CLINICAL RESEARCH: HYPERTENSION
Olmesartan, But Not Amlodipine, Improves Endothelium-Dependent Coronary Dilation in Hypertensive Patients
Masanao Naya, MD*,
Takahiro Tsukamoto, MD*, ,
Koichi Morita, MD ,
Chietsugu Katoh, MD ,
Tomoo Furumoto, MD*,
Satoshi Fujii, MD*,
Nagara Tamaki, MD and
Hiroyuki Tsutsui, MD*,*
* Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Department of Health Science, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Department of Cardiovascular Medicine, Date Red Cross Hospital, Date, Japan
Manuscript received April 10, 2007;
revised manuscript received May 24, 2007,
accepted June 11, 2007.
* Reprint requests and correspondence: Dr. Hiroyuki Tsutsui, Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan. (Email: htsutsui{at}med.hokudai.ac.jp).
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Abstract
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Objectives: We aimed to compare the effects of the angiotensin II receptor blocker (ARB) olmesartan versus the calcium channel blocker (CCB) amlodipine on coronary endothelial dysfunction in patients with hypertension.
Background: Angiotensin II receptor blockers are thought to have greater beneficial effects than CCBs on coronary vasomotion by directly blocking action of angiotensin II.
Methods: Twenty-six patients with untreated essential hypertension were prospectively assigned to treatment with either olmesartan (27.7 ± 12.4 mg/day, n = 13) or amlodipine (5.6 ± 1.5 mg/day, n = 13) for 12 weeks. Changes of corrected myocardial blood flow ( MBF) and coronary vascular resistance (CVR) from rest to cold pressor were measured by using 15O-water and positron emission tomography before and after treatment. Blood biomarkers including lipids, glucose, insulin, high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and superoxide dismutase (SOD) were also measured.
Results: Olmesartan and amlodipine reduced blood pressure (BP) to the same extent (–28.7 ± 16.2 mm Hg vs. –26.7 ± 10.8 mm Hg). In the olmesartan group, MBF tended to be greater (–0.15 ± 0.19 ml/g/min vs. 0.03 ± 0.17 ml/g/min, p = 0.09 by 2-way analysis of variance), and CVR was significantly decreased (7.9 ± 23.5 mm Hg/[ml/g/min] vs. –16.6 ± 18.0 mm Hg/[ml/g/min], p < 0.05) after treatment, whereas these parameters did not change in the amlodipine group (MBF: –0.15 ± 0.12 ml/g/min vs. –0.12 ± 0.20 ml/g/min; CVR: 6.5 ± 18.2 mm Hg/[ml/g/min] vs. 4.8 ± 23.4 mm Hg/[ml/g/min]). Serum SOD activity tended to increase (4.74 ± 4.77 U/ml vs. 5.57 ± 4.74 U/ml, p = 0.07 by 2-way analysis of variance) only in the olmesartan group.
Conclusions: Olmesartan, but not amlodipine, improved endothelium-dependent coronary dilation in hypertensive patients independent of BP reduction. These beneficial effects on coronary vasomotion might be via an antioxidant property of ARBs.
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Abbreviations and Acronyms
| | ARB = angiotensin II receptor blocker | | BP = blood pressure | | CCB = calcium channel blocker | | CPT = cold pressor test | | CVR = coronary vascular resistance | | HOMA-IR = homeostasis model assessment for insulin resistance | | IL = interleukin | | MBF = myocardial blood flow | | 15O-water = oxygen-15–labeled water | | PET = positron emission tomography | | RPP = rate pressure product | | SOD = superoxide dismutase | | TNF = tumor necrosis factor |
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Hypertension is a major risk factor of coronary artery disease (1). In hypertensive patients, coronary vasodilator response is impaired (2), which is caused not only by the elevation of blood pressure (BP) but also by inflammation and oxidative stress in the vascular wall induced by angiotensin II (3,4).
