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Effects of enalapril on 24-hour blood pressure in patients with essential hypertension
CURRENT THERAPEUTIC RESEARCH VOL. 52, NO. 3, SEPTEMBER 1992
EFFECTS OF ENALAPRIL ON 24-HOUR BLOOD PRESSURE IN PATIENTS WITH ESSENTIAL HYPERTENSION TADASHI NAKANISHI, I HAKUO TAKAHASHI,2 MASATO NISHIMURA,2 MANABU YOSHIMURA,I NAOKI SAKANE,2 AND HIROSHI SHIMOZAWA2 ~Department of Clinical Laboratory and Medicine, Kyoto Prefectural University of Medicine, and 2Department of Internal Medicine, Ooe Hospital, Kyoto, Japan
ABSTRACT The effects of enalapril on 24-hour blood pressure were evaluated in patients with essential hypertension using a noninvasive ambulatory blood pressure monitoring system. Both the systolic and diastolic blood pressures began to decrease approximately 3 hours after the oral administration of a single 5-mg dose of enalapril; this effect persisted for about 24 hours. Blood pressure adequately decreased after the administration of 10 mg of enalapril once daily in the morning for 2 weeks; the degree of reduction was smaller during the night than during the day. E n a l a p r i l administered once daily had adequate acute and chronic antihypertensive effects. The degree of the reduction in blood pressure was slight during the night. In addition, both the systolic and diastolic blood pressures in the higher pressure range markedly decreased, while those in the lower pressure range slightly decreased. These findings resemble the pattern of spontaneous physiologic reduction in blood pressure at rest, suggesting t h a t enalapril has optimal antihypertensive characteristics. This drug may also be advantageous in terms of compliance and effects on quality of life.
INTRODUCTION
Hypertension is diagnosed based on blood pressure, which is conventionally measured by auscultation at an outpatient clinic or hospital room and evaluated as casual blood pressure. However, since blood pressure fluctuates, casual blood pressure only indicates a resting value at one point in time. Recent advances in medical electronics allow noninvasive monitoring of 24-hour blood pressure with only a few restrictions. A more accurate evaluation of blood pressure is possible using 24-hour monitoring. In 1988, the US Joint National Committee recommended calcium antagonists and angiotensin I converting enzyme (ACE) inhibitors as drugs
Address correspondenceto: Tadashi Nakanishi, M.D., Department of ClinicalLaboratoryand Medicine, KyotoPrefecturalUniversityof Medicine,KawaramachiHirokoji,Kamigyo-ku,Kyoto602, Japan. Received for publication on June 5, 1992. Printed in the U.S.A. Reproductionin whole or part is not permitted. 361
0011-393X/92/$3.50
EFFECTS OF ENALAPRILON 24-HOUR BLOOD PRESSURE
of first choice for the treatment of hypertension. 1 Using 24-hour blood pressure monitoring, we have evaluated the effects of various antihypertensive drugs on blood pressure reduction, 2-11 and our results support the usefulness of ACE inhibitors. 5-7'11 The ACE inhibitor enalapril, developed by Merck & Co., 12 does not have the SH group in its structure. Thus this drug produces few penicillamine-like side effects, such as eruption, itching, and dysgeusia, which are often observed after the administration of high-dose captopril or in patients with renal impairment. 13 Enalapril has only slight ACE-blocking action b u t is a pro-drug that is converted in vivo to a potent activator. Because this activator has a long biologic half-life, the effects of the drug persist for some time. it In this study, we evaluated the effects of enalapril administered once daily on 24-hour blood pressure. P A T I E N T S AND M E T H O D S
Eleven outpatients (7 men and 4 women; mean age, 63 +- 8 years) with essential hypertension who had a casual blood pressure of at least 160/95 m m H g at two measurement points on separate days without antihypertensive therapy and 8 inpatients (4 men and 4 women; mean age, 65 -+ 11 years) with essential hypertension in whom blood pressure was stabilized after hospitalization for 1 week or longer were enrolled in the study. Secondary hypertension was excluded in all patients, and the essential hypertension was staged as grade I or II according to the World Health Organization classification. Informed consent was provided by all patients. After stabilization of the casual blood pressure, 24-hour blood pressure was recorded during a control period using an automated electronic monitoring device (ABPM630, Nippon Colin, Aichi, Japan) and analyzed using an AA200 (Nippon Colin). The acute effects of enalapril were evaluated in the 8 inpatients, and the chronic effects of the drug were evaluated in the 11 outpatients. After application of the ABPM630 at 8 AM, enalapril 5 mg was administered to each inpatient at 10 AM and the 24-hour blood pressure was recorded. Enalapril 10 mg was administered to each outpatient once daily in the morning, and the 24-hour blood pressure was recorded after 2 weeks. Blood pressure and pulse rate were recorded at 30-minute intervals during the 24-hour monitoring period. RESULTS
Compared with the control period, both the systolic and diastolic blood pressures began to decrease in the eight inpatients about 3 hours after the administration of a single 5-mg dose of enalapril (Figure 1). The blood 362
