Clinical and Experimental Pharmacology and Physiology (1992) 19, 547-553
CIRCULATING ANGIOTENSIN I1 LEVELS UNDER REPEATED ADMINISTRATION OF LISINOPRIL IN NORMAL SUBJECTS Minoru Kawamura, Masahito Imanashi,* Yohkazu Matsushima,* Keiichi Ito' and Katsuhiko Hiramori
Second Department of Internal Medicine, Iwate Medical University, Morioka, Iwate, *Division of Hypertension, National Cardiovascular Center, Osaka, and TYohkaichi National Hospital, Shiga, Japan (Received 31 October 1991; revision received 8 January 1992)
SUMMARY 1. To examine the effect of chronic administration of angiotensin I-converting enzyme (ACE) inhibitor on circulating angiotensin I1 (AH) concentration, 20 mg of lisinopril was administered once daily for 7 consecutive days to eight healthy volunteers. 2. Plasma ACE activity was inhibited to less than approximately 30% of the pretreatment level during the repeated administration. 3. Mean arterial pressure (MAP) was slightly but significantly reduced during the administration period. Plasma A11 concentration measured by an established method using high performance liquid chromatography combined with a radioimmunoassay, however, was maintained at approximately the pretreatment level when it was measured at 24 h intervals after each administration of lisinopril. 4. With the gradual recovery of ACE activity following discontinuation of administration, the plasma A11 concentration correlated with A1 concentration (r = 0.46), and also with the product of A1 and ACE activity (A1 X ACE; r = 0.80), corresponding to the formula obtained from the kinetics of ACE activity. No correlation was observed between MAP and A11 levels throughout the study period. 5. We conclude that in normal subjects repeatedly administered with ACE inhibitor, the A11 level in the circulation is still determined by an elevated level of A1 and any remaining ACE activity, thus maintaining A11 at pretreatment levels. We confirmed that it is not necessary to achieve a decrease in plasma A11 concentration through the chronic administration of ACE inhibitor in order to effectively lower blood pressure.
Key words: angiotensin I-converting enzyme, angiotensin 11, blood pressure, lisinopril, withdrawal.
INTRODUCTION Although angiotensin I-converting enzyme (ACE) inhibitors have been extensively used as the first choice treatment for hypertension (1988 Joint National Committee, 1988), the mechanism underlying the hypotensive action of these drugs remains controversial
and is not totally explained. Since the pretreatment level of plasma renin activity (PRA) correlates well with the reduction in blood pressure after acute administration of ACE inhibitors (Case et al. 1977), the hypotensive action can be interpreted as being due
Correspondence: Minoru Kawamura, M.D., Second Department of Internal Medicine, Iwate Medical University, Morioka, Iwate 020, Japan.
M. Kawamura et al.
548
to inhibition of angiotensin I1 (AII) production in the circulating renin-angiotensin system (RAS). This is supported by the studies of Shionoiri et al. (1985), who demonstrated a close correlation between the decrease in plasma A11 level and a reduction in blood pressure following acute administration of ACE inhibitor. However, the chronic administration of ACE inhibitors reduces blood pressure in many hypertensive patients in whom PRA is normal or even low (Gavras et al. 1978). ACE inhibitors are also effective in reducing blood pressure in spontaneously hypertensive rats (SHR) with low PRA (Laffan et 01. 1978; Nakata et al. 1987). Studies in humans (Biollaz et al. 1982; Giese et al. 1983; Hodsman et al. 1984; Gadsboll et al. 1986; Nussberger et al. 1989) and rats (Mento & Wilkes 1987) have indicated that the chronic administration of ACE inhibitor is not accompanied by reduced plasma A11 levels, and often the level is above pretreatment concentrations. Thus, the antihypertensive effects of ACE inhibitors are not always explained by reduced plasma A11 levels. Mento & Wilkes (1987) suggested that in the presence of ACE inhibition, A11 can be produced through the induction of other AIIforming enzymes. Furthermore, Urata et al. (1990) have reported that AII-forming activity that can be inhibited by Soyabean trypsin inhibitor was detected in different levels in human heart tissues of normal and failing hearts, suggesting that locally produced A11 may enter the bloodstream and play a variable role in different pathological states in elevating plasma A11 levels, Another possible mechanism for the increase in A11 is that AI, the substrate for ACE, is increased with ACE inhibition (Nussberger el al. 1987). This increase in substrate may account for the elevated A11 level in chronic experiments, unless inhibition of ACE activity is complete. The present study was performed to determine whether circulating A11 levels are influenced both by A1 and ACE activity in states of repeated ACE inhibition in normal subjects, and also to assess whether plasma A11 substantially influences blood pressure.