Angiotensin II receptor blockers (ARB) and calcium channel blockers (CCB) are highly used in the treatment of hypertension. Angiotensin receptor blockers have been demonstrated to reduce inflammation (5) and oxidative stress (4) via directly blocking the action of angiotensin II. Therefore, the effects of antihypertensive drugs on endothelial function may differ between ARB and CCB.
Myocardial blood flow (MBF) could be measured by using oxygen-15–labeled (15O)-water positron emission tomography (PET). Myocardial blood flow and coronary vascular resistance (CVR) response to cold pressor test (CPT) are feasible and repeatable variables for the noninvasive evaluation of coronary endothelium-dependent function (6,7). The severity of coronary endothelial dysfunction has been demonstrated to be associated with the risk of developing cardiovascular events and poor prognosis (8). Thus, this study was performed to compare the effects of ARB and CCB on endothelium-dependent coronary dilation in patients with essential hypertension. Furthermore, the relation between blood biomarkers and coronary endothelial function was also evaluated.
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Materials and Methods
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Patients.
Twenty-six consecutive untreated and uncomplicated patients with essential hypertension (12 men and 14 women; age 53.7 ± 11.0 [± SD] years) were studied from December 2004 to March 2006. They had systolic BP over 140 mm Hg and/or diastolic BP over 90 mm Hg by mercury sphygmomanometer, measured twice with an interval of 1 month. Patients with a history or clinical evidence of recent infection, malignancies, coronary artery disease, peripheral vascular disease, cerebrovascular disease, secondary hypertension, diabetes mellitus with hemoglobin A1c >5.8%, hyperlipidemia with total cholesterol >260 mg/dl, wall motion abnormalities by echocardiography, or receiving medications were excluded. The patients were prospectively assigned to antihypertensive treatment with either olmesartan (27.7 ± 12.4 mg/day, n = 13) or amlodipine (5.6 ± 1.5 mg/day, n = 13) for 12 weeks.
Informed consent was obtained from each study patient. The study was approved by the institutional ethical committee, and the procedures were in accordance with institutional guidelines.
Treatment protocol.
Blood pressure was measured before and 4, 8, and 12 weeks after treatment. At least 2 measurements were made and the mean values of these measurements were used. Patients had either 20-mg olmesartan or 5-mg amlodipine daily. If systolic BP was  140 mm Hg or diastolic BP was 90 mm Hg after 1 month, the dose was doubled to 40-mg olmesartan or 10-mg amlodipine. If systolic BP was <110 mm Hg after 1 month, the dose was halved to 10-mg olmesartan or 2.5-mg amlodipine. No adverse effects of antihypertensive drugs were experienced.
Blood chemical analysis.
Blood samples were obtained at the time of PET scans. Serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, blood sugar, insulin, high-sensitivity C-reactive protein (hs-CRP), superoxide dismutase (SOD) activity, plasma interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha were measured. Homeostasis model assessment for insulin resistance (HOMA-IR) was calculated: HOMA-IR = fasting blood sugar x insulin/405.
Echocardiography.
Left ventricular mass index was measured using the M-mode guided echocardiogram according to the method recommended by the American Society of Echocardiography.
PET scans.
Myocardial blood flow at rest and during CPT were determined using 15O-water and PET before and after treatments. All patients abstained from caffeine-containing beverages for at least 24 h and from smoking for at least 12 h before the PET study. All PET scans were performed with ECAT EXACT HR+ (Siemens/CTI, Knoxville, Tennessee) by modified methods as previously reported (9). Cold pressor test was performed as follows. The patient's right foot was immersed in ice water up to the ankle. Sixty seconds later, PET scanning of 15O-water was started, and the CPT was continued for 4 min.
Reconstruction of emission sinograms and quantification of MBF using a semiautomatic program were performed according to methods previously reported (10).
Myocardial blood flow was corrected against rate pressure product (RPP) to account for individual differences in cardiac work as follows (9); MBF was divided by RPP and multiplied by 7,500, which is the average RPP at rest of healthy controls with age of 50.1 ± 9.7 years.
