(Hypertension. 1997;29:286.)
© 1997 American Heart Association, Inc.
Arthur C. Corcoran Memorial Lecture |
Converting Enzyme Inhibitor Improves Forearm Reactive Hyperemia in Essential Hypertension
From the Department of Cardiology, Higashiosaka Municipal Central Hospital (H.I., M.N., T.S., K.K., R.M., T.H.), and the Department of Geriatric Medicine, Osaka University Medical School (J.H., T.O.), Japan.
Correspondence to Masahiro Nagano, MD, Head of the Department of Cardiology Higashiosaka Municipal Central Hospital 2-3-1 Mikuriyaminami, Higashiosaka 577 Japan. E-mail nagano{at}geriat.med.osaka-u.ac.jp
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Abstract |
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Endothelial function is known to be impaired in essential hypertensive patients. In this study, we examined whether antihypertensive drugs improve forearm vasodilatory response to reactive hyperemia in 26 patients with essential hypertension (62±2 years) without diabetes mellitus, hyperlipidemia, coronary heart disease, or cerebrovascular disease. Antihypertensive drugs were never given or were discontinued for at least 4 weeks before the study. Patients were treated with monotherapy of either temocapril (2 or 4 mg, n= 15) or amlodipine (2.5 or 5 mg, n= 11) for 6 months. Forearm blood flow was measured by strain-gauge plethysmography. Vasodilator response to the release of upper arm compression at 300 mm Hg for 5 minutes and to sublingual administration of nitroglycerin (0.3 mg) were assessed. Changes of forearm blood flow response to reactive hyperemia were significantly less in hypertensive patients (99±18%) than in age-matched normotensive control subjects (150±22%, P<.01, n=39). Blood pressure (mm Hg) was similarly decreased by the treatment with temocapril (160±4/94±2 to 139±3/83±3, P<.001) or amlodipine (165±5/94±3 to 141±4/82±3, P<.001). Response to nitroglycerin was not changed by either drug. Forearm vasodilatory response to reactive hyperemia was improved by temocapril (102±20% to 168±25%, P<.01) but not by amlodipine (97±16% to 114±14%, NS). These results indicate that the treatment with the angiotensin-converting enzyme inhibitor temocapril improved forearm vasodilatory response to reactive hyperemia, suggesting its beneficial effect on endothelial function.
Key Words: amlodipine • antihypertensive drug • atherosclerosis • hyperemia • nitroglycerin • plethysmography • temocapril
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Introduction |
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Endothelial cells play a pivotal role in the modulation of vascular tone by releasing vasoactive substances, such as endothelin, prostaglandin, and endothelium-derived relaxing factor (EDRF).1,2 In the early stage of atherogenesis, endothelial cell function is known to be disturbed.3 This results in impairment of the vasodilator response to acetylcholine, which requires intact endothelial function.4 There is considerable evidence that the endothelium-dependent vasodilation is impaired in human essential hypertension.5–10 The effects of various antihypertensive drugs on hypertension-induced endothelial dysfunction have been examined widely. In animal studies, angiotensin-converting enzyme (ACE) inhibitors have been shown to improve endothelial function.11–14 However, in human hypertension, the results are not consistent; several investigators demonstrated that ACE inhibitors improved endothelial dysfunction in hypertensive patients,15–17 while others failed to show an improvement.18,19 The effect of calcium antagonists has not been fully examined except in rats13 and an acute human study.16 Celermajer et al20 evaluated endothelial function by Doppler system in the brachial and femoral arteries during reactive hyperemia and after sublingual administration of nitroglycerin. Both procedures induce vasodilation; however, the former is partly mediated by EDRF,21,22 while the latter acts directly on smooth muscle cells. In this study, we used Celermajor's method with modification to evaluate the effects of an ACE inhibitor, temocapril, and a calcium antagonist, amlodipine, on forearm vasodilator response in patients with essential hypertension. These drugs were given as monotherapy for 6 months in hypertensive patients without any overt clinical evidence of atherosclerosis.
