AJH
1992;5:900-911
The Importance of the Renin-Angiotensin-Aldosterone System*
Bjorn Dahldf, Hans Herlitz, Mattias Aurell, and Lennart
Our study attempted to evaluate the importance of changes in the circulating renin-angiotensinaldosterone system (RAAS) and in hemodynamics in relation to observed changes in cardiovascular structure. We studied previously untreated men (n = 28) with essential nonmalignant hypertension and a supine casual diastolic blood pressure > 95 mm Hg on three to four separate ( > 1-week interval) occasions measured in triplicate. We used intraarterial blood pressure, dye-dilution technique, plethysmography (hands), eye-ground photos, Mmode echocardiography, radio immunoassays, and multiple regression analysis. Patients were randomized to 6 months of double-blind treatment with either enalapril or hydrochlorothiazide, following 4 to 6 weeks on placebo. We found that enalapril blocked the plasma angiotensin converting enzyme (ACE) with a secondary increment in plasma renin activity (PRA) and reductions in angiotensin II (AH) and aldosterone. Blood pressure was lowered through a reduction in total peripheral resistance (TPR). Hydrochlorothiazide increased PRA, All, and aldosterone, and lowered blood pressure mainly through a reduction in cardiac output. Enalapril was significantly more effective than hydrochlorothiazide in reversing struc-
*See also the editorial on page 923 of this issue. Received February 20, 1992. Accepted September 1, 1992. From the Department of Medicine, University of Goteborg, Ostra Hospital, Goteborg, Sweden (BD, LH); and the Department of Nephrology, University of Goteborg, Sahlgren's Hospital, Goteborg, Sweden (HH, MA). This study was supported in part by The Swedish Hypertension Society and Merck, Sharp, and Dahme AB, Sweden. Address correspondence and reprint requests to Bjorn Dahlof, MD, Department of Medicine, University of Goteborg, S-416 85 Goteborg, Sweden. © 2992 by the American Journal of Hypertension, Inc.
Hansson
tural changes in the retinal and hand vasculature as well as in the heart. A reduction in cardiac hypertrophy was seen even in the occasional enalapriltreated patient, in whom little or no reduction in blood pressure occurred. In the stepwise regression analyses, the changes in retinal and hand vascular structure were most strongly related to various changes in the RAAS, explaining 15 to 34% of the variance. For the changes in cardiac structure, the type of therapy (enalapril or hydrochlorothiazide) appeared to be the most important factor, explaining between 29 and 50% of the variance. The changes in cardiac structure were even more strongly related to changes in the RAAS for the enalapril treated patients and explained up to 55% of the variance in cardiac structure. It can be concluded that the reversal of structural vascular changes during antihypertensive therapy was more dependent on the blockade of the RAAS than on lowering of the blood pressure. Am J Hypertens 1992;5:900-911
KEY WORDS: Structural vascular changes, cardiac hypertrophy, blood pressure, renin-angiotensinaldosterone system.
S
tructural cardiovascular changes in hypertension are important from a pathogenetic point of view. They are also powerful markers of the increased risk of complications in hypertens i o n . It is also interesting to note that not only blood pressure, but the renin status has been linked to vascular injury and impairment of prognosis. As to the pathogenetic aspects, increased medial thickness of the resistance vessels, which is a character1,2
1-5
6
7
0895-7061/92/$5.00
Downloaded from https://academic.oup.com/ajh/article-abstract/5/12_Pt_1/900/175959 by Universitaetsbibliothek Muenchen user on 06 February 2019
Reversal of Cardiovascular Structural Changes When Treating Essential Hypertension
AJH-DECEMBER
1992-VOL
5, NO. 12, PART 1
R A A S AND CV STRUCTURE
1,2
8,11
12-25
1,2,9-11,26
27
cardiovascular changes have previously been reported. There was a tendency toward a more effective reduction in blood pressure with enalapril; however, the difference between therapies was not significant. Enalapril was significantly more effective than hydrochlorothiazide in reversing structural vascular changes in the retina and in the hand, as well as cardiac hypertrophy. Because enalapril and hydrochlorothiazide affect the RAAS differently, the present analysis was performed to evaluate the importance of the changes in the circulating RAAS and of hemodynamics in relation to the changes in structural vascular changes in the hand and retina as well as in left ventricular mass and wall thickness. The study was approved by the Ethics Committee of the University of Goteborg and performed according to the Declaration of Helsinki. All patients had given their written and oral consent to participate. 42-44
42-44
PATIENTS AND M E T H O D S
27-31
32
33-34