The MBF, an index of coronary endothelial function, was calculated as corrected MBF during CPT minus corrected MBF at rest (11). Coronary vascular resistance was calculated by dividing mean BP by MBF to exclude the effects of coronary perfusion pressure as previously reported (11). Coronary vascular resistance during CPT was also used as an index of coronary endothelial function (8,11). The CVR was calculated as CVR during CPT minus CVR at rest.
Statistical analyses.
All data were expressed as mean ± SD. Baseline characteristics between groups were compared by an unpaired t test. Within treatment groups, the changes of corrected MBF and CVR from rest to CPT were compared by a paired t test. Between-group comparisons with regard to hemodynamic, blood biomarkers, RPP, MBF, and CVR before and after treatment were performed by 2-way analysis of variance (ANOVA) with repeated measures, followed by Scheffé's test if the interaction was significant. Univariate analysis of the association between serum SOD activity and CVR during CPT was performed with the use of linear regression. A p < 0.05 was considered to be statistically significant.
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Results
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Study patients.
Table 1
shows the baseline clinical characteristic data for the study patients. Both olmesartan and amlodipine reduced BP 12 weeks after treatment (p = 0.51 by 2-way ANOVA with repeated measures) (Table 2), and the extent of BP reduction was the same between groups (–28.7 ± 16.2 mm Hg vs. –26.7 ± 10.8 mm Hg, p = 0.71).
MBF response to CPT.
The increase in RPP from rest to CPT was comparable before and after treatment between groups (olmesartan: 2,410 ± 1,823 mm Hg/min vs. 2,523 ± 1,528 mm Hg/min; amlodipine: 2,925 ± 1,298 mm Hg/min vs. 2,639 ± 1,504 mm Hg/min, p = 0.49 by 2-way ANOVA with repeated measures). Before treatment, corrected MBF was significantly decreased from rest to CPT in both groups. After treatment, corrected MBF did not change from rest to CPT in olmesartan group, whereas it tended to decrease in amlodipine group (Fig. 1). Corrected MBF during CPT was significantly increased after treatment in the olmesartan group but not in the amlodipine group (Fig. 1). The increase of MBF tended to be greater in the olmesartan group than in amlodipine group (p = 0.09 by 2-way ANOVA with repeated measures) (Fig. 2).
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Figure 1 Corrected MBF in Response to CPT Before and After Treatment
Corrected myocardial blood flow (MBF) in response to cold pressor test (CPT) before and after treatment with olmesartan (n = 13; left panel) and amlodipine (n = 13; right panel). The central bar on the vertical bars represents the mean ± SD.
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CVR response to CPT.
Before treatment, CVR did not change from rest to CPT in either group. After treatment, CVR significantly decreased from rest to CPT in the olmesartan group, but not in the amlodipine group (Fig. 3). Coronary vascular resistance during CPT significantly decreased after treatment in the olmesartan group, but not in the amlodipine group. The decrease of CVR was significantly greater in the olmesartan group than in the amlodipine group (p < 0.05 by 2-way ANOVA with repeated measures) (Fig. 4). The CVR significantly decreased after olmesartan but not after amlodipine (Fig. 4).
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Figure 3 CVR in Response to CPT Before and After Treatment
The coronary vascular resistance (CVR) in response to cold pressor test (CPT) before and after treatment with olmesartan (n = 13; left panel) and amlodipine (n = 13; right panel). The central bar on the vertical bars represents the mean ± SD.
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Blood biochemical markers.
Blood biomarkers including total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, blood sugar, insulin, HOMA-IR, TNF-alpha, IL-6, and hs-CRP were comparable between groups (Table 3). Serum SOD tended to increase in the olmesartan group compared with the amlodipine group (p = 0.07 by 2-way ANOVA with repeated measures). There was a significant negative correlation between the changes in serum SOD activity and CVR during CPT in the olmesartan group, whereas no such correlation was observed in the amlodipine group (Fig. 5).