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Methods |
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Subjects
The subjects were 26 patients with essential hypertension aged 52 to 80 years (mean±SEM, 62±2 years) and another 37 age- and sex-matched normotensive individuals as control. Hypertension was defined as systolic blood pressure at the outpatient department of 160 mm Hg or higher and/or diastolic blood pressure of 95 mm Hg or higher in the sitting position on at least three separate visits. Secondary hypertension was excluded by routine physical and laboratory examinations. Subjects with diabetes mellitus, dyslipidemia, arrhythmia, or cerebrovascular disease were excluded by clinical and laboratory examinations. Subjects suspected to have coronary artery disease from their clinical symptoms or electrocardiogram underwent coronary angiography and those with coronary artery disease were excluded from the study. Hypertensive patients were administered either temocapril (n=15, Sankyo Co Ltd) or amlodipine (n=11, Sumitomo Pharmaceuticals) once daily for 6 months. Initial dose was 2 mg for temocapril or 2.5 mg for amlodipine. When the blood pressure was not decreased by 20/10 mm Hg or to below 150/ 90 mm Hg, the dose of either drug was doubled. When blood pressure control was not achieved with monotherapy of either drug, the subject was excluded from the study. All patients had either never been treated (n=13) or had discontinued antihypertensive drugs such as ß-blocker (n=3), converting enzyme inhibitor (n=5), or calcium antagonist (n=5) for at least 4 weeks before the study.
Measurement of Forearm Blood Flow
The study was conducted in a temperature-controlled dark quiet room. Subjects rested for 15 minutes in the supine position before the study. Forearm blood flow was measured by strain-gauge plethysmography (model EC5R, DE Hokanson, Inc).23 A mercury-in-Silastic strain gauge that had been electrically calibrated was placed on the widest part of the forearm. The pressure of the collecting cuff was set at 40 mm Hg and occlusion pressure of the wrist cuff was 200 mm Hg or 20 mm Hg more than systolic blood pressure. After obtaining the baseline value of forearm blood flow, the upper arm was compressed by inflation of a pneumatic tourniquet at a pressure of 300 mm Hg for 5 minutes. At 60 and 90 seconds after cuff deflation, the second measurement was performed. At least 15 minutes after the last measurement, blood flow was measured to confirm that the blood flow had returned to the basal level. Then, nitroglycerin was sublingually administered at 300 µg by one puff of a spray device (Miokol Spray, Toa Eiyo). Then the measurement was repeated at 3, 4, and 5 minutes after the administration. This response was used as control. Forearm blood flow was recorded for 5 seconds and expressed as milliliters of blood flow per minute per 100 mL of fore-arm volume. Maximum changes in blood flow after both interventions were expressed as the percent change of the pretreatment values. The overall recordings were analyzed by the same investigator blinded to the subjects' background. Biochemical factors were measured in blood collected in the morning after overnight fasting. The study protocol was approved by the Ethical Committee. Informed consent was obtained from each subject before the study.
Statistical Analysis
Data are expressed as mean±SEM Differences between two groups were assessed by the unpaired t test with two tails, and those among groups were assessed by analysis of variance followed by Bonferroni's test. Differences of changes in blood pressure and vasodilator responses by the treatment with antihypertensive drugs were assessed by analysis of variance with repeated measurements. A value of P<.05 was regarded as significant.
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Results |
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Table 1 shows the background of study subjects. Compared with normotensive subjects, blood pressure and left ventricular mass index were higher in hypertensive groups, while these parameters were similar in the two hypertensive groups. Other factors were not different among the three groups (Table 1). Baseline values of forearm blood flow (milliliters per minute per 100 mL) were 4.4±0.3 in normotensive subjects, 4.9±0.3 in temocapril-treated, and 4.4±0.4 in amlodipine-treated hypertensive patients (NS). Administration of nitroglycerin induced a similar increase of forearm blood flow in normotensive subjects and hypertensive patients (Fig 1). However, forearm response to reactive hyperemia in hypertensive patients was significantly less than that in normotensive subjects (Fig 1). Blood pressure was well controlled by 2 mg (n=10) or 4 mg (n=5) temocapril, or 2.5 mg (n=5) or 5 mg (n=6) amlodipine. Treatment with monotherapy of either temocapril or amlodipine for 6 months produced a similar reduction of blood pressure and left ventricular mass index, while heart rate was not changed by either drug (Table 2) Vasodilator response to reactive hyperemia and nitroglycerin before treatment was similar between the two groups. Nitroglycerin-induced vasodilation was not altered by treatment with either drug (Fig 2). Forearm vascular response to reactive hyperemia was not changed by amlodipine but was significantly improved by temocapril (Fig 3).