Hydralazine can inhibit the pressor effect and the cardiac hypertrophy induced by All (infused in a slow pressor dose in rats), suggesting a predominant pressor mechanism for the cardiac hypertrophic response. However, hydralazine does not inhibit the development of All-induced structural vascular changes, suggesting that at least part of the vascular effect is not pressure dependent. This dissociation of the hypertrophic response in heart and vessels could result from reninangiotensin mediated effects. Thus, cardiac myocyte growth appears to be predominantly pressure dependent, while cardiac interstitial fibrous tissue responds instead to angiotensin and aldosterone. While circulating renin-angiotensin-aldosterone appears to be the main humoral influence affecting cardiac and vascular tissue responses, a local tissue renin system has also been proposed, but not v e r i f i e d . As for the importance of the circulating RAAS as a predicting factor of cardiovascular morbidity and mortality, both retrospective and prospective studies have demonstrated a relationship between renin status and risk. The link between renin and cardiovascular risk becomes especially interesting in view of the strong risk prediction offered by left ventricular hypertrophy on the one h a n d and the association between the RAAS and cardiovascular h y p e r t r o p h y on the other. To further elucidate the importance of the RAAS in relation to cardiovascular structure, we attempted the present analysis in previously untreated hypertensive men. They all had mild to moderate essential hypertension and were randomized to double-blind treatment with either enalapril or hydrochlorothiazide in monotherapy. The changes in hemodynamics and structural 35
36
37
38,84-86
40,41
3,5
27-36
Design The study was double-blind, randomized, and performed in previously untreated white hypertensive men. It included 28 patients with a mean age of 46 years (SEM 2.1), a mean weight of 86 kg (1.9) and a body mass index of 27 kg/m (0.6). After 4 to 6 weeks on placebo, the patients were randomized to enalapril or hydrochlorothiazide in monotherapy if their diastolic blood pressure (DBP) was > 95 mm Hg on three to four occasions with at least 1 week in between. Blood pressure was measured in triplicate on each occasion with a mercury sphygmomanometer and an appropriate cuff size. Korotkoff phases 1 and 5 were taken as the systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively. There were no significant differences between the two treatment groups in the baseline characteristics as previously reported. 2
42-44
Hemodynamics and Structural Vascular Changes The patients underwent an extensive invasive hemodynamic, plethysmographic, cardiac, and eyeground investigation at placebo baseline and after 6 months of active therapy, as previously described in detail. " In brief, blood pressure was recorded intraarterially through an indwelling arterial catheter. Mean arterial blood pressure (MAP) was obtained by electrical dampening. The mean of at least five measurements recorded during 1 h was used for calculations. Cardiac output (CO) was measured with the dyedilution technique and total peripheral resistance (TPR) was calculated based upon CO and M A P . " Minimal resistance in the hands ( R ^ ) was derived from maximal blood flow recorded with water plethysmography at ischemia induced by heating, arterial occlusion, and work until exhaustion. " 42
44-46
4 4 , 4 7
44,51
53
5 0
44
Downloaded from https://academic.oup.com/ajh/article-abstract/5/12_Pt_1/900/175959 by Universitaetsbibliothek Muenchen user on 06 February 2019
istic feature of established hypertension, may be both a consequence and a contributory cause of high blood pressure. The blood pressure amplification caused by cardiovascular hypertrophy may be of greater quantitative importance in maintaining blood pressure elevation than are basic underlying (eg, endocrine or renal) mechanisms. In fact, structural cardiovascular changes participate in a vicious circle not only by maintaining an elevated blood pressure, but also by causing progression to more severe hypertension. Furthermore, both experimental and clinical studies have shown that lowering of increased blood pressure is not the sole factor needed to achieve regression of cardiovascular h y p e r t r o p h y . The importance of the renin-angiotensin-aldosterone system (RAAS) in this context is of great interest. It has been suggested that the structural cardiovascular amplifying mechanisms are activated, or at least modulated, by trophic f a c t o r s . Angiotensin II (All), a powerful vasoconstrictor also has growth stimulating properties. Thus, in experimental studies All has mitogenic properties and promotes the growth of both human and rat cultured vascular smooth muscle c e l l s , fibroblasts, and cardiac m y o c y t e s .