0 4 ) prior to administration of ACE inhibitor (lisinopril) at 09.00. Blood pressure was measured 5 min before blood sampling. On Days 1 to 6, lisinopril was administered at 09.00, and placebo was administered at 09.00 on Days 7 to 11. On Days 1 to 11,blood was drawn at 08.45 and blood pressure was measured 5 min before blood sampling. Capsules containing 20 mg of lisinopril or placebo were prepared by the manufacturer (Shionegi Co, Osaka, Japan). The volunteers were maintained on a fixed metabolic diet containing 120-150 mmol sodium and 50-80 mmol potassium per day throughout the study, Meals were given at 07.45, 12.00 and 18.00 every day except on day 4, when breakfast was not given. Therefore, the data on days 4 and 5 were omitted from analysis. Plasma concentrations of A1 and A11 were measured with an extraction system that used a Sep-Pak column followed by high performance liquid chromatography and radioimmunoassay as reported previously (Kawamura et al. 1987, 1989). The coefficients of variation of A1 and A11 were 0.04-0.07 for intra-assay and 0.08-0.09 for inter-assay. A commercial kit was used to assay plasma ACE activity (Fujirebio Ltd, Tokyo, Japan; Kasahara & Ashihara I98 1). Angiotensinogen concentration and plasma renin activity (PRA) were determined as previously described (Kawamura et al. 1990). Blood pressure was measured by nurses using an automatic ultrasound sphygmomanometer with recorder. The mean arterial pressure (MAP) was calculated by adding one-third of the pulse pressure to the diastolic pressure, All values were expressed as mean f s.e.m. One-way analysis of variance was performed to determine the effects of lisinopril on the measured variables over time, using a Macintosh IIcx computer with a Stat View 11. The Scheffe F-test was used to assess the significance of differences. Linear regression analysis was performed and the correlation coefficient was calculated by the method of least squares. The correlation of differences between correl a t h coefficients was evaluated as described by Zar (1984). Differences and correlation coefficients with P
CIRCULATING ANGIOTENSIN I1 LEVELS UNDER REPEATED ADMINISTRATION OF LISINOPRIL IN NORMAL SUBJECTS Minoru Kawamura, Masahito Imanashi,* Yohkazu Matsushima,* Keiichi Ito' and Katsuhiko Hiramori
Second Department of Internal Medicine, Iwate Medical University, Morioka, Iwate, *Division of Hypertension, National Cardiovascular Center, Osaka, and TYohkaichi National Hospital, Shiga, Japan (Received 31 October 1991; revision received 8 January 1992)
SUMMARY 1. To examine the effect of chronic administration of angiotensin I-converting enzyme (ACE) inhibitor on circulating angiotensin I1 (AH) concentration, 20 mg of lisinopril was administered once daily for 7 consecutive days to eight healthy volunteers. 2. Plasma ACE activity was inhibited to less than approximately 30% of the pretreatment level during the repeated administration. 3. Mean arterial pressure (MAP) was slightly but significantly reduced during the administration period. Plasma A11 concentration measured by an established method using high performance liquid chromatography combined with a radioimmunoassay, however, was maintained at approximately the pretreatment level when it was measured at 24 h intervals after each administration of lisinopril. 4. With the gradual recovery of ACE activity following discontinuation of administration, the plasma A11 concentration correlated with A1 concentration (r = 0.46), and also with the product of A1 and ACE activity (A1 X ACE; r = 0.80), corresponding to the formula obtained from the kinetics of ACE activity. No correlation was observed between MAP and A11 levels throughout the study period. 5. We conclude that in normal subjects repeatedly administered with ACE inhibitor, the A11 level in the circulation is still determined by an elevated level of A1 and any remaining ACE activity, thus maintaining A11 at pretreatment levels. We confirmed that it is not necessary to achieve a decrease in plasma A11 concentration through the chronic administration of ACE inhibitor in order to effectively lower blood pressure.
Key words: angiotensin I-converting enzyme, angiotensin 11, blood pressure, lisinopril, withdrawal.
