, 1979 Lund-Johansen P. Central hemodynamics inessential hypertension at rest and during exercise: spontane ous changes and effects of diuretics, 13-receptor blockers and vasodilators. In Franz IW (Ed.)'Exercise blood pressure in hypertensive patients , pp. 107-123, Springer Verlag, Berlin, 1981 Nathwan i D, Reevers RA, Marquez-Julio A. Left ventricular hypertrophy in mild hypertension: correlation with exercise blood pressure. American Heart Journal 109: 386-387, 1985 Patyna WD. The effects of a reserpine-diuretic comb ination and

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of Jl-receptor blockers on blood pressure at rest and during exercise. In Franz IW (Ed.) Exercise blood pressure in hypertensive patients , pp. 139-144, Springer Verlag, Berlin, 1981 Ren J, Hakki A, Kotler MN. Exercise systolic blood pressure: a powerful determinant of increased left ventricular mass in patients with hypertension . Journal of the American College of Cardiology 5: 1224-1231, 1985 Reybrouck T, Amery A, Billiet L. Hemodynamic response to graded exercise after chronic Jl~adrenergic blockade. Journal of Applied Physiology 42: 133-138, 1977 Schulte W, Neus H, Noffke HK, Maisch B. Zur Problematik der Hypertonieeinteilung nach klinischen Blutdruckwerten. Medizinische Welt 43: 1669, 1978 Sokolow M, Perloff D, Cowan R. A IO-year prospective study of the incidence of cardiovascular events in hypertensive patients utilizing ambulatory blood pressure measurements. In Ninth Scientific Meeting of the International Society of Hypertension, Mexico City, 1982 Stein G. The' heart load ofseveral kinds of sports in rehabilitation after heart infarction (Abstract 9) II. World Congress on Cardiac Rehabilitation, Jerusalem , 1981

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Stoker JBN, Greeharan RJ, Linden J, Barbour MP, Lorimer AR, et al. Effects of exercise in hypertension controlled with metoprolol or methyldopa. Clinical Science 57: 391-392, 1979 ' Taylor SH. The circulation in hypertension . In Burley DM et al. (Eds) Hypertension - its nature and treatment, p. 29,'Metropolis, London, 1975 ' Von Eiff AW, Neus H, Schulte W. Stressreagibilitat als Charakteristikum von Blutdruckgruppen. Verhandlungen der Deutschen Gesellschaft fUr Innere Medizin 84: 792. 1978 Zerzawy R. Telemetrie von arteriellem Druck und Herzfrequenz unter alltaglichen und sportlichen Belastungenirn Vergleich zur Fahradergometrie.Tn Franz IW'(Ed .) Belastungsbluldruck bei Hochdruckkranken, pp, 161Cl70, Springer Verlag, Berlin. 1981

Correspondence and reprints: Prof. Dr ' J. W. Franz, Cardiac Rehabilitation Center, BfA, 7865 Todtmoos, Federal Republic of Germany.

Ergometry as a basis for judging the antihypertensive effect.

Short Communication Drugs 40 (Suppl. 4): 54-57, 1990 00 12-6667/90/0400-0054/$2.00/0 © Adis International Limited All rights reserved. DRSUP1932a Er...
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