Clinical Science and Molecular Medicine (1976) 51, 2019-202s.
Dissociation of blood angiotensin I1 and plasma renin activity during chronic treatment in essential hypertension M. P. SAMBHI, J. D . BARRETT, P. EGGENA A N D C. THANANOPAVARN Hypertension Dicision, Department of Medicine, Sepulueda V A Hospital, UCLA San Fernando Valley Medical Program, Sepulueda, California, U S A .
SY 1. Plasma renin activity and circulating amounts of blood angiotensin I1 were measured in twentysix patients with uncomplicated essential hypertension. 2. Measurements were made during a control period and at 1, 4, 9 and 14 weeks of diuretic treatment with metolazone or hydrochlorothiazide. 3. Linear regression analysis indicated a progressive change in the relation of plasma renin activity and blood angiotensin 11. 4. During chronic diuretic therapy (beyond 14 weeks) blood angiotensin I1 had stabilized to low and relatively fixed values across a wide range of plasma renin activities.
Key words: angiotensin I1,anti-hypertensive therapy, diuretics, renin activity.
Bett, Coghlan, Cran & Scroggins, 1971; Mendelsohn, Johnston, Doyle, Scroggins, Denton & Coghlan, 1972) although PRA increased as expected (Mendelsohn et a/., 1972). In contrast, both PRA and angiotensin I1 were shown to parallel each other and were elevated in response to sodium restriction in hypertensive subjects (Mendelsohn et a/., 1972). Blood angiotensin 11 values during diuretic administration to normal and hypertensive subjects were shown to be elevated acutely but remained in the normal range during the chronic period (Catt, Cain, Coghlan, Zimmet, Cran & Best, 1970). This study reports a progressive dissociation between PRA and blood angiotensin I1 in diuretictreated patients with essential hypertension. Methods
Introduction Gocke, Gerten, Sherwood & Laragh (1969) reported that a positive linear relationship existed between renin activity and amounts of angiotensin I I in plasma of normal subjects and in several disease states. In a large number of unselected patients with hypertension, Beevers, Brown, Davies, Fraser, Lebel, Lever, Medina, Morton, Robertson, Schalekamp, Tree & Waite (1973) also reported a strong positive correlation between PRA") and plasma angiotensin 11. Other studies have pointed out situations when the two parameters dissociate from one another. Circulating amounts of angiotensin I1 did not change in normotensive individuals in response to 5 days of sodium restriction (Best, ('I Abbreviation: PRA, plasma renin activity. Correspondence: Dr Mohinder P. Sambhi, Chief, Division of Hypertension, Veterans Administration Hospital, 161 I I Plummer Street, Sepulveda. California 91343, U.S.A.
Twenty-six patients with benign essential hypertension were followed in the present study. Patients were selected by exclusion of identifiable causes for secondary hypertension, and those manifesting clinical evidence of target organ damage were not included. All medications were discontinued for a period of at least 4 weeks, at which time control values of the two variables were determined: PRA was measured by radioimmunoassay of generated angiotensin I (Eggena, Barrett, Sambhi & Wiedeman, 1974) and blood angiotensin I1 was measured by radioimmunoassay of extracts of whole blood (10 vol. of sodium chloride solution) after chromatographic separation and acid treatment to remove interfering proteins (J. D. Barrett, P. Eggena & M. P. Sambhi, unpublished observations). Patients were divided into two groups: one received metolazone (5 mg daily); the other was given hydrochlorothiazide (50 mg twice daily). Measurements were repeated at 1, 4, 9 and 14 weeks of therapy.
201s
202s
M . P. Sambhi et al. there is a progressive dissociation in the relation between PRA and blood angiotensin 11. During chronic diuretic therapy, blood angiotensin I1 values return to control levels over the entire range despite stimulated PRA values. The mechanisms underlying the observed dissociation between PRA and the circulating amounts of angiotensin I1 remain to be elucidated. It can be speculated that long-term adaptive changes, including induction of enzymes and/or their modification by inhibitors and activators, has occurred, thus altering the generation rate or the metabolic clearance of angiotensin (M.P. Sambhi, P. Eggena, J. D. Barrett, M. L. Tuck, C. Thananopavarn & C. E. Wiedeman, unpublished observations).
35 PRA (ng 3 h - I r n l - l )
FIG. 1. Linear least-square regression analysis of plasma renin activity (PRA) and blood angiotensin I I (AII) are shown. The absolute values of these variables are, for the control period (PRA: 7.2k 1.0 SE;AIl: 12.5?2.6), and after I week (PRA: 26.7k3.3; All: 22.8k4.6). 4 weeks (PRA: 19.1k2.2; AII: 14.6+2.5), 9 weeks (PRA: 19.4k2.2; Al l: 12.2k 1.6) and 14 weeks (PRA: 20.0k3.3; AII: 10.8k 1.6) of diuretic therapy. The correlation coefficients gradients and their SE for each of the five regression equations are listed below: Period
Control I week 4 weeks 9 weeks 14 weeks
Slope
0.97k0.4 0.76k0.2 0.43k0.2 0.43k0.1 0.06k0.08
Intercept
Syx
7.1k4.5 24.0 3.6k6.2 24.3 6.5k4.1 15.5 2 . 5 k 2 . 4 7.7 8 . 7 k 2 . 2 7.7
r
P
0.33 0.55 0.35 0.61 0.16
Dissociation of blood angiotensin I1 and plasma renin activity during chronic treatment in essential hypertension M. P. SAMBHI, J. D . BARRETT, P. EGGENA A N D C. THANANOPAVARN Hypertension Dicision, Department of Medicine, Sepulueda V A Hospital, UCLA San Fernando Valley Medical Program, Sepulueda, California, U S A .