901
902
DAHLOF ET AL
AJH-DECEMBER
42
54
43,55
Renin-Angiotensin-Aldosterone System All blood samples were taken 24 to 26 h postdose and after over night fasting. Plasma Renin Activity Plasma renin activity (PRA) was measured by radioimmunoassay (RIA) according to the method of Giese et a l . Inactivation of the angiotensinases was achieved by a dialysis of the plasma sample, ie, after incubation angiotensin I (Al) was extracted by means of SP Sephadex (Pharmacia LKB Biotechnology, Upsala, Sweden) and the eluate was used for the assay. Separation of the bound fraction was achieved with G-25 Sephadex. The inter assay coefficient of variation was 8 . 8 % and the normal range between 0.2 and 2 ng/ mL/h. 56
Converting Enzyme Activity Plasma angiotensin converting enzyme (ACE, U) was determined by RIA, in which the enzyme mediates the cleavage of a synthetic substrate, H-hippuryl-glycyl-glycine, into H-hippuric acid and the dipeptide. The assay kit used was ACEDirekt (Buhlman Laboratories AG, Basel, Switzerland). 3
expressed as //mol/mol/24 h. We compared the aldos terone to creatinine content of the urine to compensate for minor errors in urine collection. The creatinine con tent of the urine was unchanged between baseline and 6 months (P = .5). Aldosterone and creatinine levels were determined with commercially available radioimmuno assay kits (Serono Inc., Geneva, Switzerland). Statistics Data are reported as the arithmetic mean ± SEM. Within-group comparisons and between-group comparisons have been made with Pitman's nonparametric distribution-free permutation test. Data con cerned with structural changes and hemodynamics have been reported previously " ; therefore, only the percentage changes and relevant Ρ values (tested with Pitman's nonparametric permutation test) are given here. Pearson correlation coefficients for univariate analyses were calculated when appropriate. All tests were two-sided. Ρ < .05 was considered statistically sig nificant. To determine which of the independent variables — age, therapy, or change in PRA, ACE, All, Aldosterone, MAP, and TPR—were of importance for the changes in structural cardiovascular dependent vari ables, stepwise regression analyses were performed. Each of the dependent structural cardiovascular v a r i a b l e s — R ^ , IROAW, VI, LVM, PWT, IVST, and RWT—were analyzed for all patients (n = 28) as well as for each therapy group separately. 60
42
After 6 months of therapy the average doses of enalapril and hydrochlorothiazide given to patients were 35 and 53 mg, respectively. Average supine blood pressure was reduced from 153/103 to 133/88 mm Hg and from 154/102 to 147/94 mm Hg on enalapril and hydro-
TABLE 1. THE RENIN-ANGIOTENSINALDOSTERONE SYSTEM (RAAS)
3
58
59
Aldosterone Urine was collected during 24 h from 08:00 to 08:00 the following day. The collection of urine was started when the patient had emptied his bladder in the morning and ended with inclusion of the overnight urine the following day. The aldosterone excretion was related to the creatinine content of the urine and was
44
RESULTS
Randomized to
57
Angiotensin II Angiotensin II (A II) was measured by RIA according to a modification of the method of Kappelgaard et a l . using Sep-Pak as described by Morton and W e b b . Cross-reaction to Al was not detectable ( < 2 % ) . The within-assay variation was 1 1 % and the normal range between 5 and 15 pg/mL.
5, NO. 12, PART 1
Enalapril η = 14 PRA (ng/mL/h) ACE (U) All(pg/mL) Aldosterone (μπαοΙ/πΊοΙ creatinine/ 24 h)
0.99 (0.24) 35.3 (3.5) 5.5 (0.8) 3.7 (0.6)
Hydrochloro thiazide η = 14 0.68 (0.11) 40.2 (3.2) 5.9 (0.9) 3.6 (0.3)
All η = 28 0.84 (0.13) 37.8 (2.4) 5.7 (0.6) 3.6 (0.3)
Mean values (SEM) at baseline for patients randomized to the two treat ment groups are given. Measurements made 24 to 26 h after intake of a placebo tablet. There were no significant differences between treatment groups.