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Figure 5 Relationship Between the Changes of CVR During CPT and Serum SOD Activity After Treatment
Relationship between the changes in CVR during CPT and serum superoxide dismutase (SOD) activity after treatment with olmesartan (n = 13) (A) and amlodipine (n = 13) (B). Abbreviations as in Figure 3.
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Discussion
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The present study demonstrated that 12-week treatment of hypertensive patients with olmesartan, but not amlodipine, improved endothelium-dependent coronary dilation despite comparable BP reduction. Serum SOD activity tended to increase only in the olmesartan group. Notably, there was a significant relationship between the improvement of coronary endothelial dysfunction and the increase in serum SOD by olmesartan.
Previous studies (12) demonstrated that CCB improves the vasodilation of the epicardial coronary arteries in hypertensive patients. However, in the case of nonobstructed coronary arteries, MBF is not regulated by the conduit epicardial coronary arteries, but rather by the coronary microcirculation, as is the largest part of the resistance of the coronary tree. Therefore, the present study suggested that ARB, but not CCB, might improve the endothelial function in coronary microcirculation, which is most prone to be affected by damaging cardiovascular risk factors such as hypertension (2). Consequently, any treatment strategy mostly targeting coronary microcirculation would be expected to prevent early episodes of myocardial ischemia by keeping coronary resistance as low as possible during high flow demand situations. The present study has thus provided direct evidence to suggest that ARB has such beneficial effects on coronary microcirculation.
Some groups previously reported the similar effects of angiotensin-converting enzyme inhibitors on MBF in response to dipyridamole (13). However, they compared the effects of angiotensin-converting enzyme inhibitors to those by placebo, which did not allow us to comment on any effects beyond BP lowering. In addition, a previous study (14) found a beneficial effect of an ACE inhibitor (lisinopril) but not ARBs (losartan) on MBF response to dipyridamole. However, first, not all ARBs have the same effects on coronary microcirculation (i.e., olmesartan seems to have such an effect, but not losartan). Second, the present study used the CPT, which is an established stimulus mostly dependent on endothelial function (6,7,11), whereas the previous study used dipyridamole, which is less endothelium-dependent.
The present study demonstrated that the augmentation of serum SOD by olmesartan might be involved in the improvement of coronary endothelial function. In addition, ARB can directly inhibit angiotensin II-mediated superoxide production (15). These results suggest that the antioxidant effects of olmesartan are specific for this ARB and differ from unspecific effects of vitamin C. More importantly, these effects of olmesartan can explain the contrasting results, in which ARB losartan failed to improve MBF response to dipyridamole (14), whereas olmesartan could exert beneficial effects on coronary microcirculation, as seen in the present study.
Study limitations.
First, the present study was not a blinded, randomized study. However, the characteristics of the study patients were well matched between the 2 groups (Tables 1 to 3). Importantly, MBF, CVR, and blood biomarkers were measured and analyzed by another group of investigators who were blinded to the treatment groups. Second, central BP measurement, as in the CAFE (Conduit Artery Function Evaluation) study (16), which might affect MBF more effectively than peripheral BP, was not available in the present study. Therefore, a further study is clearly needed to evaluate the relation between the central BP and MBF.
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Conclusions
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The ARB olmesartan, but not the CCB amlodipine, improved endothelium-dependent coronary dilation assessed by 15O-water PET in hypertensive patients independent of BP lowering. These beneficial effects might contribute to the cardioprotective benefits of ARB in the treatment of hypertension, which warrants further investigation.
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Acknowledgments
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The authors are grateful to Dr. Eiji Yoshioka for expert technical assistance of statistical analysis.
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Footnotes
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This research was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, and from Daiichi Sankyo Co. Ltd., and by the Research Grant for Cardiovascular Diseases (16C-8) from the Ministry of Health, Labour, and Welfare, Japan.
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References
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Abstract
Materials and Methods