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Discussion |
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Our results show that forearm vasodilator response to reactive hyperemia is impaired in patients with essential hypertension without any overt atherosclerotic disease or risk factors for atherosclerosis. In addition, forearm response to reactive hyperemia in hypertensive patients was improved by 6 months of treatment with an ACE inhibitor, temocapril, but not by a calcium antagonist, amlodipine. Impaired endothelial function in essential hypertensive patients has been demonstrated by several investigators5–8,18,24 including us.9,10 However, other reports showed preserved endothelial function in these patients.25,26 The reason for the difference between these studies is not clear. As discussed previously,26 heterogeneity of endothelial function may exist in hypertensive patients,27 and the background of subjects may also differ among studies. For example, we excluded patients with dyslipidemia who required drug treatment, resulting in a relatively lower level of total cholesterol in our normotensive subjects (4.9±0.2 mmol/L) than in another study (6.0±0.1 mmol/L).26 Therefore, the lack of difference in endothelial function between normotensive and hypertensive subjects in their study may have been due to mild hyperlipidemia in the normotensive subjects, which might have impaired endothelial function. Our data indicated that the ACE inhibitor temocapril improves forearm vascular response to reactive hyperemia, while amlodipine does not alter it. Treatment with amlodipine and temocapril produced similar blood pressure reduction at 6 months after the treatment. Both drugs are long-lasting antihypertensive drugs that are usually given once a day. Therefore, it is unlikely that the difference in the duration of normotension may explain the results obtained in this study.
The mechanism by which ACE inhibitor improves flow-mediated vasodilation is thought to be multifactorial. First, ACE inhibitors induce accumulation of bradykinin by inhibition of kininase II. Bradykinin causes the release of EDRF from endothelial cells. Treatment with ACE inhibitor may therefore increase the release of EDRF from endothelium.28,29 Second, ACE inhibitors are known to suppress the renin-angiotensin system not only in the circulation but also in the cardiovascular system, eg, the heart30 and vascular tissue.31 Angiotensin II is not only one of the most potent vasoconstrictors known but also stimulates the release of other vasoconstricting factors such as endothelin32 and prostaglandin H233 from endothelial cells. These data suggest that ACE inhibitors may improve vasomotor function by reducing levels of these vasoconstricting substances. Finally, angiotensin II is reported to increase the activity of vascular NADH oxidase in vitro34 and in vivo.35 This oxidase is a source of vascular superoxide which inactivates nitric oxide. Therefore, ACE inhibitors may reduce angiotensin II level and superoxide activity, resulting in the restoration of nitric oxide-mediated vasodilation.
Our results indicate that treatment with amlodipine has no effect on forearm response to reactive hyperemia in hypertensive patients. It is possible that the duration of amlodipine treatment was not sufficient to cause beneficial effects on endothelial cells. However, it has been reported that EDRF release from endothelial cells is calcium dependent.36,37 In in vitro studies, calcium channel agonist caused endothelium-dependent vasodilation,38 while calcium antagonist diminished EDRF release,39 suggesting that treatment with a calcium antagonist attenuates endothelium-dependent vasodilation. Another study showed that verapamil, diltiazem, and nifedipine had no effect on basal and bradykinin-stimulated release of nitric oxide from aortic endothelial cells in culture.40 Although direct effects of amlodipine on endothelial cells were not shown, these studies and our data suggest that calcium antagonists do not affect endothelial function. Although the averaged value of vasodilator response was not changed by amlodipine, actual value in 6 patients showed the increase in forearm response to reactive hyperemia. Therefore, it is possible that the longer treatment of amlodipine improves vasodilator response.
The mechanism of postischemic hyperemia is thought to be multifactorial. In the human forearm, reactive hyperemia after 3 to 5 minutes' occlusion was decreased by inhibition of prostaglandin synthesis with ibuprofen or adenosine receptor antagonist theophilline.41 Tagawa et al42 reported the role of nitric oxide in reactive hyperemia in human forearm vessels. Inhibition of NO synthesis by NG-monomethyl-L-arginine partly decreased total reactive hyperemic flow. Therefore, factors derived from endothelial cells also account for the vasodilation during reactive hyperemia, suggesting that vasodilator response to reactive hyperemia may partly reflect the endothelial function.
A goal of hypertension treatment is not only to lower the blood pressure but to treat hypertension-induced target organ disease. ACE inhibitors are known to be useful for the treatment of left ventricular hypertrophy,43 congestive heart failure,44 and chronic renal insufficiency.45 In the TREND (Trial on Reversing Endothelial Dysfunction) study,46 the effect of an ACE inhibitor quinapril on endothelial function was assessed using double-blinded, randomized, placebo-controlled design. In normotensive patients with coronary artery disease, response of coronary arteries to acethylcholine was evaluated by quantitative coronary angiography. Six months' treatment with quinapril improved the response to acethylcholine, suggesting the improvement of endothelial function by quinapril. These and our results suggest that ACE inhibitors are useful for treating essential hypertensive patients having cardiovascular complications. We did not measure the blood flow until 60 seconds after the release of arm compression. Therefore, it is possible that the peak response occurs within 60 seconds, which might be affected by the anti-hypertensive drugs. Our results suggest that temocapril attenuates the poor vasodilator response to reactive hyperemia. Similar results were obtained by using other ACE inhibitors,15–17 though further study is required to know whether this effect is peculiar to a specific type of ACE inhibitor. We examined the effect of two antihypertensive drugs in the different groups of patients. The crossover design may be more appropriate to evaluate the effects of the different classes of drugs.