Downloaded from https://academic.oup.com/ajh/article-abstract/5/12_Pt_1/900/175959 by Universitaetsbibliothek Muenchen user on 06 February 2019
The vascular changes of the retina were evaluated from eyeground photos by an experienced retinal sur geon who was not aware of the sequence of photos, treatment, blood pressure, or any other pertinent patient data. A new refined scale from 0 to 4 was used for classification of increased reflection of the arterial wall (IROAW), narrowing of arteries, arteriovenous com pression, and a scale from 0 to 12 for the combination of all three, referred to as the vascular index (VI). Cardiac morphology was investigated with 2Dguided, M-mode echocardiography according to the guidelines of the American Society of Echocardiogra phy (ASE). Posterial wall thickness (PWT), interven tricular septal thickness (IVST), and left ventricular inner diameter (LVID) in diastole were measured by two independent observers blinded for treatment. Rela tive wall thickness (RWT) was calculated according to the formula: RWT = PWT + IVST/LVID. Left ven tricular mass (LVM) was calculated using a validated formula.
1992-VOL
AJH-DECEMBER
1992-VOL
[
5, NO. 12, PART 1
I Enalapril
903
RAAS AND CV STRUCTURE
Hydrochlorothiazide
% 10
150
MAP
Rmin
TPR
Aldosterone
All
ACE
J
100
*
50
n.s. n.s. -10 n.s. -50 -15 -100
J
p=0.0000
p=0.0054
.0070
-17% * p=0.0151
|
p=0.0105
FIGURE 1. Percentage changes in PRA, ACE, All, and Aldos-20 terone (24 to 26 h postdose) from baseline to 6 months of treatment with enalapril (n = 14) and hydrochlorothiazide (n = 14) respec tively. PRA — plasma renin activity, ACE = angiotensin convert Hydrochlorothiazide Enalapril ing enzyme activity, All = angiotensin II, aldosterone = aldosterone in urine in relation to creatinine. Change from FIGURE 2. Percentage change in TPR, MAP, and R of the baseline: *P
1992;5:900-911
The Importance of the Renin-Angiotensin-Aldosterone System*
Bjorn Dahldf, Hans Herlitz, Mattias Aurell, and Lennart
Our study attempted to evaluate the importance of changes in the circulating renin-angiotensinaldosterone system (RAAS) and in hemodynamics in relation to observed changes in cardiovascular structure. We studied previously untreated men (n = 28) with essential nonmalignant hypertension and a supine casual diastolic blood pressure > 95 mm Hg on three to four separate ( > 1-week interval) occasions measured in triplicate. We used intraarterial blood pressure, dye-dilution technique, plethysmography (hands), eye-ground photos, Mmode echocardiography, radio immunoassays, and multiple regression analysis. Patients were randomized to 6 months of double-blind treatment with either enalapril or hydrochlorothiazide, following 4 to 6 weeks on placebo. We found that enalapril blocked the plasma angiotensin converting enzyme (ACE) with a secondary increment in plasma renin activity (PRA) and reductions in angiotensin II (AH) and aldosterone. Blood pressure was lowered through a reduction in total peripheral resistance (TPR). Hydrochlorothiazide increased PRA, All, and aldosterone, and lowered blood pressure mainly through a reduction in cardiac output. Enalapril was significantly more effective than hydrochlorothiazide in reversing struc-
*See also the editorial on page 923 of this issue. Received February 20, 1992. Accepted September 1, 1992. From the Department of Medicine, University of Goteborg, Ostra Hospital, Goteborg, Sweden (BD, LH); and the Department of Nephrology, University of Goteborg, Sahlgren's Hospital, Goteborg, Sweden (HH, MA). This study was supported in part by The Swedish Hypertension Society and Merck, Sharp, and Dahme AB, Sweden. Address correspondence and reprint requests to Bjorn Dahlof, MD, Department of Medicine, University of Goteborg, S-416 85 Goteborg, Sweden. © 2992 by the American Journal of Hypertension, Inc.