T. NAKANISHIET AL.
pressure remained decreased all day. The pulse rate in these patients was not affected. In the outpatient group, both the systolic and diastolic pressures were decreased all day 2 weeks after the once-daily administration of enalapril 10 mg in the morning (Figure 2). The systolic blood pressure decreased more than the diastolic blood pressure, and the reduction in blood pressure was greater during the day than at night. The pulse rate was not affected by enalapril. The intra-day variation in blood pressure after the administration of enalapril 10 mg once every morning was evaluated by the cumulative percentage method. Daily administration of this drug decreased mean systolic pressure by 18 mmHg (from 175 -+ 16 mmHg to 157 ± 19 mmHg) at the 90% level, by 19 mmHg (from 152 ± 17 mmHg to 133 -+ 12 mmHg) at the 50% level, and by 15 mmHg (from 131 -+ 21 mmHg to 116 ± 12 mmHg) BP
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Figure 1. Effects of a single 5-mg dose of enalapril on the intra-day variation in blood pressure (BP) and pulse rate (PR) in eight inpatients. The arrow shows the time of oral administration. 363
EFFECTS OF ENALAPRIL ON 24-HOUR BLOOD PRESSURE
BP mmHg 2OO
15C
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0 0:00 6100 12100 18=:00 241:00 Figure 2. Effects of 10 mg of enalapril administered once daily for 2 weeks on the intra-day variation in blood pressure (BP) and pulse rate (PR) in 11 outpatients. The square shows the time of administration.
at the 10% level. Mean diastolic pressure was decreased by 9 mmHg (from 100 -+ 10 mmHg to 91 ± 11 mmHg) at the 90% level, by 9 mmHg (from 85 -+ 11 mmHg to 76 -+ 11 mmHg) at the 50% level, and by 6 mmHg (from 70 ± 14 mmHg to 64 - 11 mmHg) at the 10% level (Figure 3). Both the systolic and diastolic pressures markedly decreased, but the degree of reduction was smaller in the lower pressure range. No side effects were reported in this study. DISCUSSION
Untreated hypertension not only damages major organs such as the brain, heart, and kidneys and decreases patient activity, but it also affects survival. To prevent the complications of hypertension, various antihypertensive drugs have been developed, and satisfactory results have been obtained in terms of blood pressure reduction. 364
T. NAKANISHI
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F i g u r e 3. Effects of 10 m g of enalapril a d m i n i s t e r e d once daily for 2 w e e k s on blood pressure
(BP) by c u m u l a t i v e percentage analysis.