In conclusion, the present results suggest that the forearm vasodilator response to reactive hyperemia was impaired in essential hypertensive patients. This impairment was attenuated by an ACE inhibitor, temocapril, but not a calcium antagonist, amlodipine, in patients without overt atherosclerotic disease.
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Acknowledgment |
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The authors gratefully acknowledge Dr Wendy Gray for assistance in editing the manuscript.
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M. Sanada, Y. Higashi, K. Nakagawa, S. Sasaki, I. Kodama, M. Tsuda, N. Nagai, and K. Ohama Relationship between the angiotensin-converting enzyme genotype and the forearm vasodilator response to estrogen replacement therapy in postmenopausal women J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1529 - 1535. [Abstract] [Full Text] [PDF]
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Y. Higashi, S. Sasaki, K. Nakagawa, H. Matsuura, G. Kajiyama, and T. Oshima Effect of the angiotensin-converting enzyme inhibitor imidapril on reactive hyperemia in patients with essential hypertension: relationship between treatment periods and resistance artery endothelial function J. Am. Coll. Cardiol., March 1, 2001; 37(3): 863 - 870. [Abstract] [Full Text] [PDF]
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 J. C. Kaski and L. F. Valenzuela Garcia Therapeutic options for the management ofpatients with cardiac syndrome X Eur. Heart J., February 2, 2001; 22(4): 283 - 293. [PDF]
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K. Matsumoto, R. Morishita, A. Moriguchi, N. Tomita, M. Aoki, H. Sakonjo, K. Matsumoto, T. Nakamura, J. Higaki, and T. Ogihara Inhibition of Neointima by Angiotensin-Converting Enzyme Inhibitor in Porcine Coronary Artery Balloon-Injury Model Hypertension, February 1, 2001; 37(2): 270 - 274. [Abstract] [Full Text] [PDF]
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Y. Higashi, S. Sasaki, K. Nakagawa, T. Ueda, A. Yoshimizu, S. Kurisu, H. Matsuura, G. Kajiyama, and T. Oshima A comparison of angiotensin-converting enzyme inhibitors, calcium antagonists, beta-blockers and diuretic agents on reactive hyperemia in patients with essential hypertension: a multicenter study J. Am. Coll. Cardiol., February 1, 2000; 35(2): 284 - 291. [Abstract] [Full Text] [PDF]
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T. J. Anderson, E. Elstein, H. Haber, and F. Charbonneau Comparative study of ACE-inhibition, angiotensin II antagonism, and calcium channel blockade on flow-mediated vasodilation in patients with coronary disease (BANFF study) J. Am. Coll. Cardiol., January 1, 2000; 35(1): 60 - 66. [Abstract] [Full Text] [PDF]
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Y. Higashi, S. Sasaki, N. Sasaki, K. Nakagawa, T. Ueda, A. Yoshimizu, S. Kurisu, H. Matsuura, G. Kajiyama, and T. Oshima Daily Aerobic Exercise Improves Reactive Hyperemia in Patients With Essential Hypertension Hypertension, January 1, 1999; 33(1): 591 - 597. [Abstract] [Full Text] [PDF]
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H. Ishizuka, K. Konno, H. Naganuma, K. Nishimura, H. Kouzuki, H. Suzuki, B. Stieger, P. J. Meier, and Y. Sugiyama Transport of Temocaprilat into Rat Hepatocytes: Role of Organic Anion Transporting Polypeptide J. Pharmacol. Exp. Ther., October 1, 1998; 287(1): 37 - 42. [Abstract] [Full Text]
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Y. Higashi, T. Oshima, S. Sasaki, Y. Nakano, M. Kambe, H. Matsuura, and G. Kajiyama Angiotensin-Converting Enzyme Inhibition, But Not Calcium Antagonism, Improves a Response of the Renal Vasculature to L-Arginine in Patients With Essential Hypertension Hypertension, July 1, 1998; 32(1): 16 - 24. [Abstract] [Full Text] [PDF]
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H. Tomiyama, Y. Kimura, H. Mitsuhashi, T. Kinouchi, H. Yoshida, T. Kushiro, and N. Doba Relationship Between Endothelial Function and Fibrinolysis in Early Hypertension Hypertension, January 1, 1998; 31(1): 321 - 327. [Abstract] [Full Text] [PDF]
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