INTRODUCTION Although angiotensin I-converting enzyme (ACE) inhibitors have been extensively used as the first choice treatment for hypertension (1988 Joint National Committee, 1988), the mechanism underlying the hypotensive action of these drugs remains controversial
and is not totally explained. Since the pretreatment level of plasma renin activity (PRA) correlates well with the reduction in blood pressure after acute administration of ACE inhibitors (Case et al. 1977), the hypotensive action can be interpreted as being due
Correspondence: Minoru Kawamura, M.D., Second Department of Internal Medicine, Iwate Medical University, Morioka, Iwate 020, Japan.
M. Kawamura et al.
548
to inhibition of angiotensin I1 (AII) production in the circulating renin-angiotensin system (RAS). This is supported by the studies of Shionoiri et al. (1985), who demonstrated a close correlation between the decrease in plasma A11 level and a reduction in blood pressure following acute administration of ACE inhibitor. However, the chronic administration of ACE inhibitors reduces blood pressure in many hypertensive patients in whom PRA is normal or even low (Gavras et al. 1978). ACE inhibitors are also effective in reducing blood pressure in spontaneously hypertensive rats (SHR) with low PRA (Laffan et 01. 1978; Nakata et al. 1987). Studies in humans (Biollaz et al. 1982; Giese et al. 1983; Hodsman et al. 1984; Gadsboll et al. 1986; Nussberger et al. 1989) and rats (Mento & Wilkes 1987) have indicated that the chronic administration of ACE inhibitor is not accompanied by reduced plasma A11 levels, and often the level is above pretreatment concentrations. Thus, the antihypertensive effects of ACE inhibitors are not always explained by reduced plasma A11 levels. Mento & Wilkes (1987) suggested that in the presence of ACE inhibition, A11 can be produced through the induction of other AIIforming enzymes. Furthermore, Urata et al. (1990) have reported that AII-forming activity that can be inhibited by Soyabean trypsin inhibitor was detected in different levels in human heart tissues of normal and failing hearts, suggesting that locally produced A11 may enter the bloodstream and play a variable role in different pathological states in elevating plasma A11 levels, Another possible mechanism for the increase in A11 is that AI, the substrate for ACE, is increased with ACE inhibition (Nussberger el al. 1987). This increase in substrate may account for the elevated A11 level in chronic experiments, unless inhibition of ACE activity is complete. The present study was performed to determine whether circulating A11 levels are influenced both by A1 and ACE activity in states of repeated ACE inhibition in normal subjects, and also to assess whether plasma A11 substantially influences blood pressure.
0 4 ) prior to administration of ACE inhibitor (lisinopril) at 09.00. Blood pressure was measured 5 min before blood sampling. On Days 1 to 6, lisinopril was administered at 09.00, and placebo was administered at 09.00 on Days 7 to 11. On Days 1 to 11,blood was drawn at 08.45 and blood pressure was measured 5 min before blood sampling. Capsules containing 20 mg of lisinopril or placebo were prepared by the manufacturer (Shionegi Co, Osaka, Japan). The volunteers were maintained on a fixed metabolic diet containing 120-150 mmol sodium and 50-80 mmol potassium per day throughout the study, Meals were given at 07.45, 12.00 and 18.00 every day except on day 4, when breakfast was not given. Therefore, the data on days 4 and 5 were omitted from analysis. Plasma concentrations of A1 and A11 were measured with an extraction system that used a Sep-Pak column followed by high performance liquid chromatography and radioimmunoassay as reported previously (Kawamura et al. 1987, 1989). The coefficients of variation of A1 and A11 were 0.04-0.07 for intra-assay and 0.08-0.09 for inter-assay. A commercial kit was used to assay plasma ACE activity (Fujirebio Ltd, Tokyo, Japan; Kasahara & Ashihara I98 1). Angiotensinogen concentration and plasma renin activity (PRA) were determined as previously described (Kawamura et al. 1990). Blood pressure was measured by nurses using an automatic ultrasound sphygmomanometer with recorder. The mean arterial pressure (MAP) was calculated by adding one-third of the pulse pressure to the diastolic pressure, All values were expressed as mean f s.e.m. One-way analysis of variance was performed to determine the effects of lisinopril on the measured variables over time, using a Macintosh IIcx computer with a Stat View 11. The Scheffe F-test was used to assess the significance of differences. Linear regression analysis was performed and the correlation coefficient was calculated by the method of least squares. The correlation of differences between correl a t h coefficients was evaluated as described by Zar (1984). Differences and correlation coefficients with P