SY 1. Plasma renin activity and circulating amounts of blood angiotensin I1 were measured in twentysix patients with uncomplicated essential hypertension. 2. Measurements were made during a control period and at 1, 4, 9 and 14 weeks of diuretic treatment with metolazone or hydrochlorothiazide. 3. Linear regression analysis indicated a progressive change in the relation of plasma renin activity and blood angiotensin 11. 4. During chronic diuretic therapy (beyond 14 weeks) blood angiotensin I1 had stabilized to low and relatively fixed values across a wide range of plasma renin activities.
Key words: angiotensin I1,anti-hypertensive therapy, diuretics, renin activity.
Bett, Coghlan, Cran & Scroggins, 1971; Mendelsohn, Johnston, Doyle, Scroggins, Denton & Coghlan, 1972) although PRA increased as expected (Mendelsohn et a/., 1972). In contrast, both PRA and angiotensin I1 were shown to parallel each other and were elevated in response to sodium restriction in hypertensive subjects (Mendelsohn et a/., 1972). Blood angiotensin 11 values during diuretic administration to normal and hypertensive subjects were shown to be elevated acutely but remained in the normal range during the chronic period (Catt, Cain, Coghlan, Zimmet, Cran & Best, 1970). This study reports a progressive dissociation between PRA and blood angiotensin I1 in diuretictreated patients with essential hypertension. Methods
Introduction Gocke, Gerten, Sherwood & Laragh (1969) reported that a positive linear relationship existed between renin activity and amounts of angiotensin I I in plasma of normal subjects and in several disease states. In a large number of unselected patients with hypertension, Beevers, Brown, Davies, Fraser, Lebel, Lever, Medina, Morton, Robertson, Schalekamp, Tree & Waite (1973) also reported a strong positive correlation between PRA") and plasma angiotensin 11. Other studies have pointed out situations when the two parameters dissociate from one another. Circulating amounts of angiotensin I1 did not change in normotensive individuals in response to 5 days of sodium restriction (Best, ('I Abbreviation: PRA, plasma renin activity. Correspondence: Dr Mohinder P. Sambhi, Chief, Division of Hypertension, Veterans Administration Hospital, 161 I I Plummer Street, Sepulveda. California 91343, U.S.A.
Twenty-six patients with benign essential hypertension were followed in the present study. Patients were selected by exclusion of identifiable causes for secondary hypertension, and those manifesting clinical evidence of target organ damage were not included. All medications were discontinued for a period of at least 4 weeks, at which time control values of the two variables were determined: PRA was measured by radioimmunoassay of generated angiotensin I (Eggena, Barrett, Sambhi & Wiedeman, 1974) and blood angiotensin I1 was measured by radioimmunoassay of extracts of whole blood (10 vol. of sodium chloride solution) after chromatographic separation and acid treatment to remove interfering proteins (J. D. Barrett, P. Eggena & M. P. Sambhi, unpublished observations). Patients were divided into two groups: one received metolazone (5 mg daily); the other was given hydrochlorothiazide (50 mg twice daily). Measurements were repeated at 1, 4, 9 and 14 weeks of therapy.
201s
202s
M . P. Sambhi et al. there is a progressive dissociation in the relation between PRA and blood angiotensin 11. During chronic diuretic therapy, blood angiotensin I1 values return to control levels over the entire range despite stimulated PRA values. The mechanisms underlying the observed dissociation between PRA and the circulating amounts of angiotensin I1 remain to be elucidated. It can be speculated that long-term adaptive changes, including induction of enzymes and/or their modification by inhibitors and activators, has occurred, thus altering the generation rate or the metabolic clearance of angiotensin (M.P. Sambhi, P. Eggena, J. D. Barrett, M. L. Tuck, C. Thananopavarn & C. E. Wiedeman, unpublished observations).
35 PRA (ng 3 h - I r n l - l )
FIG. 1. Linear least-square regression analysis of plasma renin activity (PRA) and blood angiotensin I I (AII) are shown. The absolute values of these variables are, for the control period (PRA: 7.2k 1.0 SE;AIl: 12.5?2.6), and after I week (PRA: 26.7k3.3; All: 22.8k4.6). 4 weeks (PRA: 19.1k2.2; AII: 14.6+2.5), 9 weeks (PRA: 19.4k2.2; Al l: 12.2k 1.6) and 14 weeks (PRA: 20.0k3.3; AII: 10.8k 1.6) of diuretic therapy. The correlation coefficients gradients and their SE for each of the five regression equations are listed below: Period
Control I week 4 weeks 9 weeks 14 weeks
Slope
0.97k0.4 0.76k0.2 0.43k0.2 0.43k0.1 0.06k0.08
Intercept
Syx
7.1k4.5 24.0 3.6k6.2 24.3 6.5k4.1 15.5 2 . 5 k 2 . 4 7.7 8 . 7 k 2 . 2 7.7
r
P
0.33 0.55 0.35 0.61 0.16