Hansson
tural changes in the retinal and hand vasculature as well as in the heart. A reduction in cardiac hypertrophy was seen even in the occasional enalapriltreated patient, in whom little or no reduction in blood pressure occurred. In the stepwise regression analyses, the changes in retinal and hand vascular structure were most strongly related to various changes in the RAAS, explaining 15 to 34% of the variance. For the changes in cardiac structure, the type of therapy (enalapril or hydrochlorothiazide) appeared to be the most important factor, explaining between 29 and 50% of the variance. The changes in cardiac structure were even more strongly related to changes in the RAAS for the enalapril treated patients and explained up to 55% of the variance in cardiac structure. It can be concluded that the reversal of structural vascular changes during antihypertensive therapy was more dependent on the blockade of the RAAS than on lowering of the blood pressure. Am J Hypertens 1992;5:900-911
KEY WORDS: Structural vascular changes, cardiac hypertrophy, blood pressure, renin-angiotensinaldosterone system.
S
tructural cardiovascular changes in hypertension are important from a pathogenetic point of view. They are also powerful markers of the increased risk of complications in hypertens i o n . It is also interesting to note that not only blood pressure, but the renin status has been linked to vascular injury and impairment of prognosis. As to the pathogenetic aspects, increased medial thickness of the resistance vessels, which is a character1,2
1-5
6
7
0895-7061/92/$5.00
Downloaded from https://academic.oup.com/ajh/article-abstract/5/12_Pt_1/900/175959 by Universitaetsbibliothek Muenchen user on 06 February 2019
Reversal of Cardiovascular Structural Changes When Treating Essential Hypertension
AJH-DECEMBER
1992-VOL
5, NO. 12, PART 1
R A A S AND CV STRUCTURE
1,2
8,11
12-25
1,2,9-11,26
27
cardiovascular changes have previously been reported. There was a tendency toward a more effective reduction in blood pressure with enalapril; however, the difference between therapies was not significant. Enalapril was significantly more effective than hydrochlorothiazide in reversing structural vascular changes in the retina and in the hand, as well as cardiac hypertrophy. Because enalapril and hydrochlorothiazide affect the RAAS differently, the present analysis was performed to evaluate the importance of the changes in the circulating RAAS and of hemodynamics in relation to the changes in structural vascular changes in the hand and retina as well as in left ventricular mass and wall thickness. The study was approved by the Ethics Committee of the University of Goteborg and performed according to the Declaration of Helsinki. All patients had given their written and oral consent to participate. 42-44
42-44
PATIENTS AND M E T H O D S
27-31
32
33-34
Hydralazine can inhibit the pressor effect and the cardiac hypertrophy induced by All (infused in a slow pressor dose in rats), suggesting a predominant pressor mechanism for the cardiac hypertrophic response. However, hydralazine does not inhibit the development of All-induced structural vascular changes, suggesting that at least part of the vascular effect is not pressure dependent. This dissociation of the hypertrophic response in heart and vessels could result from reninangiotensin mediated effects. Thus, cardiac myocyte growth appears to be predominantly pressure dependent, while cardiac interstitial fibrous tissue responds instead to angiotensin and aldosterone. While circulating renin-angiotensin-aldosterone appears to be the main humoral influence affecting cardiac and vascular tissue responses, a local tissue renin system has also been proposed, but not v e r i f i e d . As for the importance of the circulating RAAS as a predicting factor of cardiovascular morbidity and mortality, both retrospective and prospective studies have demonstrated a relationship between renin status and risk. The link between renin and cardiovascular risk becomes especially interesting in view of the strong risk prediction offered by left ventricular hypertrophy on the one h a n d and the association between the RAAS and cardiovascular h y p e r t r o p h y on the other. To further elucidate the importance of the RAAS in relation to cardiovascular structure, we attempted the present analysis in previously untreated hypertensive men. They all had mild to moderate essential hypertension and were randomized to double-blind treatment with either enalapril or hydrochlorothiazide in monotherapy. The changes in hemodynamics and structural 35