The renin-angiotensin-aldosterone system is closely involved in the development and persistence of various hypertensive diseases. In recent years, the role of the renin-angiotensin system of the vascular tissue in regulating blood pressure has led to the development of antihypertensive therapy that inhibits this system. ACE inhibitors are thought to prevent or decrease cardiomegaly, a disease associated with hypertension, and their use has been increasing. In addition, among various antihypertensive drugs, ACE inhibitors have been reported to enhance quality of life. 15-2° Our studies on the intra-day variation in blood pressure induced by ACE inhibitors have also yielded good results. 6-s'll In this study, we evaluated the effects of single-dose (5 mg) and oncedaily administration (10 mg in the morning) of enalapril on the intra-day variation in blood pressure. The single dose of enalapril had acute effects. Onset of action is important when administering antihypertensive agents. Drugs that have no acute effects do not produce rapid symptomatic improvement, which may result in noncompliance on the part of the patient or the development of complications such as hypertensive encephalopathy and cerebral hemorrhage. Enalapril administered once daily at a dose of 10 mg decreased high blood pressures markedly and low blood pressures slightly. Thus enalapril may be advantageous because, to prevent complications, blood pressure must not be excessively reduced. 21 In daily clinical practice, 24-hour blood pressure monitoring is an 365
EFFECTSOF ENALAPRILON24-HOURBLOODPRESSURE
important index of the effects of antihypertensive therapy. Our results suggest that enalapril is useful for 24-hour blood pressure control. References: 1. The 1988 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1988; 148:1023-1038. 2. Nakanishi T, Nishimura M, Kubota S, Hirabayashi M. Effects ofnifedipine retard tablets in hypertension: Evaluation using a noninvasive portable automatic sphygmomanometer and a new method of assessment. Curr Ther Res 1989; 46:681-691. 3. Nakanishi T, Nishimura M, Kubota S, Hirabayashi M. Effects of nilvadipine on 24-hour blood pressure in patients with essential hypertension: A new evaluation method. Curr Ther Res 1989; 46:1096-1105. 4. Nakanishi T, Nishimura M, Kubota S, Hirabayashi M. Effects of nipradilol on 24-hour blood pressure in patients with essential hypertension. Curr TherRes 1990; 48:198-205. 5. Nakanishi T, Kubota S, Hirabayashi M, et al. Cumulative percentage analysis of the efficacy of antihypertensive medication using ambulatory blood pressure monitoring. Curr Ther Res 1990; 48:325-333. 6. Nakanishi T, Nishimura M, Kubota S, et al. Evaluation of acute and chronic effects of various antihypertensive drugs using a non-invasive ambulatory blood pressure monitoring system. Prog Med 1989; 9:2659-2672. 7. Nakanishi T, Nishimura M, Kubota S, Hirabayashi M. Effects of derapril (Adecut tablets) on intra-day variation of blood pressure in essential hypertension. J New Reined Clin 1990; 39:831-837. 8. Nakanishi T, Takahashi H, Yoshimura M, Hirabayashi M. Effects of nitrendipine (Baylotensin) on intra-day variation of blood pressure in essential hypertension. Jpn J Clin Exp Med 1991; 68:271-276. 9. Nakanishi T, Takahashi H, Yoshimura M, Hirabayashi M. Effects of combined use of nipradilol on patients with essential hypertension who do not respond to Ca antagonists. Ther Res 1991; 12:1943-1948. 10. Nakanishi T, Takahashi H, Yoshimura M, Hirabayashi M. Effects of nisoldipine on intra-day variation of blood pressure in essential hypertension. TherRes 1991; 12:14811486. 11. Nakanishi T, ACEI WHY series (12). Why are ACE inhibitors appropriate in terms of intra-day variation of blood pressure? Mod Med 1991; 20:36-37. 12. Patchett AA. A new class of angiotensin-converting enzyme inhibitors. Nature 1980; 288:280-283. 13. Case DB, Atlas SA, Laragh JH, et al. Clinical experience with blockade of the reninangiotensin-aldosterone-system by an oral converting enzyme inhibitor (SQ14, 225, Captopril) in hypertensive patients. Prog Cardiovasc Dis 1978; 21:195-206. 14. Billaz J. Three new long acting converting-enzyme inhibitors: Relationship between plasma converting-enzyme activity and response to angiotensin I. Clin Pharmacol Ther 1981; 29:665-670. 15. Katayama S, Maruno Y, Inaba M. Captopril and quality of life. Prog Med 1986; 6:16211628. 366
T. NAKANISHIETAL.
16. Ogihara T, Mikami H. Treatment of hypertension with converting enzyme inhibitors in elderly patients and quality of life. Geriatr M e d 1988; 26:291-299. 17. Schoenberger JA, Testa M, Ross AD. Efficacy, safety and quality-of-life assessment of captopril antihypertensive therapy in clinical practice. Arch Intern Med 1990; 150:301306. 18. Kobayashi A, Hayashi H, Kisamori K, et al. Anti-hypertensive therapy in essential hypertension and quality of life. Comparison between enalapril maleate and a thiazide diuretic by a cross-over test. Geriatr Med 1989; 27:713-728. 19. Higaki J, Ogihara T, Mikami H, et al. Effect of enalapril treatment on the quality of life of elderly patients with essential hypertension with complications. Curr Ther Res 1989; 45:604-610. 20. Higaki J, Mikami H, Otsuka A, et al. Effects of two years of enalapril treatment on the quality of life of elderly patients with essential hypertension complicated by other diseases. Curr Ther Res 1990; 47:620-628. 21. Stewart I McD G. Relation of reduction in pressure to first myocardial infarction in patients receiving treatment for severe hypertension. Lancet 1979; 1:861-865.