36
37
38,84-86
40,41
3,5
27-36
Design The study was double-blind, randomized, and performed in previously untreated white hypertensive men. It included 28 patients with a mean age of 46 years (SEM 2.1), a mean weight of 86 kg (1.9) and a body mass index of 27 kg/m (0.6). After 4 to 6 weeks on placebo, the patients were randomized to enalapril or hydrochlorothiazide in monotherapy if their diastolic blood pressure (DBP) was > 95 mm Hg on three to four occasions with at least 1 week in between. Blood pressure was measured in triplicate on each occasion with a mercury sphygmomanometer and an appropriate cuff size. Korotkoff phases 1 and 5 were taken as the systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively. There were no significant differences between the two treatment groups in the baseline characteristics as previously reported. 2
42-44
Hemodynamics and Structural Vascular Changes The patients underwent an extensive invasive hemodynamic, plethysmographic, cardiac, and eyeground investigation at placebo baseline and after 6 months of active therapy, as previously described in detail. " In brief, blood pressure was recorded intraarterially through an indwelling arterial catheter. Mean arterial blood pressure (MAP) was obtained by electrical dampening. The mean of at least five measurements recorded during 1 h was used for calculations. Cardiac output (CO) was measured with the dyedilution technique and total peripheral resistance (TPR) was calculated based upon CO and M A P . " Minimal resistance in the hands ( R ^ ) was derived from maximal blood flow recorded with water plethysmography at ischemia induced by heating, arterial occlusion, and work until exhaustion. " 42
44-46
4 4 , 4 7
44,51
53
5 0
44
Downloaded from https://academic.oup.com/ajh/article-abstract/5/12_Pt_1/900/175959 by Universitaetsbibliothek Muenchen user on 06 February 2019
istic feature of established hypertension, may be both a consequence and a contributory cause of high blood pressure. The blood pressure amplification caused by cardiovascular hypertrophy may be of greater quantitative importance in maintaining blood pressure elevation than are basic underlying (eg, endocrine or renal) mechanisms. In fact, structural cardiovascular changes participate in a vicious circle not only by maintaining an elevated blood pressure, but also by causing progression to more severe hypertension. Furthermore, both experimental and clinical studies have shown that lowering of increased blood pressure is not the sole factor needed to achieve regression of cardiovascular h y p e r t r o p h y . The importance of the renin-angiotensin-aldosterone system (RAAS) in this context is of great interest. It has been suggested that the structural cardiovascular amplifying mechanisms are activated, or at least modulated, by trophic f a c t o r s . Angiotensin II (All), a powerful vasoconstrictor also has growth stimulating properties. Thus, in experimental studies All has mitogenic properties and promotes the growth of both human and rat cultured vascular smooth muscle c e l l s , fibroblasts, and cardiac m y o c y t e s .
901
902
DAHLOF ET AL
AJH-DECEMBER
42
54
43,55
Renin-Angiotensin-Aldosterone System All blood samples were taken 24 to 26 h postdose and after over night fasting. Plasma Renin Activity Plasma renin activity (PRA) was measured by radioimmunoassay (RIA) according to the method of Giese et a l . Inactivation of the angiotensinases was achieved by a dialysis of the plasma sample, ie, after incubation angiotensin I (Al) was extracted by means of SP Sephadex (Pharmacia LKB Biotechnology, Upsala, Sweden) and the eluate was used for the assay. Separation of the bound fraction was achieved with G-25 Sephadex. The inter assay coefficient of variation was 8 . 8 % and the normal range between 0.2 and 2 ng/ mL/h. 56
Converting Enzyme Activity Plasma angiotensin converting enzyme (ACE, U) was determined by RIA, in which the enzyme mediates the cleavage of a synthetic substrate, H-hippuryl-glycyl-glycine, into H-hippuric acid and the dipeptide. The assay kit used was ACEDirekt (Buhlman Laboratories AG, Basel, Switzerland). 3