367
EFFECTS OF ENALAPRIL ON 24-HOUR BLOOD PRESSURE IN PATIENTS WITH ESSENTIAL HYPERTENSION TADASHI NAKANISHI, I HAKUO TAKAHASHI,2 MASATO NISHIMURA,2 MANABU YOSHIMURA,I NAOKI SAKANE,2 AND HIROSHI SHIMOZAWA2 ~Department of Clinical Laboratory and Medicine, Kyoto Prefectural University of Medicine, and 2Department of Internal Medicine, Ooe Hospital, Kyoto, Japan
ABSTRACT The effects of enalapril on 24-hour blood pressure were evaluated in patients with essential hypertension using a noninvasive ambulatory blood pressure monitoring system. Both the systolic and diastolic blood pressures began to decrease approximately 3 hours after the oral administration of a single 5-mg dose of enalapril; this effect persisted for about 24 hours. Blood pressure adequately decreased after the administration of 10 mg of enalapril once daily in the morning for 2 weeks; the degree of reduction was smaller during the night than during the day. E n a l a p r i l administered once daily had adequate acute and chronic antihypertensive effects. The degree of the reduction in blood pressure was slight during the night. In addition, both the systolic and diastolic blood pressures in the higher pressure range markedly decreased, while those in the lower pressure range slightly decreased. These findings resemble the pattern of spontaneous physiologic reduction in blood pressure at rest, suggesting t h a t enalapril has optimal antihypertensive characteristics. This drug may also be advantageous in terms of compliance and effects on quality of life.
INTRODUCTION
Hypertension is diagnosed based on blood pressure, which is conventionally measured by auscultation at an outpatient clinic or hospital room and evaluated as casual blood pressure. However, since blood pressure fluctuates, casual blood pressure only indicates a resting value at one point in time. Recent advances in medical electronics allow noninvasive monitoring of 24-hour blood pressure with only a few restrictions. A more accurate evaluation of blood pressure is possible using 24-hour monitoring. In 1988, the US Joint National Committee recommended calcium antagonists and angiotensin I converting enzyme (ACE) inhibitors as drugs
Address correspondenceto: Tadashi Nakanishi, M.D., Department of ClinicalLaboratoryand Medicine, KyotoPrefecturalUniversityof Medicine,KawaramachiHirokoji,Kamigyo-ku,Kyoto602, Japan. Received for publication on June 5, 1992. Printed in the U.S.A. Reproductionin whole or part is not permitted. 361
0011-393X/92/$3.50
EFFECTS OF ENALAPRILON 24-HOUR BLOOD PRESSURE
of first choice for the treatment of hypertension. 1 Using 24-hour blood pressure monitoring, we have evaluated the effects of various antihypertensive drugs on blood pressure reduction, 2-11 and our results support the usefulness of ACE inhibitors. 5-7'11 The ACE inhibitor enalapril, developed by Merck & Co., 12 does not have the SH group in its structure. Thus this drug produces few penicillamine-like side effects, such as eruption, itching, and dysgeusia, which are often observed after the administration of high-dose captopril or in patients with renal impairment. 13 Enalapril has only slight ACE-blocking action b u t is a pro-drug that is converted in vivo to a potent activator. Because this activator has a long biologic half-life, the effects of the drug persist for some time. it In this study, we evaluated the effects of enalapril administered once daily on 24-hour blood pressure. P A T I E N T S AND M E T H O D S
Eleven outpatients (7 men and 4 women; mean age, 63 +- 8 years) with essential hypertension who had a casual blood pressure of at least 160/95 m m H g at two measurement points on separate days without antihypertensive therapy and 8 inpatients (4 men and 4 women; mean age, 65 -+ 11 years) with essential hypertension in whom blood pressure was stabilized after hospitalization for 1 week or longer were enrolled in the study. Secondary hypertension was excluded in all patients, and the essential hypertension was staged as grade I or II according to the World Health Organization classification. Informed consent was provided by all patients. After stabilization of the casual blood pressure, 24-hour blood pressure was recorded during a control period using an automated electronic monitoring device (ABPM630, Nippon Colin, Aichi, Japan) and analyzed using an AA200 (Nippon Colin). The acute effects of enalapril were evaluated in the 8 inpatients, and the chronic effects of the drug were evaluated in the 11 outpatients. After application of the ABPM630 at 8 AM, enalapril 5 mg was administered to each inpatient at 10 AM and the 24-hour blood pressure was recorded. Enalapril 10 mg was administered to each outpatient once daily in the morning, and the 24-hour blood pressure was recorded after 2 weeks. Blood pressure and pulse rate were recorded at 30-minute intervals during the 24-hour monitoring period. RESULTS
Compared with the control period, both the systolic and diastolic blood pressures began to decrease in the eight inpatients about 3 hours after the administration of a single 5-mg dose of enalapril (Figure 1). The blood 362