expressed as //mol/mol/24 h. We compared the aldos terone to creatinine content of the urine to compensate for minor errors in urine collection. The creatinine con tent of the urine was unchanged between baseline and 6 months (P = .5). Aldosterone and creatinine levels were determined with commercially available radioimmuno assay kits (Serono Inc., Geneva, Switzerland). Statistics Data are reported as the arithmetic mean ± SEM. Within-group comparisons and between-group comparisons have been made with Pitman's nonparametric distribution-free permutation test. Data con cerned with structural changes and hemodynamics have been reported previously " ; therefore, only the percentage changes and relevant Ρ values (tested with Pitman's nonparametric permutation test) are given here. Pearson correlation coefficients for univariate analyses were calculated when appropriate. All tests were two-sided. Ρ < .05 was considered statistically sig nificant. To determine which of the independent variables — age, therapy, or change in PRA, ACE, All, Aldosterone, MAP, and TPR—were of importance for the changes in structural cardiovascular dependent vari ables, stepwise regression analyses were performed. Each of the dependent structural cardiovascular v a r i a b l e s — R ^ , IROAW, VI, LVM, PWT, IVST, and RWT—were analyzed for all patients (n = 28) as well as for each therapy group separately. 60
42
After 6 months of therapy the average doses of enalapril and hydrochlorothiazide given to patients were 35 and 53 mg, respectively. Average supine blood pressure was reduced from 153/103 to 133/88 mm Hg and from 154/102 to 147/94 mm Hg on enalapril and hydro-
TABLE 1. THE RENIN-ANGIOTENSINALDOSTERONE SYSTEM (RAAS)
3
58
59
Aldosterone Urine was collected during 24 h from 08:00 to 08:00 the following day. The collection of urine was started when the patient had emptied his bladder in the morning and ended with inclusion of the overnight urine the following day. The aldosterone excretion was related to the creatinine content of the urine and was
44
RESULTS
Randomized to
57
Angiotensin II Angiotensin II (A II) was measured by RIA according to a modification of the method of Kappelgaard et a l . using Sep-Pak as described by Morton and W e b b . Cross-reaction to Al was not detectable ( < 2 % ) . The within-assay variation was 1 1 % and the normal range between 5 and 15 pg/mL.
5, NO. 12, PART 1
Enalapril η = 14 PRA (ng/mL/h) ACE (U) All(pg/mL) Aldosterone (μπαοΙ/πΊοΙ creatinine/ 24 h)
0.99 (0.24) 35.3 (3.5) 5.5 (0.8) 3.7 (0.6)
Hydrochloro thiazide η = 14 0.68 (0.11) 40.2 (3.2) 5.9 (0.9) 3.6 (0.3)
All η = 28 0.84 (0.13) 37.8 (2.4) 5.7 (0.6) 3.6 (0.3)
Mean values (SEM) at baseline for patients randomized to the two treat ment groups are given. Measurements made 24 to 26 h after intake of a placebo tablet. There were no significant differences between treatment groups.
Downloaded from https://academic.oup.com/ajh/article-abstract/5/12_Pt_1/900/175959 by Universitaetsbibliothek Muenchen user on 06 February 2019
The vascular changes of the retina were evaluated from eyeground photos by an experienced retinal sur geon who was not aware of the sequence of photos, treatment, blood pressure, or any other pertinent patient data. A new refined scale from 0 to 4 was used for classification of increased reflection of the arterial wall (IROAW), narrowing of arteries, arteriovenous com pression, and a scale from 0 to 12 for the combination of all three, referred to as the vascular index (VI). Cardiac morphology was investigated with 2Dguided, M-mode echocardiography according to the guidelines of the American Society of Echocardiogra phy (ASE). Posterial wall thickness (PWT), interven tricular septal thickness (IVST), and left ventricular inner diameter (LVID) in diastole were measured by two independent observers blinded for treatment. Rela tive wall thickness (RWT) was calculated according to the formula: RWT = PWT + IVST/LVID. Left ven tricular mass (LVM) was calculated using a validated formula.
1992-VOL
AJH-DECEMBER
1992-VOL
[
5, NO. 12, PART 1
I Enalapril
903
RAAS AND CV STRUCTURE
Hydrochlorothiazide
% 10
150
MAP
Rmin
TPR
Aldosterone
All
ACE
J
100
*
50
n.s. n.s. -10 n.s. -50 -15 -100
J
p=0.0000
p=0.0054
.0070
-17% * p=0.0151
|
p=0.0105
FIGURE 1. Percentage changes in PRA, ACE, All, and Aldos-20 terone (24 to 26 h postdose) from baseline to 6 months of treatment with enalapril (n = 14) and hydrochlorothiazide (n = 14) respec tively. PRA — plasma renin activity, ACE = angiotensin convert Hydrochlorothiazide Enalapril ing enzyme activity, All = angiotensin II, aldosterone = aldosterone in urine in relation to creatinine. Change from FIGURE 2. Percentage change in TPR, MAP, and R of the baseline: *P