T. NAKANISHIET AL.
pressure remained decreased all day. The pulse rate in these patients was not affected. In the outpatient group, both the systolic and diastolic pressures were decreased all day 2 weeks after the once-daily administration of enalapril 10 mg in the morning (Figure 2). The systolic blood pressure decreased more than the diastolic blood pressure, and the reduction in blood pressure was greater during the day than at night. The pulse rate was not affected by enalapril. The intra-day variation in blood pressure after the administration of enalapril 10 mg once every morning was evaluated by the cumulative percentage method. Daily administration of this drug decreased mean systolic pressure by 18 mmHg (from 175 -+ 16 mmHg to 157 ± 19 mmHg) at the 90% level, by 19 mmHg (from 152 ± 17 mmHg to 133 -+ 12 mmHg) at the 50% level, and by 15 mmHg (from 131 -+ 21 mmHg to 116 ± 12 mmHg) BP
15o
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121oo
181oo
2410o
~2':oo
,8;00
24100
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l~inl
0 :~00
I
6 !.00
Figure 1. Effects of a single 5-mg dose of enalapril on the intra-day variation in blood pressure (BP) and pulse rate (PR) in eight inpatients. The arrow shows the time of oral administration. 363
EFFECTS OF ENALAPRIL ON 24-HOUR BLOOD PRESSURE
BP mmHg 2OO
15C
loc
5C
0 control • enalapril 10 mg 01:oo
6100
12100
18100
24:00
PRJrnin
5O
0 0:00 6100 12100 18=:00 241:00 Figure 2. Effects of 10 mg of enalapril administered once daily for 2 weeks on the intra-day variation in blood pressure (BP) and pulse rate (PR) in 11 outpatients. The square shows the time of administration.
at the 10% level. Mean diastolic pressure was decreased by 9 mmHg (from 100 -+ 10 mmHg to 91 ± 11 mmHg) at the 90% level, by 9 mmHg (from 85 -+ 11 mmHg to 76 -+ 11 mmHg) at the 50% level, and by 6 mmHg (from 70 ± 14 mmHg to 64 - 11 mmHg) at the 10% level (Figure 3). Both the systolic and diastolic pressures markedly decreased, but the degree of reduction was smaller in the lower pressure range. No side effects were reported in this study. DISCUSSION
Untreated hypertension not only damages major organs such as the brain, heart, and kidneys and decreases patient activity, but it also affects survival. To prevent the complications of hypertension, various antihypertensive drugs have been developed, and satisfactory results have been obtained in terms of blood pressure reduction. 364
T. NAKANISHI
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F i g u r e 3. Effects of 10 m g of enalapril a d m i n i s t e r e d once daily for 2 w e e k s on blood pressure
(BP) by c u m u l a t i v e percentage analysis.
The renin-angiotensin-aldosterone system is closely involved in the development and persistence of various hypertensive diseases. In recent years, the role of the renin-angiotensin system of the vascular tissue in regulating blood pressure has led to the development of antihypertensive therapy that inhibits this system. ACE inhibitors are thought to prevent or decrease cardiomegaly, a disease associated with hypertension, and their use has been increasing. In addition, among various antihypertensive drugs, ACE inhibitors have been reported to enhance quality of life. 15-2° Our studies on the intra-day variation in blood pressure induced by ACE inhibitors have also yielded good results. 6-s'll In this study, we evaluated the effects of single-dose (5 mg) and oncedaily administration (10 mg in the morning) of enalapril on the intra-day variation in blood pressure. The single dose of enalapril had acute effects. Onset of action is important when administering antihypertensive agents. Drugs that have no acute effects do not produce rapid symptomatic improvement, which may result in noncompliance on the part of the patient or the development of complications such as hypertensive encephalopathy and cerebral hemorrhage. Enalapril administered once daily at a dose of 10 mg decreased high blood pressures markedly and low blood pressures slightly. Thus enalapril may be advantageous because, to prevent complications, blood pressure must not be excessively reduced. 21 In daily clinical practice, 24-hour blood pressure monitoring is an 365
EFFECTSOF ENALAPRILON24-HOURBLOODPRESSURE
important index of the effects of antihypertensive therapy. Our results suggest that enalapril is useful for 24-hour blood pressure control. References: 1. The 1988 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1988; 148:1023-1038. 2. Nakanishi T, Nishimura M, Kubota S, Hirabayashi M. Effects ofnifedipine retard tablets in hypertension: Evaluation using a noninvasive portable automatic sphygmomanometer and a new method of assessment. Curr Ther Res 1989; 46:681-691. 3. Nakanishi T, Nishimura M, Kubota S, Hirabayashi M. Effects of nilvadipine on 24-hour blood pressure in patients with essential hypertension: A new evaluation method. Curr Ther Res 1989; 46:1096-1105. 4. Nakanishi T, Nishimura M, Kubota S, Hirabayashi M. Effects of nipradilol on 24-hour blood pressure in patients with essential hypertension. Curr TherRes 1990; 48:198-205. 5. Nakanishi T, Kubota S, Hirabayashi M, et al. Cumulative percentage analysis of the efficacy of antihypertensive medication using ambulatory blood pressure monitoring. Curr Ther Res 1990; 48:325-333. 6. Nakanishi T, Nishimura M, Kubota S, et al. Evaluation of acute and chronic effects of various antihypertensive drugs using a non-invasive ambulatory blood pressure monitoring system. Prog Med 1989; 9:2659-2672. 7. Nakanishi T, Nishimura M, Kubota S, Hirabayashi M. Effects of derapril (Adecut tablets) on intra-day variation of blood pressure in essential hypertension. J New Reined Clin 1990; 39:831-837. 8. Nakanishi T, Takahashi H, Yoshimura M, Hirabayashi M. Effects of nitrendipine (Baylotensin) on intra-day variation of blood pressure in essential hypertension. Jpn J Clin Exp Med 1991; 68:271-276. 9. Nakanishi T, Takahashi H, Yoshimura M, Hirabayashi M. Effects of combined use of nipradilol on patients with essential hypertension who do not respond to Ca antagonists. Ther Res 1991; 12:1943-1948. 10. Nakanishi T, Takahashi H, Yoshimura M, Hirabayashi M. Effects of nisoldipine on intra-day variation of blood pressure in essential hypertension. TherRes 1991; 12:14811486. 11. Nakanishi T, ACEI WHY series (12). Why are ACE inhibitors appropriate in terms of intra-day variation of blood pressure? Mod Med 1991; 20:36-37. 12. Patchett AA. A new class of angiotensin-converting enzyme inhibitors. Nature 1980; 288:280-283. 13. Case DB, Atlas SA, Laragh JH, et al. Clinical experience with blockade of the reninangiotensin-aldosterone-system by an oral converting enzyme inhibitor (SQ14, 225, Captopril) in hypertensive patients. Prog Cardiovasc Dis 1978; 21:195-206. 14. Billaz J. Three new long acting converting-enzyme inhibitors: Relationship between plasma converting-enzyme activity and response to angiotensin I. Clin Pharmacol Ther 1981; 29:665-670. 15. Katayama S, Maruno Y, Inaba M. Captopril and quality of life. Prog Med 1986; 6:16211628. 366
T. NAKANISHIETAL.
16. Ogihara T, Mikami H. Treatment of hypertension with converting enzyme inhibitors in elderly patients and quality of life. Geriatr M e d 1988; 26:291-299. 17. Schoenberger JA, Testa M, Ross AD. Efficacy, safety and quality-of-life assessment of captopril antihypertensive therapy in clinical practice. Arch Intern Med 1990; 150:301306. 18. Kobayashi A, Hayashi H, Kisamori K, et al. Anti-hypertensive therapy in essential hypertension and quality of life. Comparison between enalapril maleate and a thiazide diuretic by a cross-over test. Geriatr Med 1989; 27:713-728. 19. Higaki J, Ogihara T, Mikami H, et al. Effect of enalapril treatment on the quality of life of elderly patients with essential hypertension with complications. Curr Ther Res 1989; 45:604-610. 20. Higaki J, Mikami H, Otsuka A, et al. Effects of two years of enalapril treatment on the quality of life of elderly patients with essential hypertension complicated by other diseases. Curr Ther Res 1990; 47:620-628. 21. Stewart I McD G. Relation of reduction in pressure to first myocardial infarction in patients receiving treatment for severe hypertension. Lancet 1979; 1:861-865.
367